Immunogenicity and safety of different immunisation schedules of the VLA15 Lyme borreliosis vaccine candidate in adults, adolescents, and children: a randomised, observer-blind, placebo-controlled, phase 2 trial.

BACKGROUND

Increasing incidence rates, insufficient effectiveness of exposure prevention strategies, and the potential for serious outcomes despite antibiotic treatment highlight the need for a preventive vaccine against Lyme borreliosis. VLA15, an investigational Lyme borreliosis vaccine based on outer surface protein A (OspA) variants from clinically relevant Borrelia burgdorferi sensu lato genospecies in North America and Europe, has shown safety and immunogenicity in adults when administered with various three-dose schedules. We aimed to investigate the safety and immunogenicity of two-dose and three-dose schedules of VLA15 within a broader population, including children and adolescents, who are among those at increased risk of Lyme borreliosis.

METHODS

This randomised, observer-blind, placebo-controlled phase 2 trial is taking place at 14 clinical study centres in Lyme borreliosis-endemic areas in the USA. Healthy, eligible participants aged 5-65 years were enrolled in a 2:1:1 ratio to age cohorts of 18-65 years, 12-17 years, and 5-11 years through a staggered age-descending enrolment process. Within each age cohort, participants were randomly assigned with an electronic data capture system in a 1:1:1 ratio to receive intramuscular injections of 180 μg VLA15 at months 0, 2, and 6 (VLA15 M0-2-6 group); 180 μg VLA15 at months 0 and 6, and placebo at month 2 (VLA15 M0-6 group); or placebo at months 0, 2, and 6. Unmasked individuals included site staff and clinical research associates involved in randomisation and handling the investigational product, as well as specific individuals, both internal and external to the sponsor, who regularly reviewed trial safety data (including statisticians preparing relevant tables). All other individuals were masked; unmasking after the database snapshot for month 7 analyses for each age cohort was limited to the trial sponsor, collaboration partner, and statisticians. The primary immunogenicity endpoint was OspA serotype (ST)-specific IgG geometric mean titres (GMTs) assessed by ELISAs at month 7 (ie, 1 month after the third vaccination) and was evaluated in the per-protocol analysis set. The primary safety endpoint was the frequency of solicited local and systemic adverse events occurring within 7 days after each and any vaccination and were assessed in the safety analysis set (ie, all individuals who received at least one vaccination). This report includes safety and immunogenicity data through to month 12. This trial is ongoing but no longer recruiting participants, and is registered with Clinicaltrials.gov (NCT04801420).

FINDINGS

Between March 15, 2021, and Feb 24, 2022, 625 participants (321 [51%] female, 304 [49%] male) received one or more vaccinations and were included in the safety analysis set. Of these, 190 participants were included in the VLA15 M0-2-6 group, 187 were included in the VLA15 M0-6 group, and 208 were included in the placebo group; 40 additional VLA15 recipients could not be allocated to either VLA15 group because their vaccination schedules were non-compliant with both VLA15 groups due to missed or incorrect vaccinations; however, these individuals were included in safety analyses. OspA-specific ELISA IgG GMTs at month 7 in the overall population (aged 5-65 years) were significantly higher in the VLA15 M0-2-6 group (333·2 [95% CI 275·2-403·4; ST1] to 656·0 [560·2-768·2; ST2] units per mL) and VLA15 M0-6 group (197·3 [156·2-249·3; ST1] to 460·3 [370·6-571·8; ST2] units per mL) compared with the placebo group (21·9 [20·2-23·7; ST2] to 24·3 [22·1-26·7; ST6] units per mL; p<0·0001 for all comparisons); GMTs were also significantly higher in the VLA15 M0-2-6 group than in the VLA15 M0-6 group (all p<0·0001 except for ST2 [p=0·0010] and ST3 [p=0·011]). Among VLA15 recipients, GMTs were highest in children followed by adolescents and then adults. Solicited local adverse events after any vaccination occurred more frequently among VLA15 recipients (M0-2-6, 178 [94%; 95% CI 89-96] of 190; M0-6, 176 [94%; 90-97] of 187) than placebo recipients (71 [34%; 28-41] of 208; p<0·0001 for both comparisons); the same was true for solicited systemic adverse events (M0-2-6, 128 [67%; 95% CI 60-74] of 190, p=0·0015 vs placebo; M0-6, 128 [68%; 61-75] of 187, p=0·0007 vs placebo; placebo, 107 [51%; 45-58] of 208). Most solicited adverse events were mild or moderate in severity; none was grade 4. There were no significant differences in the frequencies of unsolicited adverse events, related unsolicited adverse events, unsolicited serious adverse events (serious adverse events), and adverse events of special interest across groups in the overall population. None of the severe unsolicited adverse events, serious adverse events, or adverse events of special interest were considered related to vaccination and no deaths occurred through to month 12 of the trial.

INTERPRETATION

These findings confirm previously observed safety and immunogenicity profiles of VLA15 in adults and extend them to children aged 5 years and older and adolescents. The greater immunogenicity of VLA15 among children and adolescents might translate to increased flexibility in the real-world clinical setting.

FUNDING

Pfizer and Valneva.