SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3

For the publisher:

We conducted a global, randomized, placebo-controlled trial of phase 1-2-3, in which two 30 μg doses of BNT162b2 (Pfizer-BioNTech) were administered 21 days apart (ClinicalTrials.gov number , NCT04368728). These doses of vaccine had mainly low-grade side effects and provided 95% efficacy against 2019 coronavirus disease (Covid-19) from 7 days to approximately 2 months after dose 2.¹ Efficacy decreased to 84% between 4 and approximately 6 months after dose 2.² Since vaccine authorization, viral variants have replaced the original strain, with the currently dominant highly transmissible variant B.1.617.2 (delta).³ Although the effectiveness of the vaccine against serious illness, hospitalization, and death remains high, decreased immunity and viral diversification create a possible need for a third dose of vaccine.

Therefore, we administered a third dose of 30 μg of BNT162b2 7.9 to 8.8 months after the dose of 2 to 11 participants aged 18 to 55 years and 12 participants aged 65 to 85 years. from the U.S. sites in Part 1 of the main phase of the ongoing trial. (Additional details of the test are provided in Table S1 and the text in the supplementary appendix, as well as in the test protocol, both available with the full text of this letter at NEJM.org). Local reactions and systemic events after dose 3 were predominantly mild to moderate and were similar to those after dose 2 (Figs. S1 and S2). No unsolicited adverse events were reported the month following dose 3.

Figure 1. Figure 1. Neutralizing responses after two and three doses of BNT162b2.

50% neutralization titers against a wild-type target strain (USA-WA1 / 2020) and against lineage B.1.351 (beta) and target strains of lineage B.1.617.2 (delta) are shown for both age groups. The geometric mean values ​​from the severe acute respiratory syndrome coronavirus 2 plaque reduction neutralization tests (SARS-CoV-2) are shown for the serum specimens obtained at the time points shown on the x-axes of the participants. of the dose 3 immunogenicity population (11 participants in the 18–55 age group and 12 participants in the 65–85 age group). 𝙸 Bars indicate 95% confidence intervals. Neutralization titles against the wild-type virus were determined twice (once together with the titles against each variant), and each title against the wild-type virus is reported separately with the corresponding variant title. Differences between neutralization titer determinations versus wild-type virus represent experimental variations in repeated tests. The values ​​above the error bars are geometric mean titles. The data points shown in the bar graph represent individual neutralization titles of 50%. Individual titers for all participants were displayed for all time points except before dose 1, when all values ​​were below the lower limit of quantification (LLOQ) of 20; results below the LLOQ were set at 0.5 times the LLOQ. The geometric mean ratios (GMR) of the titles against the wild-type variants and virus are shown below the graph. In panel A, the geometric mean increase (GMFR) in titles against the wild-type strain before dose 3 to 1 month after dose 3 was 25.7 (95% confidence interval) [CI], 12.4 to 53.3) for younger adults and 49.4 (95% CI, 29.2 to 83.3) for older adults. The corresponding GMFRs against the beta variant were 38.7 (95% CI, 19.8 to 75.5) and 78.3 (95% CI, 40.7 to 150.6), respectively.

We determined 50% serum neutralization titers against severe wild-type acute respiratory syndrome (USA-WA1 / 2020) coronavirus 2 (SARS-CoV-2) and a recombinant beta variant strain (i.e., the ear gene of the beta variant in wild-type background genetics), as described above.⁴ Serum samples were obtained before dose 1, at 7 days and 1 month after dose 2, and before and at 7 days and 1 month after dose 3 (Figure 1A). These data supported four key conclusions. First, for approximately 8 months from 7 days after dose 2 to dose 3, the geometric mean titers of SARS-CoV-2 neutralization (GMT) in this subgroup of phase 1 participants of the ‘trial decreased much more rapidly than the efficacy of the vaccine participants in the fundamental phase 2-3 trial.² Second, one month after dose 3, wild-type virus neutralization GMTs increased to more than 5-fold (in 18- to 55-year-olds) and to more than 7-fold higher (65 to 55-year-olds). – 85 years) as GMT one month after dose 2. Third, beta-neutralizing GMTs increased more after dose 3 than GMTs against wild-type virus, up more than 15 times higher (in younger adults) and more than 20 times higher (in older adults) than after dose 2, reducing the gap between wild-type virus neutralization and beta variant. Fourth, neutralization GMTs decreased from 7 days to 1 month after dose 2, but increased from 7 days to 1 month after dose 3. A similar broader neutralization pattern was observed (i.e. ie, against variant strains) and higher GMT after dose 3 in GMT assays of neutralization against recombinant virus with delta variant ear protein on a wild-type genetic background: the geometric mean proportion of neutralizing GMT (delta variant to wild type) 1 month after dose 3 was 0.85 in younger adults and 0.92 in older adults (Figure 1B).

Increases in the magnitude and amplitude of neutralization and improvements in humoral response kinetics have also been observed with booster doses of the prepandemic influenza vaccine administered after a series of primary immunizations.⁵ The safety and immunogenicity of a booster dose of BNT162b2 administered 7 to 9 months after the main two-dose series suggests that a third dose could prolong protection and further increase the amplitude of protection.

Ann R. Falsey, MD
University of Rochester, Rochester, New York

Robert W. Frenck, Jr., MD
Cincinnati Children’s Hospital, Cincinnati, OH

Edward E. Walsh, MD
University of Rochester, Rochester, New York

Nicholas Kitchin, MD
Pfizer Vaccine Research and Development, Hurley, UK
[email protected]

Judith Absalon, MD
Alejandra Gurtman, MD
Vaccine research and development Pfizer, Pearl River, New York

Stephen Lockhart, DM
Ruth Bailey, B.Sc.
Pfizer Vaccine Research and Development, Hurley, UK

Kena A. Swanson, Ph.D.
Vaccine research and development Pfizer, Pearl River, New York

Xia Xu, Ph.D.
Vaccine research and development Pfizer, Collegeville, Pennsylvania

Kenneth Koury, Ph.D.
Warren Kalina, Ph.D.
David Cooper, Ph.D.
Vaccine research and development Pfizer, Pearl River, New York

Jing Zou, Ph.D.
Xuping Xie, Ph.D.
Hongjie Xia, Ph.D.
University of Texas Medical Office, Galveston, TX

Ozlem Tureci, MD
Eleni Lagkadinou, MD, Ph.D.
BioNTech, Mainz, Germany

Kristin R. Tompkins, B.Sc.
Vaccine research and development Pfizer, Pearl River, New York

Pei-Yong Shi, Ph.D.
University of Texas Medical Office, Galveston, TX

Kathrin U. Jansen, Ph.D.
Vaccine research and development Pfizer, Pearl River, New York

Ugur Sahin, MD
BioNTech, Mainz, Germany

Philip R. Dormitzer, MD, Ph.D.
William C. Gruber, MD
Vaccine research and development Pfizer, Pearl River, New York

This letter was published on September 15, 2021 on NEJM.org.

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