A randomized, observer-blind, phase 1 study of immune responses to three human adenovirus type 26 vector-based vaccines

<h4>Background</h4>Adenovirus 26 (Ad26) vector-based vaccines have shown immunogenicity and safety in various infectious disease settings. However, the impact of each vaccine component (vector/insert) on the immune response has yet to be explored in a controlled setting across multiple vaccines.<h4>Methods</h4>In this randomised, observer-masked, multicentre phase 1 study, participants aged 18-59 years were assigned to receive one of three vaccine regimens: Ad26.COV2.S (5 × 10¹⁰ viral particles [vp]), Ad26.RSV.PreF/Protein (1 × 10¹¹ vp + 150 μg RSV preF protein), or the Ad26.ZEBOV (5 × 10¹⁰ vp), MVA-BN-Filo (1 × 10⁸ InfU) vaccine regimen. The primary endpoint was the change in cytokines, chemokines, and other innate immune response mediators. Transcriptomics and proteomics analyses were also performed.<h4>Findings</h4>From October 2022-August 2023, 160 participants received a study vaccine (Ad26.COV2.S, n = 66; Ad26.RSV.PreF/Protein, n = 48; Ad26.ZEBOV, n = 46). Median age was 35·5 years. All vaccines were well tolerated. Across vaccines, cytokine levels peaked on Day 2 and returned to baseline by Day 8. Highest geometric mean increases were observed with Ad26.RSV.PreF/Protein vaccine, followed by Ad26.COV2.S and Ad26.ZEBOV. The Ad26.RSV.PreF/Protein vaccine elicited the most differentially expressed genes and proteins, while Ad26.ZEBOV had the fewest. All vaccines induced strong innate responses associated with innate and antiviral immunity, hallmarked by interferons. Transcriptional responses were consistent among vaccines, differing primarily in magnitude rather than genes expressed.<h4>Interpretation</h4>All three vaccine regimens induced specific immunogenic responses, were well tolerated, and triggered strong innate and antiviral immunity responses within 2 days post-vaccination, with no distinct immune signature observed across vaccines per transcriptomics/proteomics analyses.<h4>Funding</h4>This study was funded by Johnson & Johnson.