Relative importance of repeated vaccine doses and prior infection on SARS-CoV-2 XBB infection

In COVID-19 pandemic, individuals had repeated infections and repeated vaccination, receiving four doses or more within year. A robust examination on this unprecedented practice of repeated booster doses and prior infection would be needed. A prospective cohort of 10234 individuals aged 5 years and older with and without omicron BA.2 infection in Hong Kong, did weekly testing, regardless of symptom and exposure status during the XBB wave (February 13 - May 7, 2023). The protective effect of natural infection and 4th dose vaccination was estimated with a Cox proportional hazards regression model with time-dependent covariates, allowing for changes in vaccination status over time, after adjustment for demographic factors and chronic conditions. Compared to individuals having no prior infection nor 4th dose, having a prior infection provided a significant protection of 62% (95%CI:51,71) against asymptomatic and symptomatic SARS-CoV-2 omicron XBB infection. Receiving a 4th dose in addition to prior infection tended to have a protective effectiveness of 83% (−20,98). Receiving a 4th dose per se without a prior infection, however, was associated with a significant high hazard of infections (−82%, 95%CI:-210,-7, p=0.03). Compared to 3rd dose, VE for the second booster becomes practically non-significant or negative. Our findings indicated that prior BA.2 infection conferred the most substantial protection against SARS-CoV-2 XBB infection, including mild and asymptomatic cases. Further study on the additional effect of repeated vaccine doses on emerging variants over time are warranted.