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Clinical Trial
. 2020 Dec 17;383(25):2439-2450.
doi: 10.1056/NEJMoa2027906. Epub 2020 Oct 14.

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

Edward E Walsh  1 , Robert W Frenck Jr  1 , Ann R Falsey  1 , Nicholas Kitchin  1 , Judith Absalon  1 , Alejandra Gurtman  1 , Stephen Lockhart  1 , Kathleen Neuzil  1 , Mark J Mulligan  1 , Ruth Bailey  1 , Kena A Swanson  1 , Ping Li  1 , Kenneth Koury  1 , Warren Kalina  1 , David Cooper  1 , Camila Fontes-Garfias  1 , Pei-Yong Shi  1 , Özlem Türeci  1 , Kristin R Tompkins  1 , Kirsten E Lyke  1 , Vanessa Raabe  1 , Philip R Dormitzer  1 , Kathrin U Jansen  1 , Uğur Şahin  1 , William C Gruber  1
Affiliations
Clinical Trial

Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

Edward E Walsh et al. N Engl J Med. .

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.).

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Figures

Figure 1
Figure 1. Screening and Randomization of the Participants.
The 54 participants who were not assigned to a trial group were screened but did not undergo randomization because trial enrollment had closed. All the participants received two doses of the vaccine (BNT162b1 or BNT162b2) or placebo, except for the participants who were assigned to receive 100 μg of BNT162b1 or placebo, who received one dose.
Figure 2
Figure 2. Local Reactions Reported within 7 Days after the Administration of Vaccine or Placebo, According to Age Group.
Panel A shows local reactions in participants 18 to 55 years of age, and Panel B those in participants 65 to 85 years of age. Injection-site (local) reactions were recorded in electronic diaries for 7 days after each injection. Pain at the injection site was graded as mild (does not interfere with activity), moderate (interferes with activity), severe (prevents daily activity), or grade 4 (led to an emergency department visit or hospitalization). Redness and swelling were graded as mild (2.0 to 5.0 cm in diameter), moderate (>5.0 to 10.0 cm in diameter), severe (>10.0 cm in diameter), or grade 4 (necrosis or exfoliative dermatitis for redness and necrosis for swelling). 𝙸 bars represent 95% confidence intervals. The numbers above the 𝙸 bars show the overall percentage of the participants in each group who reported the specified local reaction. No participant who received either vaccine candidate reported a grade 4 local reaction.
Figure 3
Figure 3. Selected Systemic Events Reported within 7 Days after the Administration of Vaccine or Placebo, According to Age Group.
Panel A shows systemic reactions in participants 18 to 55 years of age, and Panel B those in participants 65 to 85 years of age. Data on fever, chills, and fatigue are reported here. (Data on headache, vomiting, diarrhea, muscle pain, and joint pain are reported in Fig. S1.) Data on systemic events were recorded in electronic diaries for 7 days after each injection. The fever scale is shown in the key. Chills and fatigue were graded as being mild (does not interfere with activity), moderate (interferes somewhat with activity), severe (prevents daily activity), or grade 4 (led to an emergency department visit or hospitalization). 𝙸 bars represent 95% confidence intervals. The numbers above the 𝙸 bars show the overall percentage of participants in each group who reported the specified systemic event. No participant who received either vaccine candidate reported a grade 4 systemic event or a temperature higher than 40.0°C.
Figure 4
Figure 4. Immunogenicity of BNT162b1 and BNT162b2.
Participants in groups of 15 received an injection with the indicated dose levels of one of either of the BNT162 vaccine candidates (12 participants) or placebo (3 participants) on days 1 and 21. Arrows indicate days of vaccination. Responses in the placebo recipients in each of the dose-level groups are combined. Serum samples were obtained before injection (on day 1) and on days 21, 28, and 35 after the first dose. The blood samples obtained on days 28 and 35 are those obtained 7 days and 14 days, respectively, after the second dose. Human coronavirus disease 2019 (Covid-19) or SARS-CoV-2 infection convalescent serum (HCS) samples were obtained from 38 donors at least 14 days after polymerase chain reaction–confirmed diagnosis and at a time when the donors were asymptomatic. Panel A shows the geometric mean concentrations of recombinant S1-binding IgG (lower limit of quantitation, 1.267; dashed line), and Panel B the 50% SARS-CoV-2–neutralizing geometric mean titers (lower limit of quantitation, 20; dashed line). On days that vaccine or placebo was administered, samples were obtained before the injection. Each data point represents a serum sample, and the top of each vertical bar represents the geometric mean with the 95% confidence interval (𝙸 bar). Data points associated with placebo, HCS samples, or the 10-μg dose of vaccine are shown as circles, those for the 20-μg dose as squares, and those for the 30-μg dose as triangles. The numbers above the bars show the geometric mean concentration or geometric mean titer in the group. All the vaccine groups had 12 valid results from samples that could be evaluated at each time point except for the following: among participants who received BNT162b2, 11 results from day 28 in younger participants who received 30 μg, 10 results from day 35 in younger participants who received 30 μg, and 11 results from day 35 in older participants who received 10 μg.
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