Antibody Titers Before and After a Third Dose of the SARS-CoV-2 BNT162b2 Vaccine in Adults Aged ≥60 Years

The durability of response to the SARS-CoV-2 BNT162b2 vaccine (Pfizer-BioNTech) in adults aged 60 years and older has yet to be determined. The immune response to 2 doses of BNT162b2 is lower in individuals aged 65 to 85 years vs 18 to 55 years.¹ Among 4868 health care workers receiving 2 BNT162b2 doses, a significant waning of the humoral response (IgG, neutralizing antibodies) within 6 months of the second dose was observed, especially among adults aged 65 years and older.² After a fourth SARS-CoV-2 wave in Israel, the Israeli Ministry of Health authorized, at the end of July 2021, a third BNT162b2 vaccine dose for individuals aged 60 years and older, which was subsequently expanded to younger age groups.

We assessed antispike (anti-S) IgG antibody titers before and after a third BNT162b2 dose in individuals aged 60 years and older because this population is at high risk of developing severe SARS-CoV-2 disease and was the first to receive authorization for a third dose.

After the initial authorization of a third dose in Israel, Rabin Medical Center (RMC) offered this dose to workers and their family members and recruited study participants aged 60 years and older at the vaccination center. Exclusion criteria included prior SARS-CoV-2 infection and active malignancy. Anti-S IgG titers were determined before (August 4-12, 2021) and 10 to 19 days after (August 16-24, 2021) the third vaccination. Serum from the blood samples was immediately transmitted to the microbiological laboratory, where titers of anti-S IgG antibodies were determined with the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). Seropositivity was defined as 50 arbitrary units (AU)/mL or higher. Additional information is available in the Supplement.

The study was approved by the ethics committee of RMC. All participants provided written informed consent.

The difference in IgG values before and 10 to 19 days after the third dose was evaluated with Wilcoxon signed rank test. Spearman correlation was used to assess the correlation between the IgG values and age of the participants. Multivariable analyses were performed by fitting a generalized linear model on the log of IgG values and included age and days from the first vaccination as continuous variables, and sex and comorbidities (dyslipidemia, hypertension, obesity, diabetes, and ischemic heart disease) as categorical variables. A 2-sided P < .05 was considered significant. Statistical analysis was performed with R version 4.0.2.

Among the 97 study participants, the median age was 70 years (IQR, 67-74), and 61% were women (Table 1). Before the third dose (median, 221 days [IQR, 218-225] after the first vaccination), 94 participants (97%) were seropositive. The median titer level increased significantly after the third dose, from a median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR, 14 203-36 618) (P < .001), and all participants became seropositive (Table 1). No significant correlation was observed between age and IgG titers (R = −0.075; P = .47). No variable was significantly associated with higher IgG titers, including age, sex, days after first vaccination, and comorbidities (Table 2). No major adverse events were reported.

This study found that a third BNT162b2 dose in adults aged 60 years and older was associated with significantly increased IgG titers after 10 to 19 days, with no major adverse events.

A third dose of the SARS-CoV-2 mRNA-1273 vaccine (Moderna) induced seropositivity in 49% of kidney transplant recipients who did not respond after 2 vaccine doses,³ although this observation cannot be generalized to older adults. In a study from Israel among 1 137 804 adults aged 60 years and older who had received 2 BNT162b2 doses 5 or more months earlier, a third dose was associated with lower rates of confirmed SARS-CoV-2 infections and severe illness.⁴ This study adds serologic data to the clinical data on response to a third dose in adults aged 60 years or older.

Study limitations include the small sample size, short follow-up, and lack of cellular immunity testing and neutralizing antibody testing. Although accumulating evidence suggests that IgG response is a correlate of disease protection,⁵ cellular immunity has also been suggested to play an important role in protecting against SARS-CoV-2.⁶

Accepted for Publication: October 19, 2021.

Published Online: November 5, 2021. doi:10.1001/jama.2021.19885

Corresponding Author: Salomon M. Stemmer, MD, Davidoff Cancer Center, Rabin Medical Center, Belinson Hospital, Sackler Faculty of Medicine, Tel Aviv University, 39 Jabotinsky St, Petah Tikva 49100, Israel (salomon.stemmer@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. Drs Eliakim-Raz and Leibovici-Weisman contributed equally to this work.

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

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

Drafting of the manuscript: All authors.

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

Statistical analysis: A. Stemmer, S. M. Stemmer.

Obtained funding: S. M. Stemmer.

Administrative, technical, or material support: Eliakim-Raz, Leibovici-Weisman, Ness, Awwad, Ghantous, S. M. Stemmer.

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

Conflict of Interest Disclosures: Dr S. M. Stemmer reported receiving research grants (to his institution) from CAN-FITE, AstraZeneca, BioLineRX, BMS, Clovis Oncology, CTG Pharma, Exelixis, GEICAM, Halozyme, 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.

Data Sharing Statement: The data sets generated during this study are available from the corresponding author on request.

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