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Durability of Immune Response After COVID-19 Booster Vaccination and Association With COVID-19 Omicron Infection

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Key Points

Question  What is the durability of the immune response after 3 vaccine doses, and are antibody kinetics associated with SARS-CoV-2 Omicron infection?

Findings  In this cohort study of 3972 health care workers, reduction in antibody levels 5 months after the third BNT162b2 vaccine dose was slower than after the second, while Omicron's neutralizing response was lower compared with other variants of concern. Peak antibody levels after the third dose were associated with Omicron infection.

Meaning  This study found that the humoral response after the third vaccine dose was sustained for 5 months and that antibody kinetics were associated with Omicron infection.


Importance  The BNT162b2 two-dose vaccine (BioNTech/Pfizer) has high effectiveness that wanes within several months. The third dose is effective in mounting a significant immune response, but its durability is unknown.

Objective  To compare antibody waning after second and third doses and estimate the association of antibody kinetics with susceptibility to infection with the Omicron variant of SARS-CoV-2.

Design, Setting, and Participants  In a prospective longitudinal cohort study in a tertiary medical center in Israel, health care workers who received the BNT162b2 vaccine were followed up monthly for IgG and neutralizing antibody levels. Linear mixed models were used to compare antibody titer waning of second and third doses and to assess whether antibody dynamics were associated with Omicron transmission. Avidity, T cell activation, and microneutralization of sera against different variants of concern were assessed for a subgroup.

Exposure  Vaccination with a booster dose of the BNT162b2 vaccine.

Main Outcomes and Measures  The primary outcome was the rate of antibody titer change over time, and the secondary outcome was SARS-CoV-2 Omicron variant infection, as confirmed by reverse transcriptase–polymerase chain reaction.

Results  Overall, 4868 health care workers (mean [SD] age, 46.9 [13.7] years; 3558 [73.1%] women) and 3972 health care workers (mean [SD] age, 48.5 [14.1] years; 996 [74.9%] women) were followed up for 5 months after their second and third vaccine doses, respectively. Waning of IgG levels was slower after the third compared with the second dose (1.32%/d [95% CI, 1,29%/d to 1.36%/d] vs 2.26% [95% CI, 2.13%/d 2.38%/d]), as was waning of neutralizing antibody levels (1.32%/d [95% CI, 1.21%/d to 1.43%/d] vs 3.34%/d [95% CI, 3.11%/d to 3.58%/d]). Among 2865 health care workers assessed for Omicron incidence during an additional 2 months of follow-up, lower IgG peak (ratio of means 0.86 [95% CI, 0.80-0.91]) was associated with Omicron infection, and among participants aged 65 years and older, faster waning of IgG and neutralizing antibodies (ratio of mean rates, 1.40; [95% CI, 1.13-1.68] and 3.58 [95% CI, 1.92-6.67], respectively) were associated with Omicron infection. No waning in IgG avidity was observed 112 days after the third dose. Live neutralization of Omicron was lower compared with previous strains, with a geometric mean titer at the peak of 111 (95% CI, 75-166), compared with 942 (95% CI, 585-1518) for WT, 410 (95% CI, 266-634) for Delta; it demonstrated similar waning to 26 (95% CI, 16-42) within 4 months. Among 77 participants tested for T cell activity, mean (SD) T cell activity decreased from 98 (5.4) T cells/106 peripheral blood mononuclear cells to 59 (9.3) T cells/106 peripheral blood mononuclear cells.

Conclusions and Relevance  This study found that the third vaccine dose was associated with greater durability than the second dose; however, Omicron was associated with greater resistance to neutralization than wild type and Delta variants of concern. Humoral response dynamics were associated with susceptibility to Omicron infection.

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Article Information

Accepted for Publication: July 31, 2022.

Published: September 15, 2022. doi:10.1001/jamanetworkopen.2022.31778

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Gilboa M et al. JAMA Network Open.

Corresponding Author: Mayan Gilboa, MD, Infection Prevention and Control Unit, Sheba Medical Center, Derech Sheba 1, Tel Hashomer, Ramat Gan, Israel (mayangilboa@yahoo.com).

Author Contributions: Drs Gilboa and Regev-Yochay had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Gilboa and Regev-Yochay contributed equally as co–first authors.

Concept and design: Gilboa, Regev-Yochay, Amit, Afek, Kreiss, Lustig.

Acquisition, analysis, or interpretation of data: Gilboa, Regev-Yochay, Mandelboim, Indenbaum, Asraf, Fluss, Amit, Mendelson, Doolman, Freedman, Lustig.

Drafting of the manuscript: Gilboa, Regev-Yochay, Asraf, Fluss, Doolman, Freedman, Lustig.

Critical revision of the manuscript for important intellectual content: Gilboa, Regev-Yochay, Mandelboim, Indenbaum, Amit, Mendelson, Afek, Freedman, Kreiss, Lustig.

Statistical analysis: Asraf, Fluss, Doolman, Freedman.

Obtained funding: Kreiss, Lustig.

Administrative, technical, or material support: Gilboa, Mandelboim, Asraf, Mendelson, Doolman, Afek, Kreiss.

Supervision: Regev-Yochay, Asraf, Mendelson, Doolman, Afek, Kreiss, Lustig.

Conflict of Interest Disclosures: Dr Regev-Yochay reported receiving grants from Pfizer and personal fees from Moderna, AstraZeneca, Teva Pharmaceuticals, and Pfizer outside the submitted work. Dr Lustig reported receiving a grant from Pfizer outside the submitted work. No other disclosures were reported.

Additional Contributions: We would like to thank Sheba Medical Center management, specifically Amir Grinberg, PhD, and Anat Peles Bortz, PhD, for enabling this study. We thank Vered Roa; Esther Rosner, PhD; and Yael Beker-Ilani for coordinating this study and the Sheba information technology team, specifically Osnat Persky, Itay Menaged, and Shay Yamin, for assisting in retrieving data. All individuals mentioned in the acknowledgment section have given written permission to include their names in this segment. None of these individuals were compensated beyond their normal salaries for this work.

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