Bivalent COVID-19 booster vaccines induce cross-reactive but not BA.5-specific antibodies in polyclonal serum

The question if the bivalent mRNA COVID-19 booster vaccination, containing wild type and BA.5 spike, provides enhanced benefits against BA.5 and similar Omicron subvariants has been widely debated. One concern was an ‘original antigenic sin’-like effect which may redirect immune responses to the bivalent vaccine towards the wild type spike and may block de novo generation of BA.5 specific antibodies. Here, we characterized the response to the bivalent vaccine and we performed antibody depletion experiments. Interestingly, when we depleted serum of all antibodies to wild type RBD, we also removed all reactivity to BA.5 RBD. This suggests that all antibodies induced by the bivalent vaccine – at least with the limit of detection of our assay in polyclonal serum - are in fact cross-reactive. This further suggests that, on a serum antibody level, the bivalent vaccine did not induce a de novo response to BA.5. ### Competing Interest Statement The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor. Dr. Simon is listed on the SARS-CoV-2 serological assays patent. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Dr. Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures and Avimex and he is a co-founder and scientific advisory board member of CastleVax. The Krammer laboratory is also collaborating with Pfizer on animal models for SARS-CoV-2. ### Funding Statement We thank all the participants of the Personalized Virology Initiatives longitudinal studies for their generous and continued support of research. This effort was supported by the Serological Sciences Network (SeroNet) in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Order No. 75N91021F00001. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This work was also partially funded by the Centers of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C), the Centers of Excellence for Influenza Research and Response (CEIRR, contract # 75N93021C00014), by the Collaborative Influenza Vaccine Innovation Centers (CIVICs contract # 75N93019C00051) and by institutional funds. ### 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: Sera and data were obtained from two observational studies: the PARIS study (Protection Associated with Rapid Immunity to SARS-CoV-2, approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai Institutional Review Board, IRB-20-03374/STUDY-20-00442) and the observational longitudinal clinical sample collection from patients with emerging viral infections research study (approved by the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai Institutional Review Board- IRB-17-00791/STUDY-16-01215). Participants from both studies provided informed consent prior to sample and data collection. 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors