Reservoir Targeted Vaccine for Lyme Borreliosis Induces a Yearlong, Neutralizing Antibody Response to OspA in White-Footed Mice

Abstract

Lyme disease is caused by the spirochete Borrelia burgdorferi. The enzootic cycle of this pathogen requires that Ixodes spp. acquire B. burgdorferi from infected wildlife reservoirs and transmit it to other uninfected wildlife. At present, there are no effective measures to control B. burgdorferi; there is no human vaccine available, and existing vector control measures are generally not acceptable to the public. However, if B. burgdorferi could be eliminated from its reservoir hosts or from the ticks that feed on them, the enzootic cycle would be broken, and the incidence of Lyme disease would decrease. We developed OspA-RTV, a reservoir targeted bait vaccine (RTV) based on the immunogenic outer surface protein A (OspA) of B. burgdorferi aimed at breaking the natural cycle of this spirochete. White-footed mice, the major reservoir species for this spirochete in nature developed a systemic OspA-specific IgG response as a result of ingestion of the bait formulation. This immune response protected white-footed mice against B. burgdorferi infection upon tick challenge and cleared B. burgdorferi from the tick vector. In performing extensive studies to optimize the OspA-RTV for field deployment, we determined that mice that consumed the vaccine over periods of 1 or 4 months developed a yearlong, neutralizing anti-OspA systemic IgG response. Furthermore, we defined the minimum number of OspA-RTV units needed to induce a protective immune response.Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in North America and Europe (2), and the area of where the disease is endemic is expanding (28,39,57). B. burgdorferi infection produces a progressive disease with a wide array of clinical manifestations involving the skin, heart, joints, and central and peripheral nervous system (46,(49)(50)(51). Disseminated infection can cause permanent damage to some of these systems (50). Lyme disease can be successfully treated with antibiotics, but recovery can involve a substantial convalescence period (31,40,41,58). No human vaccine is commercially available.In eastern North America, B. burgdorferi is transmitted among wildlife hosts and humans by Ixodes scapularis (1,4,5,34). I. scapularis has a 2-year life cycle with four life-stages: egg, larva, nymph and adult (1). The nymph is the tick life stage that infects humans (3,26,55). Control measures aimed at disrupting the triad vector-B. burgdorferi-vertebrate reservoir (54) will reduce the prevalence of B. burgdorferi and consequently should reduce the incidence of human Lyme disease.Oral immunization is not invasive, and it is suitable for economical mass vaccination campaigns. Outer surface protein A (OspA) remains the most effective vaccine candidate against B. burgdorferi, with an efficacy of 80 to 100% in mice (20)(21)(22)(23)25) and 75 to 80% in humans (52). We have shown that an OspA-based vaccine delivered via oral gavage inoculation or delivered as bait breaks the transmission cycle of B. burgdorferi in the Lyme disease mouse model the Mus...

Broad diversity of host responses of the white-footed mouse Peromyscus leucopus to Borrelia infection and antigens

“…In experiments 3 and 4, the two larger sets with single sex, the animals were also infected with B. hermsii but after first being immunized 3 weeks before with single unadjuvanted doses of keyhole limpet hemocyanin (KLH), a commonly used antigen in experimental studies, including of P. leucopus (Martin et al, 2007a), and B. burgdorferi ’s OspA lipoprotein, which is the basis of a recombinant dog vaccine against Lyme disease (Conlon et al, 2000) and the principal candidate antigen for a wildlife vaccine targeting P. leucopus and possibly other reservoirs in the field (Bhattacharya et al, 2011; Meirelles Richer et al, 2011; Tsao et al, 2004). …”

“…The larval and nymphal stages of this tick heavily exploit P. leucopus as a source of their blood meals in many if not all of the areas where the aforementioned pathogens are endemic (Piesman and Schwan, 2010). P. leucopus is the first candidate for transmission-blocking vaccines targeting wildlife with the aim of reducing the prevalence of B. burgdorferi in ticks (Bhattacharya et al, 2011; Meirelles Richer et al, 2011; Tsao et al, 2004). …”

Evidence for Personal Protective Measures to Reduce Human Contact With Blacklegged Ticks and for Environmentally Based Control Methods to Suppress Host-Seeking Blacklegged Ticks and Reduce Infection with Lyme Disease Spirochetes in Tick Vectors and Rodent Reservoirs

“…Following a proof-of-concept field study in which white-footed mice were successfully needle-vaccinated against B. burgdorferi (Tsao et al 2004), there was substantial interest in the development of an oral rodent reservoir-targeted vaccine against B. burgdorferi (Gomes-Solecki et al 2006, Scheckelhoff et al 2006, Bhattacharya et al 2011, Meirelles Richer et al 2011, Voordouw et al 2013). No such vaccine is yet commercially available, although one may be on the horizon.…”

Live Attenuated Borrelia burgdorferi Targeted Mutants in an Infectious Strain Background Protect Mice from Challenge Infection

“…Unfortunately, few have generated long-lasting immunity or a response that is protective against the bacteria introduced by a tick bite, although others remain promising candidates. Several investigators have built on the success of the OspA vaccine and designed new-generation candidates that are multivalent or reservoir targeted (20,22,23,25,26).…”

“…A chimeric recombinant OspA vaccine candidate showed broad protection in a mouse trial (21). Other vaccination approaches have targeted reservoir animals (22)(23)(24)(25)(26)(27).…”