Background Global COVID-19 vaccination adapts to protect populations from emerging variants. This communication presents interim findings from the new Omicron XBB adapted PHH-1V81 vaccine compared to a XBB adapted mRNA vaccine against XBB and JN.1 SARS-CoV-2 strains. Methods In a Phase IIb/III pivotal trial, adults previously vaccinated with a primary scheme and at least one booster dose of an EU-approved mRNA vaccine randomly received either PHH-1V81 or BNT162b2 XBB.1.5 vaccine booster as a single dose. The primary efficacy endpoint assessed neutralisation titers against the Omicron XBB.1.16 variant at day 14. Secondary endpoints evaluated neutralization titers and cellular immunity against different variants. Safety endpoints comprised solicited reactions up to day 7 post-vaccination and serious adverse events until the cut-off date of the interim analysis. Changes in humoral responses were reported as GMT and GMFR assessed by PBNA or VNA. Results At the cut-off date, immunogenicity assessments included 599 participants. Both boosters elicited neutralizing antibodies against XBB.1.5, XBB.1.16 and JN.1 with PHH-1V81 inducing a higher response for all variants. PHH-1V8 booster triggers a superior neutralizing antibodies response against XBBs variants compared to the mRNA vaccine. Subgroup analysis consistently revealed higher neutralizing antibody responses with PHH-1V81 across age groups, number of prior vaccination shots, and SARS-CoV-2 infection history. Safety analysis involved 607 participants at the day 14 visit, revealing favourable safety profiles without any serious vaccine-related adverse events at cut-off date of the interim analysis (12th December 2023). Conclusions PHH-1V81 demonstrates superiority on humoral immunogenicity compared to mRNA vaccine agains XBB variants and non-inferiority against JN.1 with favourable safety profile and lower reactogenicity, confirming its potential as vaccine candidate. Trial registration numbers: NCT06181292; EU CT No: 2023-508458-25-00

JB has received institutional grants from HIPRA, Grifols, Nesapor Europe and MSD. Outside of this work he is the CEO and founder of AlbaJuna Therapeutics, S.L. JM has received research funding, consultancy fees, lecture sponsorships and has served on advisory boards for MSD, Gilead Sciences, Viiv Healthcare, and Johnson & Johnson. JGP declares institutional grants from HIPRA and Grifols. JPB has received honoraria from Hipra, Novavax, Pfizer, and Seqirus for advising, research, or conferences. NIU is supported by the Spanish Ministry of Science and Innovation (grant PID2020-117145RB-I00, Spain), EU HORIZON-HLTH-2021CORONA-01 (grant 101046118, European Union) and by institutional funding of Pharma Mar, HIPRA, and Amassence. SNM declares that her institution received payment from HIPRA for conducting this trial, from Pfizer, Sanofi, MSD, GSK, Janssen, AstraZeneca and Moderna for other vaccines trials and participation on data safety monitoring boards or advisory boards for GSK.

NCT06181292

This work was supported by HIPRA SCIENTIFIC, S.L.U (HIPRA) and partially funded by the Centre for the Development of Industrial Technology (CDTI, IDI-20230889), a public organisation answering to the Spanish Ministry of Science and Innovation.

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The study protocol was reviewed and approved by the Spanish Agency of Medicines and Medical Devices and by Independent Ethics Committee from HM Hospitales, MAdrid, SPAIN (23.10.2249-GHM).

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