Antibody Titers After a Third and Fourth SARS-CoV-2 BNT162b2 Vaccine Dose in Older Adults

Introduction

At the beginning of the fifth SARS-CoV-2 wave in Israel, with the B.1.1.529 (Omicron) variant, the effectiveness of the third SARS-CoV-2 BNT162b2 vaccine (Pfizer-BioNTech) against Omicron was questioned. During the fifth wave, in January 2022, the Israeli Ministry of Health authorized a fourth BNT162b2 dose for individuals aged 60 years or older (a third dose was authorized for such individuals in July 2021, during the fourth SARS-CoV-2 wave).

This study, which is an extension of a prior study,1 compared the response to the third and fourth BNT162b2 vaccine doses among individuals aged 60 years or older by evaluating antispike (anti-S) immunoglobulin G (IgG) antibody titers before and after each dose. This population is at high risk of developing severe SARS-CoV-2 disease and was the first to receive authorization for a third and fourth vaccine dose.

Methods

This study was approved by the ethics committee of the Rabin Medical Center in Tel Aviv, Israel. All participants provided written informed consent. After the authorization of a third SARS-CoV-2 vaccine dose in Israel, the Rabin Medical Center offered this vaccine to employees who worked there, as well as their family members; other participants were recruited at the vaccination center. Exclusion criteria included prior SARS-CoV-2 infection and active malignant neoplasm. Anti-S IgG titers were assessed before (August 4-12, 2021) and 10 to 19 days after (August 16-24, 2021) the third vaccination, as well as before (January 4-20, 2022) and 8 to 17 days after (January 13-30, 2022) the fourth vaccination. Serum samples were immediately transmitted to the microbiological laboratory, where anti-S IgG titers were measured with the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories).2 Seropositivity was defined as 50 arbitrary units (AU)/mL or more. All adverse events were recorded as well. Additional information is available in the eAppendix in the Supplement. This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.

The difference in anti-S IgG values from before to after the third BNT162b2 vaccine and from before to after the fourth BNT162b2 vaccine were evaluated using the Wilcoxon signed rank test. The Spearman correlation was used to assess the correlation between the anti-S IgG titers and age. Multivariable analysis was performed by fitting a generalized linear model on the log of anti-S IgG antibody values after the fourth dose and included age, days from the first vaccination, and days from the fourth vaccination as continuous variables and sex and comorbid conditions (dyslipidemia, hypertension, obesity, type 1 or 2 diabetes, and ischemic heart disease) as categorical variables (eTable in the Supplement). The χ2 test was used to assess statistical difference in SARS-CoV-2 infection rates between patients who were vaccinated 4 times and patients who were vaccinated 3 times.

Statistical analyses are described in the eAppendix in the Supplement. A 2-sided P < .05 was considered statistically significant. Statistical analysis was performed using R, version 4.0.2 (R Group for Statistical Computing).3

Results

Ninety-nine participants (60 women [61%]; median age, 70 years [IQR, 66-74 years]) received a third BNT162b2 dose, of whom 57 received a fourth dose (Table). Of these 57 participants, 48 had IgG data before and after the third and the fourth dose and are included in the present analysis. The baseline characteristics of the 48 participants with IgG data before and after the third and the fourth dose were similar to those of the entire cohort. Before the fourth dose, all participants were seropositive. The median IgG titers increased significantly after the third dose (450 AU/mL [IQR, 297-903 AU/mL] before the dose and 27 092 [IQR, 15 423-33 074 AU/mL] a median of 14 days [IQR, 13-16 days] after the dose; P < .001) and after the fourth dose (3775 AU/mL [IQR, 2070-7096 AU/mL] before the dose and 28 708 AU/mL [IQR, 18 223-44 710 AU/mL] a median of 11 days [9-13 days] after the dose; P < .001) (Table; Figure). No significant correlation was observed between age and IgG titer after the fourth dose (R = −0.041; P = .78). In a multivariable analysis, none of the evaluated variables was associated with higher IgG titers after the fourth vaccine. No major adverse events were reported. Four of 57 participants (7%) who received 4 vaccine doses (median, 6 days [IQR, 5-7 days] after the fourth vaccine) vs 9 of 42 participants (21%) who received 4 vaccination doses (median, 162 days [IQR, 158-167 days] after the third vaccine) had SARS-CoV-2 infection (P = .07). All had asymptomatic to mild infection.

Discussion

This study found that the third and fourth BNT162b2 doses in adults aged 60 years or older were associated with a significant increase in anti-S IgG titers approximately 2 weeks after the vaccination, with no major adverse events. Data on the response to the fourth BNT162b2 dose among healthy older adults are lacking. Our findings are consistent with those from case series involving patients who received solid organ transplants, in which significant increases in antibody titers and improved humoral response were associated with the fourth BNT162b2 dose.4,5

Study limitations included the small sample size and lack of cellular immunity testing or neutralizing antibody testing, although current evidence suggests that IgG response is a correlate of disease protection.6 Also, anti-N IgG titers were not measured; however, all participants were questioned about symptoms and positive test results. The present study did not investigate waning of the immune response after the fourth dose, and therefore it did not address the key question of whether additional boosters would be required.

Accepted for Publication: May 10, 2022.

Published: July 21, 2022. doi:10.1001/jamanetworkopen.2022.23090

Corresponding Author: Noa Eliakim-Raz, MD, Internal Medicine E, Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky St, Petah Tikva, 49100, Israel (noaeliakim@gmail.com).

Author Contributions: Dr S. M. Stemmer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Eliakim-Raz, S. M. Stemmer.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Eliakim-Raz, Ghantous, Ness, Awwad, S. M. Stemmer.

Critical revision of the manuscript for important intellectual content: Eliakim-Raz, A. Stemmer, Leibovici-Weisman, S. M. Stemmer.

Statistical analysis: A. Stemmer, Ghantous, Ness, Awwad.

Obtained funding: S. M. Stemmer.

Administrative, technical, or material support: All authors.

Supervision: Eliakim-Raz, S. M. Stemmer.

Conflict of Interest Disclosures: Dr S. M. Stemmer reported receiving research grants (to the institution) from CAN-FITE, AstraZeneca, Bioline RX, Bristol Myers Squibb, Halozyme, Clovis Oncology, CTG Pharma, Exelixis, Geicam, Incyte, Lilly, Moderna, Teva Pharmaceuticals, and Roche and owning stocks and options in CTG Pharma, DocBoxMD, Tyrnovo, VYPE, Cytora, and CAN-FITE. No other disclosures were reported.

Additional Contributions: The authors thank Avital Bareket-Samish, PhD, BioInsight Ltd, for medical editing support. She received financial compensation for her contribution.

Additional Information: The data sets generated during this study are available from the corresponding author on request.