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: This study aims to assess the safety and immunogenicity of the VLA15 vaccine among healthy or high-risk populations. Design: We conducted a systematic review and meta-analysis of three randomized controlled trials. Methods: 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. Results: 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 μg and 180 μg 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: 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. Plain language summary How safe and effective is the new Lyme disease vaccine (VLA15)? A review and meta-analysis of clinical trials Lyme disease is a common infection spread by tick bites, especially in North America and Europe. There is currently no approved vaccine for humans. A new vaccine called VLA15 is being developed to protect against six types of the bacteria that cause Lyme disease. In this study, we reviewed and analyzed data from three clinical trials involving nearly 6,000 people who received either the VLA15 vaccine or a placebo. We found that people who got the vaccine were more likely to experience mild side effects like fever, headache, tiredness, and joint pain but these side effects were not severe. More importantly, the vaccine triggered strong immune responses, with higher levels of protective antibodies in the blood. This suggests that VLA15 may help prevent Lyme disease in people who are at risk. Overall, the vaccine appears to be safe and effective in producing an immune response, although continued monitoring is needed as more studies are completed.