Assessment of Neutralizing Antibody Response Against SARS-CoV-2 Variants After 2 to 3 Doses of the BNT162b2 mRNA COVID-19 Vaccine

Abstract

Importance: Although 2 and 3 doses of vaccine have been implemented against the SARS-CoV-2 pandemic, the level of immunity achieved by these additional vaccinations remains unclear.

Objective: To investigate the induction of neutralizing antibodies against the SARS-CoV-2 Omicron variant after 2 and 3 doses of the BNT162b2 messenger RNA (mRNA) vaccine among recipients of different ages.

Design, setting, and participants: A cohort study was conducted from June 1, 2021, to January 12, 2022, among 82 physicians at Kobe University Hospital who had received 2 doses of the BNT162b2 mRNA vaccine.

Main outcomes and measures: The rates of positive test results and the titers of neutralizing antibodies against the Omicron variant after 2 and 3 doses of the vaccine were compared with those against other variants and compared among 3 age groups (≤38 years [younger age group], 39-58 years [intermediate age group], and ≥59 years [older age group]).

Results: A total of 82 physicians (71 men [87%]; median age, 44 years [IQR, 33-58 years]) participated; 31 (38%) were in the younger age group, 32 (39%) were in the intermediate age group, and 19 (23%) were in the older age group. At 2 months after 2 doses of the vaccine, 23 participants (28%) had neutralizing antibodies against the Omicron variant, with a titer of 1.3 (95% CI, 1.2-1.4), which was 11.8-fold (95% CI, 9.9-13.9) lower than the titer against the D614G variant and the lowest among the variants tested. Although the titer of the neutralizing antibody against the Delta variant tended to be low among the older age group (2.9 [95% CI, 2.0-4.1]), the titers of the neutralizing antibody against the Omicron variant were low among all age groups (younger age group, 1.3 [95% CI, 1.1-1.6]; intermediate age group, 1.3 (95% CI, [95% CI, 1.1-1.5]; and older age group, 1.2 [95% CI, 1.0-1.4]). At 7 months after 2 doses of the vaccine, 5 participants (6%) had the neutralizing antibody against the Omicron variant, but after the booster (third dose) vaccination, all 72 participants who received the booster had the neutralizing antibody, and the titer was 41 (95% CI, 34-49), much higher than that at 7 months after 2 doses of the vaccine (1.0 [95% CI, 1.0-1.1]). This increase in titers was observed regardless of age groups; the titers were 44 (95% CI, 32-59) among the younger age group, 44 (95% CI, 32-59) among the intermediate age group, and 30 (95% CI, 22-41) among the older age group.

Conclusions and relevance: In this cohort study of 82 Japanese participants, 2 doses of the BNT162b2 mRNA vaccine did not induce sufficient neutralizing antibody against the Omicron variant. However, booster vaccination was associated with induction of a high level of neutralizing antibodies against the Omicron variant, irrespective of the recipient's age.

Figure 1.. Neutralizing Antibody Against SARS-CoV-2 Variants at 2 Months After 2 Doses of the BNT162b2 mRNA Vaccine

The serum samples obtained from 82 recipients were tested for neutralizing activity against the SARS-CoV-2 variants D614G, Alpha, Beta, Gamma, Delta, Kappa, and Omicron. The neutralizing antibody titer is represented by the highest serum dilution that did not show any cytopathic effects. A, The positivity rate for the neutralizing antibody against each variant. Serum samples with neutralizing activity at 2-fold dilution (the detection limit) or higher were considered positive. B, Scatterplot of the neutralizing antibody titers. The limit of detection is indicated by the horizontal dotted black line, and the short horizontal solid black lines indicate the geometric mean titer. The titers against the 7 variants were compared using the Friedman test and the Dunn test for multiple comparisons; 2-tailed P values were calculated.

Figure 2.. Comparison of Neutralizing Antibodies Against SARS-CoV-2 Variants at 2 Months After 2 Doses of the BNT162b2 mRNA Vaccine Among 3 Age Groups

The 82 participants were divided into 3 age groups: 31 participants who were 38 years or younger, 32 participants who were 39 to 58 years, and 19 participants who were 59 years or older. The recipients’ serum samples were then tested for neutralizing activities against the 7 SARS-CoV-2 variants. A, The positivity rate for neutralizing antibodies against each variant in the 3 age groups. Serum samples with neutralizing activity at 2-fold dilution (detection limit) or higher were considered positive. B, Comparison of neutralizing antibody titers against each variant among the age groups. The limit of detection is indicated by the horizontal dotted black line, and the short horizontal solid black lines indicate the geometric mean titer. The Kruskal-Wallis test and the Dunn test for multiple comparisons were performed, and 2-tailed P values were calculated.

Figure 3.. Changes in the Neutralizing Antibody Against 3 SARS-CoV-2 Variants After Booster Vaccination

The serum samples obtained from the 72 participants who received the booster vaccination were tested for neutralizing activity against the D614G, Delta, and Omicron variants at 2 and 7 months after 2 doses of the BNT162b2 mRNA vaccine and after the booster (3 total doses of vaccine). A, Changes in the positivity rates for neutralizing antibodies against each variant. Serum samples with neutralizing activity at 2-fold dilution (detection limit) or higher were considered positive. B, Changes in the neutralizing antibody titers against each variant. The limit of detection is indicated by the horizontal dotted black line, and the short horizontal solid black lines indicate the geometric mean titer. The titers were compared using the Friedman test and the Dunn test for multiple comparisons; 2-tailed P values were calculated.

Figure 4.. Comparison of Changes in the Neutralizing Antibody Titer After Booster Vaccination Among the 3 Age Groups

The 72 recipients who received the booster vaccination were divided into 3 age groups: 31 participants who were 38 years or younger, 27 participants who were 39 to 58 years, and 14 participants who were 59 years or older. The neutralizing antibody titers against the D614G variant (A), the Delta variant (B), and the Omicron variant (C) at 2 and 7 months after 2 doses of the BNT162b2 mRNA vaccine and after the booster vaccination were compared in each age group. The limit of detection is indicated by the horizontal dotted black line, and the short horizontal solid black lines indicate the geometric mean titer. The Friedman test and the Dunn test for multiple comparisons were performed; 2-tailed P values were calculated.