ABSTRACT
The rapid development, approval, and global distribution of COVID-19 vaccines represent an unprecedented intervention in public health history, with over 13 billion doses administered worldwide in two years. However, our understanding of the HLA genetic underpinnings of COVID-19 vaccine-induced antibody responses and their clinical implications for breakthrough outcomes remain limited. To bridge this knowledge gap, we designed and performed a series of genetic and epidemiological analyses among 368,098 vaccinated individuals, and a subset of 194,371 participants who had antibody serology tests. Firstly, we corroborated earlier findings that SNPs associated with antibody response were predominantly located in Major Histocompatibility Complex region, and that the expansive HLA-DQB1*06 allele family was linked to better antibody responses. However, our findings contest the claim that DQB1*06 alleles alone significantly impact breakthrough risks. Additionally, our results suggest that the specific DQB1*06:04 subtype could be the true causal allele, as opposed to the previously reported DQB1*06:02. Secondly, we identified and validated six new functional HLA alleles that independently contribute to vaccine-induced antibody responses. Moreover, we unravelled additive effects of variations across multiple HLA genes that, concurrently, change the risk of clinically relevant breakthrough COVID-19 outcomes. Finally, we detangled the overall vaccine effectiveness and showed that antibody positivity accounts for approximately 20% protection against breakthrough infection and 50% against severe outcomes. These novel findings provide robust population evidence demonstrating how variations within HLA genes strongly, collectively, and causally influence vaccine-induced antibody responses, and the risk of COVID-19 breakthrough infection and related outcomes, with implications for subsequent functional research and personalised vaccination.
Subject(s)
COVID-19 , Breakthrough PainABSTRACT
Objective: To investigate the effectiveness of heterologous booster schedules with AZD1222 (Oxford-AstraZeneca, referred to as AZD), BNT162b2 (Pfizer-BioNTech, BNT), and mRNA-1273 (Moderna, MOD) vaccines compared with primary schedules and with homologous mRNA-vaccine booster schedules during a period of omicron predominance. Design: Population-based cohort analyses. Setting: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 28 February 2022. Participants: Adults that had received at least a primary vaccination schedule (ie, two doses) of the AZD, BNT, and/or MOD vaccines during the study period. Main outcome measures: Using the Kaplan-Meier estimator, we compared country-specific risks of SARS-CoV-2 infection and severe COVID-19 outcomes in heterologous booster vaccinated with primary schedule vaccinated (matched analyses) and homologous booster vaccinated (weighted analyses) since emergence of omicron. Results: Heterologous booster schedules improved protection against all outcomes compared with primary schedules, with the largest and most robust effects observed for severe COVID-19. Risk differences for documented infection ranged from -22.4% to -3.1% (comparative vaccine effectiveness [CVE] 9.7% to 60.9%; >63.2% for COVID-19 hospitalisation) across countries for AZD1BNT2BNT3 (AZD as primary dose followed by two doses of BNT) vs AZD1BNT2 and -22.2% to -3.2% (CVE 37.4% to 67.8%; >34.6% for hospitalisation) for BNT1BNT2MOD3 vs BNT1BNT2, the two most common heterologous booster schedules. Heterologous- and homologous booster schedules had comparable effectiveness. Risk differences of documented infection ranged from -0.4% to 4.4% (CVE -20.0% to 2.4%) for AZD1BNT2BNT3 vs BNT1BNT2BNT3 and -19.8% to 1.7% (CVE -14.6% to 53.8%) for BNT1BNT2MOD3 vs BNT1BNT2BNT3; for most comparisons, risk differences for severe COVID-19 outcomes were smaller than 1 per 1000 vaccinated. Previous infection followed by a booster dose conferred the greatest protection. Conclusion: Heterologous booster vaccine schedules are associated with an increased protection against omicron-related COVID-19 outcomes that is comparable to that afforded by homologous booster schedules.