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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. 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. 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. 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. Valneva.

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. 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). 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. 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. Pfizer and Valneva.

The natural history of asymptomatic seroconversion to Borrelia burgdorferi has been unclear. We report here, on the basis of a post hoc assessment, the frequency and outcome of asymptomatic seroconversion to B. burgdorferi in participants of a large Lyme disease vaccine trial. We show that infection with B. burgdorferi may be asymptomatic but that asymptomatic infection is unusual in the United States.

While most patients fully recover after treatment for Lyme disease with recommended antibiotic regimens, some report non-specific symptoms after treatment. When these symptoms are unexplained by other conditions and persist for ≥  6 months, this condition is called post-treatment Lyme disease symptoms or syndrome (PTLDS). The pathogenesis of PTLDS is unknown and no specific diagnostic biomarkers have been identified. In this study, we used a high-density peptide array to examine antibody responses to > 60 primary antigens of B. burgdorferi from a cohort of patients diagnosed with PTLDS and recovered patients with similar Lyme disease manifestations. Using matched serum and cerebrospinal fluid (CSF), we mapped the primary reactive B. burgdorferi epitopes associated with PTLDS. We found that VlsE had a greater antibody response within the PTLDS cohort than recovered patients. The reactivity to OspC-specific epitopes revealed a predominance of antibodies to OspC type K and A in the PTLDS cohort. However, the major immunodominant epitopes were similar in PTLDS and recovered patients, and we were unable to identify specific diagnostic targets for PTLDS. We found a more robust reactivity in the serum over CSF and did not identify antigenic regions that were specifically associated with the infection of the central nervous system.

Lyme borreliosis is the most common tick-borne disease in temperate climates of the northern hemisphere. Although in some cases Lyme borreliosis progresses to serious outcomes, no human vaccines are available for its prevention. A previous report showed positive immunogenicity and safety of VLA15, an investigational Lyme borreliosis vaccine based on Borrelia burgdorferi outer surface protein A (OspA), when administered as a 0-2-6-month or 0-6-month primary series to children, adolescents, and adults. Here, we report data from the same trial after receipt of an initial booster dose at month 18. This ongoing, 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. Participants were randomly assigned within each age cohort (18-65 years, 12-17 years, and 5-11 years) in a 1:1:1 ratio to receive intramuscular injections of VLA15 at months 0, 2, and 6; VLA15 at months 0 and 6 and placebo at month 2; or placebo at months 0, 2, and 6. In this phase of the trial, a month 18 VLA15 booster vaccination was administered to participants in both VLA15 groups (termed VLA15 M0-2-6-18 and VLA15 M0-6-18, respectively); the placebo group received placebo at month 18. Data up to month 12, including the primary endpoints, have been reported previously; this report includes data up to month 19. Secondary endpoints related to the month 18 booster vaccination included OspA serotype-specific IgG geometric mean titres (GMTs; evaluated in the per-protocol analysis set) and solicited and unsolicited adverse events (evaluated in the safety analysis set [ie, all participants who received one or more vaccinations]) from month 18 to month 19. This trial is registered at ClinicalTrials.gov, NCT04801420, and is closed for recruitment. Between March 15, 2021, and Feb, 24, 2022, 625 participants were randomly assigned and received the first vaccination. 532 (85%) of 625 participants were White, 68 (11%) were Black or African American, 13 (2%) were Asian, one (<1%) was an American Indian or Alaska Native, and 11 (2%) had their race recorded as other. 321 (51%) of 625 participants were female and 304 (49%) were male. The month 18 booster vaccination was administered to 449 participants at 13 of the trial sites (148 participants in the VLA15 M0-2-6-18 group; 143 participants in the VLA15 M0-6-18 group; 12 other VLA15 recipients; and 146 participants in the placebo group) between Sept 21, 2022, and Jan 24, 2023. The 12 other VLA15 booster recipients, of whom 11 received VLA15 and one received placebo for the month 18 booster, received at least one primary or booster VLA15 dose but could not be evaluated within a designated VLA15 group for safety because of missed or incorrect vaccinations, and were excluded from post-booster immunogenicity analyses. Of the 513 participants included in the per-protocol analysis set, 398 received the booster and 394 completed the month 19 visit. OspA-specific IgG GMTs in both VLA15 groups declined after the primary series up to month 18. At 1 month after the month 18 booster vaccination, GMTs in both VLA15 groups rose to levels that exceeded those after the primary series, ranging in the overall population from 1057·0 U/mL (95% CI 843·1–1325·1; serotype 1) to 1807·9 U/mL (1486·2–2199·3; serotype 2) in the M0-2-6-18 group and from 830·0 U/mL (621·3-1108·9; serotype 1) to 1603·1 U/mL (1239·7–2073·0; serotype 2) in the M0-6-18 group. GMTs at month 19 were higher in the paediatric cohorts compared with adults, consistent with observations after the primary vaccination series. The tolerability profile of the month 18 booster was similar to that of the primary doses and generally similar across age cohorts. Related unsolicited adverse events were reported by four (1%) of 302 VLA15 booster vaccination recipients and three (2%) of 147 placebo booster recipients within 1 month after the month 18 booster; all of these events resolved without sequelae. Unsolicited adverse events leading to trial withdrawal, unsolicited serious adverse events, and adverse events of special interest that were reported up to month 19 were all considered unrelated to trial vaccination and occurred before the month 18 booster. No deaths were reported up to month 19 of the trial. The safety and robust anamnestic immune responses associated with VLA15 boosting support its use as a strategy to increase anti-OspA antibody levels before tick season among children, adolescents, and adults. Forthcoming data after administration of subsequent annual boosters will provide further information about VLA15 antibody persistence and boostability. Valneva and Pfizer.

Borrelia burgdorferi ( Bb ) causes Lyme disease (LD), one of the most common vector-borne diseases in the Northern Hemisphere. Here, we solve the crystal structure of a mutated Bb vaccine antigen, CspZ-YA that lacks the ability to bind to host complement factor H (FH). We generate point mutants of CspZ-YA and identify CspZ-YA I183Y and CspZ-YA C187S to trigger more robust bactericidal responses. Compared to CspZ-YA, these CspZ-YA mutants require a lower immunization frequency to protect mice from LD-associated inflammation and bacterial colonization. Antigenicity of wild-type and mutant CspZ-YA proteins are similar, as measured using sera from infected people or immunized female mice. Structural comparison of CspZ-YA with CspZ-YA I183Y and CspZ-YA C187S shows enhanced interactions of two helices adjacent to the FH-binding sites in the mutants, consistent with their elevated thermostability. In line with these findings, protective CspZ-YA monoclonal antibodies show increased binding to CspZ-YA at a physiological temperature (37 °C). In summary, this proof-of-concept study applies structural vaccinology to enhance intramolecular interactions for the long-term stability of a Bb antigen while maintaining its protective epitopes, thus promoting LD vaccine development. The outer surface protein CspZ is a potential vaccine candidate of Borrelia burgdorferi for Lyme disease prevention. Here, using structure-based design, the authors generate a mutant CspZ protein with increased stability and improved immunogenicity, exposing protective epitopes.

There is insufficient evidence to support screening of various tick-borne diseases (TBD) related microbes alongside Borrelia in patients suffering from TBD. To evaluate the involvement of multiple microbial immune responses in patients experiencing TBD we utilized enzyme-linked immunosorbent assay. Four hundred and thirty-two human serum samples organized into seven categories followed Centers for Disease Control and Prevention two-tier Lyme disease (LD) diagnosis guidelines and Infectious Disease Society of America guidelines for post-treatment Lyme disease syndrome. All patient categories were tested for their immunoglobulin M (IgM) and G (IgG) responses against 20 microbes associated with TBD. Our findings recognize that microbial infections in patients suffering from TBDs do not follow the one microbe, one disease Germ Theory as 65% of the TBD patients produce immune responses to various microbes. We have established a causal association between TBD patients and TBD associated co-infections and essential opportunistic microbes following Bradford Hill's criteria. This study indicated an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections.

Lyme disease, caused by the spirochete, Borrelia burgdorferi sensu latu (Bbsl), is a tickborne infection of increasing incidence in North America, Europe and Asia. While vaccines based on Outer surface protein A (OspA) have proven highly efficacious at blocking Bbsl tick-to-human transmission, the high degree of antigenic variability among the major OspA serotypes (ST) has made the development of a broadly cross protective vaccine difficult. Recent profiling of protective human monoclonal antibodies (mAbs) has suggested the existence of conserved epitopes situated within OspA’s central β-sheet (CBS), although direct comparisons of cross-serotype functionality has been hindered by biological differences among the major Bbsl genospecies. To address these issues, we developed a panel of isogenic B. burgdorferi reporter strains expressing the seven major OspA serotypes (ST1–7) and probed them with CBS-targeting mAbs to evaluate their complement-dependent borreliacidal activity. The mAbs segregated into three distinct classes: class 1 mAbs exhibited potent killing against all seven OspA serotypes, while classes 2 and 3 had restricted or no activity against two of the seven serotypes. Structural analysis of Fabs derived from each class of mAbs in complex with OspA ST1 showed that they target overlapping epitopes spanning β-strands 6–10 and involve contact with largely invariant residues. Further analysis of B. burgdorferi reporter strains expressing OspA variants from 17 additional Bbsl genospecies identified Lys-107 as a determinant of susceptibility for nearly all CBS mAbs. Taken together, these findings raise the prospect of structure-based design of a broadly protective monovalent Lyme disease vaccine.

A high prevalence of infection with Borrelia burgdorferi in ixodid ticks is correlated with a high incidence of Lyme disease. The transmission of B. burgdorferi to humans can be disrupted by targeting 2 key elements in its enzootic cycle: the reservoir host and the tick vector. In a prospective 5-year field trial, we show that oral vaccination of wild white-footed mice resulted in outer surface protein A-specific seropositivity that led to reductions of 23% and 76% in the nymphal infection prevalence in a cumulative, time-dependent manner (2 and 5 years, respectively), whereas the proportion of infected ticks recovered from control plots varied randomly over time. Significant decreases in tick infection prevalence were observed within 3 years of vaccine deployment. Implementation of such a long-term public health measure could substantially reduce the risk of human exposure to Lyme disease.

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. 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. 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. 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. Valneva.