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Background: Incidence rates of Lyme borreliosis, a tickborne disease attributed to infection by Borrelia species, are increasing, and limitations to existing treatments potentiate the possibility of severe outcomes. Nevertheless, there are no licensed vaccines for Lyme borreliosis prevention in humans. This study investigated the immunogenicity and safety of a booster dose of VLA15, an investigational outer surface protein A (OspA)-based Lyme borreliosis vaccine that has previously shown safety and immunogenicity when administered as a primary vaccination series, following a primary VLA15 vaccination series., Methods: We report the results of the booster phase of a randomised, observer-blinded, placebo-controlled, multicentre, phase 2 study that enrolled healthy adults aged 18-65 years from five US clinical study centres to receive 135 μg or 180 μg VLA15 or placebo at months 0, 2, and 6 in the main study phase. Participants who received 180 μg VLA15 in the main study phase and did not have relevant protocol deviations were eligible for the booster phase (months 18-30). Participants were randomly reassigned (2:1) to receive an intramuscular injection of a VLA15 booster or placebo 1 year after the completion of primary vaccination (month 18) via a randomisation list generated by an unmasked statistician with a block size of six. Individuals involved in data safety monitoring, rerandomisation, vaccine handling, and vaccine accountability were unmasked; the study sponsor and statisticians were only unmasked after analysis of data up to 1 month after booster administration. All other individuals remained masked throughout the booster phase. The outcomes for the booster phase were the immunogenicity (evaluated in the booster per-protocol population) and safety (evaluated for all participants who received the booster) of the booster dose up to month 30. The study is registered at ClinicalTrials.gov (NCT03970733) and is completed., Findings: Between Feb 4 and March 23, 2021, 58 participants (28 men and 30 women) were screened, randomly assigned, and received VLA15 (n=39) or placebo (n=19). One participant in the placebo group was lost to follow-up. The IgG geometric mean titres for each OspA serotype (serotypes 1-6) in the VLA15 group peaked at 1 month after the booster dose (1277·0 U/mL [95% CI 861·8-1892·3] to 2194·5 U/mL [1566·8-3073·7] vs 23·6 U/mL [18·1-30·8] to 36·8 U/mL [26·4-51·3] in the placebo group [p<0·0001 for all serotypes]), remained elevated at month 24 (137·4 U/mL [95·8-196·9] to 265·8 U/mL [202·9-348·2] vs 22·3 U/mL [17·7-28·0] to 29·1 U/mL [20·8-40·6] in the placebo group; p<0·0001 for all serotypes), and declined by month 30 (54·1 U/mL [38·6-75·7] to 101·6 U/mL [77·6-133·1] vs 21·9 U/mL [18·0-26·6] to 24·9 U/mL [19·0-32·6] in the placebo group; p<0·0001 for all serotypes except serotype 1 [p=0·0006]). Solicited local adverse events were reported more frequently in the VLA15 group (35 [92%, 95% CI 79-97] of 38 participants) than the placebo group (six [32%, 15-54] of 19 participants; p<0·0001) after booster vaccination. There was no significant difference in the frequency of solicited systemic adverse events between groups (20 [59%, 42-74] of 34 participants in the VLA15 group vs six [38%, 18-61] of 16 participants in the placebo group). Related unsolicited adverse events (none severe) were reported by two (5%, 1-17) of 39 participants in the VLA15 group and none (0%, 0-17) of 19 participants in the placebo group. There were no severe solicited local or systemic adverse events or deaths during the study., Interpretation: A booster dose of VLA15 is safe and induces substantial anamnestic immune responses against all six OspA serotypes. As with previously investigated OspA-based Lyme borreliosis vaccines, waning immune responses were observed with VLA15, and annual boosters might therefore be required., Funding: Valneva., Competing Interests: Declaration of interests SKG, MS, KD, LW, VK, MO, RH, WB, SE-L, and NB are current or former employees of Valneva and may hold stock or stock options. AK, JL-S, and UD are paid consultants for Valneva., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Rising Lyme borreliosis incidence rates, potential for severe outcomes, and limitations in accurate and timely diagnosis for treatment initiation suggest the need for a preventive vaccine; however, no vaccine is currently available for human use. We performed two studies in adults to optimise the dose level and vaccination schedule for VLA15, an investigational Lyme borreliosis vaccine targeting outer surface protein A (OspA) serotypes 1-6, which are associated with the most common pathogenic Borrelia species in Europe and North America., Methods: Both randomised, observer-blind, placebo-controlled, multicentre phase 2 studies included participants aged 18-65 years without recent history of Lyme borreliosis or tick bites. Study one was conducted at nine clinical research and study centre sites in the USA (n=6), Germany (n=2), and Belgium (n=1); study two was conducted at five of the study one US sites. Based on a randomisation list created by an unmasked statistician for each study, participants were randomly assigned via an electronic case report form randomisation module to receive 90 μg (study one only), 135 μg, or 180 μg VLA15 or placebo by intramuscular injection at months 0, 1, and 2 (study one) or 0, 2, and 6 (study two). Study one began with a run-in phase to confirm safety, after which the Data Safety Monitoring Board recommended the removal of the 90 μg group and continuation of the study. In the study one run-in phase, randomisation was stratified by study site, whereas in the study one main phase and in study two, randomisation was stratified by study site, age group, and baseline B burgdorferi (sensu lato) serostatus. All individuals were masked, other than staff involved in randomisation, vaccine preparation or administration, or safety data monitoring. The primary endpoint for both studies was OspA-specific IgG geometric mean titres (GMTs) at 1 month after the third vaccination and was evaluated in the per-protocol population. Safety endpoints were evaluated in the safety population: all participants who received at least one vaccination. Both studies are registered at ClinicalTrials.gov (study one NCT03769194 and study two NCT03970733) and are completed., Findings: For study one, 573 participants were screened and randomly assigned to treatment groups between Dec 21, 2018, and Sept, 26, 2019. For study two, 248 participants were screened and randomly assigned between June 26 and Sept 3, 2019. In study one, 29 participants were assigned to receive 90 μg VLA15, 215 to 135 μg, 205 to 180 μg, and 124 to placebo. In study two, 97 participants were assigned to receive 135 μg VLA15, 100 to 180 μg, and 51 to placebo. At 1 month after the third vaccination (ie, month 3), OspA-specific IgG GMTs in study one ranged from 74·3 (serotype 1; 95% CI 46·4-119·0) to 267·4 units per mL (serotype 3; 194·8-367·1) for 90 μg VLA15, 101·9 (serotype 1; 87·1-119·4) to 283·2 units per mL (serotype 3; 248·2-323·1) for 135 μg, and 115·8 (serotype 1; 98·8-135·7) to 308·6 units per mL (serotype 3; 266·8-356·8) for 180 μg. In study two, ranges at 1 month after the third vaccination (ie, month 7) were 278·5 (serotype 1; 214·9-361·0) to 545·2 units per mL (serotype 2; 431·8-688·4) for 135 μg VLA15 and 274·7 (serotype 1; 209·4-360·4) to 596·8 units per mL (serotype 3; 471·9-754·8) for 180 μg. Relative to placebo, the VLA15 groups had more frequent reports of solicited local adverse events (study one: 94%, 95% CI 91-96 vs 26%, 19-34; study two: 96%, 93-98 vs 35%, 24-49 after any vaccination) and solicited systemic adverse events (study one: 69%, 65-73 vs 43%, 34-52; study two: 74%, 67-80 vs 51%, 38-64); most were mild or moderate. In study one, unsolicited adverse events were reported by 52% (48-57) of participants in the VLA15 groups and 52% (43-60) of those in the placebo groups; for study two these were 65% (58-71) and 69% (55-80), respectively. Percentages of participants reporting serious unsolicited adverse events (study one: 2%, 1-4; study two: 4%, 2-7) and adverse events of special interest (study one: 1%, 0-2; study two: 1%, 0-3) were low across all groups. A single severe, possibly related unsolicited adverse event was reported (worsening of pre-existing ventricular extrasystoles, which resolved after change of relevant concomitant medication); no related serious adverse events or deaths were reported., Interpretation: VLA15 was safe, well tolerated, and elicited robust antibody responses to all six OspA serotypes. These findings support further clinical development of VLA15 using the 180 μg dose and 0-2-6-month schedule, which was associated with the greatest immune responses., Funding: Valneva., Competing Interests: Declaration of interests NB, LW, VK, MO, NW, RH, MS, KD, SE-L, and WB are current or former employees of Valneva and may hold stock or stock options. UD, AK, and JL-S are paid consultants for Valneva., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)