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Beginnings of malaria vaccine?

Functional assays demonstrate promise of MSP3 target, a potential first step in a long process, according to scientists

By | November 8, 2005

In initial clinical trials of the first Merozoite Surface Protein 3 (MSP3) malaria vaccine, researchers have shown in vitro and in vivo evidence that the vaccine might work better than natural immunity. Functional assays demonstrated that vaccine-elicited antibodies are up to twice as effective at monocyte-dependent parasite killing than those found in African adults from endemic areas, a study in PLOS Medicine reports.

"What is really amazing is [that we could] induce with so little antigen what requires…daily [exposure to] the parasite for twenty years," first author Pierre Druilhe at the Pasteur Institute in Paris told The Scientist.

But while the functional assay approach "adds to the already impressive body of evidence supporting MSP3" as a target, according to Vasee Moorthy at the John Radcliffe Hospital in Oxford, England, he and others agreed that researchers have many trials and many errors to get through before they create a viable vaccine for the billions at risk for malaria.

In this phase I clinical trial, Druilhe's team vaccinated 30 naïve European adults with varying amounts of synthetic, highy conserved MSP3 peptide—which includes three B-cell and four T-cell epitopes—and either alum or Montanide as an adjuvant. Just 3 injections over several months elicited a strong immune response, both cellular and humoral. The immune response to the alum-paired vaccine was more robust and lasted particularly long—more than twelve months—which was unexpected, according to Carole Long at the National Institute of Allergy and Infectious Disease, since this adjuvant, though safer, has been ineffective in previous mice and primate trials. The duration of the response is also promising, according to the paper, since poor immune memory is a major issue in developing malarial vaccines. Still, only 60% of subjects responded to the vaccine, indicating a major limitation of the current formulation, said Long, who did not participate in this study.

To find out how well the immune response the authors detected could actually fight malaria in this early trial stage, they followed clinical testing with functional assays. MSP3 is one of several promising vaccine targets that are expressed when the parasite invades red blood cells. Previous work in Druilhe's lab has shown that rather than directly inhibiting this invasion, IgG antibodies elicited against MSP3 work by triggering monocytes to kill the parasite, a process known as antibody-dependent cellular inhibition (ADCI). In this trial, the dominant antibodies induced in the subjects were IgG1 and IgG3, the same cytophilic antibodies that are associated with the ADCI effect.

The team used an ADCI assay to test the sera of responding study participants, incubating either these sera or those of naturally immune African adults with normal monocytes in falciparum-infected blood culture. The authors found a strong association between MSP-3 antibody positivity and presence of ADCI activity, suggesting that ADCI activity is antigen-specific, according to the accompanying Perspectives. And in most cases, immunization yielded antibodies with a parasite-killing effect equally strong or up to two times stronger that than those induced through natural immunity, a "very surprising" result, Long said. "I don't quite understand it," she added.

Switching to an in vivo approach, the authors then transferred a subset of volunteers' sera samples along with normal monocytes into a humanized mouse model which the team had developed earlier: P. falciparum-infected SCID mice grafted with human red blood cells. Most or all of the parasites were killed as a result, even with sera taken from the alum group after 12 months. Druilhe said he was encouraged by the specificity of the results, and the potency of even low antibody concentrations, though he called the test "more [of] an in vivo culture bag [that is] closer to a sophisticated in vitro model than in vivo."

According to Long, "the most important work is yet to come, when they take this into phase two with people in endemic areas" and measure if the vaccine actually confers protection.

"Right now, we don't know what the relevance of the functional assays is," said Moorthy, who did not participate in this study. But according to him, "the really exciting thing will be if…you see protection against disease [in further clinical trials], you can correlate it with these functional assays. And at that point, you may be able to improve the vaccine very rapidly."

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