A novel multivalent OspA vaccine against Lyme borreliosis shows promise in Phase I/II studies

Keywords::

• Borrelia
• Lyme borreliosis
• OspA
• tick
• vaccine

Lyme borreliosis (LB) is a multisystem inflammatory disease involving the skin, joints, heart and nervous system [1,2]. Approximately 30,000 LB cases are reported annually in the USA [101], and about 85,000 annual LB cases are estimated to occur in Europe [102]. LB can be treated with antibiotics [1,2], but some patients remain unaware of an infection before the onset of severe disease symptoms [1]. Moreover, about 60% of non-treated infections in the USA cause Lyme arthritis, and about 10% of patients in this geography develop antibiotic-refractory arthritis [1]. LB is caused by a number of bacterial species of the Borrelia burgdorferi sensu lato (s.l.) complex. Four species, B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii and B. bavariensis cause the majority of human disease in Europe, whereas only a single species, B. burgdorferi s.s., causes LB in the USA [1,2].

Two monovalent recombinant vaccines based on outer-surface protein A (OspA) serotype-1 derived from B. burgdorferi s.s. were developed independently by Pasteur Merieux-Connaught and SmithKlineBeecham in the 1990s. In large, placebo-controlled Phase III studies in the USA, these vaccines were demonstrated to be safe and to provide 92 and 76% efficacy, respectively, against LB caused by infection with B. burgdorferi s.s. [3,4]. The vaccine developed by SmithKlineBeecham (LYMErix) was licensed for human use in 1998. However, a non-substantiated hypothesis that LYMErix triggered arthritis in some vaccine recipients [5,6] was one of a number of factors which contributed to the limited acceptance and subsequent discontinuation of the vaccine in 2002 [7,8].

In May 2013, the first clinical trial of a new candidate vaccine to prevent LB was published in The Lancet Infectious Diseases [9]. This Phase I/II study demonstrated a novel multivalent OspA vaccine to be safe and well tolerated in healthy adults, and to induce potent antibody responses against all major Borrelia species causing LB in the USA, Europe and, potentially, worldwide. The results of this study provide hope that a safe and effective vaccine will soon be available to prevent this potentially serious disease.

The new multivalent OspA vaccine is based on the same general principle as the previous monovalent OspA serotype-1 vaccines, in that it is based on recombinant, lipidated OspA antigens produced in Escherichia coli, and induces OspA antibody responses which prevent transmission of disease-causing Borrelia from the tick to the vaccinated individual; however, a number of innovative features distinguish the new vaccine from the first-generation OspA vaccines. First, whereas the monovalent OspA-1 vaccine was only designed to protect against B. burgdorferi s.s., the single species which causes human disease in the USA, the new multivalent vaccine contains protective epitopes derived from six OspA serotypes. Antibody responses induced by the multivalent vaccine should therefore protect not only against B. burgdorferi s.s., but also against B. afzelii, B. bavariensis and B. garinii. Importantly, the multivalent vaccine should protect against 99% of neuroborreliosis, a severe form of LB occurring in Europe, which is primarily caused by infection with B. garinii and B. bavariensis.

Second, rather than including six different OspA antigens in the multivalent vaccine, which would have necessitated the use of large doses of total OspA antigen, a novel approach has been used whereby the protective epitopes of two OspA antigens are combined to generate chimeric immunogens. Thus, only three chimeric OspA antigens are required to produce a vaccine formulation capable of providing global protection against LB, and much lower doses of total antigen are required to induce protective antibody responses. Chimeric OspA antigens were generated by fusing the proximal portion of one OspA serotype to the distal portion of a second OspA serotype, maintaining the overall three-dimensional structure of the native OspA molecules such that protective epitopes are maintained [9,10].

Third, a putative arthritogenic epitope (OspA_165–173) [5] has been removed from the OspA-1 component of the multivalent vaccine, by fusing the proximal portion of the OspA-1 sequence to the distal portion of the OspA-2 sequence. It had been speculated that partial homology between OspA_165–173 and hLFA-1_αL332–340 might trigger immune arthritis in some recipients of LYMErix [7]. Even though there are no clinical data to support this hypothesis, and subsequent studies suggested that molecular mimicry does not play a role in Lyme arthritis [6], removal of this epitope should serve to reassure some advocacy groups, who actively opposed the first-generation monovalent vaccines [11].

To provide effective protection against all Borrelia species and strains causing human disease, it is important that antibody responses induced by the six different OspA serotypes included in the novel vaccine are similarly high. The data from the Phase I/II study demonstrated this to be the case, with 91–100% of participants achieving total IgG antibody titers ≥1000 against the six different OspA serotypes after the primary immunization schedule, and 91–100% of participants achieving antibody titers ≥5000 against OspA serotypes 1–6 after the booster immunization [9].

Importantly, antibodies induced by the multivalent vaccine were also demonstrated to bind to and kill B. burgdorferi, B. afzelii, B. bavariensis and B. garinii [9]. These data, together with preclinical evidence of protection against challenge in mouse infection models [10], indicate that the novel vaccine has the potential to induce antibody responses which will protect immunized individuals against all relevant Borellia species and strains.

In Phase III studies of LYMErix, an antibody titer of 1100 EIA U/ml could be established as an absolute correlate of protection [12]. In theory, it would be possible to extrapolate correlates of protection established for the monovalent vaccine at least to the OspA-1 component of the multivalent vaccine; however, the ELISA used to evaluate the immunogenicity of the monovalent vaccine is not commercially available, and it is impossible to compare absolute antibody titers reported for the previously licensed vaccine with those induced by the OspA-1 component of the multivalent vaccine. It is also not clear how the previously established correlate of protection for the monovalent OspA-1 vaccine would translate to the other OspA serotypes included in the multivalent vaccine. Efficacy of the multivalent OspA vaccine in humans will ultimately be verified in placebo-controlled Phase III studies.

Additional Phase II studies are ongoing to investigate the immunogenicity of the novel vaccine in individuals who have previously been infected with B. burgdorferi s.l., as well as studies to evaluate the longevity of the antibody response maintained through the tick season, and the requirement for additional booster immunizations. The demonstration of effective antibody responses in previously infected individuals is critical, as this population represents a substantial proportion of those at high risk for LB. Previous infection with B. burgdorferi s.l. does not prevent subsequent infection, such that individuals who have recovered from LB remain vulnerable to future disease [13].

With respect to antibody longevity, the fold-increases in OspA-1 antibody titers and antibody seropersistence between the primary and booster immunizations demonstrated in the Phase I/II studies of the multivalent vaccine [9] were highly consistent with those reported for the previously licensed monovalent vaccine administered in a similar dose-schedule [14]. Moreover, the mean fold-increases of antibody titers to OspA serotypes 2–6 elicited by the multivalent vaccine after the primary and booster immunizations were, in most cases, similar or even higher than the mean fold-increases to OspA-1 [9].

Although it is difficult to compare safety data reported for different studies, it would appear that the novel multivalent OspA vaccine is at least as well tolerated as earlier monovalent OspA vaccines. In the Phase I/II study of the multivalent OspA vaccine [9], some solicited local and systemic reactions were induced at a lower rate by alum adjuvanted formulations, than reported for the Phase III study of the previously licensed monovalent vaccine [103]. Due to the much smaller sample size in the Phase I/II study, however, it is not yet clear whether the apparently lower reactogenicity of the multivalent vaccine represents a statistically significant better tolerability or whether this might simply reflect sampling bias. The safety and tolerability of the new vaccine will be further investigated in larger studies in B. burgdorferi s.l. seronegative and seropositive individuals before proceeding with Phase III trials.

LB is not the only tick-borne disease which is preventable by vaccination. A vaccine against tick-borne encephalitis virus (TBEV) has been used in several European countries for decades, resulting in a substantial decrease in TBE in countries where the vaccine is widely used [15]. In future, it may be possible to combine the highly successful TBEV vaccine with the novel multivalent OspA vaccine to provide complete protection against both of these tick-borne diseases in Europe.

Financial & competing interests disclosure

PN Barrett and D Portsmouth are employees of Baxter, a developer of vaccines against Lyme borreliosis. PN Barrett has equity interests in the company. The authors have no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.