Vaccine Production
Background
Two large pharmaceutical companies have devoted considerable effort to developing a vaccine for Lyme disease. Double-blind, randomized, placebo-controlled clinical trials, involving more than 10,000 volunteers from areas of the United States where Lyme disease is highly endemic, have been completed for each of two B. burgdorferi recombinant OspA vaccines manufactured by GlaxoSmithKline (formerly SmithKline Beecham [SKB]) and Pasteur Merieux Connaught (PMC). These vaccines were found to be 49 to 68 percent effective in preventing Lyme disease after two injections, and 68 to 92 percent effective in preventing Lyme disease after three injections. The duration of the protective immunity generated in response to the SKB vaccine (LYMErix), which was licensed by FDA in December 1998, is not known. Consequently, the need for yearly booster injections remains to be established. Researchers and health experts anticipate the use of these vaccines in endemic areas will likely result in significantly reducing the incidence of Lyme disease in the future.
NIAID was not directly involved in the design and implementation of these particular vaccine trials; however, patents for cloning the genes used for the expression of recombinant OspA, as well as knowledge of the role of antibodies against OspA in the development of protective immunity, were derived from basic research grants funded by NIAID.
In April 2002, GlaxoSmithKline announced that even with the incidence of Lyme disease continuing to rise, sales for LYMErix declined from about 1.5 million doses in 1999 to a projected 10,000 doses in 2002. Although studies conducted by FDA failed to reveal that any reported adverse events were vaccine-associated, GlaxoSmithKline discontinued manufacturing the vaccine for economic reasons (Vaccine 20:1603, 2002).
NIAID Research
NIAID-funded investigators have developed an experimental bait delivery system for an OspA-based vaccine against B. burgdorferi in which mice are immunized orally (via gavage or bait feeding) with a strain of Escherichia coli expressing the gene for OspA. This results in the appearance of serum antibody specific for OspA. Upon exposure to Ixodes nymphs carrying multiple strains of B. burgdorferi, oral vaccination was found to protect 89% of the mice from infection and the resultant serum antibody response confirmed the presence of IgG2a/2b antibody specific for OspA.
This vaccination approach is able to generate a significant protective immune response against a variety of infectious strains of B. burgdorferi, thereby indicating that it can eliminate B. burgdorferi from a major host reservoir. It suggests that the broad delivery of an oral vaccine to wildlife reservoirs in an endemic area is likely to disrupt the transmission of Lyme disease (Vaccine, 24: 1949, 2006). These findings are consistent with the results reported by other investigators (Proc Natl Acad Sci 52: 18159, 2004), thereby affirming the utility of this approach.
In other studies, NIAID grantees have developed a murine-targeted OspA vaccine utilizing Vaccinia virus to interrupt the transmission of disease in reservoir hosts, thereby having the potential to reduce the incidence of human disease. Oral vaccination of mice with a single dose of Vaccinia expressing OspA resulted in high antibody titers to OspA, 100 percent protection of vaccinated mice from infection by B. burgdorferi, and a significant clearance of B. burgdorferi from infected ticks fed on vaccinated animals (Vaccine 24: 1949, 2006). These findings indicate that such a vaccine may effectively reduce the incidence of Lyme disease in endemic areas. Field studies of this vaccine are planned.
NIAID also is funding preclinical studies on developing and testing other candidate vaccines (for example, decorin-binding protein A or DbpA) for Lyme disease. MedImmune, Inc. (an NIAID Small Business Innovation Research grantee) and Sanofi-Aventis Pharmaceuticals, reported that a combination vaccine composed of the DbpA and OspA of B. burgdorferi is more effective than either given alone in preventing the development of borreliosis in experimental animals. On the basis of these encouraging findings, both companies have entered into an agreement to develop a new, more effective second-generation vaccine to prevent Lyme disease in humans. Although the results of previous studies indicate that DbpA induces the development of protective immunity in a murine model of Lyme borreliosis when mice are challenged (needle inoculated) intradermally with in vitro-cultivated B. burgdorferi, such mice are not protected from infection transmitted by ticks carrying virulent B. burgdorferi.
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