EXISTING VACCINES

Typically, the aim in making a vaccine is to recreate a normal immune response without exposing a patient to the pathological elements of a disease. The existing vaccine for Lyme disease follows a completely different method. The outer surface protein A of Borrelia burgdorferi is mainly expressed in the gut of the tick, whereas OspC is expressed in the vertebrate host. Thus, immune responses to B. burgdorferi do not usually include humoral or cellular adaptive immunity to OspA. The existing vaccine, LYMErix, contains lipidated recombinant OspA adsorbed to an aluminum hydroxide adjuvant, is injected into the deltoid of uninfected persons, thus creating an immune response with high titers of antibodies to OspA. These antibodies are not used to fight infection in the body. Instead, the antibodies enter the gut of the tick when it takes a blood meal. There, they neutralize the spirochetes and block different steps in development that would allow the B. burgdorferi to enter the vertebrate host. Thus, the vaccine prevents transmission of the Borrelia burgdorferi spirochete from arthropod host to human host. [1]

The LYMErix vaccine (Link).

This vaccine was shown to effectively block B. burgdorferi transmission and thus prevents Lyme disease in mice, hamsters, dogs, and monkeys.[2] Phase I and II trials showed the vaccine to be safe in human patients, so in 1995 Allen Steere and colleagues began Phase III safety and efficacy trials in a multi center (USA) double-blind trial in 10,936 healthy patients [2]. The vaccine or a placebo was administered at 0, 1, and 12 months and patients were observed for symptoms of new Lyme Disease. Additionally, serological testing was done on all vaccine subjects at 12 and 20 months after study entry to detect asymptomatic infections. Only Western Blotting was performed, as the vaccine would surely give a positive ELISA for OspA and the “vaccine-induced” 31kD band was not reported. [2]

This vaccine trial showed a 49% effectiveness in preventing Lyme Disease within the first year and 76% effectiveness during the second year, after the third injection. The serological testing showed that LYMErix was 83% effective in preventing asymptomatic infection during the first year and 100% effective during the second year. Serological testing also revealed that breakthrough cases of Lyme Disease in vaccinated individuals were due to vaccine failure as the antibody titers were significantly lower than in the protected individuals [2].

The LYMErix vaccine clinical trials results.

Around the same time period, another, unadjuvated OspA vaccine underwent similar Phase III trials and showed similar effectiveness [3]. Serological testing for asymptomatic infection was not performed. Interestingly, not all subjects received the third injection. The study found that there was no evidence of protection by the vaccine in the people who did not receive the booster injection at.mn 12 months [3]. This vaccine did not receive FDA approval or go into commercial production.

While OspA is immunogenic, the high titer antibody response is short lived [1], waning within 180 days if there is no antigenic challenge, making frequent booster injections necessary. In clinical trials, the second and third injections were given to volunteers enough time before Lyme season [2] (beginning April) to develop an adaptive immune response and fortunately close enough to Lyme season so that the short lived antibodies were present during the most likely time to get a B. burdgorferi infection.

Shortly after LYMErix was commercially available, it was pulled from the market. The company producing LYMErix, Glaxo SmithKline, claimed it was due to poor sales, but much controversy exists surrounding the end of LYMErix production [1], including the concern that LYMErix could cause autoimmune reactions in a subgroup of the population. The 1998 literature discussing the Phase III LYMErix results [2] and many other publications evidence for T cell cross-reactivity was seen between epitopes of OspA and self antigens and that approximately 10% of the population is genetically susceptible to experiencing an OspA-antibody-induced autoimmune reaction.

Treatment resistant Lyme arthritis was not shown in mice models. Mice do not have a homologous cross-reactive protein. Hamsters, however, have a similar OspA cross reactive leukocyte antigen and produce antibody response to B. burgdorferi similar to that of humans. A 2000 study showed that vaccinated hamsters that were challenged with injected B. burgdorferi did not show protective immunity, but seemed to be primed for a severe, destructive case of autoimmune arthritis [4, 5]. The conclusion from this study was thus that the epitopes of rOspA that were cross reactive with self antigens must be eliminated before rOspA can be a successful vaccine [4, 5]. This would be helpful in the cases of HLA-DR4 positive individuals and instances of infection with B. burgdorferi despite antibodies to OspA. This is especially important when considering the waning titers of OspA antibodies while there is still memory to OspA.