COVID-19 booster doses reduce sex disparities in antibody responses among nursing home residents

Abstract

Background: Data suggest that antibody responses following COVID-19 vaccines are a correlate of protection. Some studies, including the clinical trials of COVID-19 mRNA vaccines, did not stratify and evaluate whether antibody responses to COVID-19 vaccines differed between the sexes or with aging. This gap in research is particularly relevant for older populations such as nursing home residents (NHR). We hypothesized that sex differences in vaccine-induced antibody responses may intersect with age and be diminished among older adults residing in nursing homes.

Methods: We analyzed serum samples from 638 NHRs collected serially after the primary two-dose series and three subsequent booster doses of mRNA SARS-CoV-2 vaccinations. We analyzed anti-Spike IgG and neutralizing antibody titers to the Wuhan and Omicron BA.4/5 variant strains. Mixed-effects models predicting log-transformed titers were estimated to compare responses across vaccine doses, focusing on sex-differential responses. For detected post-dose sex differences, additional sample times were analyzed to assess the duration of the difference.

Results: Following the primary series, female NHRs with a prior history of SARS-CoV-2 infection had significantly higher Wuhan anti-Spike antibodies and neutralizing antibody titers than male NHRs with differences persisting up to nine months post-vaccination. Subsequent monovalent booster doses and a bivalent booster dose eliminated this disparity. We did not detect any differential response to the Omicron BA.4/5 variant.

Conclusions: The blunting of sex differences in antibody response observed following the primary series by the 1st booster dose underscores the importance of booster vaccination in this population.

Keywords: Aging; Antibody response; Immunosenescence; Nursing home residents; Older adults; Omicron; Sex differences.

Fig. 1

Timeline of analyzed doses and days to sampling. Serum samples were collected serially from participants after mRNA vaccination. This analysis focuses on the post-vaccine draws following a 2-dose mRNA Primary Series and three subsequent booster doses. The monovalent boosters are Wuhan-based while the bivalent booster contains Wuhan and Omicron BA4/5. Post-vaccine draws and the median (IQR) days following vaccine dose are indicated. Not all analyzed subjects received all listed doses. M6: Month 6, M9: Month 9

Fig. 2

Anti-Wuhan Spike and neutralizing antibody titers over time among female and male NHRs. The bar graphs show the kinetics of anti-Spike (upper panel) and neutralizing (lower panel) antibodies against the Wuhan strain across different time points among female and male NHR. Wuhan anti-Spike is measured in BAU/mL. The lower limit of detection of the neutralization assay was 1:12, while the upper limit was 1:8748. Post-primary series sera were taken 2–4 weeks after the 2nd vaccine dose, completing the primary series, while M6 and M9 post-primary series sera were taken 6–8 months and 7–10 months later, respectively. Bars and whiskers show GMT with 95% CI. Blue: Female, Red: Male. Naive subjects: no prior infection, Prior subjects (previously infected). Male and female subjects were compared with model contrasts after estimating mixed-effects linear models predicting log-transformed titer with the interaction of sex, prior infection, and sample time within strain and assay. *, **, *** are significance levels of model contrasts with p < 0.05, < 0.01, < 0.001 respectively. BAU/ml: Binding Antibody Unit/ml, pNT50: Pseudoneutralization titer 50, NHR: Nursing Home Residents, GMT: Geometric Mean Titer, CI: Confidence Interval

Fig. 3

Anti-Spike and Neutralizing Antibody titers against Wuhan (Panel A) and Omicron BA.4/5 (Panel B) strains across booster doses among female and male NHR. The bar graph shows the post-vaccination anti-Spike and neutralizing antibody titers against the Wuhan and Omicron strains across the boosters among female and male NHR. Wuhan anti-Spike is measured in BAU/mL. Note, all figures show post-boost titers except those for the post-primary series. The lower limit of detection of the neutralization assay was 1:12, while the upper limit was 1:8748. Post-vaccination sera were taken 2–4 weeks after each dose. Bars and whiskers show GMT with 95% confidence intervals. Blue: Female, Red: Male. Naive subjects: no prior infection, Prior subjects: previously infected. Male and female subjects were compared with model contrasts after estimating mixed-effects linear models predicting log-transformed titer with the interaction of sex, prior infection, and vaccine dose within strain and assay. *, **, *** are significance levels of model contrasts with p < 0.05, < 0.01, < 0.001 respectively. BAU/ml: Binding Antibody Unit/ml per milliliter for Wuhan and arbitrary units (AU)/mL for BA.4/5, pNT50: Pseudoneutralization titer 50, NHR: Nursing Home Residents, GMT: Geometric Mean Titer, CI: Confidence Interval