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Universal coronavirus vaccines: the time to start is now

Universal coronavirus vaccines: the time to start is now www.nature.com/npjvaccines COMMENT OPEN 1✉ 1 1 Luca T. Giurgea , Alison Han and Matthew J. Memoli The continued explosive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite aggressive public health measures has triggered an unprecedented international vaccine effort. However, correlates of protection, which can help guide intelligent vaccine design, are not known for SARS-CoV-2. Research on influenza immunity and vaccine development may provide valuable lessons for coronavirus efforts, especially considering similarities in rapid evolutionary potential. The apparent inevitability of future novel coronavirus outbreaks must prompt work on a universal coronavirus vaccine. npj Vaccines (2020) 5:43 ; https://doi.org/10.1038/s41541-020-0198-1 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SARS-CoV-2, and if they are, how much protection is afforded. pandemic continues to spread throughout the world with Recent data have shown 94% of patients who recover from mild explosive outbreaks underway throughout much of Europe and Covid-19 have neutralizing antibodies 2 weeks after symptom the United States. Even though the pandemic has slowed down in onset, but neutralizing antibody titers correlate only moderately some countries, other nations are still experiencing a rapid rise in with measured anti-S protein antibody . Careful study of potential cases and their healthcare systems are pushed to the limits . The patients with SARS-CoV-2 reinfection may help shed light on this case fatality ratio (CFR) varies widely by country and while question, but cases have not been documented in the literature. population characteristics and access to healthcare are critically Reports may be confounded by prolonged RNA shedding, which important factors, differences in the extent of testing of mild cases can persist over 30 days in almost 10% of patients, regardless of are likely responsible for some of the observed variation in the CFR resolution of symptoms . The viability of virus associated with through effects on the denominator. Interestingly, in the hardest prolonged shedding and consequently the infectivity of these hit areas, only a small fraction of the population has been reported patients is also unknown, considering that in a separate study of to be infected. It is unclear how much of this is due to nine patients, live SARS-CoV-2 was isolated only up to day 7 asymptomatic clinical presentations, testing availability, viral despite ongoing high viral loads by reverse transcription transmission dynamics, changes in individual behavior, and polymerase chain reaction . The distinction between viable virus aggressive isolation and quarantine actions. Some experts suspect and RNA shedding may have ramifications on study of immune a significant number of mild or asymptomatic infections go correlates of viral clearance. undiagnosed, leading to a falsely elevated CFR and making the Vaccine development against respiratory viruses is a challen- pandemic much more difficult to control in the setting of ging task. Currently, the only approved vaccines against respira- asymptomatic transmission . Public health measures helped to tory viruses are those against influenza. Despite decades of extinguish the SARS outbreak 17 years ago, but so far, they have research, modern vaccines have had limited effectiveness against only been able to slow down the coronavirus disease 2019 seasonal influenza and are unlikely to provide broad protection 12,13 against novel influenza strains capable of causing pandemics . (Covid-19) pandemic . Only in the past few years, a century after the advent of the 1918 In order to combat the disease, governments, international organizations, private companies, and academic institutions across influenza pandemic that was one of the most catastrophic events the planet have launched a multifaceted vaccine development in human history responsible for 50–100 million deaths, a response with unprecedented rapidity. At least 110 vaccine concerted effort was initiated to accelerate the development of 13,14 candidates are in preclinical testing and at least 5 vaccines have a universal influenza vaccine . Many unknowns exist with already begun early clinical testing . The focus of the response is respect to SARS-CoV-2, but research into influenza immunity and haste, understandably so, leading to use of novel technologies, vaccine development may provide valuable lessons for Covid-19 including DNA plasmids, viral vectors, virus-like particles, Baculo- and may help guide vaccination strategies. We have known for virus/mammalian expression systems, and mRNA vaccines among decades that antibodies against hemagglutinin (the dominant others. Many of these utilize sequencing information that was surface protein of the influenza particle) at a titer of 1:40 or greater made available quickly after the onset of the outbreak and can be are associated with >50% reduction in disease, but more recent developed more rapidly than classical vaccine preparation data have suggested antibody against influenza neuraminidase, strategies utilizing live virus as substrate, which necessitate the another viral surface protein, may be a superior predictor of 5 15,16 use of cumbersome biosafety protection measures . The purpose clinical outcomes . We have no such knowledge of correlates of most early candidate vaccines is development of antibodies of protection against coronaviruses, and specifically against SARS- against the Spike glycoprotein (S protein), which have been CoV-2, thereby making the process of developing an effective implicated in protection against SARS-CoV in animal models and vaccine that much more difficult. Interestingly, the importance of have been found in SARS-COV and SARS-CoV-2 convalescent anti-neuraminidase immunity in protection against influenza was 6–8 patient sera . However, we do not yet have evidence to show recognized during the H3N2 pandemic. Through serendipitous that anti-S protein antibodies are protective in humans against ongoing trials, researchers were able to seize an opportunity to LID Clinical Studies Unit, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. email: [email protected] Published in partnership with the Sealy Center for Vaccine Development 1234567890():,; L.T. Giurgea et al. obtain preinfection and postinfection sera demonstrating the After the SARS outbreak, we lost interest and failed to complete ability of anti-neuraminidase antibodies to reduce infection development of a vaccine for use in case of a recurrent outbreak. rates . We need to obtain similar information for SARS-CoV-2 to We must not make the same mistake again. Instead we must go help guide and refine vaccine development. further. We must work toward a universal coronavirus vaccine with Both influenza and coronaviruses have an inherent capacity for broad protection against a diverse number of coronaviruses. We rapid mutation due to the low fidelity of RNA polymerase and a need to understand the correlates of protection against corona- capability to form novel viruses through reassortment with a vast viruses and improve our understanding of their pathogenesis, 13,18,19 reservoir of zoonotic viruses .Influenza surface proteins have transmission, and viral evolution. These studies will be absolutely non-conserved regions which can accommodate mutations that necessary for us to intelligently design efficacious vaccines not limit the effect of antibodies without impairing enzyme activity just against SARS-CoV-2 but also against other coronaviruses that (antigenic drift), potentially leading to loss of immunity in infected are likely to emerge in the future. If work on influenza can serve as or vaccinated individuals from one season to the next . Genetic a lesson, a universal coronavirus vaccine will not be easy to drift of spike protein has been demonstrated in endemic human develop, but if we do not start work on one now, we will find coronavirus OC43, suggesting mutations can be accumulated in ourselves in a similar situation during the next outbreak. non-conserved regions over time . Furthermore, an escape mutation conferring resistance to neutralizing antibody was found Received: 27 April 2020; Accepted: 14 May 2020; in vitro after applying immune pressure to 2002/2003 SARS-CoV. Interestingly, this mutation was also found to have occurred naturally in 2003/2004 SARS-CoV strains raising the possibility that SARS-CoV-2 has the potential to evolve resistance against antibodies induced by some vaccine strategies currently under REFERENCES development . Genetic differences within the receptor-binding 1. World Health Organization. Coronavirus disease 2019 (COVID-19) situation domain (RBD) discriminating two major types of circulating SARS- report - 111. https://www.who.int/docs/default-source/coronaviruse/situation- reports/20200510covid-19-sitrep-111.pdf?sfvrsn=1896976f_2 (2020). CoV-2 indicate that the virus is already adapting . Targeting of 2. Gandhi, M., Yokoe, D. S. & Havlir, D. V. Asymptomatic transmission, the Achilles’ conserved epitopes has been proposed as a strategy to combat heel of current strategies to control Covid-19. N. Engl. J. Med. https://doi.org/ influenza’s adaptive capabilities and may be a potential strategy 10.1056/NEJMe2009758 (2020). against SARS-CoV-2 as well. Amino acid sequence similarity 3. Anderson, R. M. et al. Epidemiology, transmission dynamics and control of SARS: between SARS-CoV S protein and SARS-CoV-2 S protein has been the 2002-2003 epidemic. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 1091–1105 estimated only at 77% with significant changes present in the (2004). 19,23 RBD . In this context, many antibodies against SARS-CoV S 4. Thanh Le, T. et al. The COVID-19 vaccine development landscape. Nat. Rev. Drug protein have not shown promising SARS-CoV-2 binding and Discov. 19, 305–306 (2020). 24–26 neutralizing capacity . Similarly, antibodies against SARS-CoV-2 5. Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). RBD have not shown cross-reactivity to SARS-CoV RBD or Middle 6. Subbarao, K. et al. Prior infection and passive transfer of neutralizing antibody East respiratory syndrome-CoV RBD . Recent work has clarified prevent replication of severe acute respiratory syndrome coronavirus in the that, despite only 46.7% protein sequence similarity between the respiratory tract of mice. J. Virol. 78, 3572–3577 (2004). SARS-CoV S1 receptor-binding subdomain and the SARS-CoV-2 7. Zhong, X. et al. B-cell responses in patients who have recovered from severe S1 receptor-binding subdomain, the S1 RBD core domain is B B acute respiratory syndrome target a dominant site in the S2 domain of the highly conserved . Antibodies have been identified targeting surface spike glycoprotein. J. Virol. 79, 3401–3408 (2005). epitopes in S1 RBD core domain, which show cross-reactive B 8. Guo, L. et al. Profiling early humoral response to diagnose novel coronavirus 23,24,27 potential against both SARS-CoV and SARS-CoV-2 . These disease (COVID-19). Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa310 (2020). findings may help guide development of vaccines with broader 9. Wu, F. et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. Preprint at https://www.medrxiv. coverage, though the protective effects of such antibodies have org/content/10.1101/2020.03.30.20047365v2 (2020). yet to be demonstrated in animal models or human studies. 10. Li, N., Wang, X. & Lv, T. Prolonged SARS-CoV-2 RNA shedding: not a rare phe- An additional problem is the waning of antibody titers over nomenon. J. Med. Virol. https://doi.org/10.1002/jmv.25952 (2020). time after vaccination or recovery from live infection. Conse- 11. Wolfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. quently, individuals are left vulnerable to reinfection, as demon- Nature https://doi.org/10.1038/s41586-020-2196-x (2020). strated in influenza, even with an identical strain during the next 12. Centers for Disease Control and Prevention. Past seasons vaccine effectiveness season . Similarly, antibodies against S protein diminished over estimates. https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html time in SARS survivors . We are then faced with a critically (2019). important but unanswered question: For how long will SARS-CoV- 13. Morens, D. M. & Taubenberger, J. K. Making universal influenza vaccines: lessons from the 1918 pandemic. J. Infect. Dis. 219,S5–S13 (2019). 2 circulate? Whereas the SARS outbreak was extinguished, all five 14. Paules, C. I., Marston, H. D., Eisinger, R. W., Baltimore, D. & Fauci, A. S. The pathway characterized pandemic influenza viruses established endemicity, to a universal influenza vaccine. Immunity 47, 599–603 (2017). facilitated, at least in part, by antigenic drift and waning antibody 15. Memoli, M. J. et al. Evaluation of antihemagglutinin and antineuraminidase titers. Though impossible to predict with certainty, the prospect of antibodies as correlates of protection in an influenza A/H1N1 virus healthy SARS-CoV-2 also establishing endemicity is one the medical human challenge model. mBio 7, e00417-16 (2016). community needs to be prepared for, including the potential for 16. Hobson, D., Curry, R. L., Beare, A. S. & Ward-Gardner, A. The role of serum accumulation of mutations in the face of increasing immune haemagglutination-inhibiting antibody in protection against challenge infection pressure. Considering that three coronavirus outbreaks have with influenza A2 and B viruses. J. Hyg. (Lond.) 70, 767–777 (1972). occurred in the past two decades, even if SARS-CoV-2 disappears 17. Monto, A. & Kendal, A. Effect of neuraminidase antibody on Hong Kong influenza. Lancet 301, 623–625 (1973). in a similar fashion to SARS-CoV, it seems inevitable that another 18. Sui, J. et al. Broadening of neutralization activity to directly block a dominant novel coronavirus outbreak will occur in the future. Acknowl- antibody-driven SARS-coronavirus evolution pathway. PLoS Pathog. 4, e1000197 edging the limitations in cross-protection of most SARS-CoV- (2008). induced antibodies against SARS-CoV-2, it is quite likely that 19. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of vaccines tailored to SARS-CoV-2 would not offer protection against probable bat origin. Nature 579, 270–273 (2020). 25,26 novel coronaviruses . Even with advances in the rapidity of 20. Sandbulte, M. R. et al. Discordant antigenic drift of neuraminidase and hemag- vaccine development technology, the delay between epidemic glutinin in H1N1 and H3N2 influenza viruses. Proc. Natl Acad. Sci. USA 108, onset and implementation of a novel vaccine candidate in the 20748–20753 (2011). community is responsible for immense societal costs. npj Vaccines (2020) 43 Published in partnership with the Sealy Center for Vaccine Development 1234567890():,; L.T. Giurgea et al. 21. Ren, L. et al. Genetic drift of human coronavirus OC43 spike gene during adaptive COMPETING INTERESTS evolution. Sci. Rep. 5, 11451 (2015). The authors declare no competing interests. 22. Tang, X. et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci. Rev. https://doi.org/10.1093/nsr/nwaa036 (2020). 23. Yuan, M. et al. A highly conserved cryptic epitope in the receptor-binding ADDITIONAL INFORMATION domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633 (2020). Correspondence and requests for materials should be addressed to L.T.G. 24. Tian, X. et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg. Microbes Infect. 9, Reprints and permission information is available at http://www.nature.com/ 382–385 (2020). reprints 25. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263 (2020). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 26. Lan, J. et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to in published maps and institutional affiliations. the ACE2 receptor. Nature 581, 215–220 (2020). 27. Wang, C. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 11, 2251 (2020). 28. Memoli, M. J. et al. Influenza A reinfection in sequential human challenge: Open Access This article is licensed under a Creative Commons implications for protective immunity and “universal” vaccine development. Clin. Attribution 4.0 International License, which permits use, sharing, Infect. Dis. 70, 748–753 (2020). adaptation, distribution and reproduction in any medium or format, as long as you give 29. Liu, W. et al. Two-year prospective study of the humoral immune response of appropriate credit to the original author(s) and the source, provide a link to the Creative patients with severe acute respiratory syndrome. J. Infect. Dis. 193, 792–795 Commons license, and indicate if changes were made. The images or other third party (2006). material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory ACKNOWLEDGEMENTS regulation or exceeds the permitted use, you will need to obtain permission directly This research was supported [in part] by the Intramural Research Program of the from the copyright holder. To view a copy of this license, visit http://creativecommons. NIH, NIAID. org/licenses/by/4.0/. AUTHOR CONTRIBUTIONS This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 L.T.G. contributed to literature review and writing. A.H. and M.J.M. contributed to writing. Published in partnership with the Sealy Center for Vaccine Development npj Vaccines (2020) 43 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Vaccines Springer Journals

Universal coronavirus vaccines: the time to start is now

Giurgea, Luca T.; Han, Alison; Memoli, Matthew J.
npj Vaccines , Volume 5 (1) – May 28, 2020
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Abstract

www.nature.com/npjvaccines COMMENT OPEN 1✉ 1 1 Luca T. Giurgea , Alison Han and Matthew J. Memoli The continued explosive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite aggressive public health measures has triggered an unprecedented international vaccine effort. However, correlates of protection, which can help guide intelligent vaccine design, are not known for SARS-CoV-2. Research on influenza immunity and vaccine development may provide valuable lessons for coronavirus efforts, especially considering similarities in rapid evolutionary potential. The apparent inevitability of future novel coronavirus outbreaks must prompt work on a universal coronavirus vaccine. npj Vaccines (2020) 5:43 ; https://doi.org/10.1038/s41541-020-0198-1 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SARS-CoV-2, and if they are, how much protection is afforded. pandemic continues to spread throughout the world with Recent data have shown 94% of patients who recover from mild explosive outbreaks underway throughout much of Europe and Covid-19 have neutralizing antibodies 2 weeks after symptom the United States. Even though the pandemic has slowed down in onset, but neutralizing antibody titers correlate only moderately some countries, other nations are still experiencing a rapid rise in with measured anti-S protein antibody . Careful study of potential cases and their healthcare systems are pushed to the limits . The patients with SARS-CoV-2 reinfection may help shed light on this case fatality ratio (CFR) varies widely by country and while question, but cases have not been documented in the literature. population characteristics and access to healthcare are critically Reports may be confounded by prolonged RNA shedding, which important factors, differences in the extent of testing of mild cases can persist over 30 days in almost 10% of patients, regardless of are likely responsible for some of the observed variation in the CFR resolution of symptoms . The viability of virus associated with through effects on the denominator. Interestingly, in the hardest prolonged shedding and consequently the infectivity of these hit areas, only a small fraction of the population has been reported patients is also unknown, considering that in a separate study of to be infected. It is unclear how much of this is due to nine patients, live SARS-CoV-2 was isolated only up to day 7 asymptomatic clinical presentations, testing availability, viral despite ongoing high viral loads by reverse transcription transmission dynamics, changes in individual behavior, and polymerase chain reaction . The distinction between viable virus aggressive isolation and quarantine actions. Some experts suspect and RNA shedding may have ramifications on study of immune a significant number of mild or asymptomatic infections go correlates of viral clearance. undiagnosed, leading to a falsely elevated CFR and making the Vaccine development against respiratory viruses is a challen- pandemic much more difficult to control in the setting of ging task. Currently, the only approved vaccines against respira- asymptomatic transmission . Public health measures helped to tory viruses are those against influenza. Despite decades of extinguish the SARS outbreak 17 years ago, but so far, they have research, modern vaccines have had limited effectiveness against only been able to slow down the coronavirus disease 2019 seasonal influenza and are unlikely to provide broad protection 12,13 against novel influenza strains capable of causing pandemics . (Covid-19) pandemic . Only in the past few years, a century after the advent of the 1918 In order to combat the disease, governments, international organizations, private companies, and academic institutions across influenza pandemic that was one of the most catastrophic events the planet have launched a multifaceted vaccine development in human history responsible for 50–100 million deaths, a response with unprecedented rapidity. At least 110 vaccine concerted effort was initiated to accelerate the development of 13,14 candidates are in preclinical testing and at least 5 vaccines have a universal influenza vaccine . Many unknowns exist with already begun early clinical testing . The focus of the response is respect to SARS-CoV-2, but research into influenza immunity and haste, understandably so, leading to use of novel technologies, vaccine development may provide valuable lessons for Covid-19 including DNA plasmids, viral vectors, virus-like particles, Baculo- and may help guide vaccination strategies. We have known for virus/mammalian expression systems, and mRNA vaccines among decades that antibodies against hemagglutinin (the dominant others. Many of these utilize sequencing information that was surface protein of the influenza particle) at a titer of 1:40 or greater made available quickly after the onset of the outbreak and can be are associated with >50% reduction in disease, but more recent developed more rapidly than classical vaccine preparation data have suggested antibody against influenza neuraminidase, strategies utilizing live virus as substrate, which necessitate the another viral surface protein, may be a superior predictor of 5 15,16 use of cumbersome biosafety protection measures . The purpose clinical outcomes . We have no such knowledge of correlates of most early candidate vaccines is development of antibodies of protection against coronaviruses, and specifically against SARS- against the Spike glycoprotein (S protein), which have been CoV-2, thereby making the process of developing an effective implicated in protection against SARS-CoV in animal models and vaccine that much more difficult. Interestingly, the importance of have been found in SARS-COV and SARS-CoV-2 convalescent anti-neuraminidase immunity in protection against influenza was 6–8 patient sera . However, we do not yet have evidence to show recognized during the H3N2 pandemic. Through serendipitous that anti-S protein antibodies are protective in humans against ongoing trials, researchers were able to seize an opportunity to LID Clinical Studies Unit, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. email: [email protected] Published in partnership with the Sealy Center for Vaccine Development 1234567890():,; L.T. Giurgea et al. obtain preinfection and postinfection sera demonstrating the After the SARS outbreak, we lost interest and failed to complete ability of anti-neuraminidase antibodies to reduce infection development of a vaccine for use in case of a recurrent outbreak. rates . We need to obtain similar information for SARS-CoV-2 to We must not make the same mistake again. Instead we must go help guide and refine vaccine development. further. We must work toward a universal coronavirus vaccine with Both influenza and coronaviruses have an inherent capacity for broad protection against a diverse number of coronaviruses. We rapid mutation due to the low fidelity of RNA polymerase and a need to understand the correlates of protection against corona- capability to form novel viruses through reassortment with a vast viruses and improve our understanding of their pathogenesis, 13,18,19 reservoir of zoonotic viruses .Influenza surface proteins have transmission, and viral evolution. These studies will be absolutely non-conserved regions which can accommodate mutations that necessary for us to intelligently design efficacious vaccines not limit the effect of antibodies without impairing enzyme activity just against SARS-CoV-2 but also against other coronaviruses that (antigenic drift), potentially leading to loss of immunity in infected are likely to emerge in the future. If work on influenza can serve as or vaccinated individuals from one season to the next . Genetic a lesson, a universal coronavirus vaccine will not be easy to drift of spike protein has been demonstrated in endemic human develop, but if we do not start work on one now, we will find coronavirus OC43, suggesting mutations can be accumulated in ourselves in a similar situation during the next outbreak. non-conserved regions over time . Furthermore, an escape mutation conferring resistance to neutralizing antibody was found Received: 27 April 2020; Accepted: 14 May 2020; in vitro after applying immune pressure to 2002/2003 SARS-CoV. Interestingly, this mutation was also found to have occurred naturally in 2003/2004 SARS-CoV strains raising the possibility that SARS-CoV-2 has the potential to evolve resistance against antibodies induced by some vaccine strategies currently under REFERENCES development . Genetic differences within the receptor-binding 1. World Health Organization. Coronavirus disease 2019 (COVID-19) situation domain (RBD) discriminating two major types of circulating SARS- report - 111. https://www.who.int/docs/default-source/coronaviruse/situation- reports/20200510covid-19-sitrep-111.pdf?sfvrsn=1896976f_2 (2020). CoV-2 indicate that the virus is already adapting . Targeting of 2. Gandhi, M., Yokoe, D. S. & Havlir, D. V. Asymptomatic transmission, the Achilles’ conserved epitopes has been proposed as a strategy to combat heel of current strategies to control Covid-19. N. Engl. J. Med. https://doi.org/ influenza’s adaptive capabilities and may be a potential strategy 10.1056/NEJMe2009758 (2020). against SARS-CoV-2 as well. Amino acid sequence similarity 3. Anderson, R. M. et al. Epidemiology, transmission dynamics and control of SARS: between SARS-CoV S protein and SARS-CoV-2 S protein has been the 2002-2003 epidemic. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359, 1091–1105 estimated only at 77% with significant changes present in the (2004). 19,23 RBD . In this context, many antibodies against SARS-CoV S 4. Thanh Le, T. et al. The COVID-19 vaccine development landscape. Nat. Rev. Drug protein have not shown promising SARS-CoV-2 binding and Discov. 19, 305–306 (2020). 24–26 neutralizing capacity . Similarly, antibodies against SARS-CoV-2 5. Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). RBD have not shown cross-reactivity to SARS-CoV RBD or Middle 6. Subbarao, K. et al. Prior infection and passive transfer of neutralizing antibody East respiratory syndrome-CoV RBD . Recent work has clarified prevent replication of severe acute respiratory syndrome coronavirus in the that, despite only 46.7% protein sequence similarity between the respiratory tract of mice. J. Virol. 78, 3572–3577 (2004). SARS-CoV S1 receptor-binding subdomain and the SARS-CoV-2 7. Zhong, X. et al. B-cell responses in patients who have recovered from severe S1 receptor-binding subdomain, the S1 RBD core domain is B B acute respiratory syndrome target a dominant site in the S2 domain of the highly conserved . Antibodies have been identified targeting surface spike glycoprotein. J. Virol. 79, 3401–3408 (2005). epitopes in S1 RBD core domain, which show cross-reactive B 8. Guo, L. et al. Profiling early humoral response to diagnose novel coronavirus 23,24,27 potential against both SARS-CoV and SARS-CoV-2 . These disease (COVID-19). Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa310 (2020). findings may help guide development of vaccines with broader 9. Wu, F. et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. Preprint at https://www.medrxiv. coverage, though the protective effects of such antibodies have org/content/10.1101/2020.03.30.20047365v2 (2020). yet to be demonstrated in animal models or human studies. 10. Li, N., Wang, X. & Lv, T. Prolonged SARS-CoV-2 RNA shedding: not a rare phe- An additional problem is the waning of antibody titers over nomenon. J. Med. Virol. https://doi.org/10.1002/jmv.25952 (2020). time after vaccination or recovery from live infection. Conse- 11. Wolfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. quently, individuals are left vulnerable to reinfection, as demon- Nature https://doi.org/10.1038/s41586-020-2196-x (2020). strated in influenza, even with an identical strain during the next 12. Centers for Disease Control and Prevention. Past seasons vaccine effectiveness season . Similarly, antibodies against S protein diminished over estimates. https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html time in SARS survivors . We are then faced with a critically (2019). important but unanswered question: For how long will SARS-CoV- 13. Morens, D. M. & Taubenberger, J. K. Making universal influenza vaccines: lessons from the 1918 pandemic. J. Infect. Dis. 219,S5–S13 (2019). 2 circulate? Whereas the SARS outbreak was extinguished, all five 14. Paules, C. I., Marston, H. D., Eisinger, R. W., Baltimore, D. & Fauci, A. S. The pathway characterized pandemic influenza viruses established endemicity, to a universal influenza vaccine. Immunity 47, 599–603 (2017). facilitated, at least in part, by antigenic drift and waning antibody 15. Memoli, M. J. et al. Evaluation of antihemagglutinin and antineuraminidase titers. Though impossible to predict with certainty, the prospect of antibodies as correlates of protection in an influenza A/H1N1 virus healthy SARS-CoV-2 also establishing endemicity is one the medical human challenge model. mBio 7, e00417-16 (2016). community needs to be prepared for, including the potential for 16. Hobson, D., Curry, R. L., Beare, A. S. & Ward-Gardner, A. The role of serum accumulation of mutations in the face of increasing immune haemagglutination-inhibiting antibody in protection against challenge infection pressure. Considering that three coronavirus outbreaks have with influenza A2 and B viruses. J. Hyg. (Lond.) 70, 767–777 (1972). occurred in the past two decades, even if SARS-CoV-2 disappears 17. Monto, A. & Kendal, A. Effect of neuraminidase antibody on Hong Kong influenza. Lancet 301, 623–625 (1973). in a similar fashion to SARS-CoV, it seems inevitable that another 18. Sui, J. et al. Broadening of neutralization activity to directly block a dominant novel coronavirus outbreak will occur in the future. Acknowl- antibody-driven SARS-coronavirus evolution pathway. PLoS Pathog. 4, e1000197 edging the limitations in cross-protection of most SARS-CoV- (2008). induced antibodies against SARS-CoV-2, it is quite likely that 19. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of vaccines tailored to SARS-CoV-2 would not offer protection against probable bat origin. Nature 579, 270–273 (2020). 25,26 novel coronaviruses . Even with advances in the rapidity of 20. Sandbulte, M. R. et al. Discordant antigenic drift of neuraminidase and hemag- vaccine development technology, the delay between epidemic glutinin in H1N1 and H3N2 influenza viruses. Proc. Natl Acad. Sci. USA 108, onset and implementation of a novel vaccine candidate in the 20748–20753 (2011). community is responsible for immense societal costs. npj Vaccines (2020) 43 Published in partnership with the Sealy Center for Vaccine Development 1234567890():,; L.T. Giurgea et al. 21. Ren, L. et al. Genetic drift of human coronavirus OC43 spike gene during adaptive COMPETING INTERESTS evolution. Sci. Rep. 5, 11451 (2015). The authors declare no competing interests. 22. Tang, X. et al. On the origin and continuing evolution of SARS-CoV-2. Natl Sci. Rev. https://doi.org/10.1093/nsr/nwaa036 (2020). 23. Yuan, M. et al. A highly conserved cryptic epitope in the receptor-binding ADDITIONAL INFORMATION domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633 (2020). Correspondence and requests for materials should be addressed to L.T.G. 24. Tian, X. et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg. Microbes Infect. 9, Reprints and permission information is available at http://www.nature.com/ 382–385 (2020). reprints 25. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263 (2020). Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims 26. Lan, J. et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to in published maps and institutional affiliations. the ACE2 receptor. Nature 581, 215–220 (2020). 27. Wang, C. et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat. Commun. 11, 2251 (2020). 28. Memoli, M. J. et al. Influenza A reinfection in sequential human challenge: Open Access This article is licensed under a Creative Commons implications for protective immunity and “universal” vaccine development. Clin. Attribution 4.0 International License, which permits use, sharing, Infect. Dis. 70, 748–753 (2020). adaptation, distribution and reproduction in any medium or format, as long as you give 29. Liu, W. et al. Two-year prospective study of the humoral immune response of appropriate credit to the original author(s) and the source, provide a link to the Creative patients with severe acute respiratory syndrome. J. Infect. Dis. 193, 792–795 Commons license, and indicate if changes were made. The images or other third party (2006). material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory ACKNOWLEDGEMENTS regulation or exceeds the permitted use, you will need to obtain permission directly This research was supported [in part] by the Intramural Research Program of the from the copyright holder. To view a copy of this license, visit http://creativecommons. NIH, NIAID. org/licenses/by/4.0/. AUTHOR CONTRIBUTIONS This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020 L.T.G. contributed to literature review and writing. A.H. and M.J.M. contributed to writing. Published in partnership with the Sealy Center for Vaccine Development npj Vaccines (2020) 43

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