Risk of BA.5 infection in individuals exposed to prior SARS-CoV-2 variants

The SARS-CoV-2 omicron BA.5 subvariant is progressively displacing earlier subvariants, BA.1 and BA.2, in many countries. One possible explanation is the ability of BA.5 to evade immune responses elicited by prior BA.1 and BA.2 infections. The impact of BA.1 infection on the risk of reinfection with BA.5 is a critical issue because adapted vaccines under current clinical development are based on BA.1. We used the national Portuguese COVID-19 registry to analyze the risk of BA.5 infection in individuals without a documented infection or previously infected during periods of distinct variants’ predominance (Wuhan-Hu-1, alpha, delta, BA.1/BA.2). National predominance periods were established according to the national SARS-CoV-2 genetic surveillance data (when one variant represented >90% of the sample isolates). We found that prior SARS-CoV-2 infection reduced the risk for BA.5 infection. The protection effectiveness, related to the uninfected group, for a first infection with Wuhan-Hu-1 was 52.9% (95% CI, 51.9 – 53.9%), for Alpha 54.9% (51.2 – 58.3%), for Delta 62.3% (61.4 – 63.3%), and for BA.1/BA.2 80.0% (79.7 – 80.2%). The results ought to be interpreted in the context of breakthrough infections within a population with a very high vaccine coverage (>98% of the study population completed the primary vaccination series). In conclusion, infection with BA.1/BA.2 reduces the risk for breakthrough infections with BA.5 in a highly vaccinated population. This finding is critical to appraise the current epidemiological situation and the development of adapted vaccines. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Parts of this work were funded by the European Union Horizon 2020 research and innovation program (ERA project No 952377 - iSTARS); and Fundacao para a Ciencia e a Tecnologia (FCT, Portugal) through 081_596653860 and PTDC/MAT-APL/31602/2017. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used public data from the SARS-CoV-2 genetic diversity surveillance of human sample isolates, Instituto Nacional de Saude Dr. Ricardo Jorge, Lisbon, Portugal (link under data availability); The Ethics Committee of the Centro Academico de Medicina de Lisboa gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.