Next Article in Journal
Is a COVID-19 Vaccine Likely to Make Things Worse?
Previous Article in Journal
GspD, The Type II Secretion System Secretin of Leptospira, Protects Hamsters against Lethal Infection with a Virulent L. interrogans Isolate
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Editorial

Flu RNA Vaccine: A Game Changer?

INRAE, Oniris, BIOEPAR, 44300 Nantes, France
Vaccines 2020, 8(4), 760; https://doi.org/10.3390/vaccines8040760
Received: 27 November 2020 / Revised: 9 December 2020 / Accepted: 10 December 2020 / Published: 14 December 2020
(This article belongs to the Section Influenza Virus Vaccines)
Influenza virus infection is a major One Health concern worldwide. Indeed, Orthomyxoviridae and more specifically Alphainfluenzavirus and Betainfluenzavirus are responsible for flu disease, which is mostly associated with respiratory and systemic clinical signs in various species including humans, pigs, horses, ferrets and birds [1]. Zoonoses involving influenza virus strains are common, and even clear evidence of bidirectional human–swine transmission has been reported [2]. A large-scale use of therapeutic approaches—such as oseltamivir phosphate, zanamivir, and newer drugs such as baloxavir marboxil—is not possible and could favor the emergence of antiviral drug resistances, the first line of defense against influenza viruses remains to be the vaccination of the exposed populations. However, vaccination against influenza viruses still presents several drawbacks, the main ones being a relatively low effectiveness and strain mismatches. Currently available vaccines in humans are 40–60% effective and offer poor protection or no protection against other strains, especially if they are from a different subtype of influenza virus [3,4,5,6,7,8]. Thus, there is undoubtedly room for improvement in the challenging world of flu vaccines.
A growing interest has been shown for a new generation of vaccination approaches using nucleic acids such as DNA or RNA. However, because of their suboptimal potency in early clinical studies [9] and the low but persistent risk of the integration of DNA sequences into the host genome [10], DNA vaccines failed to emerge in human medicine, although a limited number of vaccines reached the market in veterinary medicine [11] (West-Nile Innovator® DNA, Oncept® Canine Melanoma Vaccine and Elanco’s Clynav® vaccine to control salmon pancreas disease). On the contrary, mRNA vaccines which were not initially actively developed due to important concerns regarding their low stability, gained considerable interest due to the coronavirus disease 2019 (COVID-19) crisis, and are currently close to the market in human medicine. In 2020, many interesting and comprehensive reviews [12,13,14] and original papers [15,16,17,18,19] summarizing the current knowledge on RNA vaccines and presenting some major breakthroughs in their development were published. RNA vaccines have never been so close to the market, and we can reasonably expect to see at least a first one against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection available by the end of the year, and the beginning of 2021. Indeed, two RNA vaccines against SARS-CoV-2 are currently terminating phase 3 clinical trial with some preliminary reports already published [16,17,19] and many other ones are following. With these new vaccines available soon, there is no doubt we will soon see more RNA vaccines, designed to prevent or even treat various medical conditions, including cancer, on the market. Specifically regarding flu vaccines, one of the biotech company involved in the race for the development of an effective RNA vaccine to prevent COVID-19 had already announced their intention to enter the seasonal flu market given the high medical need for more effective flu vaccines. The interest of RNA vaccines for flu vaccination has also been comprehensively reviewed [20]. Vaccination against influenza viruses faces multiple important challenges that need to be resolved to bring universal and more effective vaccines onto the market [20]. Amongst the commonly described challenges are: (1) the lack of protection of current vaccine formulations against antigenic drift and shift—the two main mechanisms of evolution in Orthomyxoviruses; (2) the short-lived immune response after vaccination; (3) the sometimes weak immune antibody response resulting from pre-existing immunity; (4) potential adverse effects of live attenuated vaccines when they are used; (5) the interference of maternally-derived antibodies (MDA) with the induction of a protective immune response in infants; (6) the common use of adjuvants, especially for inactivated vaccines, not always very well-accepted by the population. Based on the current research, RNA vaccines developed against flu could broadly induce protective immune responses and could overcome some of the issues mentioned above [20,21]. Antigenic drift—RNA segment reassortment resulting from coinfection events—is a major concern for health authorities because it can cause the rapid emergence of potentially pandemic influenza viruses [1,22]. This is why the circulation of influenza viruses between their wild bird reservoirs and some mammalian hosts such as pigs which can act as “mixing vessels” [23] is closely monitored [22]. In the case of emergence, there is an absolute need for the fast development of effective vaccines widely available for the exposed populations. Two of the main advantages of RNA vaccines are that they can be easily updated once the genome sequence of the emerging influenza virus strain has been accurately identified, and they do not require toxic materials or cell cultures that could be contaminated with viruses. Besides these two major advantages, they do not require the systematic use of adjuvants, they do not exhibit any risk of reversion to virulence unlike many attenuated vaccines, and they commonly elicit well-balanced—humoral and cellular—immune responses. Regarding the contemporary drawbacks, a few can be identified. The main one is still the relatively low stability of the RNA—even though progress has been made—and the need for freezer conditions for the distribution and the administration, RNA being more likely to break apart above freezing temperatures [24]. Another limitation is the potential negative impact of type 1 and 3 interferons induced in response to vaccine RNA molecules on antigen expression [24]. Then, even if the risk of genomic integration is widely considered as null and is not a biosafety concern, eukaryotic cells have been shown to be able to provide, to some extent, reverse transcription activity [25,26,27,28]. Further research on that eukaryotic reverse transcription activity, in the context of RNA vaccination, might be of interest for the scientific community [14].
Until now, in vitro transcribed (IVT) messenger RNA (mRNA) influenza virus vaccines were among the most studied RNA vaccines developed against infectious diseases in humans and animals. Two main types of mRNA vaccines have been developed against influenza virus infection: the non-replicating mRNA vaccines and the self-amplifying mRNA vaccines [20], with possibly different types of RNA (prokaryotic, eukaryotic and transfer RNA amongst others) [29]. Both approaches are in the pipelines of the three current major players in the field of RNA vaccines: Moderna Therapeutics (Cambridge, MA, USA) [30], EpiVax (Providence, RI, USA) and CureVac AG (Tübingen, Germany). Moderna, is working on a non-replicating mRNA vaccine with modified nucleosides incorporated associated to lipid nanoparticles (LNP) while CureVac AG, chose a strategy based on sequence-optimized unmodified mRNA–LNP. The EpiVax vaccine which targets highly pathogenic H7N9 subtype influenza virus is currently in phase 1 clinical trial. The impressive acceleration of RNA vaccine research caused by COVID-19 will probably continue to push forward the development of influenza virus RNA vaccines in the coming years. Besides RNA vaccines against flu and COVID-19, many others against rabies [31,32], Zika [33,34], Chikungunya [35], and other pathogens [20] are also in the pipeline at various stages of development.
Data about RNA vaccines are now accumulating very quickly and the first RNA vaccines have been released in the UK on December 2020 (and several countries are following). Are they going to be as effective and as convenient in their use than their competitors based on different approaches (see for instance [36]) sometimes also very innovative and attractive? Will they bring enough advantages compared to other vaccines to be considered as real game changers? We currently—December 2020—still do not know, but we will for sure very soon. It is just a question of time.

Acknowledgments

I thank Fanny Renois (Oniris) for the careful reading of the manuscript.

Conflicts of Interest

The author declares no conflict of interest.

References

  1. Wright, P.F.; Neumann, G.; Kawaoka, Y. Orthomyxoviridae. In Fields Virology, 6th ed.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2013; pp. 1146–1243. [Google Scholar]
  2. Chastagner, A.; Enouf, V.; Peroz, D.; Hervé, S.; Lucas, P.; Quéguiner, S.; Gorin, S.; Beven, V.; Behillil, S.; Leneveu, P.; et al. Bidirectional Human–Swine Transmission of Seasonal Influenza A(H1N1)pdm09 Virus in Pig Herd, France, 2018. Emerg. Infect. Dis. 2019, 25, 1940–1943. [Google Scholar] [CrossRef] [PubMed][Green Version]
  3. Jackson, M.L.; Chung, J.R.; Jackson, L.A.; Phillips, C.H.; Benoit, J.; Monto, A.S.; Martin, E.T.; Belongia, E.A.; McLean, H.Q.; Gaglani, M.; et al. Influenza Vaccine Effectiveness in the United States during the 2015–2016 Season. N. Engl. J. Med. 2017, 377, 534–543. [Google Scholar] [CrossRef] [PubMed]
  4. Belongia, E.A.; Kieke, B.A.; Donahue, J.G.; Greenlee, R.T.; Balish, A.; Foust, A.; Lindstrom, S.; Shay, D.K. Marshfield Influenza Study Group Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004–2005 season to the 2006–2007 season. J. Infect. Dis. 2009, 199, 159–167. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Belongia, E.A.; Kieke, B.A.; Donahue, J.G.; Coleman, L.A.; Irving, S.A.; Meece, J.K.; Vandermause, M.; Lindstrom, S.; Gargiullo, P.; Shay, D.K. Influenza vaccine effectiveness in Wisconsin during the 2007–2008 season: Comparison of interim and final results. Vaccine 2011, 29, 6558–6563. [Google Scholar] [CrossRef] [PubMed]
  6. Ferdinands, J.M.; Gaglani, M.; Martin, E.T.; Middleton, D.; Monto, A.S.; Murthy, K.; Silveira, F.P.; Talbot, H.K.; Zimmerman, R.; Alyanak, E.; et al. Prevention of Influenza Hospitalization Among Adults in the United States, 2015–2016: Results from the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). J. Infect. Dis. 2019, 220, 1265–1275. [Google Scholar] [CrossRef] [PubMed]
  7. McLean, H.Q.; Thompson, M.G.; Sundaram, M.E.; Kieke, B.A.; Gaglani, M.; Murthy, K.; Piedra, P.A.; Zimmerman, R.K.; Nowalk, M.P.; Raviotta, J.M.; et al. Influenza Vaccine Effectiveness in the United States During 2012–2013: Variable Protection by Age and Virus Type. J. Infect. Dis. 2015, 211, 1529–1540. [Google Scholar] [CrossRef][Green Version]
  8. Ohmit, S.E.; Thompson, M.G.; Petrie, J.G.; Thaker, S.N.; Jackson, M.L.; Belongia, E.A.; Zimmerman, R.K.; Gaglani, M.; Lamerato, L.; Spencer, S.M.; et al. Influenza vaccine effectiveness in the 2011–2012 season: Protection against each circulating virus and the effect of prior vaccination on estimates. Clin. Infect. Dis. 2014, 58, 319–327. [Google Scholar] [CrossRef]
  9. Kutzler, M.A.; Weiner, D.B. DNA vaccines: Ready for prime time? Nat. Rev. Genet. 2008, 9, 776–788. [Google Scholar] [CrossRef]
  10. Geall, A.J.; Mandl, C.W.; Ulmer, J.B. RNA: The new revolution in nucleic acid vaccines. Semin. Immunol. 2013, 25, 152–159. [Google Scholar] [CrossRef]
  11. Redding, L.; Weiner, D.B. DNA vaccines in veterinary use. Expert. Rev. Vaccines 2009, 8, 1251–1276. [Google Scholar] [CrossRef][Green Version]
  12. Pardi, N.; Hogan, M.J.; Weissman, D. Recent advances in mRNA vaccine technology. Curr. Opin. Immunol. 2020, 65, 14–20. [Google Scholar] [CrossRef] [PubMed]
  13. Bloom, K.; van den Berg, F.; Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther. 2020. [Google Scholar] [CrossRef] [PubMed]
  14. Cimolai, N. Do RNA vaccines obviate the need for genotoxicity studies? Mutagenesis 2020. [Google Scholar] [CrossRef]
  15. Laczkó, D.; Hogan, M.J.; Toulmin, S.A.; Hicks, P.; Lederer, K.; Gaudette, B.T.; Castaño, D.; Amanat, F.; Muramatsu, H.; Oguin, T.H.; et al. A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice. Immunity 2020, 53, 724–732.e7. [Google Scholar] [CrossRef]
  16. Mulligan, M.J.; Lyke, K.E.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Neuzil, K.; Raabe, V.; Bailey, R.; Swanson, K.A.; et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020, 586, 589–593. [Google Scholar] [CrossRef]
  17. Jackson, L.A.; Anderson, E.J.; Rouphael, N.G.; Roberts, P.C.; Makhene, M.; Coler, R.N.; McCullough, M.P.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; et al. An mRNA Vaccine against SARS-CoV-2—Preliminary Report. N. Engl. J. Med. 2020, 383, 1920–1931. [Google Scholar] [CrossRef]
  18. Walsh, E.E.; Frenck, R.W.; Falsey, A.R.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Neuzil, K.; Mulligan, M.J.; Bailey, R.; et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N. Engl. J. Med. 2020. [Google Scholar] [CrossRef]
  19. Anderson, E.J.; Rouphael, N.G.; Widge, A.T.; Jackson, L.A.; Roberts, P.C.; Makhene, M.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; Pruijssers, A.J.; et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N. Engl. J. Med. 2020. [Google Scholar] [CrossRef]
  20. Scorza, F.B.; Pardi, N. New Kids on the Block: RNA-Based Influenza Virus Vaccines. Vaccines 2018, 6, 20. [Google Scholar] [CrossRef] [PubMed][Green Version]
  21. Zhuang, X.; Qi, Y.; Wang, M.; Yu, N.; Nan, F.; Zhang, H.; Tian, M.; Li, C.; Lu, H.; Jin, N. mRNA Vaccines Encoding the HA Protein of Influenza A H1N1 Virus Delivered by Cationic Lipid Nanoparticles Induce Protective Immune Responses in Mice. Vaccines 2020, 8, 123. [Google Scholar] [CrossRef] [PubMed][Green Version]
  22. Morse, S.S.; Mazet, J.A.K.; Woolhouse, M.; Parrish, C.R.; Carroll, D.; Karesh, W.B.; Zambrana-Torrelio, C.; Lipkin, W.I.; Daszak, P. Prediction and prevention of the next pandemic zoonosis. Lancet 2012, 380, 1956–1965. [Google Scholar] [CrossRef]
  23. Ma, W.; Kahn, R.E.; Richt, J.A. The pig as a mixing vessel for influenza viruses: Human and veterinary implications. J. Mol. Genet. Med. 2008, 3, 158–166. [Google Scholar] [CrossRef] [PubMed]
  24. Zhang, C.; Maruggi, G.; Shan, H.; Li, J. Advances in mRNA Vaccines for Infectious Diseases. Front. Immunol. 2019, 10, 594. [Google Scholar] [CrossRef] [PubMed][Green Version]
  25. Järås, M.; Edqvist, A.; Rebetz, J.; Salford, L.G.; Widegren, B.; Fan, X. Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression. Blood 2006, 108, 1084–1091. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Su, Y.; Ghodke, P.P.; Egli, M.; Li, L.; Wang, Y.; Guengerich, F.P. Human DNA polymerase η has reverse transcriptase activity in cellular environments. J. Biol. Chem. 2019, 294, 6073–6081. [Google Scholar] [CrossRef][Green Version]
  27. Schwertz, H.; Rowley, J.W.; Schumann, G.G.; Thorack, U.; Campbell, R.A.; Manne, B.K.; Zimmerman, G.A.; Weyrich, A.S.; Rondina, M.T. Endogenous LINE-1 (Long Interspersed Nuclear Element-1) Reverse Transcriptase Activity in Platelets Controls Translational Events through RNA-DNA Hybrids. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 801–815. [Google Scholar] [CrossRef]
  28. Shimizu, A.; Nakatani, Y.; Nakamura, T.; Jinno-Oue, A.; Ishikawa, O.; Boeke, J.D.; Takeuchi, Y.; Hoshino, H. Characterisation of cytoplasmic DNA complementary to non-retroviral RNA viruses in human cells. Sci. Rep. 2014, 4, 5074. [Google Scholar] [CrossRef][Green Version]
  29. Gomes, A.C.; Roesti, E.S.; El-Turabi, A.; Bachmann, M.F. Type of RNA Packed in VLPs Impacts IgG Class Switching-Implications for an Influenza Vaccine Design. Vaccines 2019, 7, 47. [Google Scholar] [CrossRef][Green Version]
  30. Feldman, R.A.; Fuhr, R.; Smolenov, I.; Ribeiro, A.M.; Panther, L.; Watson, M.; Senn, J.J.; Smith, M.; Almarsson, Ö.; Pujar, H.S.; et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 2019, 37, 3326–3334. [Google Scholar] [CrossRef]
  31. Armbruster, N.; Jasny, E.; Petsch, B. Advances in RNA Vaccines for Preventive Indications: A Case Study of a Vaccine against Rabies. Vaccines 2019, 7, 132. [Google Scholar] [CrossRef][Green Version]
  32. Alberer, M.; Gnad-Vogt, U.; Hong, H.S.; Mehr, K.T.; Backert, L.; Finak, G.; Gottardo, R.; Bica, M.A.; Garofano, A.; Koch, S.D.; et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: An open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 2017, 390, 1511–1520. [Google Scholar] [CrossRef]
  33. Richner, J.M.; Himansu, S.; Dowd, K.A.; Butler, S.; Salazar, V.; Fox, J.M.; Julander, J.G.; Tang, W.W.; Shresta, S.; Pierson, T.C.; et al. Modified mRNA vaccines protect against Zika virus infection. Cell 2017, 168, 1114–1125.e10. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Zhong, Z.; Portela Catani, J.P.; Mc Cafferty, S.; Couck, L.; Van Den Broeck, W.; Gorlé, N.; Vandenbroucke, R.E.; Devriendt, B.; Ulbert, S.; Cnops, L.; et al. Immunogenicity and Protection Efficacy of a Naked Self-Replicating mRNA-Based Zika Virus Vaccine. Vaccines 2019, 7, 96. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Gao, S.; Song, S.; Zhang, L. Recent Progress in Vaccine Development against Chikungunya Virus. Front. Microbiol. 2019, 10. [Google Scholar] [CrossRef][Green Version]
  36. Nachbagauer, R.; Feser, J.; Naficy, A.; Bernstein, D.I.; Guptill, J.; Walter, E.B.; Berlanda-Scorza, F.; Stadlbauer, D.; Wilson, P.C.; Aydillo, T.; et al. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat. Med. 2020, 1–9. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Meurens, F. Flu RNA Vaccine: A Game Changer? Vaccines 2020, 8, 760. https://doi.org/10.3390/vaccines8040760

AMA Style

Meurens F. Flu RNA Vaccine: A Game Changer? Vaccines. 2020; 8(4):760. https://doi.org/10.3390/vaccines8040760

Chicago/Turabian Style

Meurens, François. 2020. "Flu RNA Vaccine: A Game Changer?" Vaccines 8, no. 4: 760. https://doi.org/10.3390/vaccines8040760

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop