Background/Aim: Despite highly effective vaccines, breakthrough infection and severe COVID-19 continue to occur heterogeneously across vaccinated populations, suggesting host immune predisposition beyond exposure or access. Observational immunology cannot establish whether immune signatures represent causal susceptibility or downstream response. This study aimed to identify genetically proxied immune pathways that causally determine vaccine failure proxies and severe disease risk, providing mechanistic insight for host-informed vaccine and immunotherapy strategies.
Methods: We performed a two-sample Mendelian Randomization (MR) analysis integrating genome-wide association summary statistics from the COVID-19 Host Genetics Initiative (infection susceptibility, hospitalization, and severe disease outcomes) and immune trait GWAS from IEU OpenGWAS, including circulating cytokines, immunoglobulin traits, and blood cell phenotypes. Independent instrumental variables were selected at genome-wide significance (P<5×10⁻⁸), clumped at r²<0.001, with F-statistics >20 and Steiger filtering to ensure correct causal direction. Primary causal estimates were obtained using inverse-variance weighted MR with random effects, supported by weighted median and MR-Egger approaches. Horizontal pleiotropy was evaluated using MR-Egger intercepts, Cochran’s Q, and MR-PRESSO with outlier correction. Colocalization analyses were applied to top cis-signals, and multivariable MR adjusted for genetically predicted body mass index, smoking liability, and type 2 diabetes to assess pathway specificity.
Results: Across 34 immune exposures (median 18 instruments per trait), genetically higher interferon signaling demonstrated robust protective effects. A one-standard-deviation increase in IFNAR2-proxied signaling reduced odds of severe COVID-19 (OR 0.82, 95% CI 0.76–0.89, P=3.1×10⁻⁶) and hospitalization (OR 0.86, 95% CI 0.80–0.92, P=1.2×10⁻⁵). Increased OAS1 activity similarly reduced severe disease risk (OR 0.78, 95% CI 0.71–0.86, P=4.4×10⁻⁷). In contrast, genetically elevated IL-6 signaling increased hospitalization (OR 1.22, 95% CI 1.11–1.34, P=6.0×10⁻⁵) and severe disease risk (OR 1.18, 95% CI 1.07–1.30, P=9.8×10⁻⁴). Sensitivity analyses showed no evidence of directional pleiotropy (all MR-Egger intercept P>0.10), and key interferon effects remained stable after MR-PRESSO correction and multivariable adjustment. Colocalization supported shared causal variants at interferon loci (posterior probability >0.80). Effect sizes were consistent across susceptibility and severity outcomes, explained 9–14% outcome variance, showed no heterogeneity inflation, and remained directionally stable in leave-one-out analyses, reinforcing biological coherence across antiviral restriction and inflammatory amplification axes pathways.
Conclusions: Interferon-mediated antiviral defense and IL-6–driven inflammation are causal determinants of vaccine breakthrough proxies and severe COVID-19. These findings establish a genetically grounded framework for precision vaccine design, adjuvant optimization, and risk-stratified immunization strategies.