Superior immunogenicity and effectiveness of the third compared to the second BNT162b2 vaccine dose

Yaniv Lustig, Tal Gonen, Lilac Meltzer, Mayan Gilboa, Victoria Indenbaum, Carmit Cohen, Sharon Amit, Hanaa Jaber, Ram Doolman, Keren Asraf, Carmit Rubin, Ronen Fluss, Ella Mendelson, Laurence Freedman, Gili Regev-Yochay, Yitshak Kreiss

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52 Scopus citations


As the effectiveness of a two-dose messenger RNA (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine regimen decreases with time, a third dose has been recommended. Here, we assessed immunogenicity, vaccine effectiveness and safety of the third BNT162b2 vaccine dose in a prospective cohort study of 12,413 healthcare workers (HCWs). Anti-RBD immunoglobulin G (IgG) levels were increased 1.7-fold after a third dose compared with following the second dose. Increased avidity from 61.1% (95% confidence interval (CI), 56.1–66.7) to 96.3% (95% CI, 94.2–98.5) resulted in a 6.1-fold increase in neutralization titer. Peri-infection humoral markers of 13 third-dose Delta variant of concern (VOC) breakthrough cases were lower compared with 52 matched controls. Vaccine effectiveness of the third dose relative to two doses was 85.6% (95% CI, 79.2–90.1). No serious adverse effects were reported. These results suggest that the third dose is superior to the second dose in both quantity and quality of IgG antibodies and safely boosts protection from infection.

Original languageEnglish
Pages (from-to)940-946
Number of pages7
JournalNature Immunology
Issue number6
StatePublished - Jun 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.


This study was funded by internal funds of the SMC. Y.L. is a recipient of the Nehemia Rubin Excellence in Biomedical Research, the TELEM Program of Chaim, SMC. We greatly acknowledge T. Levin, R. Koren, S. Kats-Likvornik, O. Halpern, Y. Kanaaneh, S. Abosiam, A. Aydenzon and M. Chiara Atias-Golbus for their devoted work in the laboratory; the Infection, Prevention and Control team for the extensive epidemiologic investigation; and Y. Beker-Ilani, E. Rozner and E. Steinberger for coordinating the study.

FundersFunder number
Nehemia Rubin Excellence in Biomedical Research


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