About all

Development of influenza vaccine: History and evolution of influenza control from the first monovalent vaccine to universal vaccines

Содержание

History and evolution of influenza control
from the first monovalent vaccine
to universal vaccines

J Prev Med Hyg. 2016 Sep; 57(3): E115–E120.

,1,2,3,1 and 4

I. BARBERIS

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

P. MYLES

2 Division of Epidemiology and Public Health, University of Nottingham, UK.;

S.K. AULT

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

N.L. BRAGAZZI

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

M. MARTINI

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

2 Division of Epidemiology and Public Health, University of Nottingham, UK. ;

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

Corresponding author.Correspondence: N.L. Bragazzi, Department of Health Sciences (DISSAL), University of Genoa, via Antonio Pastore 1, 16132 Genoa, Italy – E-mail: [email protected] by

Authors’ contribution

MM conceived and designed the overview. IB and PM performed a search of the literature and contributed to the draft of the article. SA and NLB revised critically the manuscript. MM supervised the manuscript. All authors read and approved the final version of the manuscript.

Received 2016 Jul 8; Accepted 2016 Aug 25.

© Copyright by Pacini Editore SRL, Pisa, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. For details, please refer to http://creativecommons.org/licenses/by-nc-nd/3.0/This article has been cited by other articles in PMC.

Summary

Influenza is a highly infectious airborne disease with an important epidemiological and societal burden; annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths. A hundred years after this virus was first isolated, influenza vaccines are an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. Innovative tools, such as recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. The recurring mutations of influenza strains has prompted the recent introduction of a quadrivalent inactivated vaccine. In the near future, scientific research will strive to produce a long-lasting universal vaccine containing an antigen that will offer protection against all influenza virus strains.

Key words: Influenza, Vaccination, History of medicine

Introduction

Influenza viruses are negative-sense, single-stranded RNA viruses belonging to the Orthomyxoviridae family, together with Isavirus, Thogotovirus and Quaranjavirus. Three types of influenza viruses, namely influenza A, B and C, are capable of determining epidemics and pandemics in humans, with influenza A being the most common circulating type and causing significant illness, being most prone to antigenic shifts and the more likely type to lead to a pandemic [1, 2]. Recently, a new genus (termed influenza virus D) has been discovered in pigs and cattle with influenza-like illness syndrome in the United States [3, 4] and in Europe [5].

Influenza is a highly infectious airborne disease that affects a significant percentage of the world’s population; local annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths [6].

The aim of this mini-review is to provide a brief overview of the history and evolution of influenza and influenza control using vaccines.

A history of influenza: from the classical
period to the nineteenth century

In 412 BC, in the “Book of Epidemics”, Hippocrates described a putative influenza-like illness syndrome called “fever of Perinthus” or “cough of Perinthus” [7]. While some scholars claim that this is probably the first historical description of influenza (a winter and a spring epidemic of an upper respiratory tract infection occurring regularly every year at Perinthus, a port-town in Marmaraereglisi, a northern part of Greece, now Turkey), others, including the notable 19th-century editor of Hippocrates, Émile Littré (1801-1881), think that a diagnosis of diphtheria would better fit the description of complications (pneumonia, fits of coughing and wheezing, angina and paralysis of soft palate and limbs). On the other hand, symptoms such as disturbed vision and night blindness suggest a combination of diseases, including deficiency syndromes (e.g. vitamin A deficiency) [8]. In the years 1173 and 1500, two other influenza outbreaks were described, though in scant detail [9-11]. The name “influenza” originated in the 15th century in Italy, from an epidemic attributed to the “influence of the stars”, which, according to Ginctrac, raged across Europe and perhaps in Asia and Africa [12].

It seems that influenza also reached the Americas. Scholars and historians debate whether influenza was already present in the New World or whether it was carried by contaminated pigs transported on ships. Some Aztec texts speak of a “pestilential catarrh” outbreak in 1450-1456 in an area now corresponding to Mexico, but these manuscripts are difficult to interpret correctly and this hypothesis seems controversial [13].

The first reliable documents regarding influenza-like illness syndrome date from 1510, when the virus spread from Africa to Europe. The first pandemic, or worldwide epidemic, occurred in 1557, though some scholars deny that it really was an outbreak of influenza. The first pandemic/ worldwide epidemic that undoubtedly fits the description of influenza appeared in 1580, beginning in Asia and Russia and spreading to Europe via Asia Minor and North-West Africa. In Rome, it caused the death of over 8,000 people, while in Spain it decimated the populations of entire cities. Subsequently, it also affected the Americas [14].

Over the centuries, other pandemics were described worldwide. From 1404 to the middle of the 19th century, 31 influenza epidemics were recorded, including eight large-scale pandemics. Subsequently, others appeared, including three in the 20th century [14]. Some of the most notable outbreaks occurred in 1729, in 1781-1782 (a pandemic spreading from China to Russia, Europe and North America), in 1830-1833 (a pandemic which again spread from China to India, the Philippines, Indonesia, Russia, Europe and North America), in 1847-1848, and in 1898-1900 (spreading from Europe to India, Australia, and North and South America) [14].

One of the most devastating was the pandemic of “Spanish” influenza in 1918–1919, which caused an estimated 21 million deaths worldwide and was defined by Waring as “the greatest medical holocaust in history” [14, 15].

At the end of the 19th century, the etiology of this disease had yet not been well clarified; it was believed that the disease, termed “winter catarrh”, was caused by bacteria (the so-called bacterial hypothesis), such as pneumococcus, streptococcus or Haemophilus influenzae. This latter was also named Bacillus influenzae or Pfeiffer’s bacillus, after Richard Pfeiffer (1858-1945), who described it during the 1889-1892 influenza epidemic. This bacillus had already been discovered by the Polish microbiologist Bujwid Odo Feliks Kazimierz (1857- 1942) in biopsy material a year earlier [16].

In the same period, the French microbiologists Charles Nicolle (1866-1936), Charles Lébally and René Dujarric de la Rivière (1885-1969) of the Pasteur Institute showed that the flu pathogen could pass through a fine filter. However, despite their brilliant experiments, the viral hypothesis continued to be neglected until the virus was isolated [16, 17].

In 1889, some Spanish doctors believed that influenza was a variant of dengue fever, whilst others attributed influenza outbreaks to a variety of causes including cannon fire on the western front, the building of the Madrid underground, air pollution, sunspots, or the spread of the habit of smoking poor-quality tobacco [18].

The thirties: virus isolation and the first
experimental vaccines

During the 1918-1919 pandemic, some scientists began to suspect that bacteria were not the real agent of influenza disease. One of these was the scholar Richard Edwin Shope (1901-1966), who deeply investigated swine flu in 1920. However, it was only in 1932-1933 that the English scientists Wilson Smith (1897-1965), Sir Christopher Andrewes (1896-1988) and Sir Patrick Laidlaw (1881-1940), working at the Medical Research Council at Mill Hill, first isolated the influenza A virus from nasal secretions of infected patients, thereby demonstrating the intranasal human transmission of this virus [19, 20]. A few years later, the American virologist and epidemiologist Thomas Francis Junior (1900-1969) and Smith, in England, were able to transmit the virus to mice [21]. Subsequently, in 1935, Sir Frank Macfarlane Burnet (1899-1985) and Smith separately discovered that the flu virus could be grown on the chorio-allantoid membrane of embryonated hens’ eggs [22], and in 1936 the first neutralized antibodies generated by infection by human influenza virus were isolated [23].

In the next five years, important developments took place: the demonstration that the virus inactivated by formalin was immunogenic in humans, purification of the virus by means of high-speed centrifugation, and the discovery that the influenza virus grew easily in fertilized hen eggs, a procedure that is still used today to manufacture most influenza vaccines [23].

The first clinical trials of influenza vaccines were conducted in the mid-1930s [24, 25].

A study by Smith, Andrewes and Stuart-Harris was conducted among military forces in England in 1937 using a subcutaneous vaccination with an inactivated strain isolated from a mouse lung [25].

In 1938, Francis, together with Jonas Edward Salk (1914-1995), managed to protect USA military forces. Salk would subsequently use this successful experience to develop an effective polio vaccine in 1952 [26, 27].

The forties: inactivated influenza
vaccines

Influenza vaccination had two main objectives: (i) to protect against disease, and (ii) to achieve a high vaccination rate in order to ensure protection in unvaccinated people. The first vaccine was an inactivated, monovalent preparation which only contained a subtype of the influenza A virus [26, 27].

In December 1942, large studies were begun to be conducted on the first influenza virus vaccines; these provided the first official proof that inactivated influenza vaccines could yield effective protection against flu epidemics [28].

The efficacy and safety of inactivated vaccines were first studied between 1942 and 1945; in the meantime, a new strain of flu virus was discovered, the influenza virus type B, which is the main cause of seasonal epidemics, as was the phenomenon of so-called “influenza mismatch”. Influenza mismatch is caused by major and minor mutations of circulating viruses. As a result, the virus contained in the vaccine does not match the circulating strain, determining a reduction in the effectiveness of subtype A influenza vaccines.

A new route of influenza immunization was tested in December 1942, with the subcutaneous inactivated bivalent vaccine containing viruses of type A and type B. The following years, the first bivalent vaccine was licensed in the United States and became available for use in the general population [29, 30].

The fifties: influenza mismatch
and influenza surveillance

The first system for the surveillance of circulating influenza virus strains in several countries worldwide was created in 1952 by the World Health Organization (WHO) in order to monitor the various virus mismatches reported. This important innovative tool enabled the composition of seasonal influenza vaccines to be determined on the basis of the epidemiology of influenza in the previous season [31]. In 1946, as a result of viral mutation, a new variant of influenza A (h2N1), A/FM/1/47, appeared in Australia. This gave rise to a new influenza subtype, the h3N2 strain, which caused the pandemic known as Asian flu [32].

The following year, the US Commission on Influenza recommended that a representative of this strain be included in subsequent vaccines.

The emergence of an HA subtype different from those circulating in previous seasons determined the need for pandemic influenza vaccines [31].

The sixties: split vaccines

New inactivated compounds were tested for safety and efficacy during seasonal epidemics in the 1960s, in particular two new formulations were created: split and subunit vaccines. The 1968 pandemic led to the development of trivalent inactivated vaccines (TIVs) against influenza viruses; moreover the development of new split or subunit vaccines led to a decrease of adverse reactions in children. These vaccines were split using ether and/or detergent, and haemagglutinin and neuraminidase were, in the case of subunit vaccines, purified and enriched [33].

In the same period, the first flu vaccines were licensed in Europe, while in the US annual influenza vaccination was recommended for individuals at major risk of influenza complications.

In 1968, the new virus strain h4N2 (Hong Kong) appeared, completely replacing the previous type A strain (h3N2, or Asian influenza), and led to another global pandemic with high morbidity and mortality [34]. In the same year, a new type of vaccine, the split vaccine, was authorized in the US after several clinical studies had demonstrated that it was less reactogenic than whole virus vaccines, especially in the early years of life [35].

The seventies: genetic reassortment

Split vaccines were widely used during the pandemic swine influenza in 1976 and in 1977, when the h2N1 subtype re-emerged worldwide. However, they were seen to be less immunogenic than whole virus vaccines in “primed” subjects who had never been vaccinated. Indeed, it was shown that two vaccine doses were needed in order to ensure effective protection [36].

At the beginning of the 1970s, an important innovation was introduced into the production of influenza vaccines: the genetic reassortment of influenza virus strains; this technique enabled the vaccine strains to grow faster in embryonated hen eggs [37].

The first subunit vaccine was created between 1976 and 1977. This contained only the surface antigens, hemagglutinin (HA) and neuraminidase (NA), which were isolated by means of successive purification steps.

This innovative tool proved to be highly immunogenic and well tolerated in humans, especially in children, although two doses were needed to guarantee vaccine effectiveness during epidemics [38].

The eighties: subunit vaccines

In 1980, the first subunit vaccines were licensed in the United Kingdom and are currently available in several countries worldwide.

In 1978, as a result of a major mutation, a new virus strain, h2N1, appeared on the global epidemiological scene. This strain, which was similar to a virus circulating in 1958, emerged in Russia and began to co-circulate, either simultaneously or alternately, with the previous one [39].

Antigenic drift, caused by frequent changes in the composition of the virus, determined the need to update the vaccine composition each year. This necessity prompted both the implementation of the first surveillance systems and the production of the first trivalent vaccine, which included three formulation strains (one strain of influenza A/ h2N1, an influenza virus A /h4N2 and a type B virus), in order to ensure effective protection during the 1978 pandemic.

Live attenuated influenza vaccines

In the period 1935-1941, the first clinical trials involving live attenuated influenza vaccines were conducted. The efficacy of these seasonal vaccines was guaranteed by the correspondence between the circulating strain and the strain contained in the vaccine and by the virus dose grown in hen egg embryos [34].

In 1944, Stanley described in detail the preparation and properties of an influenza virus vaccine produced in embryonated hen eggs; this vaccine was concentrated and purified by means of differential centrifugation and inactivated by means of various procedures [23].

In 1949, an important change in vaccine development involved the introduction of the use of cell cultures for virus growth.

In 1997,the so-called “avian flu” pandemic broke out in Hong Kong. This was caused by influenza virus A/ H5N1, a highly pathogenic strain.

In order to contain this pandemic, the techniques of genetic rearrangement developed in those years enabled a huge number of vaccine doses to be produced in a short time by applying recombinant DNA technology to the influenza A/H5N1 virus [34].

Recent years

In recent years, scientific research developed new techniques of immunization, which may be more immunogenic and better tolerated during administration, thereby reducing adverse events. In 2003, for instance, the FDA in the United States authorized the use of an intranasally administered live attenuated vaccine, called FluMist®, in adults [40]. In the 2003-2004 influenza season, an outbreak in Asia was caused by an influenza A/H5N1 strain. This was later used to produce a vaccine, which was licensed in the United States by the FDA in 2007.

More recent years saw the development of adjuvanted vaccines, such as those containing alum adjuvants and the oil in water adjuvant MF-59, which significantly enhanced antigenicity [6].

Specifically, MF-59-adjuvanted vaccines were used in the elderly and in young children, and proved to elicit a good response even to pandemic strains with which subjects had not been primed by natural influenza infection. Similar responses were obtained through the use of other emulsions, such as stable emulsion (SE) and AS03, which were included in the 2009 pandemic influenza vaccines [36].

In the most recent pandemic season (2009), the influenza virus h2N1, which was transmitted to humans by pigs, was estimated to have caused more than 200,000 deaths in the first 12 months of its circulation [41].

A massive effort to produce vaccine for the new h2N1 strain began shortly after scientists identified the virus. The virus proved to grow slowly during the manufacturing process, which relies on cultivation of the virus in chicken eggs. Because of manufacturing delay, the vaccine was available in most countries after the second peak of influenza cases at the end of October leaving most people not immunized while influenza h2N1 virus was circulating [42].

In the elderly, the vaccine efficacy normally decreases, because of immunosenescence. For this reason, in 2009 the Advisory Committee on Immunization Practices (ACIP) recommended and authorized the use of high-dose Fluzone ®, a new formulation containing a 4-fold higher HA dose than the traditional trivalent vaccine [43].

In 2011, as a result of developments in research into new vaccine delivery techniques, the FDA first authorized the intradermal administration of Fluzone®. This new route of administration involved antigen-presenting cells (APCs) in the dermis; these cells process antigens for subsequent presentation in the lymphoid organs, resulting in the stimulation of both innate and adaptive immunity. The intradermal vaccines elicited a better immunological response than intramuscular vaccines, particularly in the elderly; in healthy adults, it yielded an immune response comparable to that elicited by the traditional vaccines, while saving on the HA dose [44-48]. In 2012, the FDA approved Fluarix®, the first quadrivalent vaccine in the United States. This split vaccine contained two influenza A strains and two influenza B antigens. The presence of an additional influenza B strain reduced the possibility of a mismatch between the circulating viruses and the vaccine composition, while maintaining the same immunogenicity and safety as standard trivalent vaccines [49].

In 2013, the FDA approved FluBlock®, a recombinant trivalent influenza vaccine, for use in people aged between 18 and 49 years. FluBlock® was licensed in a spray formulation and was the first trivalent influenza vaccine made by using recombinant DNA technology. Derived from Baculovirus, it contained a 3-fold higher HA dose than traditional trivalent vaccines [50, 51]. The scale-up potential of the insect cell/baculovirus vector system may offer advantages in terms of rapid antigen change and response to a pandemic situation [31].

Currently, scientists are exploring the fascinating prospect of developing a universal vaccine by exploiting T-cells and by attempting to elicit broadly neutralizing antibodies. Moreover, efforts are being made to design M2e- or stalk-based vaccines, since these proteins (the type-2 matrix protein and the stalk domain of HA, respectively) are quite well conserved from an evolutionary standpoint [52, 53].

Conclusions

In the hundred years since the influenza virus was isolated, influenza vaccine preparations have evolved to ensure effective protection, while maintaining a good safety and tolerability profile.

The recurring mutations of influenza strains prompted the introduction of a quadrivalent inactivated vaccine, the composition of which is determined on the basis of the most frequent strains isolated in the previous season during continuous surveillance by the WHO.

Current research priorities include the development of a universal influenza vaccine that could offer protection against all influenza virus strains, thereby overcoming the challenges faced due to antigenic drift and shift or of co-circulation of different viral strains. Another important priority is to identify sustainable vaccine production platforms capable of rapidly meeting the large global demands for influenza vaccine in the face of an influenza pandemic.

ACKNOWLEDGMENTS

No funding declared for this overview. The authors thank Dr. Bernard Patrick for revising the manuscript.

References

1. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part I: Influenza life-cycle and currently available drugs. J Prev Med Hyg. 2014;55:69–85. [PMC free article] [PubMed] [Google Scholar]2. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part II: Future compounds against influenza virus. J Prev
Med Hyg. 2014;55:109–129. [PMC free article] [PubMed] [Google Scholar]3. Hause BM, Collin EA, Liu R, Huanq B, Shenq Z, Lu W, Wanq D, Nelson EA, Li F. Characterization of a novel influenza virus
in cattle and Swine: proposal for a new genus in the Orthomyxoviridae
family. MBio. 2014;5:e00031–e00114. [PMC free article] [PubMed] [Google Scholar]4. Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F. Cocirculation
of two distinct genetic and antigenic lineages of proposed
influenza D virus in cattle. J Virol. 2015;89:1036–1042. [PMC free article] [PubMed] [Google Scholar]6. Soema PC, Kompier R, Amorij JP, Kersten GF. Current and
next generation influenza vaccines: Formulation and production
strategies. Eur J Pharm Biopharm. 2015;94:251–263. [PubMed] [Google Scholar]7. Pappas G, Kiriaze IJ, Falagas ME. Insights into infectious disease
in the era of Hippocrates. Int J Infect Dis. 2008;12:347–350. [PubMed] [Google Scholar]8. Kohn GC. Encyclopedia of Plague and Pestilence: From Ancient
Times to the Present. Infobase Publishing; 2007. [Google Scholar]9. Beveridge WIB. Influenza: The Last Great Plague. London: Heineman Educational Books; 1977. [Google Scholar]10. Wood JM. Influenza. In: Crovari P, Principi N, editors. Le vaccinazioni. Pisa: Pacini Editore; 2000. [Google Scholar]11. Kuszewski K, Brydak L. The epidemiology and history of influenza. Biomed Pharmacoter. 2000;54:188–195. [PubMed] [Google Scholar]

12. Gintrac H. Grippe. In: Nouveau dictionnaire de médicine et de chirurgie pratiques, directeur de la redaction: le docteur Jaccoud. 1872, Tome 16, page. 728-753.

13. Souza CM. The Spanish flu epidemic: a challenge to Bahian
medicine. Hist Cienc Saude Manguinhos. 2008;15:945–972. [PubMed] [Google Scholar]14. Potter CW. A history of influenza. J Appl Microbiol. 2001;91:572–579. [PubMed] [Google Scholar]15. Waring J.I. A History of Medicine in South Carolina 1900-70. South Carolina Medical Association; 1971. [Google Scholar]16. Bazin H. Vaccination: a history. France: Editions John Libbey
Eurotext Montrouge; 2011. [Google Scholar]17. Renaud F, Hansen W, Freney J. Dictionnaire des precurseurs en
bacteriologie. SFM Éditions Eska; 2005. 249 pages. [Google Scholar]18. Craddock S, Giles-Vernick T, Gunn JL. Influenza and Public
Health: Learning from Past Pandemics. Earthscan; 2010. – 293
pages. [Google Scholar]19. Smith W, Andrewes CH, Laidlaw PP. A virus obtained from influenza
patients. Lancet. 1933;2:66–68. [Google Scholar]20. Smith W, Andrewes CH, Stuart Harris CH. The immunization
of human volunteers. Special Rep Ser Med Res Council. 1938;228:137–144. [Google Scholar]22. Burnett FM. Influenza virus infection of the chick embryo lung. Br J Exp Pathol. 1940;21:147–153. [Google Scholar]23. Stanley WM. The preparation and properties of influenza virus
vaccines concentrated and purified by differential centrifugation. J Exp Med. 1945;81:193–218. [PMC free article] [PubMed] [Google Scholar]26. Parodi V, Florentiis D, Martini M, Ansaldi F. Inactivated influenza
vaccines: recent progress and implications for the elderly. Drugs Aging. 2011;28:93–106. [PubMed] [Google Scholar]27. Barberis I, Martini M, Iavarone F, Orsi A. Available influenza
vaccines: immunization strategies, history and new tools for
fighting the disease. J Prev Med Hyg. 2016;57:E41–E46. [PMC free article] [PubMed] [Google Scholar]28. Francis T, jr, Salk JE, Pearson HE, Brown PN. Protective effect
of vaccination against induced influenza A. J Clin Invest. 1945;24:536–546. [PMC free article] [PubMed] [Google Scholar]29. Weir JP, Gruber MF. An overview of the regulation of influenza
vaccines in the United States. Influenza and Other Respiratory
Viruses. 2016;10:354–360. [PMC free article] [PubMed] [Google Scholar]30. Keitel WA, Neuzil KM, Treanor J. Immunogenicity, efficacy of
inactivated/live virus seasonal and pandemic vaccines. Textbook
of Influenza. Wiley-Blackwell. 2013:311–326. [Google Scholar]32. Oxford J, Gilbert A, Lambkin-Williams R. Influenza vaccines
have a short but illustrious history of dedicated science enabling
the rapid global production of A/swine (h2N1) vaccine
in the current pandemic. In: Rappuoli R, Del Giudice G, editors. Influenza vaccines for the future. Springer Verlag; 2011. [Google Scholar]33. Krammer F, Palese P. Advances in the development of influenza
virus vaccines. Nat Rev Drug Discov. 2015;14:167–182. [PubMed] [Google Scholar]34. Zaman M, Ashraf S, Dreyer NA, Toovey S. Human infection
with avian influenza virus, Pakistan, 2007. Emerg Infect Dis. 2011;17:1056–1059. [PMC free article] [PubMed] [Google Scholar]35. Parkman PD, Hopps HE, Rastogi SC, Meyer HM., Jr Summary
of clinical trials of influenza virus vaccines for adults. J Infect
Dis. 1977;136:722–730. [PubMed] [Google Scholar]36. Hampson AW. Vaccines for pandemic influenza. The history
of our current vaccines, their limitations and the requirements
to deal with a pandemic threat. Ann Acad Med Singapore. 2008;37:510–517. [PubMed] [Google Scholar]37. Crovari P, Alberti M, Alicino C. History and evolution of influenza
vaccines. J Prev Med Hyg. 2011;52:91–94. [PubMed] [Google Scholar]38. Gianchecchi E, Trombetta C, Piccirella S, Montomoli E. Evaluating
influenza vaccines: progress and perspectives. Future Virology. 2016;11:379–393. [Google Scholar]39. Kendal AP, Maassab HF, Alexandrova GI, Ghendon YZ. Development of cold-adapted recombinant live attenuated
influenza vaccines in the U.S.A. and U.S.S.R. Antiviral Res
1982. 1982;1:339–365. [Google Scholar]41. Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, et al. Estimated
global mortality associated with the first 12 months of
2009 pandemic influenza A h2N1 virus circulation: a modelling
study. Lancet Infect Dis. 2012;12:687–695. [PubMed] [Google Scholar]43. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing
the immunogenicity of high-dose and standard-dose influenza
vaccine in adults 65 years of age and older. J Infect Dis. 2009;200:172–180. [PubMed] [Google Scholar]44. Durando P, Iudici R, Alicino C, Alberti M, Florentiis, Ansaldi F, Icardi G. Adjuvants and alternative routes of administration
towards the development of the ideal influenza vaccine. Hum
Vaccin. 2011;7(Suppl):29–40. [PubMed] [Google Scholar]45. Holland D, Booy R, Looze F, Eizenberg P, Mc Donald J, Karrasch J, Mc Keirnan M, Salem H, Mills G, Reid J, et al. Intradermal influenza vaccine administered using
a new microinjection system produces superior immunogenicity
in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198:650–658. [PubMed] [Google Scholar]46. Arnou R, Icardi G, Decker M, Ambrozaitis A, Kazek MP, Weber F, Damme P. Intradermal influenza vaccine for older
adults: a randomized controlled multicenter phase III study. Vaccine. 2009;27:7304–7312. [PubMed] [Google Scholar]47. Belshe RB, Newman FK, Cannon J, Duane C, Treanor J, Hoecke C, Howe BJ, Dubin G. Serum antibody responses after
intradermal vaccination against influenza. N Engl J Med. 2004;351:2286–2294. [PubMed] [Google Scholar]48. Bragazzi NL, Orsi A, Ansaldi F, Gasparini R, Icardi G. Fluzone ® Intra-dermal (Intanza® / Istivac® Intra-dermal): an updated overview. Hum Vaccin Immunother. 2016 in press. [PMC free article] [PubMed] [Google Scholar]49. Tisa V, Barberis I, Faccio V, Paganino C, Trucchi C, Martini M, Ansaldi F. Quadrivalent influenza vaccine: a new opportunity
to reduce the influenza burden. J Prev Med Hyg. 2016;57:E28–E33. [PMC free article] [PubMed] [Google Scholar]50. Treanor JJ, El Sahly H, King J, Graham I, Izikson R, Kohberger R, Patriarca P, Cox M. Protective efficacy of a trivalent recombinant
hemagglutinin protein vaccine (FluBlok) against influenza
in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011;29:7733–7739. [PubMed] [Google Scholar]51. Baxter R, Patriarca PA, Ensor K, Izikson R, Goldenthal KL, Cox M. Evaluation of the safety, reactogenicity and immunogenicity
of FluBlok trivalent recombinant baculovirus-expressed
hemagglutinin influenza vaccine administered intramuscularly
to healthy adults 50-64 years of age. Vaccine. 2011;29:2272–2278. [PubMed] [Google Scholar]52. Sridhar S. Heterosubtypic T-cell immunity to influenza in humans:
challenges for universal T-cell influenza vaccines. Front
Immunol. 2016;7:195–195. [PMC free article] [PubMed] [Google Scholar]53. Wiersma LC, Rimmelzwaan GF, Vries RD. Developing universal
influenza vaccines: hitting the nail, not just on the head. Vaccines (Basel) 2015;3:239–262. [PMC free article] [PubMed] [Google Scholar]

History and evolution of influenza control
from the first monovalent vaccine
to universal vaccines

J Prev Med Hyg. 2016 Sep; 57(3): E115–E120.

,1,2,3,1 and 4

I. BARBERIS

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

P. MYLES

2 Division of Epidemiology and Public Health, University of Nottingham, UK.;

S.K. AULT

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

N.L. BRAGAZZI

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

M. MARTINI

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

2 Division of Epidemiology and Public Health, University of Nottingham, UK.;

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

Corresponding author.Correspondence: N.L. Bragazzi, Department of Health Sciences (DISSAL), University of Genoa, via Antonio Pastore 1, 16132 Genoa, Italy – E-mail: [email protected] by

Authors’ contribution

MM conceived and designed the overview. IB and PM performed a search of the literature and contributed to the draft of the article. SA and NLB revised critically the manuscript. MM supervised the manuscript. All authors read and approved the final version of the manuscript.

Received 2016 Jul 8; Accepted 2016 Aug 25.

© Copyright by Pacini Editore SRL, Pisa, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. For details, please refer to http://creativecommons.org/licenses/by-nc-nd/3.0/This article has been cited by other articles in PMC.

Summary

Influenza is a highly infectious airborne disease with an important epidemiological and societal burden; annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths. A hundred years after this virus was first isolated, influenza vaccines are an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. Innovative tools, such as recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. The recurring mutations of influenza strains has prompted the recent introduction of a quadrivalent inactivated vaccine. In the near future, scientific research will strive to produce a long-lasting universal vaccine containing an antigen that will offer protection against all influenza virus strains.

Key words: Influenza, Vaccination, History of medicine

Introduction

Influenza viruses are negative-sense, single-stranded RNA viruses belonging to the Orthomyxoviridae family, together with Isavirus, Thogotovirus and Quaranjavirus. Three types of influenza viruses, namely influenza A, B and C, are capable of determining epidemics and pandemics in humans, with influenza A being the most common circulating type and causing significant illness, being most prone to antigenic shifts and the more likely type to lead to a pandemic [1, 2]. Recently, a new genus (termed influenza virus D) has been discovered in pigs and cattle with influenza-like illness syndrome in the United States [3, 4] and in Europe [5].

Influenza is a highly infectious airborne disease that affects a significant percentage of the world’s population; local annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths [6].

The aim of this mini-review is to provide a brief overview of the history and evolution of influenza and influenza control using vaccines.

A history of influenza: from the classical
period to the nineteenth century

In 412 BC, in the “Book of Epidemics”, Hippocrates described a putative influenza-like illness syndrome called “fever of Perinthus” or “cough of Perinthus” [7]. While some scholars claim that this is probably the first historical description of influenza (a winter and a spring epidemic of an upper respiratory tract infection occurring regularly every year at Perinthus, a port-town in Marmaraereglisi, a northern part of Greece, now Turkey), others, including the notable 19th-century editor of Hippocrates, Émile Littré (1801-1881), think that a diagnosis of diphtheria would better fit the description of complications (pneumonia, fits of coughing and wheezing, angina and paralysis of soft palate and limbs). On the other hand, symptoms such as disturbed vision and night blindness suggest a combination of diseases, including deficiency syndromes (e.g. vitamin A deficiency) [8]. In the years 1173 and 1500, two other influenza outbreaks were described, though in scant detail [9-11]. The name “influenza” originated in the 15th century in Italy, from an epidemic attributed to the “influence of the stars”, which, according to Ginctrac, raged across Europe and perhaps in Asia and Africa [12].

It seems that influenza also reached the Americas. Scholars and historians debate whether influenza was already present in the New World or whether it was carried by contaminated pigs transported on ships. Some Aztec texts speak of a “pestilential catarrh” outbreak in 1450-1456 in an area now corresponding to Mexico, but these manuscripts are difficult to interpret correctly and this hypothesis seems controversial [13].

The first reliable documents regarding influenza-like illness syndrome date from 1510, when the virus spread from Africa to Europe. The first pandemic, or worldwide epidemic, occurred in 1557, though some scholars deny that it really was an outbreak of influenza. The first pandemic/ worldwide epidemic that undoubtedly fits the description of influenza appeared in 1580, beginning in Asia and Russia and spreading to Europe via Asia Minor and North-West Africa. In Rome, it caused the death of over 8,000 people, while in Spain it decimated the populations of entire cities. Subsequently, it also affected the Americas [14].

Over the centuries, other pandemics were described worldwide. From 1404 to the middle of the 19th century, 31 influenza epidemics were recorded, including eight large-scale pandemics. Subsequently, others appeared, including three in the 20th century [14]. Some of the most notable outbreaks occurred in 1729, in 1781-1782 (a pandemic spreading from China to Russia, Europe and North America), in 1830-1833 (a pandemic which again spread from China to India, the Philippines, Indonesia, Russia, Europe and North America), in 1847-1848, and in 1898-1900 (spreading from Europe to India, Australia, and North and South America) [14].

One of the most devastating was the pandemic of “Spanish” influenza in 1918–1919, which caused an estimated 21 million deaths worldwide and was defined by Waring as “the greatest medical holocaust in history” [14, 15].

At the end of the 19th century, the etiology of this disease had yet not been well clarified; it was believed that the disease, termed “winter catarrh”, was caused by bacteria (the so-called bacterial hypothesis), such as pneumococcus, streptococcus or Haemophilus influenzae. This latter was also named Bacillus influenzae or Pfeiffer’s bacillus, after Richard Pfeiffer (1858-1945), who described it during the 1889-1892 influenza epidemic. This bacillus had already been discovered by the Polish microbiologist Bujwid Odo Feliks Kazimierz (1857- 1942) in biopsy material a year earlier [16].

In the same period, the French microbiologists Charles Nicolle (1866-1936), Charles Lébally and René Dujarric de la Rivière (1885-1969) of the Pasteur Institute showed that the flu pathogen could pass through a fine filter. However, despite their brilliant experiments, the viral hypothesis continued to be neglected until the virus was isolated [16, 17].

In 1889, some Spanish doctors believed that influenza was a variant of dengue fever, whilst others attributed influenza outbreaks to a variety of causes including cannon fire on the western front, the building of the Madrid underground, air pollution, sunspots, or the spread of the habit of smoking poor-quality tobacco [18].

The thirties: virus isolation and the first
experimental vaccines

During the 1918-1919 pandemic, some scientists began to suspect that bacteria were not the real agent of influenza disease. One of these was the scholar Richard Edwin Shope (1901-1966), who deeply investigated swine flu in 1920. However, it was only in 1932-1933 that the English scientists Wilson Smith (1897-1965), Sir Christopher Andrewes (1896-1988) and Sir Patrick Laidlaw (1881-1940), working at the Medical Research Council at Mill Hill, first isolated the influenza A virus from nasal secretions of infected patients, thereby demonstrating the intranasal human transmission of this virus [19, 20]. A few years later, the American virologist and epidemiologist Thomas Francis Junior (1900-1969) and Smith, in England, were able to transmit the virus to mice [21]. Subsequently, in 1935, Sir Frank Macfarlane Burnet (1899-1985) and Smith separately discovered that the flu virus could be grown on the chorio-allantoid membrane of embryonated hens’ eggs [22], and in 1936 the first neutralized antibodies generated by infection by human influenza virus were isolated [23].

In the next five years, important developments took place: the demonstration that the virus inactivated by formalin was immunogenic in humans, purification of the virus by means of high-speed centrifugation, and the discovery that the influenza virus grew easily in fertilized hen eggs, a procedure that is still used today to manufacture most influenza vaccines [23].

The first clinical trials of influenza vaccines were conducted in the mid-1930s [24, 25].

A study by Smith, Andrewes and Stuart-Harris was conducted among military forces in England in 1937 using a subcutaneous vaccination with an inactivated strain isolated from a mouse lung [25].

In 1938, Francis, together with Jonas Edward Salk (1914-1995), managed to protect USA military forces. Salk would subsequently use this successful experience to develop an effective polio vaccine in 1952 [26, 27].

The forties: inactivated influenza
vaccines

Influenza vaccination had two main objectives: (i) to protect against disease, and (ii) to achieve a high vaccination rate in order to ensure protection in unvaccinated people. The first vaccine was an inactivated, monovalent preparation which only contained a subtype of the influenza A virus [26, 27].

In December 1942, large studies were begun to be conducted on the first influenza virus vaccines; these provided the first official proof that inactivated influenza vaccines could yield effective protection against flu epidemics [28].

The efficacy and safety of inactivated vaccines were first studied between 1942 and 1945; in the meantime, a new strain of flu virus was discovered, the influenza virus type B, which is the main cause of seasonal epidemics, as was the phenomenon of so-called “influenza mismatch”. Influenza mismatch is caused by major and minor mutations of circulating viruses. As a result, the virus contained in the vaccine does not match the circulating strain, determining a reduction in the effectiveness of subtype A influenza vaccines.

A new route of influenza immunization was tested in December 1942, with the subcutaneous inactivated bivalent vaccine containing viruses of type A and type B. The following years, the first bivalent vaccine was licensed in the United States and became available for use in the general population [29, 30].

The fifties: influenza mismatch
and influenza surveillance

The first system for the surveillance of circulating influenza virus strains in several countries worldwide was created in 1952 by the World Health Organization (WHO) in order to monitor the various virus mismatches reported. This important innovative tool enabled the composition of seasonal influenza vaccines to be determined on the basis of the epidemiology of influenza in the previous season [31]. In 1946, as a result of viral mutation, a new variant of influenza A (h2N1), A/FM/1/47, appeared in Australia. This gave rise to a new influenza subtype, the h3N2 strain, which caused the pandemic known as Asian flu [32].

The following year, the US Commission on Influenza recommended that a representative of this strain be included in subsequent vaccines.

The emergence of an HA subtype different from those circulating in previous seasons determined the need for pandemic influenza vaccines [31].

The sixties: split vaccines

New inactivated compounds were tested for safety and efficacy during seasonal epidemics in the 1960s, in particular two new formulations were created: split and subunit vaccines. The 1968 pandemic led to the development of trivalent inactivated vaccines (TIVs) against influenza viruses; moreover the development of new split or subunit vaccines led to a decrease of adverse reactions in children. These vaccines were split using ether and/or detergent, and haemagglutinin and neuraminidase were, in the case of subunit vaccines, purified and enriched [33].

In the same period, the first flu vaccines were licensed in Europe, while in the US annual influenza vaccination was recommended for individuals at major risk of influenza complications.

In 1968, the new virus strain h4N2 (Hong Kong) appeared, completely replacing the previous type A strain (h3N2, or Asian influenza), and led to another global pandemic with high morbidity and mortality [34]. In the same year, a new type of vaccine, the split vaccine, was authorized in the US after several clinical studies had demonstrated that it was less reactogenic than whole virus vaccines, especially in the early years of life [35].

The seventies: genetic reassortment

Split vaccines were widely used during the pandemic swine influenza in 1976 and in 1977, when the h2N1 subtype re-emerged worldwide. However, they were seen to be less immunogenic than whole virus vaccines in “primed” subjects who had never been vaccinated. Indeed, it was shown that two vaccine doses were needed in order to ensure effective protection [36].

At the beginning of the 1970s, an important innovation was introduced into the production of influenza vaccines: the genetic reassortment of influenza virus strains; this technique enabled the vaccine strains to grow faster in embryonated hen eggs [37].

The first subunit vaccine was created between 1976 and 1977. This contained only the surface antigens, hemagglutinin (HA) and neuraminidase (NA), which were isolated by means of successive purification steps.

This innovative tool proved to be highly immunogenic and well tolerated in humans, especially in children, although two doses were needed to guarantee vaccine effectiveness during epidemics [38].

The eighties: subunit vaccines

In 1980, the first subunit vaccines were licensed in the United Kingdom and are currently available in several countries worldwide.

In 1978, as a result of a major mutation, a new virus strain, h2N1, appeared on the global epidemiological scene. This strain, which was similar to a virus circulating in 1958, emerged in Russia and began to co-circulate, either simultaneously or alternately, with the previous one [39].

Antigenic drift, caused by frequent changes in the composition of the virus, determined the need to update the vaccine composition each year. This necessity prompted both the implementation of the first surveillance systems and the production of the first trivalent vaccine, which included three formulation strains (one strain of influenza A/ h2N1, an influenza virus A /h4N2 and a type B virus), in order to ensure effective protection during the 1978 pandemic.

Live attenuated influenza vaccines

In the period 1935-1941, the first clinical trials involving live attenuated influenza vaccines were conducted. The efficacy of these seasonal vaccines was guaranteed by the correspondence between the circulating strain and the strain contained in the vaccine and by the virus dose grown in hen egg embryos [34].

In 1944, Stanley described in detail the preparation and properties of an influenza virus vaccine produced in embryonated hen eggs; this vaccine was concentrated and purified by means of differential centrifugation and inactivated by means of various procedures [23].

In 1949, an important change in vaccine development involved the introduction of the use of cell cultures for virus growth.

In 1997,the so-called “avian flu” pandemic broke out in Hong Kong. This was caused by influenza virus A/ H5N1, a highly pathogenic strain.

In order to contain this pandemic, the techniques of genetic rearrangement developed in those years enabled a huge number of vaccine doses to be produced in a short time by applying recombinant DNA technology to the influenza A/H5N1 virus [34].

Recent years

In recent years, scientific research developed new techniques of immunization, which may be more immunogenic and better tolerated during administration, thereby reducing adverse events. In 2003, for instance, the FDA in the United States authorized the use of an intranasally administered live attenuated vaccine, called FluMist®, in adults [40]. In the 2003-2004 influenza season, an outbreak in Asia was caused by an influenza A/H5N1 strain. This was later used to produce a vaccine, which was licensed in the United States by the FDA in 2007.

More recent years saw the development of adjuvanted vaccines, such as those containing alum adjuvants and the oil in water adjuvant MF-59, which significantly enhanced antigenicity [6].

Specifically, MF-59-adjuvanted vaccines were used in the elderly and in young children, and proved to elicit a good response even to pandemic strains with which subjects had not been primed by natural influenza infection. Similar responses were obtained through the use of other emulsions, such as stable emulsion (SE) and AS03, which were included in the 2009 pandemic influenza vaccines [36].

In the most recent pandemic season (2009), the influenza virus h2N1, which was transmitted to humans by pigs, was estimated to have caused more than 200,000 deaths in the first 12 months of its circulation [41].

A massive effort to produce vaccine for the new h2N1 strain began shortly after scientists identified the virus. The virus proved to grow slowly during the manufacturing process, which relies on cultivation of the virus in chicken eggs. Because of manufacturing delay, the vaccine was available in most countries after the second peak of influenza cases at the end of October leaving most people not immunized while influenza h2N1 virus was circulating [42].

In the elderly, the vaccine efficacy normally decreases, because of immunosenescence. For this reason, in 2009 the Advisory Committee on Immunization Practices (ACIP) recommended and authorized the use of high-dose Fluzone ®, a new formulation containing a 4-fold higher HA dose than the traditional trivalent vaccine [43].

In 2011, as a result of developments in research into new vaccine delivery techniques, the FDA first authorized the intradermal administration of Fluzone®. This new route of administration involved antigen-presenting cells (APCs) in the dermis; these cells process antigens for subsequent presentation in the lymphoid organs, resulting in the stimulation of both innate and adaptive immunity. The intradermal vaccines elicited a better immunological response than intramuscular vaccines, particularly in the elderly; in healthy adults, it yielded an immune response comparable to that elicited by the traditional vaccines, while saving on the HA dose [44-48]. In 2012, the FDA approved Fluarix®, the first quadrivalent vaccine in the United States. This split vaccine contained two influenza A strains and two influenza B antigens. The presence of an additional influenza B strain reduced the possibility of a mismatch between the circulating viruses and the vaccine composition, while maintaining the same immunogenicity and safety as standard trivalent vaccines [49].

In 2013, the FDA approved FluBlock®, a recombinant trivalent influenza vaccine, for use in people aged between 18 and 49 years. FluBlock® was licensed in a spray formulation and was the first trivalent influenza vaccine made by using recombinant DNA technology. Derived from Baculovirus, it contained a 3-fold higher HA dose than traditional trivalent vaccines [50, 51]. The scale-up potential of the insect cell/baculovirus vector system may offer advantages in terms of rapid antigen change and response to a pandemic situation [31].

Currently, scientists are exploring the fascinating prospect of developing a universal vaccine by exploiting T-cells and by attempting to elicit broadly neutralizing antibodies. Moreover, efforts are being made to design M2e- or stalk-based vaccines, since these proteins (the type-2 matrix protein and the stalk domain of HA, respectively) are quite well conserved from an evolutionary standpoint [52, 53].

Conclusions

In the hundred years since the influenza virus was isolated, influenza vaccine preparations have evolved to ensure effective protection, while maintaining a good safety and tolerability profile.

The recurring mutations of influenza strains prompted the introduction of a quadrivalent inactivated vaccine, the composition of which is determined on the basis of the most frequent strains isolated in the previous season during continuous surveillance by the WHO.

Current research priorities include the development of a universal influenza vaccine that could offer protection against all influenza virus strains, thereby overcoming the challenges faced due to antigenic drift and shift or of co-circulation of different viral strains. Another important priority is to identify sustainable vaccine production platforms capable of rapidly meeting the large global demands for influenza vaccine in the face of an influenza pandemic.

ACKNOWLEDGMENTS

No funding declared for this overview. The authors thank Dr. Bernard Patrick for revising the manuscript.

References

1. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part I: Influenza life-cycle and currently available drugs. J Prev Med Hyg. 2014;55:69–85. [PMC free article] [PubMed] [Google Scholar]2. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part II: Future compounds against influenza virus. J Prev
Med Hyg. 2014;55:109–129. [PMC free article] [PubMed] [Google Scholar]3. Hause BM, Collin EA, Liu R, Huanq B, Shenq Z, Lu W, Wanq D, Nelson EA, Li F. Characterization of a novel influenza virus
in cattle and Swine: proposal for a new genus in the Orthomyxoviridae
family. MBio. 2014;5:e00031–e00114. [PMC free article] [PubMed] [Google Scholar]4. Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F. Cocirculation
of two distinct genetic and antigenic lineages of proposed
influenza D virus in cattle. J Virol. 2015;89:1036–1042. [PMC free article] [PubMed] [Google Scholar]6. Soema PC, Kompier R, Amorij JP, Kersten GF. Current and
next generation influenza vaccines: Formulation and production
strategies. Eur J Pharm Biopharm. 2015;94:251–263. [PubMed] [Google Scholar]7. Pappas G, Kiriaze IJ, Falagas ME. Insights into infectious disease
in the era of Hippocrates. Int J Infect Dis. 2008;12:347–350. [PubMed] [Google Scholar]8. Kohn GC. Encyclopedia of Plague and Pestilence: From Ancient
Times to the Present. Infobase Publishing; 2007. [Google Scholar]9. Beveridge WIB. Influenza: The Last Great Plague. London: Heineman Educational Books; 1977. [Google Scholar]10. Wood JM. Influenza. In: Crovari P, Principi N, editors. Le vaccinazioni. Pisa: Pacini Editore; 2000. [Google Scholar]11. Kuszewski K, Brydak L. The epidemiology and history of influenza. Biomed Pharmacoter. 2000;54:188–195. [PubMed] [Google Scholar]

12. Gintrac H. Grippe. In: Nouveau dictionnaire de médicine et de chirurgie pratiques, directeur de la redaction: le docteur Jaccoud. 1872, Tome 16, page. 728-753.

13. Souza CM. The Spanish flu epidemic: a challenge to Bahian
medicine. Hist Cienc Saude Manguinhos. 2008;15:945–972. [PubMed] [Google Scholar]14. Potter CW. A history of influenza. J Appl Microbiol. 2001;91:572–579. [PubMed] [Google Scholar]15. Waring J.I. A History of Medicine in South Carolina 1900-70. South Carolina Medical Association; 1971. [Google Scholar]16. Bazin H. Vaccination: a history. France: Editions John Libbey
Eurotext Montrouge; 2011. [Google Scholar]17. Renaud F, Hansen W, Freney J. Dictionnaire des precurseurs en
bacteriologie. SFM Éditions Eska; 2005. 249 pages. [Google Scholar]18. Craddock S, Giles-Vernick T, Gunn JL. Influenza and Public
Health: Learning from Past Pandemics. Earthscan; 2010. – 293
pages. [Google Scholar]19. Smith W, Andrewes CH, Laidlaw PP. A virus obtained from influenza
patients. Lancet. 1933;2:66–68. [Google Scholar]20. Smith W, Andrewes CH, Stuart Harris CH. The immunization
of human volunteers. Special Rep Ser Med Res Council. 1938;228:137–144. [Google Scholar]22. Burnett FM. Influenza virus infection of the chick embryo lung. Br J Exp Pathol. 1940;21:147–153. [Google Scholar]23. Stanley WM. The preparation and properties of influenza virus
vaccines concentrated and purified by differential centrifugation. J Exp Med. 1945;81:193–218. [PMC free article] [PubMed] [Google Scholar]26. Parodi V, Florentiis D, Martini M, Ansaldi F. Inactivated influenza
vaccines: recent progress and implications for the elderly. Drugs Aging. 2011;28:93–106. [PubMed] [Google Scholar]27. Barberis I, Martini M, Iavarone F, Orsi A. Available influenza
vaccines: immunization strategies, history and new tools for
fighting the disease. J Prev Med Hyg. 2016;57:E41–E46. [PMC free article] [PubMed] [Google Scholar]28. Francis T, jr, Salk JE, Pearson HE, Brown PN. Protective effect
of vaccination against induced influenza A. J Clin Invest. 1945;24:536–546. [PMC free article] [PubMed] [Google Scholar]29. Weir JP, Gruber MF. An overview of the regulation of influenza
vaccines in the United States. Influenza and Other Respiratory
Viruses. 2016;10:354–360. [PMC free article] [PubMed] [Google Scholar]30. Keitel WA, Neuzil KM, Treanor J. Immunogenicity, efficacy of
inactivated/live virus seasonal and pandemic vaccines. Textbook
of Influenza. Wiley-Blackwell. 2013:311–326. [Google Scholar]32. Oxford J, Gilbert A, Lambkin-Williams R. Influenza vaccines
have a short but illustrious history of dedicated science enabling
the rapid global production of A/swine (h2N1) vaccine
in the current pandemic. In: Rappuoli R, Del Giudice G, editors. Influenza vaccines for the future. Springer Verlag; 2011. [Google Scholar]33. Krammer F, Palese P. Advances in the development of influenza
virus vaccines. Nat Rev Drug Discov. 2015;14:167–182. [PubMed] [Google Scholar]34. Zaman M, Ashraf S, Dreyer NA, Toovey S. Human infection
with avian influenza virus, Pakistan, 2007. Emerg Infect Dis. 2011;17:1056–1059. [PMC free article] [PubMed] [Google Scholar]35. Parkman PD, Hopps HE, Rastogi SC, Meyer HM., Jr Summary
of clinical trials of influenza virus vaccines for adults. J Infect
Dis. 1977;136:722–730. [PubMed] [Google Scholar]36. Hampson AW. Vaccines for pandemic influenza. The history
of our current vaccines, their limitations and the requirements
to deal with a pandemic threat. Ann Acad Med Singapore. 2008;37:510–517. [PubMed] [Google Scholar]37. Crovari P, Alberti M, Alicino C. History and evolution of influenza
vaccines. J Prev Med Hyg. 2011;52:91–94. [PubMed] [Google Scholar]38. Gianchecchi E, Trombetta C, Piccirella S, Montomoli E. Evaluating
influenza vaccines: progress and perspectives. Future Virology. 2016;11:379–393. [Google Scholar]39. Kendal AP, Maassab HF, Alexandrova GI, Ghendon YZ. Development of cold-adapted recombinant live attenuated
influenza vaccines in the U.S.A. and U.S.S.R. Antiviral Res
1982. 1982;1:339–365. [Google Scholar]41. Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, et al. Estimated
global mortality associated with the first 12 months of
2009 pandemic influenza A h2N1 virus circulation: a modelling
study. Lancet Infect Dis. 2012;12:687–695. [PubMed] [Google Scholar]43. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing
the immunogenicity of high-dose and standard-dose influenza
vaccine in adults 65 years of age and older. J Infect Dis. 2009;200:172–180. [PubMed] [Google Scholar]44. Durando P, Iudici R, Alicino C, Alberti M, Florentiis, Ansaldi F, Icardi G. Adjuvants and alternative routes of administration
towards the development of the ideal influenza vaccine. Hum
Vaccin. 2011;7(Suppl):29–40. [PubMed] [Google Scholar]45. Holland D, Booy R, Looze F, Eizenberg P, Mc Donald J, Karrasch J, Mc Keirnan M, Salem H, Mills G, Reid J, et al. Intradermal influenza vaccine administered using
a new microinjection system produces superior immunogenicity
in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198:650–658. [PubMed] [Google Scholar]46. Arnou R, Icardi G, Decker M, Ambrozaitis A, Kazek MP, Weber F, Damme P. Intradermal influenza vaccine for older
adults: a randomized controlled multicenter phase III study. Vaccine. 2009;27:7304–7312. [PubMed] [Google Scholar]47. Belshe RB, Newman FK, Cannon J, Duane C, Treanor J, Hoecke C, Howe BJ, Dubin G. Serum antibody responses after
intradermal vaccination against influenza. N Engl J Med. 2004;351:2286–2294. [PubMed] [Google Scholar]48. Bragazzi NL, Orsi A, Ansaldi F, Gasparini R, Icardi G. Fluzone ® Intra-dermal (Intanza® / Istivac® Intra-dermal): an updated overview. Hum Vaccin Immunother. 2016 in press. [PMC free article] [PubMed] [Google Scholar]49. Tisa V, Barberis I, Faccio V, Paganino C, Trucchi C, Martini M, Ansaldi F. Quadrivalent influenza vaccine: a new opportunity
to reduce the influenza burden. J Prev Med Hyg. 2016;57:E28–E33. [PMC free article] [PubMed] [Google Scholar]50. Treanor JJ, El Sahly H, King J, Graham I, Izikson R, Kohberger R, Patriarca P, Cox M. Protective efficacy of a trivalent recombinant
hemagglutinin protein vaccine (FluBlok) against influenza
in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011;29:7733–7739. [PubMed] [Google Scholar]51. Baxter R, Patriarca PA, Ensor K, Izikson R, Goldenthal KL, Cox M. Evaluation of the safety, reactogenicity and immunogenicity
of FluBlok trivalent recombinant baculovirus-expressed
hemagglutinin influenza vaccine administered intramuscularly
to healthy adults 50-64 years of age. Vaccine. 2011;29:2272–2278. [PubMed] [Google Scholar]52. Sridhar S. Heterosubtypic T-cell immunity to influenza in humans:
challenges for universal T-cell influenza vaccines. Front
Immunol. 2016;7:195–195. [PMC free article] [PubMed] [Google Scholar]53. Wiersma LC, Rimmelzwaan GF, Vries RD. Developing universal
influenza vaccines: hitting the nail, not just on the head. Vaccines (Basel) 2015;3:239–262. [PMC free article] [PubMed] [Google Scholar]

History and evolution of influenza control
from the first monovalent vaccine
to universal vaccines

J Prev Med Hyg. 2016 Sep; 57(3): E115–E120.

,1,2,3,1 and 4

I. BARBERIS

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

P. MYLES

2 Division of Epidemiology and Public Health, University of Nottingham, UK.;

S.K. AULT

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

N.L. BRAGAZZI

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

M. MARTINI

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

1 Department of Health Sciences (DISSAL), University of Genoa, Italy;

2 Division of Epidemiology and Public Health, University of Nottingham, UK.;

3 Pan American Health Organization/World Health Organization (retired), Washington, D.C., United States of America; currently Office of the Dean, School of Public Health, University of Maryland, United States of America;

4 Section of History of Medicine and Ethics, Department of Health Sciences (DISSAL), University of Genoa, Italy

Corresponding author.Correspondence: N.L. Bragazzi, Department of Health Sciences (DISSAL), University of Genoa, via Antonio Pastore 1, 16132 Genoa, Italy – E-mail: [email protected] by

Authors’ contribution

MM conceived and designed the overview. IB and PM performed a search of the literature and contributed to the draft of the article. SA and NLB revised critically the manuscript. MM supervised the manuscript. All authors read and approved the final version of the manuscript.

Received 2016 Jul 8; Accepted 2016 Aug 25.

© Copyright by Pacini Editore SRL, Pisa, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. For details, please refer to http://creativecommons.org/licenses/by-nc-nd/3.0/This article has been cited by other articles in PMC.

Summary

Influenza is a highly infectious airborne disease with an important epidemiological and societal burden; annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths. A hundred years after this virus was first isolated, influenza vaccines are an important influenza prevention strategy and the preparations used display good safety and tolerability profiles. Innovative tools, such as recombinant technologies and intra-dermal devices, are currently being investigated in order to improve the immunological response. The recurring mutations of influenza strains has prompted the recent introduction of a quadrivalent inactivated vaccine. In the near future, scientific research will strive to produce a long-lasting universal vaccine containing an antigen that will offer protection against all influenza virus strains.

Key words: Influenza, Vaccination, History of medicine

Introduction

Influenza viruses are negative-sense, single-stranded RNA viruses belonging to the Orthomyxoviridae family, together with Isavirus, Thogotovirus and Quaranjavirus. Three types of influenza viruses, namely influenza A, B and C, are capable of determining epidemics and pandemics in humans, with influenza A being the most common circulating type and causing significant illness, being most prone to antigenic shifts and the more likely type to lead to a pandemic [1, 2]. Recently, a new genus (termed influenza virus D) has been discovered in pigs and cattle with influenza-like illness syndrome in the United States [3, 4] and in Europe [5].

Influenza is a highly infectious airborne disease that affects a significant percentage of the world’s population; local annual epidemics and pandemics have occurred since ancient times, causing tens of millions of deaths [6].

The aim of this mini-review is to provide a brief overview of the history and evolution of influenza and influenza control using vaccines.

A history of influenza: from the classical
period to the nineteenth century

In 412 BC, in the “Book of Epidemics”, Hippocrates described a putative influenza-like illness syndrome called “fever of Perinthus” or “cough of Perinthus” [7]. While some scholars claim that this is probably the first historical description of influenza (a winter and a spring epidemic of an upper respiratory tract infection occurring regularly every year at Perinthus, a port-town in Marmaraereglisi, a northern part of Greece, now Turkey), others, including the notable 19th-century editor of Hippocrates, Émile Littré (1801-1881), think that a diagnosis of diphtheria would better fit the description of complications (pneumonia, fits of coughing and wheezing, angina and paralysis of soft palate and limbs). On the other hand, symptoms such as disturbed vision and night blindness suggest a combination of diseases, including deficiency syndromes (e.g. vitamin A deficiency) [8]. In the years 1173 and 1500, two other influenza outbreaks were described, though in scant detail [9-11]. The name “influenza” originated in the 15th century in Italy, from an epidemic attributed to the “influence of the stars”, which, according to Ginctrac, raged across Europe and perhaps in Asia and Africa [12].

It seems that influenza also reached the Americas. Scholars and historians debate whether influenza was already present in the New World or whether it was carried by contaminated pigs transported on ships. Some Aztec texts speak of a “pestilential catarrh” outbreak in 1450-1456 in an area now corresponding to Mexico, but these manuscripts are difficult to interpret correctly and this hypothesis seems controversial [13].

The first reliable documents regarding influenza-like illness syndrome date from 1510, when the virus spread from Africa to Europe. The first pandemic, or worldwide epidemic, occurred in 1557, though some scholars deny that it really was an outbreak of influenza. The first pandemic/ worldwide epidemic that undoubtedly fits the description of influenza appeared in 1580, beginning in Asia and Russia and spreading to Europe via Asia Minor and North-West Africa. In Rome, it caused the death of over 8,000 people, while in Spain it decimated the populations of entire cities. Subsequently, it also affected the Americas [14].

Over the centuries, other pandemics were described worldwide. From 1404 to the middle of the 19th century, 31 influenza epidemics were recorded, including eight large-scale pandemics. Subsequently, others appeared, including three in the 20th century [14]. Some of the most notable outbreaks occurred in 1729, in 1781-1782 (a pandemic spreading from China to Russia, Europe and North America), in 1830-1833 (a pandemic which again spread from China to India, the Philippines, Indonesia, Russia, Europe and North America), in 1847-1848, and in 1898-1900 (spreading from Europe to India, Australia, and North and South America) [14].

One of the most devastating was the pandemic of “Spanish” influenza in 1918–1919, which caused an estimated 21 million deaths worldwide and was defined by Waring as “the greatest medical holocaust in history” [14, 15].

At the end of the 19th century, the etiology of this disease had yet not been well clarified; it was believed that the disease, termed “winter catarrh”, was caused by bacteria (the so-called bacterial hypothesis), such as pneumococcus, streptococcus or Haemophilus influenzae. This latter was also named Bacillus influenzae or Pfeiffer’s bacillus, after Richard Pfeiffer (1858-1945), who described it during the 1889-1892 influenza epidemic. This bacillus had already been discovered by the Polish microbiologist Bujwid Odo Feliks Kazimierz (1857- 1942) in biopsy material a year earlier [16].

In the same period, the French microbiologists Charles Nicolle (1866-1936), Charles Lébally and René Dujarric de la Rivière (1885-1969) of the Pasteur Institute showed that the flu pathogen could pass through a fine filter. However, despite their brilliant experiments, the viral hypothesis continued to be neglected until the virus was isolated [16, 17].

In 1889, some Spanish doctors believed that influenza was a variant of dengue fever, whilst others attributed influenza outbreaks to a variety of causes including cannon fire on the western front, the building of the Madrid underground, air pollution, sunspots, or the spread of the habit of smoking poor-quality tobacco [18].

The thirties: virus isolation and the first
experimental vaccines

During the 1918-1919 pandemic, some scientists began to suspect that bacteria were not the real agent of influenza disease. One of these was the scholar Richard Edwin Shope (1901-1966), who deeply investigated swine flu in 1920. However, it was only in 1932-1933 that the English scientists Wilson Smith (1897-1965), Sir Christopher Andrewes (1896-1988) and Sir Patrick Laidlaw (1881-1940), working at the Medical Research Council at Mill Hill, first isolated the influenza A virus from nasal secretions of infected patients, thereby demonstrating the intranasal human transmission of this virus [19, 20]. A few years later, the American virologist and epidemiologist Thomas Francis Junior (1900-1969) and Smith, in England, were able to transmit the virus to mice [21]. Subsequently, in 1935, Sir Frank Macfarlane Burnet (1899-1985) and Smith separately discovered that the flu virus could be grown on the chorio-allantoid membrane of embryonated hens’ eggs [22], and in 1936 the first neutralized antibodies generated by infection by human influenza virus were isolated [23].

In the next five years, important developments took place: the demonstration that the virus inactivated by formalin was immunogenic in humans, purification of the virus by means of high-speed centrifugation, and the discovery that the influenza virus grew easily in fertilized hen eggs, a procedure that is still used today to manufacture most influenza vaccines [23].

The first clinical trials of influenza vaccines were conducted in the mid-1930s [24, 25].

A study by Smith, Andrewes and Stuart-Harris was conducted among military forces in England in 1937 using a subcutaneous vaccination with an inactivated strain isolated from a mouse lung [25].

In 1938, Francis, together with Jonas Edward Salk (1914-1995), managed to protect USA military forces. Salk would subsequently use this successful experience to develop an effective polio vaccine in 1952 [26, 27].

The forties: inactivated influenza
vaccines

Influenza vaccination had two main objectives: (i) to protect against disease, and (ii) to achieve a high vaccination rate in order to ensure protection in unvaccinated people. The first vaccine was an inactivated, monovalent preparation which only contained a subtype of the influenza A virus [26, 27].

In December 1942, large studies were begun to be conducted on the first influenza virus vaccines; these provided the first official proof that inactivated influenza vaccines could yield effective protection against flu epidemics [28].

The efficacy and safety of inactivated vaccines were first studied between 1942 and 1945; in the meantime, a new strain of flu virus was discovered, the influenza virus type B, which is the main cause of seasonal epidemics, as was the phenomenon of so-called “influenza mismatch”. Influenza mismatch is caused by major and minor mutations of circulating viruses. As a result, the virus contained in the vaccine does not match the circulating strain, determining a reduction in the effectiveness of subtype A influenza vaccines.

A new route of influenza immunization was tested in December 1942, with the subcutaneous inactivated bivalent vaccine containing viruses of type A and type B. The following years, the first bivalent vaccine was licensed in the United States and became available for use in the general population [29, 30].

The fifties: influenza mismatch
and influenza surveillance

The first system for the surveillance of circulating influenza virus strains in several countries worldwide was created in 1952 by the World Health Organization (WHO) in order to monitor the various virus mismatches reported. This important innovative tool enabled the composition of seasonal influenza vaccines to be determined on the basis of the epidemiology of influenza in the previous season [31]. In 1946, as a result of viral mutation, a new variant of influenza A (h2N1), A/FM/1/47, appeared in Australia. This gave rise to a new influenza subtype, the h3N2 strain, which caused the pandemic known as Asian flu [32].

The following year, the US Commission on Influenza recommended that a representative of this strain be included in subsequent vaccines.

The emergence of an HA subtype different from those circulating in previous seasons determined the need for pandemic influenza vaccines [31].

The sixties: split vaccines

New inactivated compounds were tested for safety and efficacy during seasonal epidemics in the 1960s, in particular two new formulations were created: split and subunit vaccines. The 1968 pandemic led to the development of trivalent inactivated vaccines (TIVs) against influenza viruses; moreover the development of new split or subunit vaccines led to a decrease of adverse reactions in children. These vaccines were split using ether and/or detergent, and haemagglutinin and neuraminidase were, in the case of subunit vaccines, purified and enriched [33].

In the same period, the first flu vaccines were licensed in Europe, while in the US annual influenza vaccination was recommended for individuals at major risk of influenza complications.

In 1968, the new virus strain h4N2 (Hong Kong) appeared, completely replacing the previous type A strain (h3N2, or Asian influenza), and led to another global pandemic with high morbidity and mortality [34]. In the same year, a new type of vaccine, the split vaccine, was authorized in the US after several clinical studies had demonstrated that it was less reactogenic than whole virus vaccines, especially in the early years of life [35].

The seventies: genetic reassortment

Split vaccines were widely used during the pandemic swine influenza in 1976 and in 1977, when the h2N1 subtype re-emerged worldwide. However, they were seen to be less immunogenic than whole virus vaccines in “primed” subjects who had never been vaccinated. Indeed, it was shown that two vaccine doses were needed in order to ensure effective protection [36].

At the beginning of the 1970s, an important innovation was introduced into the production of influenza vaccines: the genetic reassortment of influenza virus strains; this technique enabled the vaccine strains to grow faster in embryonated hen eggs [37].

The first subunit vaccine was created between 1976 and 1977. This contained only the surface antigens, hemagglutinin (HA) and neuraminidase (NA), which were isolated by means of successive purification steps.

This innovative tool proved to be highly immunogenic and well tolerated in humans, especially in children, although two doses were needed to guarantee vaccine effectiveness during epidemics [38].

The eighties: subunit vaccines

In 1980, the first subunit vaccines were licensed in the United Kingdom and are currently available in several countries worldwide.

In 1978, as a result of a major mutation, a new virus strain, h2N1, appeared on the global epidemiological scene. This strain, which was similar to a virus circulating in 1958, emerged in Russia and began to co-circulate, either simultaneously or alternately, with the previous one [39].

Antigenic drift, caused by frequent changes in the composition of the virus, determined the need to update the vaccine composition each year. This necessity prompted both the implementation of the first surveillance systems and the production of the first trivalent vaccine, which included three formulation strains (one strain of influenza A/ h2N1, an influenza virus A /h4N2 and a type B virus), in order to ensure effective protection during the 1978 pandemic.

Live attenuated influenza vaccines

In the period 1935-1941, the first clinical trials involving live attenuated influenza vaccines were conducted. The efficacy of these seasonal vaccines was guaranteed by the correspondence between the circulating strain and the strain contained in the vaccine and by the virus dose grown in hen egg embryos [34].

In 1944, Stanley described in detail the preparation and properties of an influenza virus vaccine produced in embryonated hen eggs; this vaccine was concentrated and purified by means of differential centrifugation and inactivated by means of various procedures [23].

In 1949, an important change in vaccine development involved the introduction of the use of cell cultures for virus growth.

In 1997,the so-called “avian flu” pandemic broke out in Hong Kong. This was caused by influenza virus A/ H5N1, a highly pathogenic strain.

In order to contain this pandemic, the techniques of genetic rearrangement developed in those years enabled a huge number of vaccine doses to be produced in a short time by applying recombinant DNA technology to the influenza A/H5N1 virus [34].

Recent years

In recent years, scientific research developed new techniques of immunization, which may be more immunogenic and better tolerated during administration, thereby reducing adverse events. In 2003, for instance, the FDA in the United States authorized the use of an intranasally administered live attenuated vaccine, called FluMist®, in adults [40]. In the 2003-2004 influenza season, an outbreak in Asia was caused by an influenza A/H5N1 strain. This was later used to produce a vaccine, which was licensed in the United States by the FDA in 2007.

More recent years saw the development of adjuvanted vaccines, such as those containing alum adjuvants and the oil in water adjuvant MF-59, which significantly enhanced antigenicity [6].

Specifically, MF-59-adjuvanted vaccines were used in the elderly and in young children, and proved to elicit a good response even to pandemic strains with which subjects had not been primed by natural influenza infection. Similar responses were obtained through the use of other emulsions, such as stable emulsion (SE) and AS03, which were included in the 2009 pandemic influenza vaccines [36].

In the most recent pandemic season (2009), the influenza virus h2N1, which was transmitted to humans by pigs, was estimated to have caused more than 200,000 deaths in the first 12 months of its circulation [41].

A massive effort to produce vaccine for the new h2N1 strain began shortly after scientists identified the virus. The virus proved to grow slowly during the manufacturing process, which relies on cultivation of the virus in chicken eggs. Because of manufacturing delay, the vaccine was available in most countries after the second peak of influenza cases at the end of October leaving most people not immunized while influenza h2N1 virus was circulating [42].

In the elderly, the vaccine efficacy normally decreases, because of immunosenescence. For this reason, in 2009 the Advisory Committee on Immunization Practices (ACIP) recommended and authorized the use of high-dose Fluzone ®, a new formulation containing a 4-fold higher HA dose than the traditional trivalent vaccine [43].

In 2011, as a result of developments in research into new vaccine delivery techniques, the FDA first authorized the intradermal administration of Fluzone®. This new route of administration involved antigen-presenting cells (APCs) in the dermis; these cells process antigens for subsequent presentation in the lymphoid organs, resulting in the stimulation of both innate and adaptive immunity. The intradermal vaccines elicited a better immunological response than intramuscular vaccines, particularly in the elderly; in healthy adults, it yielded an immune response comparable to that elicited by the traditional vaccines, while saving on the HA dose [44-48]. In 2012, the FDA approved Fluarix®, the first quadrivalent vaccine in the United States. This split vaccine contained two influenza A strains and two influenza B antigens. The presence of an additional influenza B strain reduced the possibility of a mismatch between the circulating viruses and the vaccine composition, while maintaining the same immunogenicity and safety as standard trivalent vaccines [49].

In 2013, the FDA approved FluBlock®, a recombinant trivalent influenza vaccine, for use in people aged between 18 and 49 years. FluBlock® was licensed in a spray formulation and was the first trivalent influenza vaccine made by using recombinant DNA technology. Derived from Baculovirus, it contained a 3-fold higher HA dose than traditional trivalent vaccines [50, 51]. The scale-up potential of the insect cell/baculovirus vector system may offer advantages in terms of rapid antigen change and response to a pandemic situation [31].

Currently, scientists are exploring the fascinating prospect of developing a universal vaccine by exploiting T-cells and by attempting to elicit broadly neutralizing antibodies. Moreover, efforts are being made to design M2e- or stalk-based vaccines, since these proteins (the type-2 matrix protein and the stalk domain of HA, respectively) are quite well conserved from an evolutionary standpoint [52, 53].

Conclusions

In the hundred years since the influenza virus was isolated, influenza vaccine preparations have evolved to ensure effective protection, while maintaining a good safety and tolerability profile.

The recurring mutations of influenza strains prompted the introduction of a quadrivalent inactivated vaccine, the composition of which is determined on the basis of the most frequent strains isolated in the previous season during continuous surveillance by the WHO.

Current research priorities include the development of a universal influenza vaccine that could offer protection against all influenza virus strains, thereby overcoming the challenges faced due to antigenic drift and shift or of co-circulation of different viral strains. Another important priority is to identify sustainable vaccine production platforms capable of rapidly meeting the large global demands for influenza vaccine in the face of an influenza pandemic.

ACKNOWLEDGMENTS

No funding declared for this overview. The authors thank Dr. Bernard Patrick for revising the manuscript.

References

1. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part I: Influenza life-cycle and currently available drugs. J Prev Med Hyg. 2014;55:69–85. [PMC free article] [PubMed] [Google Scholar]2. Gasparini R, Amicizia D, Lai PL, Bragazzi NL, Panatto D. Compounds with anti-influenza activity: present and future of
strategies for the optimal treatment and management of influenza.
Part II: Future compounds against influenza virus. J Prev
Med Hyg. 2014;55:109–129. [PMC free article] [PubMed] [Google Scholar]3. Hause BM, Collin EA, Liu R, Huanq B, Shenq Z, Lu W, Wanq D, Nelson EA, Li F. Characterization of a novel influenza virus
in cattle and Swine: proposal for a new genus in the Orthomyxoviridae
family. MBio. 2014;5:e00031–e00114. [PMC free article] [PubMed] [Google Scholar]4. Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F. Cocirculation
of two distinct genetic and antigenic lineages of proposed
influenza D virus in cattle. J Virol. 2015;89:1036–1042. [PMC free article] [PubMed] [Google Scholar]6. Soema PC, Kompier R, Amorij JP, Kersten GF. Current and
next generation influenza vaccines: Formulation and production
strategies. Eur J Pharm Biopharm. 2015;94:251–263. [PubMed] [Google Scholar]7. Pappas G, Kiriaze IJ, Falagas ME. Insights into infectious disease
in the era of Hippocrates. Int J Infect Dis. 2008;12:347–350. [PubMed] [Google Scholar]8. Kohn GC. Encyclopedia of Plague and Pestilence: From Ancient
Times to the Present. Infobase Publishing; 2007. [Google Scholar]9. Beveridge WIB. Influenza: The Last Great Plague. London: Heineman Educational Books; 1977. [Google Scholar]10. Wood JM. Influenza. In: Crovari P, Principi N, editors. Le vaccinazioni. Pisa: Pacini Editore; 2000. [Google Scholar]11. Kuszewski K, Brydak L. The epidemiology and history of influenza. Biomed Pharmacoter. 2000;54:188–195. [PubMed] [Google Scholar]

12. Gintrac H. Grippe. In: Nouveau dictionnaire de médicine et de chirurgie pratiques, directeur de la redaction: le docteur Jaccoud. 1872, Tome 16, page. 728-753.

13. Souza CM. The Spanish flu epidemic: a challenge to Bahian
medicine. Hist Cienc Saude Manguinhos. 2008;15:945–972. [PubMed] [Google Scholar]14. Potter CW. A history of influenza. J Appl Microbiol. 2001;91:572–579. [PubMed] [Google Scholar]15. Waring J.I. A History of Medicine in South Carolina 1900-70. South Carolina Medical Association; 1971. [Google Scholar]16. Bazin H. Vaccination: a history. France: Editions John Libbey
Eurotext Montrouge; 2011. [Google Scholar]17. Renaud F, Hansen W, Freney J. Dictionnaire des precurseurs en
bacteriologie. SFM Éditions Eska; 2005. 249 pages. [Google Scholar]18. Craddock S, Giles-Vernick T, Gunn JL. Influenza and Public
Health: Learning from Past Pandemics. Earthscan; 2010. – 293
pages. [Google Scholar]19. Smith W, Andrewes CH, Laidlaw PP. A virus obtained from influenza
patients. Lancet. 1933;2:66–68. [Google Scholar]20. Smith W, Andrewes CH, Stuart Harris CH. The immunization
of human volunteers. Special Rep Ser Med Res Council. 1938;228:137–144. [Google Scholar]22. Burnett FM. Influenza virus infection of the chick embryo lung. Br J Exp Pathol. 1940;21:147–153. [Google Scholar]23. Stanley WM. The preparation and properties of influenza virus
vaccines concentrated and purified by differential centrifugation. J Exp Med. 1945;81:193–218. [PMC free article] [PubMed] [Google Scholar]26. Parodi V, Florentiis D, Martini M, Ansaldi F. Inactivated influenza
vaccines: recent progress and implications for the elderly. Drugs Aging. 2011;28:93–106. [PubMed] [Google Scholar]27. Barberis I, Martini M, Iavarone F, Orsi A. Available influenza
vaccines: immunization strategies, history and new tools for
fighting the disease. J Prev Med Hyg. 2016;57:E41–E46. [PMC free article] [PubMed] [Google Scholar]28. Francis T, jr, Salk JE, Pearson HE, Brown PN. Protective effect
of vaccination against induced influenza A. J Clin Invest. 1945;24:536–546. [PMC free article] [PubMed] [Google Scholar]29. Weir JP, Gruber MF. An overview of the regulation of influenza
vaccines in the United States. Influenza and Other Respiratory
Viruses. 2016;10:354–360. [PMC free article] [PubMed] [Google Scholar]30. Keitel WA, Neuzil KM, Treanor J. Immunogenicity, efficacy of
inactivated/live virus seasonal and pandemic vaccines. Textbook
of Influenza. Wiley-Blackwell. 2013:311–326. [Google Scholar]32. Oxford J, Gilbert A, Lambkin-Williams R. Influenza vaccines
have a short but illustrious history of dedicated science enabling
the rapid global production of A/swine (h2N1) vaccine
in the current pandemic. In: Rappuoli R, Del Giudice G, editors. Influenza vaccines for the future. Springer Verlag; 2011. [Google Scholar]33. Krammer F, Palese P. Advances in the development of influenza
virus vaccines. Nat Rev Drug Discov. 2015;14:167–182. [PubMed] [Google Scholar]34. Zaman M, Ashraf S, Dreyer NA, Toovey S. Human infection
with avian influenza virus, Pakistan, 2007. Emerg Infect Dis. 2011;17:1056–1059. [PMC free article] [PubMed] [Google Scholar]35. Parkman PD, Hopps HE, Rastogi SC, Meyer HM., Jr Summary
of clinical trials of influenza virus vaccines for adults. J Infect
Dis. 1977;136:722–730. [PubMed] [Google Scholar]36. Hampson AW. Vaccines for pandemic influenza. The history
of our current vaccines, their limitations and the requirements
to deal with a pandemic threat. Ann Acad Med Singapore. 2008;37:510–517. [PubMed] [Google Scholar]37. Crovari P, Alberti M, Alicino C. History and evolution of influenza
vaccines. J Prev Med Hyg. 2011;52:91–94. [PubMed] [Google Scholar]38. Gianchecchi E, Trombetta C, Piccirella S, Montomoli E. Evaluating
influenza vaccines: progress and perspectives. Future Virology. 2016;11:379–393. [Google Scholar]39. Kendal AP, Maassab HF, Alexandrova GI, Ghendon YZ. Development of cold-adapted recombinant live attenuated
influenza vaccines in the U.S.A. and U.S.S.R. Antiviral Res
1982. 1982;1:339–365. [Google Scholar]41. Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, Bandaranayake D, Breiman RF, Brooks WA, Buchy P, et al. Estimated
global mortality associated with the first 12 months of
2009 pandemic influenza A h2N1 virus circulation: a modelling
study. Lancet Infect Dis. 2012;12:687–695. [PubMed] [Google Scholar]43. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing
the immunogenicity of high-dose and standard-dose influenza
vaccine in adults 65 years of age and older. J Infect Dis. 2009;200:172–180. [PubMed] [Google Scholar]44. Durando P, Iudici R, Alicino C, Alberti M, Florentiis, Ansaldi F, Icardi G. Adjuvants and alternative routes of administration
towards the development of the ideal influenza vaccine. Hum
Vaccin. 2011;7(Suppl):29–40. [PubMed] [Google Scholar]45. Holland D, Booy R, Looze F, Eizenberg P, Mc Donald J, Karrasch J, Mc Keirnan M, Salem H, Mills G, Reid J, et al. Intradermal influenza vaccine administered using
a new microinjection system produces superior immunogenicity
in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198:650–658. [PubMed] [Google Scholar]46. Arnou R, Icardi G, Decker M, Ambrozaitis A, Kazek MP, Weber F, Damme P. Intradermal influenza vaccine for older
adults: a randomized controlled multicenter phase III study. Vaccine. 2009;27:7304–7312. [PubMed] [Google Scholar]47. Belshe RB, Newman FK, Cannon J, Duane C, Treanor J, Hoecke C, Howe BJ, Dubin G. Serum antibody responses after
intradermal vaccination against influenza. N Engl J Med. 2004;351:2286–2294. [PubMed] [Google Scholar]48. Bragazzi NL, Orsi A, Ansaldi F, Gasparini R, Icardi G. Fluzone ® Intra-dermal (Intanza® / Istivac® Intra-dermal): an updated overview. Hum Vaccin Immunother. 2016 in press. [PMC free article] [PubMed] [Google Scholar]49. Tisa V, Barberis I, Faccio V, Paganino C, Trucchi C, Martini M, Ansaldi F. Quadrivalent influenza vaccine: a new opportunity
to reduce the influenza burden. J Prev Med Hyg. 2016;57:E28–E33. [PMC free article] [PubMed] [Google Scholar]50. Treanor JJ, El Sahly H, King J, Graham I, Izikson R, Kohberger R, Patriarca P, Cox M. Protective efficacy of a trivalent recombinant
hemagglutinin protein vaccine (FluBlok) against influenza
in healthy adults: a randomized, placebo-controlled trial. Vaccine. 2011;29:7733–7739. [PubMed] [Google Scholar]51. Baxter R, Patriarca PA, Ensor K, Izikson R, Goldenthal KL, Cox M. Evaluation of the safety, reactogenicity and immunogenicity
of FluBlok trivalent recombinant baculovirus-expressed
hemagglutinin influenza vaccine administered intramuscularly
to healthy adults 50-64 years of age. Vaccine. 2011;29:2272–2278. [PubMed] [Google Scholar]52. Sridhar S. Heterosubtypic T-cell immunity to influenza in humans:
challenges for universal T-cell influenza vaccines. Front
Immunol. 2016;7:195–195. [PMC free article] [PubMed] [Google Scholar]53. Wiersma LC, Rimmelzwaan GF, Vries RD. Developing universal
influenza vaccines: hitting the nail, not just on the head. Vaccines (Basel) 2015;3:239–262. [PMC free article] [PubMed] [Google Scholar]

Development of a Universal Influenza Vaccine

Introduction

The 2017–18 influenza season was a stark reminder that outbreaks of influenza virus are associated with significant morbidity and mortality worldwide. The Centers for Disease Control and Prevention reported over 30,000 laboratory-confirmed influenza-related hospitalizations and 171 confirmed pediatric deaths in the United States (1). Severe disease is most commonly seen in adults with underlying medical conditions, including cardiovascular disease, metabolic disorders, and obesity, as examples. A severity assessment classified the 2017–18 season as high overall severity for each age group (children, adolescents, adults, and older adults), something that hasn’t been observed since the 2003–04 season (1). The severity of this influenza season highlights the importance of measures to control and even prevent influenza virus infections.

Arguably, the most effective means to prevent influenza is through vaccination (https://www.cdc.gov/flu/consumer/prevention.htm). Yet the hallmark of influenza viruses is the ability to undergo rapid antigenic variation due to the accumulation of mutations within the Ab-binding sites in the hemagglutinin (HA) and neuraminidase (NA) surface proteins, abrogating the binding of some Abs (2). This antigenic drift requires that the World Health Organization advisory group of experts meet biannually to analyze influenza surveillance data generated by the World Health Organization Global Influenza Surveillance and Response System to determine if the influenza vaccine candidate viruses must be updated (http://www.who.int/influenza/vaccines/virus/recommendations/consultation201809/en/). Continual surveillance of circulating influenza viruses is crucial for the success of this process and timely production of our annual influenza vaccines (3, 4).

Currently, there are three main categories of annual vaccines approved by the Food and Drug Administration, the most common being the detergent-split inactivated influenza vaccine (IIV) (https://www.fda.gov/biologicsbloodvaccines/vaccines/approvedproducts/ucm093833.htm). IIV is composed of three or four candidate vaccine viruses (CVVs), including an influenza A h2N1 and h4N2 virus, as well as influenza B viruses representing either one or both genetically distinct clades (Victoria or Yamagata). Some examples of the IIV include Fluzone, Fluarix, and Flucelvax. CVVs used in the IIV can be grown in embryonated chicken eggs or Madin-Darby canine kidney cells, after which they are inactivated, purified, and detergent split (4). The Ag is primarily composed of the influenza HA protein, although trace amounts of NA protein may also be present. The vaccine is administered i.m. to elicit a protective Ab immune response. The second vaccine category is the recombinant influenza vaccine (RIV), known as Flublok. The RIV is solely composed of the HA protein from the chosen CVVs for that particular year (5). Unlike IIV, RIV is produced and isolated solely in egg-free systems by expressing the HA in insect cells by baculovirus (6). Finally, a live attenuated influenza vaccine (LAIV) is available as FluMist. Like the IIV, the LAIV is composed of three or four CVVs. However, these viruses have been engineered to grow at or below 33°C, limiting replication to the upper respiratory tract (URT) (7, 8). Because they are attenuated live viruses, they elicit a more robust immune response, including both B and T cell responses (9, 10).

Although vaccines are our best line of defense against influenza, they can be improved. Driving Ab responses against the antigenic sites in the HA head is problematic given the constant drift in this region. It requires continually updating the vaccine to keep up with viral evolution. Growth of CVVs in eggs for vaccine production can also lead to mutations in the HA head region, reducing the efficacy of vaccine-generated Ab responses to circulating viruses (11, 12). This has been an issue for the h4N2 component of the vaccine for several recent influenza seasons (13) (https://www.scientificamerican.com/article/ldquo-the-problem-child-of-seasonal-flu-rdquo-beware-this-winter-rsquo-s-virus/). Finally, the IIV drives a strong humoral response to the HA component, which can be impacted by the immunization and infection history of the person (14–16).

In regards to the LAIV, which was initially licensed in the United States in 2003 for use in people ages 2–49 (17), low effectiveness against influenza A(h2N1)pdm09-like viruses circulating in the United States during the 2013–14 and 2015–16 seasons resulted in the Advisory Committee on Immunization Practices recommendation that LAIV not be used in the 2017–18 season (17). On February 21, 2018, the Advisory Committee on Immunization Practices recommended the LAIV as a vaccine option for the 2018–19 season (17). The reason for the low efficacy remains unclear, but a study in the European version of the United States vaccine showed substantial amounts of defective-interfering viral RNAs from both the influenza A and influenza B viruses (18). Given these challenges, the National Institute of Allergy and Infectious Diseases announced a strategic plan to improve current influenza vaccines and eventually lead to the development of a universal influenza vaccine (19). Whereas a universal influenza vaccine would technically target all types of influenza viruses, for the purposes of the National Institute of Allergy and Infectious Diseases strategic plan, “universal” refers to protection against both group 1 and 2 influenza A viruses (independent of influenza B protection). This review will highlight some advances in a few areas of the strategic plan.

HA-directed responses

The influenza HA and NA surface proteins are the major targets of immune responses elicited by vaccination, especially humoral responses (20). HA is the receptor binding protein in influenza. It consists of a globular head and a stem that is anchored to the viral envelope. The receptor binding portion of the head determines if the virus will bind to an α2,6 (mostly human) or α2,3 (mostly avian) linkage of the sialic acid. Once the virus gets internalized via endocytosis, an HA conformational change allows the virus to be released into the cytoplasm (21). Influenza A viruses are divided into two groups based on phylogenetic analysis of the HA protein (22). Group 1 contains h2 and h3 subtypes, which can sustain circulation in humans, as well as H5, H6, and H9, which can occasionally infect humans (22). The main subtype of group 2 is h4, but H7 and h20 can occasionally infect humans and be associated with severe and even fatal disease (22).

The predominant seasonal influenza vaccine-elicited immune response targets the globular head of HA for neutralization (23, 24). Abs bind to the HA to prevent binding to sialic acid or to prevent the conformational change that leads to fusion (25, 26). However, because of the previously mentioned mutability of the HA head, these responses only protect from identical strains of influenza. Emergence of vaccine escape variants leads to reduced protective immune responses (2, 27). To overcome this challenge, new strategies are being developed to target immune responses against the stem region of HA (28–30). The HA stem is highly conserved compared with the head, making it a strong target for broadly protective immune responses (31). However, it is more difficult to mount immune responses to the stem due to the HA head’s immunodominance and steric hindrance of the stem (23, 24, 32). Thus, chimeric HA, where the head of HA is changed and the stem is maintained, have been developed (29, 33). Vaccination of mice with chimeric proteins of different group 1 virus heads (h2, H9, H6, or H5) with the same h2 stem could protect mice from challenge with a variety of group 1 viruses, suggesting more broadly protective Ab responses. However, mice were not protected from challenge with h4N2 virus, an HA group 2 virus, demonstrating that protection did not extend to intergroup influenza virus strains (29). Similar results were shown in a ferret model (33).

Another strategy used for stalk-directed immune responses is a recombinant headless stem (34). Although this strategy eliminates the immunodominance of the HA head, the resulting protein does not provide complete protection (34). Therefore, an initial dose of a vaccine that mimics a more natural infection will have to be used, along with boosting of the primary immune response to elicit protective stem-directed Ab responses. Indeed, a recent study in ferrets demonstrated that a sequential immunization regimen can redirect the immune response toward conserved epitopes. Briefly, administration of a LAIV chimeric H8/1 HA followed by a heterologous booster vaccination with a chimeric H5/1N1 formalin-inactivated nonadjuvanted whole virus resulted in low or undetectable titers in the URT after the A(h2N1)pdm09 virus challenge, supporting the further development of chimeric HA-based vaccination strategies (35). Boosting HA stem–directed Abs can be done with either chimeric (29) or recombinant stable and correctly folded headless HA stem proteins (36, 37). One advantage of utilizing chimeric HA proteins is that people who have had natural influenza infection will already have some baseline stem-directed Abs, which will benefit the boosting of the stem-directed Ab response (38–40). Of note, HA stem–directed Abs are not necessarily neutralizing and instead can employ different mechanisms, such as Ab-dependent cellular cytotoxicity, to clear the virus after a permissive viral infection (41–43). Identifying approaches that can improve Ab responses to conserved regions of the HA head and stalk are an exciting development toward improved efficacy.

NA-directed responses

The second main surface protein of influenza virus, the NA protein, is a functional enzyme that cleaves sialic acid, supporting the release of progeny virus during infection (21). Like HA, NA is divided into two groups based on phylogenetic analysis (22). The enzymatic activity of NA is the main target of antiviral drugs. Although targeting this aspect of influenza replication is not necessarily sterilizing, it does limit viral replication and therefore decreases disease symptoms and viral spread (44–46). In fact, antiviral drugs against the enzymatic activity of NA are the only clinically relevant treatment for influenza infection, aside from supportive care. Therefore, targeting immune responses against the NA protein may be an important complement to HA-directed vaccines (47). A recent clinical study challenging young healthy adults with a pandemic h2N1 virus demonstrated better correlates of NA inhibition (NI) Ab titers with fewer, less severe, and less prolonged symptoms, as well as reduced viral shedding (46). In contrast, hemagglutination inhibition titers only correlated with a reduction in virus shedding (46). Similar results were seen with pre-existing anti-HA stalk Abs as with hemagglutination inhibition titers (48). Another important aspect of NA-directed immune responses is that both inactivated and LAIV induce increases in NI Ab titers. Additionally, NI Ab titers correlate with LAIV and IIV effectiveness (49, 50).

Despite these observations, some barriers must be overcome for the successful use of NA-directed immune responses by vaccination. First, like the HA stem, NA immunogenicity can be masked by the immunodominant HA head (51). However, because of the strong emphasis on HA quantification and standardization in influenza vaccines, low NA immunogenicity could be due to a lack of sufficient NA protein present in vaccines. Although we know that vaccines contain some level of NA, given the increase in NI Ab titers after vaccination (52, 53), the content should be standardized. Yet, before this can occur, we need better NA assays. The development of new and simplified techniques to determine NI Ab titers, including enzyme linked lectin assay and ELISA using NA in its native form, will help overcome these hurdles (54, 55). Although these assays have good reproducibility among different laboratories (56), some caveats include steric hindrance or competition of HA-directed Abs with NA-directed Ab activity (51). Therefore, ELISA using recombinant native form NA is probably the best option moving forward (57).

Once Ag content and NI assays have been standardized, the next hurdle to overcome will be the evolution or antigenic drift of NA. Although NA mutability is lower than HA, vaccine escapes and antiviral resistance strains are known to arise (58, 59). However, a positive aspect of influenza viruses is that HA subtypes and NA subtypes are not concordantly paired between group 1 and group 2 members. Driving vaccine responses against the conserved regions of both HA and NA may prove an exciting and important new approach to provide protective immunity and limit antigenic drift in the virus.

Matrix protein 2–directed responses

The third surface protein of influenza virus is the matrix protein 2 (M2). M2 functions in both viral entry and egress. During entry, M2 acts as a pH-dependent proton-selective ion channel that controls the internal acidity of virus particles in endosomes, allowing for release of the nucleoprotein (NP) components (60). M2 also controls the pH of the Golgi lumen, supporting viral assembly after replication (60–62). However, other functions of M2 are being uncovered (63, 64). In terms of vaccination, M2 serves as an interesting candidate given that it is highly conserved across multiple influenza virus strains (43, 64–66). In fact, avian influenza viruses also cross-react with human sera against the ectodomain of M2 (M2e) (67). Additionally, unlike HA and NA proteins, M2e mutations are nonexistent for up to 11 passages in M2e-vaccinated mice (68), as well as rare and restricted in immunocompromised mice treated with anti-M2e Abs (69). Despite the attractive nature of M2e as a vaccine Ag, its immunogenicity is low after natural infection (70).

To overcome this block, new strategies have been developed to induce M2e-directed Ab responses. The first of these fused M2e to the hepatitis B virus core protein to form virus-like particles with the M2e portion exposed on the surface (71). Those studies demonstrated that both i.p. vaccination with adjuvants and intranasal vaccination without adjuvants protected against both group 1 and group 2 viruses (h2N1 and h4N2). Many other virus-like particle methods have now been employed with M2e (72–74). The protection elicited by Abs to M2e are not sterilizing and instead bind to the surface of virus-infected cells, most likely acting through Ab-dependent cellular cytotoxicity (75–78). The conservation and cross-protective properties of M2e are an exciting aspect of influenza vaccination improvement and will most likely prove indispensable for the development of a universal influenza vaccine. Several recent reviews beautifully cover the state of knowledge of M2 and NP-based vaccines (43, 66, 79).

T cell–directed responses

In addition to HA-, NA-, and M2-directed Ab responses, some vaccine platforms, for example the LAIV, induce T cell responses to conserved Ags in influenza viruses (9, 43, 80). Unlike most Ab vaccine responses, T cell responses are not used to neutralize the virus and prevent infection, but limit viral spread (81). This is achieved by the quick elimination of infected cells by CD8+ T cells or by the concerted direction of the immune response by CD4+ T cells. Of these, CD8+ T cells have been the major focus of influenza-directed T cell responses to date. There are many influenza virus epitopes that are recognized by CD8+ T cells (20, 81). Whereas those epitopes include HA and NA, other more highly conserved proteins like NP, matrix protein 1 (M1), and the polymerase proteins are of more interest to the universal influenza vaccination field (82, 83). The T cell epitopes against these proteins are very well conserved among different influenza virus strains (20, 81). It is no surprise, therefore, that there are many reports of CD8+ T cell responses correlating with high cross-protection against heterologous strains of influenza viruses in both mice and humans (84–88).

Although CD4+ T cell responses to influenza infection have not received as much focus as CD8+ T cells, their role is still of importance (81, 89). Memory CD4+ T cells help direct a faster Ab response to mutated or immunologically novel viral Ags, as well as the generation of new CD8+ T cell responses. In fact, a recent study using a novel platform of influenza vaccination in mice elucidated a major contribution of CD4+ T cells to the cross-protective anti-influenza immune response (79). In these experiments, a vaccinia virus encoding five proteins from an H5N1 viral strain was used for immunization and boosting of mice, followed by challenge with an h4N2 virus. This type of vaccination provided complete protection from heterologous virus challenge of mice. Previous studies using this vaccine platform showed the development of Ab responses capable of cross-reacting with different subtypes of viruses (90). However, serum transfer of vaccinated to naive mice was unable to protect from challenge with a heterologous influenza strain (79). In contrast to the lack of protection from adoptive sera transfer, transfer of either CD4+ or CD8+ T cells protected mice from heterologous challenge. Likewise, depletion of CD4+ or CD8+ T cells, separately, prior to challenge did not alter the protection conferred by the vaccine (79). Of interest, when CD4+ T cells were depleted at time of vaccination, all protection was lost. Therefore, CD4+ and CD8+ T cells seem to be playing an equivalent protective role during challenge, and CD4+ T cells play a necessary role during vaccination.

This previous method of eliciting T cell responses through vector expression is not unique (43, 91), with some studies including mainly T cell Ags (92, 93), whereas other studies combine T cell and Ab Ags (94, 95). One study showed that i.m. vaccination with a Modified Vaccinia virus Ankara (MVA) vector expressing the NP and M1 proteins greatly increased IFN-γ–producing cells after ex vivo restimulation with peptides from the vaccine construct in humans (96). In subsequent studies, participants were vaccinated and challenged with influenza virus (97). When compared with unvaccinated controls, vaccinated subjects had less pronounced symptoms and lower shedding time during infection (97). Furthermore, the MVA-NP+M1 vaccine boosted CD4+ and CD8+ T cell responses in subjects over 50 y of age (98) and can be used as an adjuvant to increase Ab responses toward IIV components without impacting T cell responses (99, 100). Another advantage of this adjuvant effect of vector vaccines is the possibility to combine with recombinant internal proteins, such as NP, to elicit the often-underappreciated role of nonneutralizing Abs against those virus components (101).

Although it is clear that T cells will be crucial for cross-protective immunity to diverse influenza virus strains, there are drawbacks that make it difficult to implement. First, as with most inflammatory responses, but especially with CD8+ T cell responses, the risk of immunopathology is high with such potent effector functions (102, 103). Therefore, it is important to balance a protective CD8+ T cell response to influenza with any associated tissue damage (81, 104). One possibility is to direct anti-influenza virus memory CD8+ T cell responses to the URT. Studies have shown that URT memory CD8+ T cells can prevent influenza virus dissemination to the lower respiratory tract (105). Therefore, a strong CD8+ T cell response in the URT could attenuate the immune response necessary in the lungs and maximize nondamaging protection. This is indeed part of the objective when utilizing LAIV, which is given intranasally and is limited to URT replication. However, this leads to another barrier in T cell–directed immune responses to influenza: immune history.

Although immune history is not a problem specific to T cell–directed influenza vaccines, it is particularly apparent in this context. When introduced, the LAIV was of interest because of its live-attenuated nature (106). Therefore, such a vaccine should induce not only the Abs necessary to target HA and NA but also T cell responses to highly conserved Ags to confer cross-protection (9, 80). Although the calculated vaccine efficacy of the LAIV decreased as the years progressed, especially for pandemic h2N1 virus, the reasons behind the inefficacy were not investigated (107). Some studies show that LAIV induces T cell responses in children and does not in adults (14). Thus, on top of defective-interfering RNA, it is possible that the strength of Ab responses to the pandemic h2N1, or other antigenically similar viruses, neutralized the vaccine virus, inhibiting the replication needed to elicit T cell responses (108). Such a limitation could be overcome with platforms such as vector vaccines expressing influenza proteins (79, 92–96). Overall, moving forward, it will be important to elicit strong B and T cell responses in our pursuit of improved influenza virus vaccines.

Challenges

Although beyond the scope of this review, it is important to note that a universal vaccine must also protect high-risk populations, including the very young, aged adults, pregnant women, people with underlying health conditions, and overweight/obese individuals. We know that the IIV is less effective in high-risk populations (for example, aged adults and overweight/obese individuals) due to underlying immune system complications (109–111). Age-related and potentially weight-related changes in immune function likely contribute to a loss of influenza vaccine efficacy. These changes are likely to limit the applicability of a “universal vaccine” to high-risk populations, outside of the herd immune effects of vaccinating children and adults with a highly efficacious universal vaccine. One strategy for vaccine development in aged is moving toward the notion of “enhanced vaccines” to prevent the serious complications of influenza rather than a universal vaccine that is going to provide sterilizing immunity in this population. These are important consideration for the improvement of current influenza vaccines, as well as in developing universal vaccines.

Global Influenza Programme

In 2017, WHO finalized the Pandemic Influenza Risk Management (PIRM) guidance, which serves to inform and harmonize national and international pandemic preparedness and response. Section 2.4 of the WHO PIRM broadly outlines the roles, responsibilities, and expectations of WHO and stakeholders for pandemic influenza vaccine response (PIVR), including processes for vaccine strain selection and production of pandemic influenza vaccines. Building on previous informal consultations in 2015, 2016, and 2017, since August 2020, WHO has collaborated with an external global task team of experts to develop a draft PIVR Operational Plan, which expands upon section 2.4 of the WHO PIRM.

The draft PIVR Operational Plan can be accessed here. WHO is seeking comments on this draft plan by 6 August, 2021 through an online questionnaire.

 

 

 

The constantly evolving nature of influenza viruses requires continuous global monitoring and frequent reformulation of influenza vaccines.

The World Health Organization (WHO) convenes technical consultations in February and September each year to recommend viruses for inclusion in seasonal influenza vaccines for the northern and southern hemispheres, respectively. These recommendations are based on information provided by the WHO Global Influenza Surveillance Network (GISN), now the WHO Global Influenza Surveillance and Response System. Since 2004, influenza A(H5N1), A(H9N2) and other subtypes of influenza viruses have also been taken into consideration by GISRS for pandemic preparedness purposes.

The development of high yield candidate vaccine viruses is a complex process, involving collaboration of laboratories involved in developing reassortants and WHO Collaborating Centres (CCs). Two technologies are currently being used: classical reassortment (available since 1971) and reverse genetics, a patent technology.

Once developed, these candidate reassortants are sent to WHO CCs for characterization of their antigenic and genetic properties before being released to interested institutions on request. Reference reagents are subsequently developed and standardized by Essential Regulatory Laboratories (ERLs), in collaboration with vaccine manufacturers and made available to manufacturers worldwide upon request.

 

Influenza Vaccine | Global Grand Challenges

The Grand Challenge

(Facilitating innovation requires understanding) how do we create ecosystems that promote creativity…that promote innovation of benefit to the world and to humanity.[1] 
Eliane Ubalijoro, McGill University, GCE Grantee

The net effect of Grand Challenges will be a massive return – these investments, really, will be traceable to saving millions of lives.[2] 
Bill Gates

This is an all-hands-on-deck time. If we get there, we can make influenza history.[3]
Bruce Gellin, Sabin Vaccine Institute

Background

2018 marks the 100-year anniversary of the most severe influenza pandemic in recorded history, which killed an estimated 50 million people worldwide – more than the total deaths caused by the First World War. The subsequent influenza pandemics of 1957, 1968, 1977, and 2009, though milder than the 1918 pandemic, demonstrated the potential of influenza viruses to cause excessive morbidity, mortality, and, more generally, severe disruptions of healthcare systems. Clearly, the threat of pandemic influenza is very real. Also, influenza viruses pose a significant threat to humankind, with seasonal influenza disease leading to an estimated 290,000 – 650,000 deaths each year.

While vaccination remains the best tool for prevention of disease, the current influenza vaccines significantly underperform compared to the effective and durable vaccines used against other vaccine-preventable diseases around the world. One key reason for this comparatively reduced effectiveness is the influenza virus’ propensity for generating mutations in its surface antigens – the very targets of today’s vaccines. Furthermore, the predominant technologies for influenza vaccine production necessitate a protracted and inefficient manufacturing cycle and a huge supporting mechanism for biennial flu vaccine strain recommendations; by the time vaccines are ready for distribution – 6+ months after strain determination – the viruses circulating during next season may not match up well with those strains in vaccines leading to less than optimal vaccine effectiveness. Although other factors also contribute to poor vaccine effectiveness, the annual formulation changes, the cost of and limited access to current influenza vaccines (regardless of how well matched they are to circulating strains), and need for annual vaccinations are barriers to protecting against global seasonal influenza, particularly among those in low- and middle-income countries. Furthermore, at best they may only offer partial or minimal protection against emerging pandemic strains. Clearly, there is an unmet public health need for a transformative, game-changing universal influenza vaccine that will protect against all influenza strains for longer duration, alleviating the need for annual formulations and vaccinations and leading to a panacea for tackling pandemic and seasonal influenza disease threats.

Please see the Impatient Optimists blog: Ending the Pandemic Threat: A Grand Challenge for Universal Influenza Vaccine Development.

Objectives

To find a game changing, universal solution to all these challenges, the Bill & Melinda Gates Foundation and the Page Family are launching the “Universal Influenza Vaccine Development Grand Challenge” during the centenary year of the 1918 flu pandemic. The goal of this Grand Challenge is to identify novel, transformative concepts that will lead to development of universal influenza vaccines offering protection from morbidity and mortality caused by all subtypes of circulating and emerging (drifted and shifted) Influenza A subtype viruses and Influenza B lineage viruses for at least three to five years. It is envisaged that such a universal influenza vaccine would address the threat from both seasonal and pandemic influenza, thus alleviating the need for annual seasonal influenza vaccination campaigns, averting significant global morbidity and mortality, and better preparing the world for the next influenza pandemic.

While other funders are supporting development of universal Influenza vaccines, three things set this Grand Challenge apart. We seek to fund ideas that are bold and innovative, bridging the funding ‘valley of death’ to translate these novel approaches into products ready for human clinical trials. We also aim to encourage interdisciplinary collaboration and cross-fertilization of ideas from outside the traditional influenza research community. Third, we seek completely transformative approaches rather than incremental research.

Our collective belief is that innovation is catalyzed through rigorous collaboration and enriching of ecosystems, and we hope this Grand Challenge will stimulate creative thinking beyond the traditional influenza community. Although not exhaustive, examples of researchers and disciplines we would like to see further integrated and supported include computational and systems biologists, virologists, immunologists, bioinformatics, artificial intelligence, deep learning, machine learning, the HIV/AIDS and cancer immunotherapy research communities, etc. Fundamentally, we are looking for unconventional approaches that effectively drive or harness immune responses in desired ways and develop universal influenza vaccines that are ready to start clinical trials by 2021.

Approach

All proposals must be aligned with the Gates Foundation’s intervention Target Product Profile (iTPP). The iTPP (detailed in the Supporting Materials) describes the desired characteristics of a universal influenza vaccine. Most importantly, new vaccines should have the potential to be used in all age groups around the world, especially in developing countries. We are looking for affordable, effective vaccines that are suitable for delivery through existing immunization programs in-country, which has implications for product presentation and stability as well as for dosing route and schedule. The vaccines need to be broadly protective across Influenza A and B strains for a minimum of three to five years. Technologies will need to be scalable to meet worldwide demand.

We are looking for proposals that:

  • Engage scientists across a variety of disciplines, including those new to the influenza field
  • Demonstrate innovative thinking by incorporating concepts or technologies not currently being used within/addressed by the influenza vaccine field
  • Present concepts and strategies that are “off the beaten track,” significantly radical in conception, and daring in premise.

Please note: grantees will have access to a wide-range of Gates Foundation-funded resources and technology platforms to support their projects

Examples of what we’re looking for may fall into broad categories:

  1. Antigen-centric: discovering new antigens/targets through Artificial Intelligence, Machine Learning, and/or Deep Learning approaches to get beyond traditional surface hemagglutinin
  2. Host-centric: approaches that (a) generate, enhance, or modify human immune protection, including sterilizing immunity (b) ensure longer term (possibly life-long) immune response (c) describe surrogates for longevity of immune response and (d) that target specific tissue or cell types for appropriate induction of local and systemic immunity leading to broader and longer protection
  3. Technology-centric: including (a) novel vaccine concepts, targets and constructs inspired by new observations or understanding about the nature of the influenza virus or the human response to it and (b) applications of radically new technologies for disease protection, such as production of immunogens using synthetic biology or radical genetic engineering approaches
  4. Enabling advances: including challenge models to quickly demonstrate safety and proof-of-concept for influenza vaccines

We also would be very happy to receive proposals that describe approaches for employing multiple interventions in combination.

In addition, we may entertain concept proposals related to use of DNA/RNA based delivery of longer acting universal influenza monoclonal antibody for passive prophylaxis or use of such monoclonals for exploring appropriate epitopes for universal influenza vaccine, if generally aligned with our iTPP.

We will NOT consider funding for:

  • Marginal improvements in current seasonal influenza vaccines
  • Precedented approaches using biosimilars to antigens or adjuvants currently in clinical development
  • Basic studies of pathogen or human biology without a clear component that tests the potential for translation into product
  • Development of assays, new reagents, adjuvants, or production technologies improving licensed and late-stage vaccines already in development
  • Therapeutic monoclonal antibodies for treatment of influenza patients.

Award

Pilot awards ($250,000 up to $ 2 million)

This request for proposals intends to fund pilot awards of up to USD $2 million over 2 years, with the anticipation that one or more pilot projects, on demonstration of promising proof-of-concept data (e.g., from animal models), may be invited to apply for a full award up to USD $10 million. Full awards would be intended to fund IND-enabling and clinical studies.

Pilot awards do not include a requirement for an industry or translation partner but such partnerships would still be welcome. Industry is also welcome to apply directly for the pilot award. Successful pilot award recipients will have the opportunity to apply for additional funding, which could include grants, program related investments and/or contracts and must include a biopharmaceutical industry or other translational partner.

We reserve the right to determine eligibility for subsequent funding for this call based on these characteristics.

Suggested Reading

Please note: these suggested readings obviously do not represent an exhaustive list of all universal influenza vaccine activities and concepts and very few, if any, are likely to meet all the requirements of our iTPP (detailed in the Supporting Materials). We include these for illustrative purposes only and encourage applicants to understand and think beyond the ideas discussed below.

1. Arun Kumar, et al. (2018) Novel Platforms for the Development of a Universal Influenza Vaccine. Frontiers in Immunology. (doi:10.3389/fimmu.2018.00600).

2. James E. Crowe, Jr. (2017) Is it Possible to Develop a “Universal” Influenza Virus Vaccine? Potential for a Universal Influenza Vaccine. Cold Spring Harbor Perspectives in Biology. (doi:10.1101/cshperspect.a029496).

3. Sarah F. Andrews, et al. (2017) Is it Possible to Develop a “Universal” Influenza Virus Vaccine? Immunogenetic Considerations Underlying B-Cell Biology in the Development of a Pan-Subtype Influenza A Vaccine Targeting the Hemagglutinin Stem. Cold Spring Harbor Perspectives in Biology. (doi:10.1101/cshperspect.a029413).

4. Florian Krammer, et al. (2017) Is it Possible to Develop a “Universal” Influenza Virus Vaccine? Toward a Universal Influenza Virus Vaccine: Potential Target Antigens and Critical Aspects for Vaccine Development. Cold Spring Harbor Perspectives in Biology. (doi:10.1101/cshperspect.a028845).

5. Davide Angeletti and Johnathan W. Yewdell. (2017) Is it Possible to Develop a “Universal” Influenza Virus Vaccine? Outflanking Antibody Immunodominance on the Road to Universal Influenza Vaccination. Cold Spring Harbor Perspectives in Biology. (doi:10.1101/cshperspect.a028852).

6. Francesco Berlanda Scorza, et al. (2016) Universal Influenza Vaccines: Shifting to Better Vaccines. Vaccine. (doi:10.1016/j.vaccine.2016.03.085).

7. Erin Sparrow, et al. (2016) Passive Immunization for Influenza through Antibody Therapies, a review of the pipeline, challenges and potential applications. Vaccine. (doi:10.1016/j.vaccine.2016.08.057).

___________________________
[1]Grand Challenges in Global Health – the First Ten Years
[2]Grand Challenges in Global Health – the First Ten Years
[3]Andrew Nusca, “Why We Need a Universal Flu Vaccine”, Fortune, 2018

Better influenza vaccines: an industry perspective | Journal of Biomedical Science

  • 1.

    WHO. World Health Organization (WHO) Influenza (Seasonal) 2018 Available from: who.int/en/news-room/fact-sheets/detail/influenza-(seasonal).

    Google Scholar 

  • 2.

    Iuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. Lancet. 2018;391(10127):1285–300.

    PubMed 

    Google Scholar 

  • 3.

    Palese P. Influenza: old and new threats. Nat Med. 2004;10:S82.

    CAS 
    PubMed 

    Google Scholar 

  • 4.

    WT RPA, Harmon MW, Rota JS, Kendal AP, Nerome K. Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983. Virology. 1990;175(1):59–68.

    Google Scholar 

  • 5.

    Hause BM, Collin EA, Liu R, Huang B, Sheng Z, Lu W, et al. Characterization of a novel influenza virus in cattle and swine: proposal for a new genus in the Orthomyxoviridae family. MBio. 2014;5(2):e00031–14.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 6.

    Parvin JD, Moscona A, Pan WT, Leider JM, Palese P. Measurement of the mutation rates of animal viruses: influenza a virus and poliovirus type 1. J Virol. 1986;59(2):377–83.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 7.

    Webster RGLW, Air GM, Schild GC. Molecular mechanisms of variation in influenza viruses. Nature. 1982;296(5853):115–21.

    CAS 
    PubMed 

    Google Scholar 

  • 8.

    Chambers BS, Parkhouse K, Ross TM, Alby K, Hensley SE. Identification of Hemagglutinin residues responsible for h4N2 antigenic drift during the 2014-2015 influenza season. Cell Rep. 2015;12(1):1–6.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 9.

    Garten RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, et al. Antigenic and genetic characteristics of swine-origin 2009 a(h2N1) influenza viruses circulating in humans. Science. 2009;325(5937):197–201.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 10.

    Ferguson NM, Galvani AP, Bush RM. Ecological and immunological determinants of influenza evolution. Nature. 2003;422:428.

    CAS 
    PubMed 

    Google Scholar 

  • 11.

    Bush RM, Bender CA, Subbarao K, Cox NJ, Fitch WM. Predicting the evolution of human influenza a. Science. 1999;286(5446):1921.

    CAS 
    PubMed 

    Google Scholar 

  • 12.

    WHO. Global Influenza Surveillance and Response System (GISRS) Available from: https://www.who.int/influenza/gisrs_laboratory/en/.

  • 13.

    Davenport FM. Control of influenza. Med J Aust. 1973;1:33–8.

    CAS 
    PubMed 

    Google Scholar 

  • 14.

    CDC. Key Facts About Influenza (Flu) 2019 Available from: https://www.cdc.gov/flu/about/keyfacts.htm.

    Google Scholar 

  • 15.

    Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24(8):1159–69.

    CAS 
    PubMed 

    Google Scholar 

  • 16.

    Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices-United States, 2018-19 influenza season. MMWR Recomm Rep. 2018;67(3):1–20.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 17.

    Ohmit SE, Victor JC, Rotthoff JR, Teich ER, Truscon RK, Baum LL, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006;355(24):2513–22.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 18.

    Tisa V, Barberis I, Faccio V, Paganino C, Trucchi C, Martini M, et al. Quadrivalent influenza vaccine: a new opportunity to reduce the influenza burden. J Preventive Med hygiene. 2016;57(1):E28–33.

    CAS 

    Google Scholar 

  • 19.

    Pandey S, Manjrekar S, Sumant O. Influenza Vaccine Market by Vaccine Type (Quadrivalent and Trivalent), Type (Seasonal and Pandemic), Technology (Egg-based and Cell-based), Age Group (Pediatric and Adult), and Route of Administration (Injection and Nasal Spray): Global Opportunity Analysis and Industry Forecast, 2019–2026. Portland: Allied Market Research; 2019. Available from: https://www.alliedmarketresearch.com/influenza-vaccines-market.

  • 20.

    McLean KA, Goldin S, Nannei C, Sparrow E, Torelli G. The 2015 global production capacity of seasonal and pandemic influenza vaccine. Vaccine. 2016;34(45):5410–3.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 21.

    WHO. Addendum to the recommended composition of influenza virus vaccines for use in the 2019–2020 northern hemisphere influenza season 2019. Available from: https://www.who.int/influenza/vaccines/virus/recommendations/201902_recommendation_addendum.pdf?ua=1. [cited 2019 11/14].

  • 22.

    Abelin A, Colegate T, Gardner S, Hehme N, Palache A. Lessons from pandemic influenza a(h2N1): the research-based vaccine industry’s perspective. Vaccine. 2011;29(6):1135–8.

    PubMed 

    Google Scholar 

  • 23.

    Skowronski DM, Janjua NZ, De Serres G, Sabaiduc S, Eshaghi A, Dickinson JA, et al. Low 2012–13 influenza vaccine effectiveness associated with mutation in the egg-adapted h4N2 vaccine strain not antigenic drift in circulating viruses. PLoS One. 2014;9(3):e92153.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 24.

    Zost SJ, Parkhouse K, Gumina ME, Kim K, Diaz Perez S, Wilson PC, et al. Contemporary h4N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci. 2017;114(47):12578.

    CAS 
    PubMed 

    Google Scholar 

  • 25.

    Widjaja L, Ilyushina N, Webster RG, Webby RJ. Molecular changes associated with adaptation of human influenza a virus in embryonated chicken eggs. Virol. 2006;350(1):137–45.

    CAS 

    Google Scholar 

  • 26.

    Nicholls JM, Chan RWY, Russell RJ, Air GM, Peiris JSM. Evolving complexities of influenza virus and its receptors. Trends Microbiol. 2008;16(4):149–57.

    CAS 
    PubMed 

    Google Scholar 

  • 27.

    Imai M, Kawaoka Y. The role of receptor binding specificity in interspecies transmission of influenza viruses. Curr Opinion Virol. 2012;2(2):160–7.

    CAS 

    Google Scholar 

  • 28.

    Ito T, Suzuki Y, Takada A, Kawamoto A, Otsuki K, Masuda H, et al. Differences in sialic acid-galactose linkages in the chicken egg amnion and allantois influence human influenza virus receptor specificity and variant selection. J Virol. 1997;71(4):3357–62.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 29.

    Hoft DF, Babusis E, Worku S, Spencer CT, Lottenbach K, Truscott SM, et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis. 2011;204(6):845–53.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 30.

    Mohn KG-I, Brokstad KA, Pathirana RD, Bredholt G, Jul-Larsen Å, Trieu MC, et al. Live attenuated influenza vaccine in children induces B-cell responses in tonsils. J Infect Dis. 2016;214(5):722–31.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 31.

    Gaglani M, Pruszynski J, Murthy K, Clipper L, Robertson A, Reis M, et al. Influenza vaccine effectiveness against 2009 pandemic influenza a(h2N1) virus differed by vaccine type during 2013-2014 in the United States. J Infect Dis. 2016;213(10):1546–56.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 32.

    Tam TWS. Intranasal influenza vaccine: why does Canada have different recommendations from the USA on its use? Paediatr Child Health. 2018;23(1):31–4.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 33.

    Singanayagam A, Zambon M, Lalvani A, Barclay W. Urgent challenges in implementing live attenuated influenza vaccine. Lancet Infect Dis. 2018;18(1):e25–32.

    PubMed 

    Google Scholar 

  • 34.

    Grohskopf LA, Sokolow LZ, Fry AM, Walter EB, Jernigan DB. Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4)—United States, 2018–19 influenza season. Morb Mortal Wkly Rep. 2018;67(22):643.

    Google Scholar 

  • 35.

    Immunization NACo. An Advisory Committee Statement (ACS): Canadian Immunization Guide Chapter on Influenza and Statement on Seasonal Influenza Vaccine for 2019-2020. Ottawa: Public Health Agency Of Canada; 2018.

    Google Scholar 

  • 36.

    CDC. Flublok Seasonal Influenza (Flu) Vaccine [Available from: https://www.cdc.gov/flu/protect/vaccine/qa_flublok-vaccine.htm.

  • 37.

    Cox MMJ, Izikson R, Post P, Dunkle L. Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults. Therapeutic Advances Vaccin. 2015;3(4):97–108.

    CAS 

    Google Scholar 

  • 38.

    Izurieta HS, Chillarige Y, Kelman J, Wei Y, Lu Y, Xu W, et al. Relative effectiveness of cell-cultured and egg-based influenza vaccines among elderly persons in the United States, 2017-2018. J Infect Dis. 2019;220(8):1255–64.

    CAS 
    PubMed 

    Google Scholar 

  • 39.

    Cox MMJ, Hashimoto Y. A fast track influenza virus vaccine produced in insect cells. J Invertebr Pathol. 2011;107:S31–41.

    CAS 
    PubMed 

    Google Scholar 

  • 40.

    Dunkle LM, Izikson R, Patriarca P, Goldenthal KL, Muse D, Callahan J, et al. Efficacy of recombinant influenza vaccine in adults 50 years of age or older. N Engl J Med. 2017;376(25):2427–36.

    CAS 
    PubMed 

    Google Scholar 

  • 41.

    CDC. Archived CDC Vaccine Price List as of 1 September 2019. Available from: https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.html.

  • 42.

    The White House, Office of the Press Secretary. Statement from the Press Secretary on the Executive Order Modernizing Influenza Vaccines in the U.S. to Promote National Security and Public Health [press release] (2019 Sep 19). Available from: https://www.whitehouse.gov/briefings-statements/statement-press-secretary-executive-order-modernizing-influenza-vaccines-u-s-promote-national-security-public-health/. Cited 2020 Feb 3.

  • 43.

    Paules CI, Marston HD, Eisinger RW, Baltimore D, Fauci AS. The pathway to a universal influenza vaccine. Immunity. 2017;47(4):599–603.

    CAS 
    PubMed 

    Google Scholar 

  • 44.

    Sah P, Alfaro-Murillo JA, Fitzpatrick MC, Neuzil KM, Meyers LA, Singer BH, et al. Future epidemiological and economic impacts of universal influenza vaccines. Proc Natl Acad Sci. 2019;116(41):20786–92.

    CAS 
    PubMed 

    Google Scholar 

  • 45.

    Smith G, Liu Y, Flyer D, Massare MJ, Zhou B, Patel N, et al. Novel hemagglutinin nanoparticle influenza vaccine with matrix-M adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted a(h4N2) subtypes. Vaccine. 2017;35(40):5366–72.

    CAS 
    PubMed 

    Google Scholar 

  • 46.

    Shinde V, Fries L, Wu Y, Agrawal S, Cho I, Thomas DN, et al. Improved titers against influenza drift variants with a nanoparticle vaccine. N Engl J Med. 2018;378(24):2346–8.

    PubMed 

    Google Scholar 

  • 47.

    Lovgren Bengtsson K, Morein B, Osterhaus AD. ISCOM technology-based matrix M adjuvant: success in future vaccines relies on formulation. Expert Rev Vaccines. 2011;10(4):401–3.

    PubMed 

    Google Scholar 

  • 48.

    Krammer F, Pica N, Hai R, Margine I, Palese P. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. J Virol. 2013;87(12):6542–50.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 49.

    Nachbagauer R, Liu WC, Choi A, Wohlbold TJ, Atlas T, Rajendran M, et al. A universal influenza virus vaccine candidate confers protection against pandemic h2N1 infection in preclinical ferret studies. NPJ Vaccines. 2017;2:26.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 50.

    Krammer F, Margine I, Hai R, Flood A, Hirsh A, Tsvetnitsky V, et al. h4 stalk-based chimeric hemagglutinin influenza virus constructs protect mice from H7N9 challenge. J Virol. 2014;88(4):2340–3.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 51.

    Krammer F, Palese P, Steel J. Advances in universal influenza virus vaccine design and antibody mediated therapies based on conserved regions of the hemagglutinin. Curr Top Microbiol Immunol. 2015;386:301–21.

    CAS 
    PubMed 

    Google Scholar 

  • 52.

    Wang CC, Chen JR, Tseng YC, Hsu CH, Hung YF, Chen SW, et al. Glycans on influenza hemagglutinin affect receptor binding and immune response. Proc Natl Acad Sci U S A. 2009;106(43):18137–42.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 53.

    Chen JR, Yu YH, Tseng YC, Chiang WL, Chiang MF, Ko YA, et al. Vaccination of monoglycosylated hemagglutinin induces cross-strain protection against influenza virus infections. Proc Natl Acad Sci U S A. 2014;111(7):2476–81.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 54.

    Tseng YC, Wu CY, Liu ML, Chen TH, Chiang WL, Yu YH, et al. Egg-based influenza split virus vaccine with monoglycosylation induces cross-strain protection against influenza virus infections. Proc Natl Acad Sci U S A. 2019;116(10):4200–5.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 55.

    Atsmon J, Caraco Y, Ziv-Sefer S, Shaikevich D, Abramov E, Volokhov I, et al. Priming by a novel universal influenza vaccine (Multimeric-001)-a gateway for improving immune response in the elderly population. Vaccine. 2014;32(44):5816–23.

    CAS 
    PubMed 

    Google Scholar 

  • 56.

    Gottlieb T, Ben-Yedidia T. Epitope-based approaches to a universal influenza vaccine. J Autoimmun. 2014;54:15–20.

    CAS 
    PubMed 

    Google Scholar 

  • 57.

    Atsmon J, Kate-Ilovitz E, Shaikevich D, Singer Y, Volokhov I, Haim KY, et al. Safety and immunogenicity of multimeric-001–a novel universal influenza vaccine. J Clin Immunol. 2012;32(3):595–603.

    CAS 
    PubMed 

    Google Scholar 

  • 58.

    van Doorn E, Liu H, Ben-Yedidia T, Hassin S, Visontai I, Norley S, et al. Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: phase IIb study protocol. Medicine (Baltimore). 2017;96(11):e6339.

    Google Scholar 

  • 59.

    Stoloff GA, Caparros-Wanderley W. Synthetic multi-epitope peptides identified in silico induce protective immunity against multiple influenza serotypes. Eur J Immunol. 2007;37(9):2441–9.

    CAS 
    PubMed 

    Google Scholar 

  • 60.

    Pleguezuelos O, Robinson S, Stoloff GA, Caparros-Wanderley W. Synthetic influenza vaccine (FLU-v) stimulates cell mediated immunity in a double-blind, randomised, placebo-controlled phase I trial. Vaccine. 2012;30(31):4655–60.

    CAS 
    PubMed 

    Google Scholar 

  • 61.

    van Doorn E, Pleguezuelos O, Liu H, Fernandez A, Bannister R, Stoloff G, et al. Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial. BMC Infect Dis. 2017;17(1):241.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 62.

    Pleguezuelos O, Robinson S, Fernandez A, Stoloff GA, Mann A, Gilbert A, et al. A synthetic influenza virus vaccine induces a cellular immune response that correlates with reduction in symptomatology and virus shedding in a randomized phase Ib live-virus challenge in humans. Clin Vaccine Immunol. 2015;22(7):828–35.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 63.

    Mitchell CA, Ramessar K, O’Keefe BR. Antiviral lectins: selective inhibitors of viral entry. Antivir Res. 2017;142:37–54.

    CAS 
    PubMed 

    Google Scholar 

  • 64.

    Mueller S, Coleman JR, Papamichail D, Ward CB, Nimnual A, Futcher B, et al. Live attenuated influenza virus vaccines by computer-aided rational design. Nat Biotechnol. 2010;28(7):723–6.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 65.

    Yang C, Skiena S, Futcher B, Mueller S, Wimmer E. Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice. Proc Natl Acad Sci U S A. 2013;110(23):9481–6.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 66.

    Stauft CB, Yang C, Coleman JR, Boltz D, Chin C, Kushnir A, et al. Live-attenuated h2N1 influenza vaccine candidate displays potent efficacy in mice and ferrets. PLoS One. 2019;14(10):e0223784.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 67.

    Sarawar S, Hatta Y, Watanabe S, Dias P, Neumann G, Kawaoka Y, et al. M2SR, a novel live single replication influenza virus vaccine, provides effective heterosubtypic protection in mice. Vaccine. 2016;34(42):5090–8.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 68.

    Hatta Y, Boltz D, Sarawar S, Kawaoka Y, Neumann G, Bilsel P. Novel influenza vaccine M2SR protects against drifted h2N1 and h4N2 influenza virus challenge in ferrets with pre-existing immunity. Vaccine. 2018;36(33):5097–103.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 69.

    Elliott STC, Keaton AA, Chu JD, Reed CC, Garman B, Patel A, et al. A synthetic micro-consensus DNA vaccine generates comprehensive influenza a h4N2 immunity and protects mice against lethal challenge by multiple h4N2 viruses. Hum Gene Ther. 2018;29(9):1044–55.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 70.

    Yan J, Morrow MP, Chu JS, Racine T, Reed CC, Khan AS, et al. Broad cross-protective anti-hemagglutination responses elicited by influenza microconsensus DNA vaccine. Vaccine. 2018;36(22):3079–89.

    CAS 
    PubMed 

    Google Scholar 

  • 71.

    Yan J, Villarreal DO, Racine T, Chu JS, Walters JN, Morrow MP, et al. Protective immunity to H7N9 influenza viruses elicited by synthetic DNA vaccine. Vaccine. 2014;32(24):2833–42.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 72.

    Choo AY, Broderick KE, Kim JJ, Sardesai NY. DNA-based influenza vaccines: evaluating their potential to provide universal protection. IDrugs. 2010;13(10):707–12.

    CAS 
    PubMed 

    Google Scholar 

  • 73.

    De Filette M, Martens W, Smet A, Schotsaert M, Birkett A, Londono-Arcila P, et al. Universal influenza a M2e-HBc vaccine protects against disease even in the presence of pre-existing anti-HBc antibodies. Vaccine. 2008;26(51):6503–7.

    PubMed 

    Google Scholar 

  • 74.

    Deng L, Cho KJ, Fiers W, Saelens X. M2e-based universal influenza a vaccines. Vaccines (Basel). 2015;3(1):105–36.

    CAS 

    Google Scholar 

  • 75.

    O’Donnell CD, Wright A, Vogel LN, Wei CJ, Nabel GJ, Subbarao K. Effect of priming with h2N1 influenza viruses of variable antigenic distances on challenge with 2009 pandemic h2N1 virus. J Virol. 2012;86(16):8625–33.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 76.

    Tate MD, Job ER, Deng YM, Gunalan V, Maurer-Stroh S, Reading PC. Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection. Viruses. 2014;6(3):1294–316.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 77.

    Medina RA, Stertz S, Manicassamy B, Zimmermann P, Sun X, Albrecht RA, et al. Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the h2N1 influenza viruses. Sci Transl Med. 2013;5(187):187ra70.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 78.

    Kobayashi Y, Suzuki Y. Evidence for N-glycan shielding of antigenic sites during evolution of human influenza a virus hemagglutinin. J Virol. 2012;86(7):3446–51.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 79.

    Wei CJ, Boyington JC, Dai K, Houser KV, Pearce MB, Kong WP, et al. Cross-neutralization of 1918 and 2009 influenza viruses: role of glycans in viral evolution and vaccine design. Sci Transl Med. 2010;2(24):24ra1.

    Google Scholar 

  • 80.

    Abe Y, Takashita E, Sugawara K, Matsuzaki Y, Muraki Y, Hongo S. Effect of the addition of oligosaccharides on the biological activities and antigenicity of influenza a/h4N2 virus Hemagglutinin. J Virol. 2004;78(18):9605–11.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 81.

    Chen JR, Ma C, Wong CH. Vaccine design of hemagglutinin glycoprotein against influenza. Trends Biotechnol. 2011;29(9):426–34.

    CAS 
    PubMed 

    Google Scholar 

  • 82.

    Zhou T, Doria-Rose NA, Cheng C, Stewart-Jones GBE, Chuang GY, Chambers M, et al. Quantification of the impact of the HIV-1-glycan shield on antibody elicitation. Cell Rep. 2017;19(4):719–32.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 83.

    Hurtley SM, Bole DG, Hoover-Litty H, Helenius A, Copeland CS. Interactions of misfolded influenza virus hemagglutinin with binding protein (BiP). J Cell Biol. 1989;108(6):2117–26.

    CAS 
    PubMed 

    Google Scholar 

  • 84.

    Roberts PC, Garten W, Klenk HD. Role of conserved glycosylation sites in maturation and transport of influenza a virus hemagglutinin. J Virol. 1993;67(6):3048–60.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 85.

    Lowell GH, Ziv S, Bruzil S, Babecoff R, Ben-Yedidia T. Back to the future: immunization with M-001 prior to trivalent influenza vaccine in 2011/12 enhanced protective immune responses against 2014/15 epidemic strain. Vaccine. 2017;35(5):713–5.

    CAS 
    PubMed 

    Google Scholar 

  • 86.

    Saelens X. The Role of Matrix Protein 2 Ectodomain in the Development of Universal Influenza Vaccines. J Infect Dis. 2019;219(Supplement 1):S68–74.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 87.

    Erbelding EJ, Post DJ, Stemmy EJ, Roberts PC, Augustine AD, Ferguson S, et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis. 2018;218(3):347–54.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 88.

    Wijnans L, Voordouw B. A review of the changes to the licensing of influenza vaccines in Europe. Influenza Other Respir Viruses. 2016;10(1):2–8.

    PubMed 

    Google Scholar 

  • 89.

    Weir JP, Gruber MF. An overview of the regulation of influenza vaccines in the United States. Influenza Other Respir Viruses. 2016;10(5):354–60.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 90.

    Schild GC, Pereira MS, Chakraverty P. Single-radial-hemolysis: a new method for the assay of antibody to influenza haemagglutinin. Applications for diagnosis and seroepidemiologic surveillance of influenza. Bull World Health Organ. 1975;52(1):43–50.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 91.

    Gianchecchi E, Torelli A, Montomoli E. The use of cell-mediated immunity for the evaluation of influenza vaccines: an upcoming necessity. Human Vaccin Immunotherapeutics. 2019;15(5):1021–30.

    CAS 

    Google Scholar 

  • 92.

    Oxford JS, Oxford JR. Clinical, scientific and ethnographic studies of influenza in quarantine. Expert Rev Vaccin. 2012;11(8):929–37.

    CAS 

    Google Scholar 

  • 93.

    Oxford JS, Gelder C, Lambkin R. Would you volunteer to be quarantined and infected with influenza virus? Expert Rev Anti-Infect Ther. 2005;3(1):1–2.

    PubMed 

    Google Scholar 

  • 94.

    Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med. 2012;18(2):274–80.

    CAS 
    PubMed 

    Google Scholar 

  • 95.

    Govaert TM, Thijs CT, Masurel N, Sprenger MJ, Dinant GJ, Knottnerus JA. The efficacy of influenza vaccination in elderly individuals. A randomized double-blind placebo-controlled trial. JAMA. 1994;272(21):1661–5.

    CAS 
    PubMed 

    Google Scholar 

  • 96.

    Petrie JG, Ohmit SE, Truscon R, Johnson E, Braun TM, Levine MZ, et al. Modest waning of influenza vaccine efficacy and antibody titers during the 2007-2008 influenza season. J Infect Dis. 2016;214(8):1142–9.

    CAS 
    PubMed 

    Google Scholar 

  • 97.

    Ferdinands JM, Fry AM, Reynolds S, Petrie JG, Flannery B, Jackson ML, et al. Intraseason waning of influenza vaccine protection: evidence from the US influenza vaccine effectiveness network, 2011–2012 through 2014–2015. Clin Infect Dis. 2017;64(5):544–50.

    PubMed 

    Google Scholar 

  • 98.

    Organization WH. WHO preferred product characteristics for next generation influenza vaccines. 2017.

    Google Scholar 

  • 99.

    Chai N, Swem LR, Reichelt M, Chen-Harris H, Luis E, Park S, et al. Two escape mechanisms of influenza a virus to a broadly neutralizing stalk-binding antibody. PLoS Pathog. 2016;12(6):e1005702.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 100.

    Doud MB, Lee JM, Bloom JD. How single mutations affect viral escape from broad and narrow antibodies to h2 influenza hemagglutinin. Nat Commun. 2018;9(1):1386.

    PubMed 
    PubMed Central 

    Google Scholar 

  • 101.

    Marcelin G, Sandbulte MR, Webby RJ. Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines. Rev Med Virol. 2012;22(4):267–79.

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • 90,000 WHO / Europe | Influenza Vaccination – 7 Good Facts

    1) Who needs the flu vaccine?

    Anyone can get the flu, but some groups of people are at higher risk of developing serious illness. WHO recommends vaccination of the elderly, young children, pregnant women and people with certain health problems. These groups are most at risk of developing severe complications from influenza and are therefore a priority for vaccination in most countries.Medical workers should also be vaccinated – both for their protection and to reduce the risk of infection in patients vulnerable to the virus.


    To the top of the page

    2) Is the flu really dangerous?

    Influenza can lead to serious illness and death, especially among the elderly, young children, pregnant women and people with chronic diseases such as diabetes, heart disease or chronic obstructive pulmonary disease. Every year, about 60,000 people over the age of 65 die from the flu.And since vaccination coverage remains low in many countries, unfortunately more deaths from influenza can be expected in these high-risk populations each winter season.


    To the top of the page

    3) How effective is the influenza vaccine?

    The influenza vaccine is the best tool at our disposal to prevent influenza and reduce the risk of serious complications and even death. The effectiveness of a vaccine in different years can be different – it depends on the types of circulating virus and their relevance to the components of the vaccine.In addition, the effectiveness depends on the health status and age of the person being vaccinated, as well as on the time since vaccination. On average, the vaccine prevents about 60% of infections in healthy adults aged 18–64 years. The flu vaccine becomes effective about 14 days after vaccination.


    To the top of the page

    4) Can a vaccine cause influenza?

    Vaccine injection cannot cause influenza because it does not contain live virus.


    To the top of the page

    5) Why is it necessary to get vaccinated every winter?

    The group’s viruses are constantly mutating, and different strains can circulate every year. In addition, immunity from vaccination diminishes over time. Seasonal influenza vaccines are updated every year to provide the greatest protection against viruses circulating during this period.


    To the top of the page

    6) Until when is it too late to get the flu shot?

    It is best to get vaccinated before the start of the flu season.Influenza vaccination campaigns usually take place in October and November, before the seasonal circulation of the virus. However, it is never too late to get a vaccine, even if the virus is already circulating; getting vaccinated increases the likelihood that you will not get sick and reduces the risk of serious consequences of the flu.


    To the top of the page

    7) Is the influenza vaccine safe?

    Seasonal influenza vaccine has been in use for over 50 years. The vaccine is received by millions of people, and its safety has been proven over time.Every year, national drug regulatory authorities conduct a thorough review of a new vaccine before licensing it. Also, countries have systems for monitoring and researching all cases of adverse events after immunization against influenza.


    To the top of the page

    90,000 INTERVIEW COVID-19 and influenza vaccines – can they be mixed?

    These questions are answered by Dr Richard Peabody, one of the leading experts at the Regional Office for Europe of the World Health Organization (WHO / Europe).He leads the Special Dangerous Pathogens Task Force and the Surveillance and Laboratory Research Unit of the WHO EBR’s Regional COVID-19 Emergency Response Support Group.

    What is flu and why is it dangerous?

    RP: Influenza is an infectious respiratory illness caused by influenza viruses that affect the nose, throat and sometimes the lungs. It can cause diseases that are mild or severe, and in some cases, in combination with other diseases, it can lead to death.On average, about 70,000 people die from influenza in the WHO European Region each year.

    On average, about 70,000 people die from influenza in the WHO European Region each year

    During the winter of 2020-2021, the incidence of influenza was very low: the measures introduced to combat the CVOID-19 pandemic have significantly reduced the spread of other respiratory diseases. But now – with the resumption of international traffic and the return of many countries to normalcy – the likelihood of contracting and spreading the influenza virus is higher.And this year, people may be more at risk of contracting the virus.

    We are also still in the midst of the COVID-19 pandemic, with a highly contagious variant of delta circulating, which could result in a potential “double pandemic” of influenza and COVID-19 this winter. The parallel circulation of both viruses could have serious consequences for vulnerable populations and increase the pressure on health systems just at a time when hospitals are already running at their limits.

    What is the difference between COVID-19 and the flu? How can you determine what exactly you have contracted? What to do if symptoms appear?

    RP: Both viruses belong to the group of highly infectious respiratory diseases and have many common symptoms such as cough, fever, shortness of breath and / or loss of taste and smell. Due to the difficulty in identifying the disease by its symptoms alone, one should immediately isolate from other people to reduce the risk of spreading infection, especially among vulnerable populations, and get tested for COVID-19 as soon as possible.

    Photo UNICEF / K. Andrade

    WHO urges to be vaccinated before the beginning of the flu season. This will help protect the body from the dangerous virus.

    Both viruses can cause serious illness, but COVID-19 is more likely to lead to complications, hospitalization and, in some cases, death – therefore, it is extremely important to get a test.

    Who is recommended to get vaccinated against the influenza virus and when is it best to do it?

    RP: WHO recommends getting vaccinated against influenza for almost everyone, but first of all for those who belong to one of these five groups.This should be done before or or immediately after the start of the flu season. Usually in October-November.

    Medical professionals . Because healthcare workers are more likely to be exposed to influenza by their profession, they are more likely to transmit the infection to others, including those at risk of severe illness. In addition, our health services depend on these workers, so we need to keep them healthy and able to carry out their professional duties rather than going off sick leave because of the flu, especially at times of the year when health services are often most stressed.
    People over 65 years old . As we age, the immune system weakens and our bodies become less effective at fighting off infections, including the flu, which puts older people at greater risk of severe illness, may even need hospitalization, and die of illness.
    People with co-morbid conditions such as diabetes, lung or heart disease. A weakened immune system can increase the risk of severe illness, hospitalization, and possible death.
    Pregnant women . The available evidence suggests that pregnant women are more at risk of severe influenza, which can adversely affect the health of their unborn child. Vaccination protects the pregnant woman, the fetus and the already born child.
    Children under the age of five . Young children are more likely to be more severely ill and can infect others, including older relatives.

    What types of influenza does the vaccine protect against?

    RP: There are two main types of human influenza virus, influenza A and influenza B, which lead to annual influenza epidemics (so-called influenza seasons).In Europe, both trivalent (to protect against three strains of influenza virus) and quadrivalent vaccines (to protect against four strains) are used, which cover both types of the virus.

    How safe and effective are influenza vaccines?

    RP: Influenza vaccines have been in existence for over 60 years and are successfully used by millions of people around the world. Each year, national drug regulatory authorities scrutinize each influenza vaccine before issuing a license.In addition, there are systems for monitoring and investigating reported adverse events following immunization. Although side effects occur from time to time, they are very rare and usually not serious. Flu vaccination is the best way to prevent illness and reduce the risk of serious complications and even death.

    WHO considers it permissible to administer both vaccines in the same dose …

    To ensure optimal protection, influenza vaccines are updated annually based on observations from scientists tracking virus strains identified earlier in the year.The degree to which these vaccines work depends on a number of factors, including your age, current health status, and the virus strains that will circulate during the winter. However, we generally expect that you will be about 60 percent protected from influenza within two weeks of being vaccinated (this is the usual time it takes for the vaccine to take effect).

    Will there be enough vaccines for everyone, given that the number of flu cases could be higher this year?

    RP: Each year, countries plan to purchase sufficient quantities of vaccines to reach the populations in need.While we have reason to talk about a balance between supply and demand, it is important that health workers and vulnerable populations are prioritized in vaccination programs.

    Does the COVID-19 vaccine protect against influenza? Conversely, does the influenza vaccine protect against COVID-19?

    RP: No, they are different viruses and therefore require different vaccines.

    In many countries, they talk about the safety of simultaneous vaccination against influenza and coronavirus.Does WHO recommend getting COVID-19 and influenza vaccines at the same time?

    RP: Despite the limited evidence on the simultaneous administration of vaccines against COVID-19 and influenza (so-called co-administration), the available data do not indicate any increase in adverse effects. Therefore, WHO considers it permissible to administer both vaccines to citizens during one dose, especially since the risk of severe flu or COVID-19 for the adult population is quite high.

    If I have COVID-19, can I get the flu shot?

    RP: It is best to wait until a negative COVID-19 test is obtained before getting the flu shot to avoid mistakenly attributing symptoms to the vaccine.

    Does the presence of COVID-19 increase the risk of getting the flu or a more serious illness?

    RP: At this time, we do not have sufficient data to say with certainty whether the presence of COVID-19 increases the risk of contracting the flu.After the emergence of the virus early last year, a self-isolation regime was introduced in the countries of the region in March, so during the year the circulation of the influenza virus was very low, and therefore it is difficult for us to judge with certainty the impact of coinfection.

    At the same time, if a patient with COVID-19 is hospitalized and his lungs are affected, then he will certainly have an increased risk of a severe course of the disease in case of influenza infection.

    What else can you do to protect yourself and others from infections and diseases this winter?

    RP: Both COVID-19 and influenza belong to the group of respiratory viral infections, which can be infected in the same way – mainly as a result of inhalation of viral particles that enter the air during coughing, sneezing, speech or breathing of an infected person, and also through contact with viruses on infected surfaces.In other words, the same protective measures apply to influenza as for COVID-19:
    • Wash your hands regularly;
    • wear a mask if necessary;
    • keep a safe distance – we recommend at least 1 meter;
    • Avoid closed, confined and crowded areas;
    • Provide good ventilation of the premises, ventilate regularly;
    • cough or sneeze into a tissue or the crook of the elbow (not the palm) to avoid spreading the disease;
    • Get vaccinated against both viruses as soon as possible.

    90,000 Vector set: influenza and COVID-19 vaccine will be adjusted for the season | Articles

    The single flu and coronavirus vaccine of the Vector Center will differ from EpiVacCorona – it will be based on influenza A and B viruses . At the same time, the drug being developed will be adjusted for new strains of influenza, and COVID-19 every season through the use of genetic engineering and reverse genetics. This was announced to Izvestia at the Novosibirsk Scientific Center, noting that the vaccine is undergoing laboratory tests.Meanwhile, WHO told Izvestia that the organization’s expert group is studying the simultaneous administration of vaccines against influenza and COVID-19 and calls on all drug developers to analyze this issue. Experts interviewed by Izvestia warned: vaccination against only one of the viruses does not in any way reduce the severity of the course of the other disease , since we are talking about the production of different antibodies.

    Another vaccine

    The Novosibirsk Scientific Center “Vector” announced the development of a combined vaccine against influenza and COVID-19 back in October 2020.As Izvestia was told at the center, laboratory studies of the drug are still ongoing.

    – From the point of view of platform , this will be a vector vaccine based on influenza A and B viruses. The key feature is that vaccination will provide protection against both seasonal flu and COVID-19. It is important to note that the live vector vaccine will induce local mucosal immunity of mucous membranes , which is an important condition for protection against respiratory diseases, – specified in “Vector”.- The use of genetic engineering technologies and methods of reverse genetics makes it possible to update both the influenza component and COVID-19 for each new season.

    Photo: TASS / Vladimir Gerdo

    The center also explained: for the production of vaccines, existing technological sites can be used, “including, if necessary, with the production of a vaccine in developing chicken embryos.”

    It is too early to talk about the start of clinical trials with the participation of volunteers, Vektor noted and explained this by the fact that “the experimental vaccine under development still has many previous stages of study, including preclinical studies” .

    The vaccine being developed by the center will not be based on the drug “EpiVacCorona”, which forms immunity through the use of artificially synthesized peptides. The principle of the new flu and coronavirus vaccine – vector .

    Everything is one

    In Russia, flu and COVID-19 vaccines are also being developed at the V.I. N.F. Gamalei. As its director, Academician Alexander Gintsburg, told Izvestia earlier, clinical trials of the new drug are planned to begin at the end of 2022 .The platform for a unified vaccination, he said, has already been created. It is based on a hybrid rotavirus vaccine, in parallel with it, a drug is being developed against various variants of the coronavirus.

    We should welcome the development of new combined vaccines and wish the Vector Center success, Alexei Agranovsky, Professor of the Virology Department of the Biological Faculty of Moscow State University, told Izvestia. However, he noted that the main problem of immunization remains inadequate coverage of the population and the impact of anti-vaccination sentiments .

    Photo: Moscow City News Agency / Kirill Zykov

    – It is necessary to inoculate a significant part of the population with the most effective vaccines, but so far I do not see bright prospects. This is now the number one task, if you do not cope with it, then the combined vaccines will no longer be so important, the expert concluded.

    Earlier, the general director of “Vector” Rinat Maksyutov said that the need to create a single vaccine against coronavirus and influenza is caused by the fact that simultaneous infection significantly increases the severity of the course of seasonal influenza and mortality from it .

    As the head of the department of microbiology of latent infections, virologist of the Gamaleya Center Viktor Zuev told Izvestia, influenza vaccination does not reduce the severity of COVID-19, since these are two different viruses and, accordingly, two different drugs are required.

    During vaccination, antibodies are injected into the human body, and the immune response is formed against the antigen that was introduced by , the expert emphasized. – If a person has been vaccinated against influenza, the coronavirus infection is unlikely to proceed more easily, these are different antigens.I do not think that adding antibodies against influenza to the body will ease the course of the disease from the coronavirus.

    Photo: TASS

    Viktor Zuev noted that, among other things, for this reason, the whole world is watching with such attention what new strains of coronavirus appear. You need to make sure that existing vaccines created for certain variants of viruses work against them.

    – Each new strain increases something. The Delta strain, for example, is more pathogenic than the Alpha strain that emerged at the end of 2019.Therefore, we all breathed a sigh of relief when our director (head of the Gamaleya Center Alexander Gintsburg. – Izvestia) announced that Sputnik V was effective against the Delta strain, ”the expert said.

    Injecting two at once

    The virologist also noted that after a flu shot recommends waiting at least two to three weeks before getting vaccinated against coronavirus . The consequences of giving both vaccines at the same time are still being studied.

    At the beginning of September, the Minister of Health of the Russian Federation Sergey Murashko announced that preclinical studies of the simultaneous administration of vaccines against influenza and coronavirus had begun in Russia.On October 4, the minister described the preliminary results as encouraging.

    The Ministry of Health of the Russian Federation did not provide a prompt response to Izvestia’s inquiry about when the research would be completed.

    Photo: Izvestia / Dmitry Korotaev

    WHO also recommends that vaccine developers evaluate the effectiveness of the simultaneous use of drugs against COVID-19 and against influenza, the press service of the world organization told Izvestia.

    The WHO Expert Working Group on Influenza was asked to review the available data on the combined use of COVID-19 vaccines and influenza vaccines to develop future policy on this issue , the organization said.

    On September 30, the University of Bristol UK published a study that showed that it is safe to be vaccinated against both COVID-19 and influenza at the same time, it does not negatively affect the immune response caused by both vaccines. Both injections were given to the subjects on the same day, but in different hands.

    Advice to citizens: Influenza vaccination

    Today the question of whether to get vaccinated or not has divided society into two irreconcilable groups: supporters and opponents of vaccination.At the same time, there are those who have not decided, and are in confusion about what to do or not? Whom to trust? Where to find reliable information about vaccines, in the face of a continuous stream of scientific, scientific and pseudoscientific information. We say an unequivocal “Yes”!

    In addition to the main problem of whether to be vaccinated against influenza at all, citizens are also concerned about other issues:

    What are the goals of influenza vaccination?

    The main goal of influenza vaccination is to protect the population from a massive and uncontrolled spread of infection, from an influenza epidemic.It is important to understand that by vaccinating the population, doctors save the lives of those who risk dying from complications. Risk groups include young children in whom immunity is in the process of formation, the elderly, those who suffer from chronic diseases, people with immunodeficiency states.

    Influenza is an infection, in most cases it is difficult, there is simply no light course of influenza.

    If the majority are vaccinated, a minority of those who do not receive the vaccine for one reason or another have minimal chances of being infected.And it is for this that collective immunity is created. The vaccinated population prevents the spread of the virus. Each of us knows that the flu virus spreads very quickly.

    What is in the influenza vaccine?

    The influenza vaccine protects against influenza viruses, which epidemiologists predict will be the most common in the coming season. Traditional influenza vaccines (“trivalent” vaccines) are designed to protect against three influenza viruses;

    influenza A (h2N1) virus

    influenza A (h4N2) virus

    and influenza B virus

    There are also vaccines designed to protect against four influenza viruses (“tetravalent” vaccines).They protect against the same viruses as the trivalent vaccine and contain an additional B virus.

    World Health Organization Recommended Composition of Seasonal Influenza Vaccines for Use in the Northern Hemisphere during the 2019-2020 Influenza Season:

    • virus like A / Brisbane / 02/2018 (h2N1) pdm09
    • virus A (h4N2)
    • B / Colorado / 06/2017-like virus (line B / Victoria / 2/87)
    • B / Phuket / 3073/2013-like virus (line B / Yamagata / 16/88).

    The first three strains are recommended for inclusion in trivalent influenza vaccines and the latter is the recommended complementary strain for tetravalent influenza vaccines.

    Why do I get vaccinated annually?

    The annual vaccinations are due to the constant variability (mutation) of influenza viruses. As a result, vaccines are updated as needed to keep pace with changes in influenza viruses.

    Three years ago I got the flu vaccine, and last year I got seriously ill and was diagnosed with the flu.What does this mean?

    This fact confirms the need for vaccination against influenza annually. First, virus strains change very quickly. Secondly, the body’s immune response to vaccination weakens over time. In your case, a three-year-old vaccination does not imply any protection for the body.

    Can you get the flu from a vaccine?

    It is impossible to get the flu from the vaccine, however, some vaccinated do not feel well for some time immediately after vaccination.This reaction is not common, but it is normal. Weakness, muscle pain, a short-term rise in temperature to 37 ° C, pain at the injection site may disturb.

    Such a reaction can signal that the body has entered into a fight with the introduced viral particles and that antibodies are being produced at the moment. In this way, the immune system prepares the body’s defense against influenza viruses.

    BUT! Even if you are among those who are doing great after getting the vaccine, this does not mean that your immune system is not responding or the flu vaccine is not working.

    If I get the flu shot, will I get the flu?

    Even if you get sick with the flu, being vaccinated against the flu, you will get the disease in a mild form and without complications, for this purpose, vaccination is carried out. Protecting a person 100% from the flu is a secondary goal. Either way, the flu vaccine works!

    Flu vaccines are safe! Don’t miss your chance to protect yourself from the flu!

    Vaccination against influenza – Orenburg Regional Clinical Hospital №2

    COVID-19 and influenza vaccination, impact on disease.


    When is it better to vaccinate


    Who is vaccinated free of charge


    Flu shot – the first “for” !!!


    The best protection against influenza – vaccination !!

    FLU VACCINATION.Questions and Answers

    As the autumn season approaches, the period of vaccine prophylaxis against influenza begins. The topic is relevant and always raises many questions. Irina Vasilievna Bulatova, an immunologist at the Orenburg Regional Clinical Infectious Diseases Hospital, is ready to answer them.

    – Why is vaccination needed if it does not guarantee protection against infection?

    – Vaccination against influenza is needed not so much in order not to get sick at all, but so that there are no complications, especially in persons with concomitant diseases.Our task is to protect precisely from the severe course of the disease. We have had cases of people suffering from diabetes mellitus, heart failure, and, unfortunately, they ended sadly, but these patients were not vaccinated! And those who received the vaccine, if they get sick, then in a mild form.

    – How effective and safe is the influenza vaccine?

    – The drug must pass quality control and certification. The vaccine is not live – inactivated. We have not had a single complication reaction to these vaccines, with which we have been working for several years (Sovigripp, Grippol +).In previous years, there were only isolated cases of allergic reactions – moreover, among allergy sufferers.

    – The strains of influenza viruses change every year, but the composition of the vaccine?

    – Every year a new vaccine is produced, taking into account the serotype that will circulate in our territory. That is why domestic vaccines should be preferred. In France, for example, they will make their own serotype, in America – another. The Russian vaccine contains the most important components against virus A and a serotype against virus type B.These are the viruses that spread throughout our region.

    – Who is at risk and eligible for free vaccination?

    – We have a wide category of citizens who will be vaccinated for free. This year their number is more than last year – 1 million 58 thousand people. This is more than 50% of the region’s population. Firstly, these are children from 6 months to 18 years old (schoolchildren, preschoolers, students) – the coverage rate here is 98%. Secondly, these are people over 60 years old.We also vaccinate pregnant women, people with chronic diseases, health workers, service workers, transport workers, educational institutions, and conscripts.

    – Can employees of enterprises and organizations get a flu shot at the employer’s expense?

    – I would like, of course, that employers also think about their employees. There is an obvious benefit here. Firstly, the entire team will be at their workplaces, there will be no idle time, sick leaves. And if one sick person comes and infects his colleagues, then at some point it may turn out that there is no one to work.Therefore, the employer needs to think about this and take care of ordering vaccines in advance.

    – When is it advisable to get the flu shot?

    – In advance, namely in September-October. So that immunity has time to develop before the onset of an increase in the incidence. And against the background of an epidemic, it is inappropriate to vaccinate – a person was vaccinated today, tomorrow he contacted a sick person, he developed symptoms – and mistrust of the vaccine begins. And the vaccine just hasn’t had time to work yet.Therefore, it is necessary to vaccinate the healthy, and so that the environment is healthy.

    – Isn’t it dangerous to get a flu shot during the spread of the coronavirus?

    – Why do we say that it is very important to be vaccinated against influenza in this unfavorable Covid-19 season? Because (this has already been proven) those who are vaccinated against the flu, in case of infection with the coronavirus, get sick more easily. If an unvaccinated person falls ill with covid, the immune system is weakened, and immediately the influenza virus clings to this virus (he has contacted somewhere).And when paired, they start to give a very violent reaction. And, of course, the disease is difficult. Therefore, it is during this season that it is very important that we are vaccinated against the flu.

    90,000 COVID-19 flu vaccination

    Influenza is an infectious disease that can affect people of all ages and genders. According to statistics, millions of people around the world die from influenza and its complications every year. Thus, the flu poses a serious danger to human life and health.

    Vaccine prophylaxis is the most reliable and effective method of protection against influenza!

    What are the specifics of influenza vaccination in 2021?

    The realities are such that the coronavirus (SARS-CoV-2) causing the infection of COVID-19 continues to circulate among the population, and during the seasonal rise in the incidence of ARVI, the co-circulation of different viruses is expected. In this case, infection can occur with several viruses at once, or a new one will join an already developed viral disease.

    First of all, a combination of COVID-19 infection and seasonal flu in humans is dangerous. Both viruses have the property of adversely affecting, first of all, lung tissue, causing severe pneumonia.

    Influenza vaccination provides an individual health benefit by preventing influenza, reducing the severity of illness and the risk of hospitalization. Vaccination will reduce the overall exposure of the population to respiratory diseases and reduce the burden on the health system during the circulation of COVID-19 infection (18.06.2020 Dr Hans Henri P. Kluge, WHO Regional Director for Europe, press briefing on the situation overview).

    Can people who have had COVID-19 get vaccinated against influenza?

    People who have had COVID-19 can get the flu. Vaccinations are also the best way to prevent the flu.

    Existing vaccines do not provide a 100% guarantee that you will not get the flu, however, protection from the severe course of the disease and the development of complications in the vaccinated will be formed.

    Currently, there is no other way as effective and inexpensive prevention as vaccination.

    Can an influenza vaccine improve immunity against COVID-19?

    Influenza vaccine provides specific immunity against influenza A and B viruses.

    However, there is some scientific evidence that influenza vaccination can be beneficial in preventing COVID-19 infection. Vaccination with modern adjuvant vaccines is accompanied not only by the formation of specific antibodies to strains of the influenza virus, but also by early activation of the cellular mechanisms of the antiviral immune response, leading to a decrease in the incidence of influenza and ARI, and, most likely, coronavirus infection (Kostinov M.P. – Professor, Doctor of Medicine, Russian allergist-immunologist, vaccinologist, Honored Scientist of the Russian Federation, 2020).

    How to get vaccinated against influenza correctly during the period of mass vaccination against COVID-19?

    Previously, COVID-19 vaccines were recommended to be administered separately at a minimum interval of 14 days before or after any other vaccines. This was done because of excessive caution during the period when these vaccines were new, and not because of any known safety or immunogenicity issues.However, a significant amount of data has now been collected regarding the safety of COVID-19 vaccines, which are currently approved or cleared by the FDA (USA) and WHO.

    COVID-19 vaccines can now be administered without regard to the timing of other vaccines. This allows COVID-19 vaccine and other vaccines to be administered concurrently on the same day as well as co-administration within 14 days (Interim Clinical Considerations for Use of COVID-19 Vaccines | CDC).

    In the winter of 2021-2022, we still run the risk of contracting two infections at the same time.The COVID-19 epidemic continues in the world, new strains of the coronavirus (delta strain) appear, and if an outbreak of seasonal flu also begins, then both diseases can aggravate each other and lead to adverse consequences for the life and health of people.

    That is why now it is very important to get vaccinated not only against coronavirus, but also against the flu!

    Does the flu vaccine protect against COVID-19 infection? | World Events – Estimates and Forecasts from Germany and Europe | DW

    Can a flu shot reduce the risk of contracting COVID-19? And if so, why? A group of American doctors from the University of Michigan studied this issue and made a number of very interesting conclusions.The results of their research were published in the American Journal of Infection Control.

    Doctors analyzed the data of 27 201 patients from the US state of Michigan, who passed the COVID-19 test by July 15, 2020.

    Nurses connect a patient with COVID-19 to a ventilator

    Of these, 12,997 were previously vaccinated against influenza. Among the latter, the proportion of those infected with coronavirus was lower than among those who were not vaccinated against influenza – 4.0 and 4.9 percent, respectively.

    In addition, COVID-19 patients who were vaccinated against influenza were less likely to need to be hospitalized and connected to a ventilator, and spent less time in the hospital. As for the mortality rate from the consequences of COVID-19, there were no significant differences between the two groups.

    Does the flu vaccine strengthen natural immunity?

    A key question for experts is whether medical and microbiological reasons can explain the study’s findings.For example, the fact that influenza vaccination can stimulate the body’s natural immunity, which operates independently of acquired immunity.

    3D image of the SARS-Cov-2 coronavirus

    The latter is based on antibodies: for example, in the fight against coronavirus infection, they primarily affect the COVID-19 spike protein and thereby neutralize the virus.

    In turn, natural immunity consists of a number of different elements and reacts to the pathogen, that is, to foreign bodies, very nonspecifically.The natural defense system includes, for example, different types of white blood cells (white blood cells) as well as cytokines (proteins that regulate various immune responses and inflammatory processes).

    It has long been proven that vaccination against various diseases generally strengthens the body’s immune system. Epidemiological studies have shown many years ago that children who have undergone vaccination retain a higher immunity against a number of pathogens for a long time than their unvaccinated peers.

    Are those vaccinated against influenza more cautious?

    But there is also an assumption that those vaccinated against influenza are less likely to become infected with coronavirus, and because they behave more carefully. Typically, representatives of risk groups (the elderly and people with chronic diseases) are vaccinated against influenza more often than young and healthy people. In the United States, for example, many residents of retirement age voluntarily observe the regime of self-isolation, while people of working age are often forced to go to work.

    Indirect evidence, however, refutes this hypothesis. First, in older people, COVID-19 disease is usually more severe, but this trend is not observed in the American study.

    In addition, preliminary results from another study conducted in 2020 support the version of strengthening the immune system. Scientists found that among Dutch hospital workers who received a flu shot in the winter of 2019-2020, there were fewer cases of coronavirus infection than among doctors who were not vaccinated.At the same time, in both groups there were no people over 70 years old and all surveyed were employed – accordingly, they were in direct contact with a large number of patients.

    See also:

    • BioNTech and Pfizer vaccine: a German-American success story

      Vaccine Made in Germany

      In Germany, the USA, Israel and a number of other countries, the vast majority of the population will be vaccinated against the coronavirus with the BioNTech mRNA vaccine / Pfizer.For simplicity, it is often called “Pfizer”, although it would be more accurate to say “Bayontek”. At the heart of its success is a strategic alliance between an innovative German biotech development firm and an experienced American pharmaceutical giant.

    • Vaccine BioNTech and Pfizer: A German-American Success Story

      Success of Migrant Children

      BioNTech was founded in 2008 in Mainz with the participation of financial investors, Professor of Medicine Ugur ahin, son of a Turkish guest worker at the Ford car factory and his wife in Cologne, Cologne Ozlem Tyurechi, daughter of a Turkish doctor who came to Germany.She became director of medical research for a new company that focused on individualized immunotherapy for cancer and other serious illnesses.

    • Vaccine BioNTech and Pfizer: German-American Success Story

      Office on the street “At the gold mine”

      The head office of BioNTech is located in Mainz on the street with the historical name “At the gold mine”, which is now, of course, in every possible way journalists. On January 12, 2020, Ugur Shahin, after reading an article about a new virus in Wuhan, China in the medical journal The Lancet, and realizing that it was heading for a pandemic, immediately began to create a vaccine based on RNA technologies developed over a decade.

    • BioNTech and Pfizer Vaccine: A German-American Success Story

      Pfizer: Testing and Manufacturing

      On March 17, 2020, BioNTech entered into a strategic alliance with Pfizer. Two years earlier, they had already begun developing an mRNA influenza vaccine. The corporation from New York, founded in 1849 by two immigrants from Germany and now one of the three leaders in world pharmaceuticals, organized clinical trials of the German drug in six countries and provided its production facilities.

    • BioNTech and Pfizer Vaccine: A German-American Success Story

      The first COVID-19 vaccine in the US and EU

      In December 2020, after the completion of the third phase of clinical trials, the development of BioNTech and Pfizer became the first vaccine against COVID-19. allowed for use both in the United States and in the European Union. By that time, the EU already had an agreement to purchase 200 million doses and an option for an additional 100 million doses. In Germany, on December 27, retirees in the 80+ age group received their very first vaccinations in nursing homes.

    • BioNTech and Pfizer’s Vaccine: A German-American Success Story

      Pfizer’s Belgium plant supplies the world

      The two companies have an ambitious goal of producing 2 billion doses in 2021. Pfizer’s three U.S. sites supply the North American market, while Pfizer’s plant in Puurs, Belgium, is tasked with supplying Europe and the rest of the world. Already in January, it became clear that its capacity would not be sufficient to meet global demand, and their urgent expansion began, which led to a drop in production volumes for about a month.

    • BioNTech and Pfizer’s vaccine: a German-American success story

      Marburg will provide 750 million doses per year

      Before the vaccine was developed, BioNTech had a relatively small production capacity in Germany. Now it took a large enterprise. On September 17, 2020, the company bought a plant in Marburg from the Swiss pharmaceutical concern Novartis. After urgent reconstruction and re-equipment, it went into operation on February 10. The plan for the first half of 2021 is 250 million doses, the design capacity is 750 million doses per year.

    • BioNTech and Pfizer vaccine: a German-American success story

      Logistics requires cold calculation

      A feature of the BioNTech / Pfizer vaccine is that it requires ultra-low temperatures down to minus 80 degrees. Therefore, during transportation, special thermal boxes are used. Each contains 23 kilograms of dry ice, laid in three layers: this provides cold for ten days. And each is equipped with thermal sensors connected to the GPS satellite system.The picture shows the arrival of a batch of vaccines in Italy.

    • BioNTech and Pfizer Vaccine: A German-American Success Story

      Israel Confirmed Vaccine Effectiveness

      No country vaccinated its population in December-February as rapidly as Israel, and no other did not study it so closely the effectiveness of the BioNTech / Pfizer vaccine. On February 21, the Israeli Ministry of Health announced that two weeks after the second vaccination, the risk of getting sick is reduced by 95.8%, and the threat of being hospitalized or dying by 98.9%.

    • BioNTech and Pfizer Vaccine: A German-American Success Story

      Commendation Order

      Germany thanked its scientists with the country’s highest award – the Order of the Merit Cross.