A Double-Inactivated Severe Acute Respiratory Syndrome Coronavirus Vaccine Provides Incomplete Protection in Mice and Induces Increased Eosinophilic Proinflammatory Pulmonary Response upon Challenge
Open accessAbstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) is an important emerging virus that is highly pathogenic in aged populations and is maintained with great diversity in zoonotic reservoirs. While a variety of vaccine platforms have shown efficacy in young-animal models and against homologous viral strains, vaccine efficacy has not been thoroughly evaluated using highly pathogenic variants that replicate the acute end stage lung disease phenotypes seen during the human epidemic. Using an adjuvanted and an unadjuvanted double-inactivated SARS-CoV (DIV) vaccine, we demonstrate an eosinophilic immunopathology in aged mice comparable to that seen in mice immunized with the SARS nucleocapsid protein, and poor protection against a nonlethal heterologous challenge. In young and 1-year-old animals, we demonstrate that adjuvanted DIV vaccine provides protection against lethal disease in young animals following homologous and heterologous challenge, although enhanced immune pathology and eosinophilia are evident following heterologous challenge. In the absence of alum, DIV vaccine performed poorly in young animals challenged with lethal homologous or heterologous strains. In contrast, DIV vaccines (both adjuvanted and unadjuvanted) performed poorly in aged-animal models. Importantly, aged animals displayed increased eosinophilic immune pathology in the lungs and were not protected against significant virus replication. These data raise significant concerns regarding DIV vaccine s…
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In animal models of other coronaviruses and prior inactivated RSV or measles vaccines, VAERD is usually linked to Th2-biased CD4+ responses with elevated IL-4, IL-5, or IL-13.
“In animal models of infections with other coronaviruses and for previous whole-cell inactivated vaccines developed for respiratory syncytial virus and measles virus, VAERD has usually been associated with the development of T helper 2 cell (TH2 cell)-biased CD4+ T cell responses, with significantly increased levels of interleukin-4 (IL-4), IL-5 and/or IL-13 (refs12,126,165–174).”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [170]
Cites
SARS: systematic review of treatment effects
Stockman, L. J., Bellamy, R., & Garner, P. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030343 · Cited by 1,217 · see citing works
Donnelly, C. A., Ghani, A. C., Leung, G. M., Hedley, A. J., Fraser, C., Riley, S., Abu-Raddad, L. J., Ho, L.-M., Thach, T.-Q., Chau, P., et al. (2003) · The Lancet · doi:10.1016/s0140-6736(03)13410-1 · Cited by 940 · see citing works
Gruver, A., Hudson, L., & Sempowski, G. (2007) · The Journal of Pathology · doi:10.1002/path.2104 · Cited by 834 · see citing works
Cameron, M. J., Ran, L., Xu, L., Danesh, A., Bermejo-Martin, J. F., Cameron, C. M., Muller, M. P., Gold, W. L., Richardson, S. E., Poutanen, S. M., et al. (2007) · Journal of Virology · doi:10.1128/jvi.00527-07 · Cited by 386 · see citing works
Rockx, B., Corti, D., Donaldson, E., Sheahan, T., Stadler, K., Lanzavecchia, A., & Baric, R. (2008) · Journal of Virology · doi:10.1128/jvi.02377-07 · Cited by 134 · see citing works
Self-citation
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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
Baden, L. R., El Sahly, H. M., Essink, B., Kotloff, K., Frey, S., Novak, R., Diemert, D., Spector, S. A., Rouphael, N., Creech, C. B., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2035389 · Cited by 10,119 · see citing works
The trinity of COVID-19: immunity, inflammation and intervention
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A., & Ng, L. F. P. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0311-8 · Cited by 4,360 · see citing works
Folegatti, P. M., Ewer, K. J., Aley, P. K., Angus, B., Becker, S., Belij-Rammerstorfer, S., Bellamy, D., Bibi, S., Bittaye, M., Clutterbuck, E. A., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31604-4 · Cited by 2,419 · see citing works
SARS-CoV-2 vaccines in development
Krammer, F. (2020) · Nature · doi:10.1038/s41586-020-2798-3 · Cited by 2,098 · see citing works
SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness
Corbett, K. S., Edwards, D. K., Leist, S. R., Abiona, O. M., Boyoglu-Barnum, S., Gillespie, R. A., Himansu, S., Schäfer, A., Ziwawo, C. T., DiPiazza, A. T., et al. (2020) · Nature · doi:10.1038/s41586-020-2622-0 · Cited by 1,615 · see citing works
Self-citationSARS-CoV-2 Vaccines: Status Report
Amanat, F., & Krammer, F. (2020) · Immunity · doi:10.1016/j.immuni.2020.03.007 · Cited by 1,120 · see citing works
Estimating the burden of SARS-CoV-2 in France
Salje, H., Tran Kiem, C., Lefrancq, N., Courtejoie, N., Bosetti, P., Paireau, J., Andronico, A., Hozé, N., Richet, J., Dubost, C.-L., et al. (2020) · Science · doi:10.1126/science.abc3517 · Cited by 1,038 · see citing works
ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques
van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J. N., Port, J. R., Avanzato, V. A., Bushmaker, T., Flaxman, A., Ulaszewska, M., et al. (2020) · Nature · doi:10.1038/s41586-020-2608-y · Cited by 914 · see citing works
Immunological considerations for COVID-19 vaccine strategies
Jeyanathan, M., Afkhami, S., Smaill, F., Miller, M. S., Lichty, B. D., & Xing, Z. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-00434-6 · Cited by 1,015 · see citing works
Liu, L., Wei, Q., Lin, Q., Fang, J., Wang, H., Kwok, H., Tang, H., Nishiura, K., Peng, J., Tan, Z., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.123158 · Cited by 830 · see citing works
Rapid COVID-19 vaccine development
Graham, B. S. (2020) · Science · doi:10.1126/science.abb8923 · Cited by 771 · see citing works
A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice
Leist, S. R., Dinnon, K. H., Schäfer, A., Tse, L. V., Okuda, K., Hou, Y. J., West, A., Edwards, C. E., Sanders, W., Fritch, E. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.050 · Cited by 613 · see citing works
Self-citationAntibody-dependent enhancement and SARS-CoV-2 vaccines and therapies
Lee, W. S., Wheatley, A. K., Kent, S. J., & DeKosky, B. J. (2020) · Nature Microbiology · doi:10.1038/s41564-020-00789-5 · Cited by 676 · see citing works
Immunological mechanisms of vaccine-induced protection against COVID-19 in humans
Sadarangani, M., Marchant, A., & Kollmann, T. R. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00578-z · Cited by 560 · see citing works
T cell-mediated immune response to respiratory coronaviruses
Channappanavar, R., Zhao, J., & Perlman, S. (2014) · Immunologic Research · doi:10.1007/s12026-014-8534-z · Cited by 512 · see citing works
Airway Memory CD4+ T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses
Zhao, J., Zhao, J., Mangalam, A. K., Channappanavar, R., Fett, C., Meyerholz, D. K., Agnihothram, S., Baric, R. S., David, C. S., & Perlman, S. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.006 · Cited by 496 · see citing works
Self-citationOrtiz-Prado, E., Simbaña-Rivera, K., Gómez- Barreno, L., Rubio-Neira, M., Guaman, L. P., Kyriakidis, N. C., Muslin, C., Jaramillo, A. M. G., Barba-Ostria, C., Cevallos-Robalino, D., et al. (2020) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2020.115094 · Cited by 458 · see citing works
SARS-like WIV1-CoV poised for human emergence
Menachery, V. D., Yount, B. L., Sims, A. C., Debbink, K., Agnihothram, S. S., Gralinski, L. E., Graham, R. L., Scobey, T., Plante, J. A., Royal, S. R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1517719113 · Cited by 418 · see citing works
Self-citationWinkler, E. S., Gilchuk, P., Yu, J., Bailey, A. L., Chen, R. E., Chong, Z., Zost, S. J., Jang, H., Huang, Y., Allen, J. D., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.026 · Cited by 366 · see citing works
COVID-19 vaccines: The status and perspectives in delivery points of view
Chung, J. Y., Thone, M. N., & Kwon, Y. J. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.011 · Cited by 375 · see citing works
Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection
Menachery, V. D., Dinnon, K. H., Yount, B. L., McAnarney, E. T., Gralinski, L. E., Hale, A., Graham, R. L., Scobey, T., Anthony, S. J., Wang, L., et al. (2020) · Journal of Virology · doi:10.1128/jvi.01774-19 · Cited by 205 · see citing works
Self-citationWalls, A. C., Miranda, M. C., Schäfer, A., Pham, M. N., Greaney, A., Arunachalam, P. S., Navarro, M.-J., Tortorici, M. A., Rogers, K., O’Connor, M. A., et al. (2021) · Cell · doi:10.1016/j.cell.2021.09.015 · Cited by 185 · see citing works
“Previous studies showed that double-inactivated SARS-CoV vaccines could lead to eosinophil infiltration in the lungs and subsequent immune pathology (Bolles et al., 2011).”
BackgroundSelf-citationEliciting B cell immunity against infectious diseases using nanovaccines
Singh, A. (2021) · Nature Nanotechnology · doi:10.1038/s41565-020-00790-3 · Cited by 169 · see citing works
Avoiding pitfalls in the pursuit of a COVID-19 vaccine
Peeples, L. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2005456117 · Cited by 152 · see citing works
Lambert, P.-H., Ambrosino, D. M., Andersen, S. R., Baric, R. S., Black, S. B., Chen, R. T., Dekker, C. L., Didierlaurent, A. M., Graham, B. S., Martin, S. D., et al. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.05.064 · Cited by 119 · see citing works
Self-citationImmunogenicity and efficacy of mRNA COVID-19 vaccine MRT5500 in preclinical animal models
Kalnin, K. V., Plitnik, T., Kishko, M., Zhang, J., Zhang, D., Beauvais, A., Anosova, N. G., Tibbitts, T., DiNapoli, J., Ulinski, G., et al. (2021) · npj Vaccines · doi:10.1038/s41541-021-00324-5 · Cited by 82 · see citing works
Zang, J., Gu, C., Zhou, B., Zhang, C., Yang, Y., Xu, S., Bai, L., Zhang, R., Deng, Q., Yuan, Z., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-00199-1 · Cited by 67 · see citing works
Immunogenicity of novel mRNA COVID-19 vaccine MRT5500 in mice and non-human primates
Kalnin, K. V., Plitnik, T., Kishko, M., Zhang, J., Zhang, D., Beauvais, A., Anosova, N. G., Tibbitts, T., DiNapoli, J. M., Huang, P.-W. D., et al. (2020) · doi:10.1101/2020.10.14.337535 · Cited by 18 · see citing works
- Authors
- Bolles, M., Deming, D., Long, K., Agnihothram, S., Whitmore, A., Ferris, M., Funkhouser, W., Gralinski, L., Totura, A., Heise, M., & Baric, R. S.
- Affiliations
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Baric, Ralph S.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2011-12
- Volume
- 85
- Issue
- 23
- Pages
- 12201-12215
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- PMC
- PMC3209347
- OpenAlex
- W1995367098
- Cited by
- 477
- References
- 5
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 20 · 2023: 27 · 2022: 54 · 2021: 136 · 2020: 158 · 2019: 10 · 2018: 6 · 2017: 5 · 2016: 14 · 2015: 8 · 2014: 12 · 2013: 5 · 2012: 7
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Virology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- UNC Libraries
- Funders
- National Institutes of Health
- University of North Carolina at Chapel Hill
- National Institute of General Medical Sciences (T32GM008719)
- National Institute of Allergy and Infectious Diseases (U54AI081680, AI075297, R01AI075297, U54AI080680)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- SARS-CoV, inactivated vaccine, vaccine efficacy, eosinophilia, pulmonary immunopathology, aged mice, heterologous challenge, alum adjuvant, nucleocapsid protein, vaccine safety, vaccine failure, SARS-CoV-2
- MeSH terms
- Animals, Antibodies, Viral, Chlorocebus aethiops, Enzyme-Linked Immunosorbent Assay, Female, Lung, Mice, Inbred BALB C, Neutralization Tests, Pulmonary Eosinophilia, RNA, Messenger, Vaccination, Vero Cells, Viral Envelope Proteins, Viral Vaccines, Blotting, Western, Vaccines, Inactivated, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus, Mice, Real-Time Polymerase Chain Reaction
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