Evaluation of bivalent Omicron BA.1 booster vaccination after different priming regimens in healthcare workers (SWITCH ON): a randomized controlled trial

Background Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and Omicron spike protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We compared the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent Omicron BA.1 vaccines in individuals who were primed with adenovirus- or mRNA-based vaccines. Methods In this open-label, multicenter, randomized, controlled trial, healthcare workers primed with Ad26.COV2.S or mRNA-based vaccines were boosted with mRNA-1273.214 or BNT162b2 OMI BA.1. The primary endpoint was the fold change in S1-specific IgG antibodies pre- and 28 days after booster vaccination. Secondary outcomes were fast response, (antibody levels on day 7), reactogenicity, neutralization of circulating variants and (cross-reactive) SARS-CoV-2-specific T-cell responses. Findings No effect of different priming regimens was observed on bivalent vaccination boosted S1-specific IgG antibodies. The largest increase in S1-specific IgG antibodies occurred between day 0 and 7 after bivalent booster. Neutralizing antibodies targeting the variants in the bivalent vaccine (ancestral SARS-CoV-2 and Omicron BA.1) were boosted. In addition, neutralizing antibodies against the circulating Omicron BA.5 variant increased after BA.1 bivalent booster. T-cell responses were boosted and retained reactivity with variants from the Omicron sub-lineage. Interpretation Bivalent booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 resulted in a rapid recall of humoral and cellular immune responses independent of the initial priming regimen. Although no preferential boosting of variant-specific responses was observed, the induced antibodies and T-cells cross-reacted with Omicron BA.1 and BA.5. It remains crucial to monitor immunity at the population level, and simultaneously antigenic drift at the virus level, to determine the necessity (and timing) of COVID-19 booster vaccinations. Funding The Netherlands Organization for Health Research and Development (ZonMw) grant agreement 10430072110001. Evidence before this study Vaccination against coronavirus disease-2019 (COVID-19) initially provided high levels of protection from both infection and severe disease. However, the emergence of antigenically distinct variants resulted in frequent breakthrough infections, especially with the emergence of variants from the Omicron sub-lineages. The frequent mutations in the Spike protein, and specifically the receptor binding domain (RBD), resulted in the recommendation by the WHO advisory group to update vaccines with novel antigens. Bivalent mRNA-based vaccines, encoding the Spike protein from both the ancestral SARS-CoV-2 and Omicron BA.1 (and later on BA.5) were subsequently introduced. Initial small comparative studies have been released on the evaluation of these bivalent vaccines, but it is essential is to evaluate the immunogenicity and reactogenicity of the vaccines against the background of different priming regimens. Added value of this study The SWITCH ON trial evaluated the bivalent booster vaccines BNT162b2 OMI BA.1 and mRNA-1273.214 vaccine in a cohort of Dutch healthcare workers. Study participants were primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2. The study investigated three important topics: (1) immunogenicity of Omicron BA.1 bivalent vaccines after Ad26.COV2.S- or mRNA-based vaccine priming, (2) rapid immunological recall responses, indicative of preserved humoral and cellular immunological memory, and (3) cross-reactivity with relevant variants after booster vaccination. Implication of all the available evidence Vaccination with the bivalent booster mRNA-1273.214 or BNT162b2 OMI BA.1 resulted in a rapid recall of humoral and cellular immune responses independent of the initial priming regimen. The largest fraction of (neutralizing) antibodies and virus-specific T-cells was recalled within 7 days post booster vaccination. Although no preferential boosting of variant-specific responses was observed, the induced antibodies and T-cells cross-reacted with Omicron BA.1, which was included in the vaccine, but also the more antigenically distinct BA.5. It remains crucial to monitor immunity at the population level, and simultaneously antigenic drift at the virus level, to determine the necessity (and timing) of COVID-19 booster vaccinations. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05471440 ### Funding Statement The Netherlands Organization for Health Research and Development (ZonMw) grant agreement 10430072110001. The funder had no role in the design, execution of the study, or in the analysis and interpretation of the data. ### 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: Ethics committee of Erasmus MC (Rotterdam, The Netherlands) gave ethical approval for this work (MEC-2022-0462). 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.