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An investigational three-dose Lyme vaccine (VLA15) against Borrelia outer surface protein A (OspA)-specific serotypes generated immunogenicity and appeared safe, according to results of two linked phase II trials.

After administration of VLA15 on a 0/2/6-month vaccine schedule (study two), OspA-specific IgG geometric mean titers (GMTs) ranged from 278.5 to 545.2 units/mL with the 135-μg vaccine dose at 1 month after the third dose, and 274.7 to 596.8 units/mL for the 180-μg dose, reported Susanne Eder-Lingelbach, MSc, of Valneva Austria in Vienna, and colleagues in .

In study one, which used a 0/1/2-month schedule, mean GMTs ranged from 101.9 to 283.2 units/mL for the 135-μg vaccine dose and 115.8 to 308.6 units/mL for the 180-μg dose, depending on the OspA serotype.

The VLA15 vaccine contains three lipidated fusion proteins that each link the C-terminal domains of two OspA serotypes, so that it targets six serotypes in total. In animal studies, VLA15 induced protection in mice from Borrelia species common in North America (B. burgdorferi) and Europe (B. burgdorferi, B. afzelii, B. garinii, and B. bavariensis).

The 180-µg dose generated the best OspA-specific antibody response in both studies, Eder-Lingelbach and team noted, but pointed out that differences in antibody response between the 135-µg and 180-µg groups were not statistically significant for most serotypes, except for serotypes 4 (P=0.041) and 6 (P=0.028) at month 18 in the second trial.

No Lyme borreliosis vaccines are available for use in humans, and the VLA15 vaccine is the only one in advanced clinical development, the authors pointed out. "These findings support the continued development of a 180 µg VLA15 dose administered using an extended schedule to prevent Lyme borreliosis, which remains a common and growing threat in regions of the Northern Hemisphere," Eder-Lingelbach and colleagues wrote.

In a previous phase I trial, the vaccine appeared safe and generated immunogenicity in young adults. The current trials enrolled people ages 18 to 65.

GMTs in both studies tended to be higher in participants ages 18 to 49 when compared with those ages 50 to 65. However, a sensitivity analysis did not find significant differences between age groups, except for serotype 2 at month 18 in the second study (P=0.047).

Lyme borreliosis vaccine candidates targeting the OspA protein first emerged in the 1990s, explained Raymond Dattwyler, MD, and Paul Arnaboldi, PhD, of the New York Medical College in Valhalla, in an . "A great deal of research has taken place over the last 40 years but discovery of alternative vaccine candidates has proven to be elusive. Despite public fears and some drawbacks, OspA remains the best human vaccine candidate."

At 1 month after the third vaccine dose in both studies, antibody functionality was demonstrated using serum bactericidal assays, which were significantly correlated with ELISA assay titers. However, administration of VLA15 using a 0/2/6-month schedule led to a 1.4- to 2.7-fold increase in OspA-specific IgG antibodies compared with the 0/1/2-month schedule at 1 month after the third vaccination, the authors noted.

Antibody levels peaked at 1 month after vaccination in both trials, and waned rapidly over the following 5 to 6 months, but decreased more slowly in those who received the 0/2/6-month regimen.

The editorialists noted that the VLA15 vaccine required multiple initial doses to induce an immune response protective against Lyme borreliosis, and rapid drops in the titers after the third dose could mean that more than one booster dose per year might be necessary to maintain protective levels of antibodies. "Public acceptance of multiple vaccine doses could be problematic," they pointed out.

They also noted that during the development of the first OspA vaccine (LYMErix) in the 1990s, the lead investigator of that trial voiced concern that the vaccine might generate a cross-reactive immune response that could result in antibiotic-refractory Lyme arthritis and autoimmunity. "That concern was scientifically invalid," Dattwyler and Arnaboldi explained, but it led to public fear about the vaccine.

"That fear continues despite all evidence that OspA vaccines do not cause arthritis or autoimmunity," they wrote. "More valid concerns about OspA-based vaccines are antigenicity and the intensity and duration of the protective antibody response."

The antibody response produced by the vaccine acts in the tick's midgut to block spirochete transmission to the host and does not work directly in the host. "Vaccine efficacy requires that the host titer of anti-OspA be maintained at a high level," Dattwyler and Arnaboldi noted.

VLA15 Safety

Participants who received the VLA15 vaccine reported adverse events more frequently than the placebo groups. In study one and study two, 94% and 96% of participants reported solicited local adverse events, respectively, compared with 26% and 35% in the placebo groups. The most common solicited local adverse events were tenderness and pain.

Solicited systemic adverse events in the vaccine groups were reported by 69% and 74% of participants in study one and two, respectively, versus 43% and 51% of those who received placebo. The most commonly reported systemic adverse events were myalgia, headache, and fatigue, which were primarily mild or moderate. Serious unsolicited adverse events were infrequent, reported by 2% and 4% in studies one and two, respectively. No deaths were reported.

Study one took place at nine centers in the U.S., Germany, and Belgium, and randomized 573 healthy adults to receive 90-µg, 135-µg, or 180-µg doses of the vaccine or placebo at months 0, 1, and 2. After a safety run-in period, the 90-µg group was discontinued.

Study two took place at five sites in the U.S. (also included in study one), and randomized 248 adults to receive 135-µg or 180-µg doses of the vaccine or placebo at months 0, 2, and 6. Study two also included a booster phase at month 18; results from that phase will be reported in the future.

Eder-Lingelbach and colleagues acknowledged that the different schedules were not evaluated head-to-head, but in separate trials. They also noted that serotype 1 is the only serotype with a known immunologic correlate of vaccine-induced immunity, so that predicted protection from the vaccine can't be extrapolated to other serotypes. Robust immune responses observed among the older participants in the study cannot be extrapolated to those over the age of 65. In addition, the majority of participants were white, which limits the generalizability of the studies' results.

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