Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [&ge;]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.