Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates
Edward E Walsh, Robert W Frenck Jr, Ann R Falsey, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, Kathleen Neuzil, Mark J Mulligan, Ruth Bailey, Kena A Swanson, Ping Li, Kenneth Koury, Warren Kalina, David Cooper, Camila Fontes-Garfias, Pei-Yong Shi, Özlem Türeci, Kristin R Tompkins, Kirsten E Lyke, Vanessa Raabe, Philip R Dormitzer, Kathrin U Jansen, Uğur Şahin, William C Gruber, Edward E Walsh, Robert W Frenck Jr, Ann R Falsey, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, Kathleen Neuzil, Mark J Mulligan, Ruth Bailey, Kena A Swanson, Ping Li, Kenneth Koury, Warren Kalina, David Cooper, Camila Fontes-Garfias, Pei-Yong Shi, Özlem Türeci, Kristin R Tompkins, Kirsten E Lyke, Vanessa Raabe, Philip R Dormitzer, Kathrin U Jansen, Uğur Şahin, William C Gruber
Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States.
Methods: In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle-formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 μg, 20 μg, 30 μg, and 100 μg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 μg of BNT162b1), participants received one dose.
Results: A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples.
Conclusions: The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2-3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).
Copyright © 2020 Massachusetts Medical Society.
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References
- Johns Hopkins University Coronavirus Resource Center. COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. 2020 ().
- Sahin U, Muik A, Derhovanessian E, et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T-cell responses. Nature 2020. September 30 (Epub ahead of print).
- Pardi N, Tuyishime S, Muramatsu H, et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 2015;217:345-351.
- Karikó K, Muramatsu H, Welsh FA, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther 2008;16:1833-1840.
- Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020. August 12 (Epub ahead of print).
- He Y, Zhou Y, Liu S, et al. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine. Biochem Biophys Res Commun 2004;324:773-781.
- Güthe S, Kapinos L, Möglich A, Meier S, Grzesiek S, Kiefhaber T. Very fast folding and association of a trimerization domain from bacteriophage T4 fibritin. J Mol Biol 2004;337:905-915.
- Bachmann MF, Zinkernagel RM. Neutralizing antiviral B cell responses. Annu Rev Immunol 1997;15:235-270.
- Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263.
- Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A 2017;114(35):E7348-E7357.
- Xie X, Muruato A, Lokugamage KG, et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 2020;27(5):841-848.e3.
- Muruato AE, Fontes-Garfias CR, Ren P, et al. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nat Commun 2020;11:4059-4059.
- Foster GR, Masri SH, David R, et al. IFN-α subtypes differentially affect human T cell motility. J Immunol 2004;173:1663-1670.
- Hopkins RJ, Daczkowski NF, Kaptur PE, et al. Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of Anthrax Vaccine Adsorbed plus CPG 7909 (AV7909) in healthy adult volunteers. Vaccine 2013;31:3051-3058.
- Regules JA, Beigel JH, Paolino KM, et al. A recombinant vesicular stomatitis virus Ebola vaccine. N Engl J Med 2017;376:330-341.
- Lai L, Davey R, Beck A, et al. Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick. JAMA 2015;313:1249-1255.
- Feldman RA, Fuhr R, Smolenov I, 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.
- Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2022483.
- Kondili M, Roux M, Vabret N, Bailly-Bechet M. Innate immune system activation by viral RNA: how to predict it? Virology 2016;488:169-178.
- Muñoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet 2009;373:1949-1957.
- Boraschi D, Del Giudice G, Dutel C, Ivanoff B, Rappuoli R, Grubeck-Loebenstein B. Ageing and immunity: addressing immune senescence to ensure healthy ageing. Vaccine 2010;28:3627-3631.
- Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance — United States, January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep 2020;69:759-765.
Source: PubMed