Age-Dependent Reduction in Neutralization against Alpha and Beta Variants of BNT162b2 SARS-CoV-2 Vaccine-Induced Immunity

Abstract

Vaccines against severe acute respiratory syndrome coronavirus-2 have been introduced. To investigate the relationship between vaccine-induced humoral immunity and patient age, we measured antibody levels and neutralization in vaccinated sera. Sera from 13 to 17 days after the second dose of the BNT162b2 vaccine were collected from health care workers at the University of Toyama (n = 740). Antibody levels were measured by the anti-receptor binding domain antibody test (anti-RBD test), and neutralization against wild-type (WT), α- and β-variant pseudotyped viruses were assayed using a high-throughput chemiluminescent reduction neutralizing test (htCRNT; positivity cutoff, 50% neutralization at serum dilution 1:100). Basic clinical characteristics were obtained from questionnaires. Antibodies were confirmed in all participants in both the anti-RBD test (median, 2,112 U/ml; interquartile range [IQR], 1,275 to 3,390 U/ml) and the htCRNT against WT (median % inhibition, >99.9; IQR, >99.9 to >99.9). For randomly selected sera (n = 61), 100.0% had positive htCRNT values against the α- and β-derived variants. Among those who answered the questionnaire (n = 237), the values of the anti-RBD test were negatively correlated with age in females (P < 0.01). An age-dependent decline in neutralization was observed against the variants but not against the wild-type virus (wild type, P = 0.09; α, P < 0.01; β, P < 0.01). The neutralizing activity induced by BNT162b2 was obtained not only against the wild-type virus, but also against the variants; however, there was an age-dependent decrease in the latter. Age-related heterogeneity of vaccine-acquired immunity is a concern in preventive strategies in the era dominated by variants. IMPORTANCE Since mRNA vaccines utilize wild-type SARS-CoV-2 spike protein as an antigen, there are potential concerns about acquiring immunity to variants of this virus. The neutralizing activity in BNT162b2-vaccinated individuals was higher against the wild-type virus than against its variants; this effect was more apparent in older age groups. This finding suggests that one of the weaknesses of the mRNA vaccine is the high risk of variant infection in the elderly population. Because the elderly are at a higher risk of SARS-CoV-2 infection, the age-dependent decline of neutralization against viral variants should be considered while planning vaccination programs that include boosters.

Keywords: BNT162b2; SARS-CoV-2; neutralizing antibodies; receptor-binding domain; variants.

FIG 1

Relationship between anti-RBD antibody levels and neutralization. Neutralization levels against pseudotyped viruses measured by htCRNT (blue) and anti-RBD antibody levels measured by a commercially available test (pink) were plotted (n = 740). The results of both tests are plotted on the XY coordinate (purple). The value of htCRNT is defined as the mean of duplicate assays using 100-fold diluted serum. Bars indicate medians with interquartile ranges. htCRNT, high-throughput chemiluminescent reduction neutralizing test; RBD, receptor-binding domain.

FIG 2

Cross-reaction against variants in representative sera. (A) Neutralizing activity against wild-type (WT), α-, and β-derived variants (n = 61). (B) The relationship between neutralizing activity and anti-RBD antibody levels. **, P < 0.01. Bars indicate medians with interquartile ranges.

FIG 3

Relationship of vaccine-induced antibody levels and demographic characteristics in questionnaire-answered population. (A) Anti-RBD antibody levels in males and females (n = 237). (B) Anti-RBD antibody levels and local or systemic symptoms (n = 237). (C) Relationship between anti-RBD antibody levels and age. (D) Relationship between htCRNT levels using 100-fold dilutions of sera and age (for WT pseudotyped virus; n = 237, for α- and β-derived variants; n = 21). (E) Relationship between htCRNT levels using 400-fold dilutions of sera and age (n = 21). *, P < 0.05; **, P < 0.01; ns, not significant. Bars indicate medians with interquartile ranges. RBD, receptor-binding domain; htCRNT, high-throughput chemiluminescent reduction neutralizing test.