Another Shot at Lyme Disease

The first vaccine that Erol Fikrig helped develop against Lyme disease targeted a surface protein of the Borrelia burgdorferei bacterium. That approach was good, but it didn’t guarantee protection against the disease. Now he’s taking a different approach: targeting a protein in tick saliva that helps the pathogen infect the host.

That tick protein is an extra “slicker” on top of the usual surface-protein coat that protects Borrelia. “We aren’t targeting the pathogen’s own armor, but the extra cloak provided by the tick vector,” says Fikrig, an HHMI investigator at Yale University School of Medicine.

Fikrig’s research team has made progress in battling Borrelia and has answered broader questions about how bacterial pathogens interact with their vectors and environments.

Named for a cluster of cases in the Connecticut towns of Old Lyme and Lyme in 1975, Lyme disease infects at least 10,000 to 20,000 Americans each year. Left untreated, it can cause serious damage to the heart, joints, and central nervous system.

Fikrig and fellow HHMI investigator Richard Flavell developed the first Lyme vaccine in mice in 1990, and Fikrig was part of the team that performed the human studies for the vaccine, which was first marketed in 1998. It focused on outer surface protein A (OspA), a dominant protein on Borrelias surface. The vaccine was 80 percent effective—good but not great—and, citing concerns about profitability, the manufacturer stopped production in 2002.

Looking for a new approach to blocking Lyme transmission, Fikrig shifted his focus to the tick. Unlike mosquitoes and tsetse flies, ticks must stay attached to the host for two or three days to transmit the Borrelia infection.

“My question was: Is the microbe’s interaction with tick saliva essential to Borrelias ability to infect humans?” Fikrig says. In a round of experiments with mouse models, his group found that the pathogen causes the tick to overproduce salivary protein 15 (Salp-15), which acts as a shield from the host’s immune system.

Fikrig and colleagues developed an antiserum against Salp-15 and injected it into several mice. They treated the same number of mice with an inactive serum and then exposed all the rodents to Borrelia coated with Salp-15. A week later, every control mouse—but only half of the mice treated with the Salp-15 antiserum—showed signs of Lyme disease, with the bacterial burden significantly less in the mice treated with antiserum. At three weeks, 40 percent of the mice injected with the antiserum were free of symptoms, with lower levels of Borrelia in key tissues.

Since the Salp-15 antibodies made Borrelia less infective in the host, Fikrig decided to combine the Salp-15 antiserum with the older vaccine. His team injected different groups of mice with a low dose of either an OspA antibody or a Salp-15 antiserum and another group with a low-dose combination of the two. All the mice, including an untreated control group, were then exposed to Borrelia-infected ticks. The researchers used a lower-than-therapeutic OspA dose to get a clearer sense of the impact of the Salp-15 antigen, Fikrig says.

The scientists reported in 2009 in Cell Host and Microbe that the mice treated with the combined dose fared the best, with only about a quarter showing symptoms of Lyme. Those mice also had the lowest burden of bacterial infection. In contrast, 90 percent of the mice injected only with the low-dose OspA vaccine (and 100 percent of the untreated mice) showed symptoms of Borrelia infection.

If a pharmaceutical firm eventually conducts human studies on the combination vaccine, Fikrig says a higher-dose OspA vaccine would likely be combined with the Salp-15 antiserum to achieve greater effectiveness. In the meantime, his team is exploring the molecular biology of the tick–parasite interaction.

“We’re now investigating the molecular mechanism of how the antibodies provide the protection,” he says, “and we are trying to determine the exact function of Salp-15 in both the tick and the host.”

-- Robert Koenig
HHMI Bulletin, November 2010

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