Exploring the safety and immunogenicity of the VLA15 vaccine among healthy or high-risk population: a systematic review and meta-analysis of randomized controlled trials

Background: Lyme disease, the most common vector-borne illness in the Northern Hemisphere, is caused by Borrelia burgdorferi and transmitted via tick bites. With rising global incidence and no approved human vaccine, VLA15, a novel recombinant vaccine targeting six OspA serotypes, shows promise as an effective preventive strategy. Objective(s): This study aims to assess the safety and immunogenicity of the VLA15 vaccine among healthy or high-risk populations. Design(s): We conducted a systematic review and meta-analysis of three randomized controlled trials. Method(s): This systematic review and meta-analysis, registered in PROSPERO (CRD420251058818), was conducted following PRISMA guidelines. A thorough search of PubMed, EMBASE, Cochrane Library, Scopus, ScienceDirect, and ClinicalTrials.gov was performed up to May 2025. Data extraction and quality assessment (using Cochrane ROB 2) were performed independently by reviewers. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using random-effects models. Result(s): Three RCTs, including 5907 participants (4500 VLA15; 1407 placebo), met inclusion criteria. VLA15 recipients showed a significantly higher risk of adverse events: fever (RR 2.65, 95% CI: 1.77-3.96), headache (RR 1.40, 95% CI: 1.21-1.62), fatigue (RR 1.33, 95% CI: 1.15-1.55), and arthralgia (RR 2.50, 95% CI: 1.67-3.76), all with p < 0.0001. Subgroup analysis revealed a dose-response trend for arthralgia, particularly at 135 mug and 180 mug doses. However, nausea (RR = 1.34, p = 0.10) and severe unsolicited AEs (RR = 1.22, p = 0.42) were not statistically significant, suggesting no meaningful increase in these risks. Immunogenicity outcomes consistently favored VLA15, showing elevated IgG levels, GMTs, and seroconversion rates. Conclusion(s): VLA15 exhibits strong immunogenicity and acceptable safety, despite an increased risk of mild-to-moderate adverse events. Continued research and monitoring are warranted to support its use in Lyme disease prevention. Copyright © The Author(s), 2025. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages