Diminishing reactogenicity with preserved immunogenicity in COVID-19 vaccines: A longitudinal observation from primary to updated booster vaccine cohorts.

Background: Encouraging annual updated COVID-19 vaccinations for high-risk populations is crucial for public health. However, concerns about significant reactogenicity persist, contributing to vaccine hesitancy. To investigate evolving COVID-19 vaccine reactogenicity and immunogenicity, we conducted a longitudinal analysis across three COVID-19 vaccine cohorts.

Methods: The Primary Vaccine Cohort, receiving wild-type (WT) 1st to 3rd doses and WT-BA.4/5 bivalent vaccine; the XBB.1.5 Monovalent Vaccine (MoV) Cohort; and the ongoing JN.1 MoV Cohort were investigated. Reactogenicity was assessed using electronic diaries for eight days, and serological responses were measured through quantitative anti-spike protein antibody (Sab) assay. Plaque reduction neutralization testing (PRNT) was performed against WT SARS-CoV-2 and vaccine-specific variants.

Results: A total of 290 participants with 690 vaccine doses and 1222 sampling points was included. Total symptom scores decreased serially from the WT 1st dose to JN.1 MoV, with changes pronounced in the younger age group (< 45 years; Spearman r = -0.13, P = 0.008). Changes were not evident in the older age group (≥ 45 years) with consistently low reactogenicity. Severe reactions also steadily declined from 26.2 % (WT 1st) to 3.3 % (JN.1 MoV). Serological analysis revealed plateauing post-vaccination Sab titers with increasing pre-vaccination levels and robust PRNT responses against vaccine strains. Age negatively correlated with Sab levels after the 1st WT dose but not in subsequent doses. Multivariable analysis found no significant association between reactogenicity and immunogenicity.

Conclusion: The observed decline in reactogenicity, alongside sustained immunological responses, supports the safety and efficacy of annual COVID-19 booster vaccination programs.