Safety and Immunogenicity of XBB.1.5-Containing mRNA Vaccines

Background: Subvariants of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) omicron XBB-lineage have the potential to escape immunity provided by prior infection or vaccination. For Covid-19 immunizations beginning in the Fall 2023, the U.S. FDA has recommended updating to a monovalent omicron XBB.1.5-containing vaccine. Methods: In this ongoing, phase 2/3 study participants were randomized 1:1 to receive 50-µg doses of mRNA-1273.815 monovalent (50-µg omicron XBB.1.5 spike mRNA) or mRNA-1273.231 bivalent (25-µg omicron XBB.1.5 and 25-µg omicron BA.4/BA.5 spike mRNAs)vaccines, administered as 5th doses, to adults who previously received a primary series and 3rd dose of an original mRNA coronavirus disease 2019 (Covid-19) vaccine, and a 4th dose of a bivalent (omicron BA.4/BA.5 and original SARS-CoV-2) vaccine. Interim safety and immunogenicity data 15 days post-vaccination are presented. Results: In April 2023, participants received mRNA-1273.815 (n=50) and mRNA-1273.231 (n=51). The median intervals from the prior dose of BA.4/BA.5-containing bivalent vaccine were 8.2 and 8.3 months for the mRNA-1273.815 and mRNA-1273.231 groups, respectively. Both vaccines increased neutralizing antibody (nAb) geometric mean titers against all variants tested at day 15 post-booster nAb compared to pre-booster levels. Geometric mean fold-rises from pre-booster titers after the monovalent booster were higher against XBB.1.5, XBB.1.16 and SARS-CoV-2 (D614G) than those of the bivalent booster and were comparable against BA.4/BA.5 and BQ1.1 variants for both vaccines. The monovalent vaccine also elicited nAb responses against omicron XBB.2.3.2, EG.5.1, and FL.1.5.1 that were similar to those seen for XBB.1.5 in a subset (n=20) of participants. The occurrence of solicited adverse reactions and unsolicited adverse events were overall similar to those previously reported for the original mRNA-1273 50-µg and omicron BA.4/BA.5-containing bivalent mRNA-1273 vaccines. Conclusion: In this interim analysis, XBB.1.5-containing monovalent and bivalent vaccines elicited potent neutralizing responses against variants of the omicron XBB-lineage (XBB.1.5, XBB.1.6, XBB.2.3.2) as well as more recent (EG.5.1, FL.1.5.1) variants. The safety profile of the XBB.1.5-containing vaccine was consistent with those of prior vaccines. These results support the Covid-19 vaccine update in 2023-2024 to a monovalent XBB.1.5-containing vaccine. ### Competing Interest Statement JW, BE, and AB have nothing to disclose; DCM reports funding from Moderna, Inc. for pseudovirus neutralization assays performed in the study; LRB is a co-primary principal investigator of the COVE trial funded by NIAID and conducted in conjunction with Moderna, Inc. SC, NMcG, BG, DKE, AN, DL, LEA, JF, WD, JMM and RD are employees of Moderna, Inc. and may hold stock/stock options in the company. JET is a Moderna consultant. ### Clinical Trial NCT04927065 ### Funding Statement This study was funded by Moderna, Inc., Cambridge, Massachusetts, USA. ### 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 central Institutional Review Board (Advarra, Inc., 6100 Merriweather Drive, Columbia, MD 21044) approved the protocol and consent forms. 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 As the trial is ongoing, access to patient-level data and supporting clinical documents with qualified external researchers may be available upon request and subject to review once the trial is complete.