Association between COVID-19 vaccine immunogenicity and protection against infection and severe disease in clinically vulnerable patient populations: a systematic review and meta-analysis of observational studies

Background The use of measured immune responses in informing risk of breakthrough COVID-19 infection and infection outcomes after vaccination against SARS-CoV-2 in clinically vulnerable patients has not been applied clinically.

Objectives The aim of this study was to investigate the association between measured vaccine immunogenicity and vaccine effectiveness in clinically vulnerable populations.

Data sources PubMed, MEDLINE, EMBASE, and Cochrane Library.

Study eligibility criteria Studies published between March 2020 and January 2025, which reported data on COVID-19 vaccine immunogenicity (antibody and T-cell) and subsequent infection outcomes.

Participants Patients defined as clinically vulnerable by QCOVID criteria, who had received at least the primary course of COVID-19 vaccination.

Assessment of risk of bias The Newcastle–Ottawa Quality Assessment Scale was used to assess the risk of bias.

Methods of data synthesis A random effects meta-analysis model was used to pool relative risks of COVID-19 breakthrough infection (BTI), hospitalization, and death. Unadjusted data were used for the primary analysis due to the lack of adjusted data available in individual studies.

Results We identified 3305 articles, of which 45 observational studies were included in the review. Negative antibody response following COVID-19 vaccination was associated with higher risks of BTI (Relative Risk (RR), 1.82 (1.45–2.29), p < 0.01, I² = 84.03%), COVID-19-related hospitalization (RR, 5.88 (4.08–8.47), p < 0.01, I² = 25.59%) and death (RR, 3.66 (1.87–7.15), p < 0.01), I² = 0%). Lack of T-cell response was associated with a higher risk of BTI (RR, 2.08 (1.08–4.04), p 0.03, I² = 65.99). Using the Newcastle–Ottawa Quality Assessment Scale, 5 (11%) studies were of good quality, 2 (7%) of fair quality, and 37 (82%) of poor quality.

Conclusions Within the methodological limitations, this study has shown that lack of antispike antibody responses was associated with BTI and severe infection outcomes in clinically vulnerable populations. Further research is required to investigate the current utility of testing to inform the ongoing management of clinically vulnerable persons, such as vaccine booster schedules.