The Bill & Melinda Gates Foundation, of Seattle, Wash., has awarded $156 million to PATH, a Seattle-based international nonprofit organization, to support the PATH Malaria Vaccine Initiative (MVI) in building new vaccines that will interrupt the cycle of malaria parasite transmission and help realize the "accelerating to zero" agenda. Such vaccines would ensure parasite reintroduction is prevented by providing what could be called an "immunological bed net."
This approach to developing malaria vaccines goes beyond preventing malaria illness to preventing infection and transmission of the parasite. People living in regions affected by malaria often develop natural immunity, and while they may not show symptoms of malaria following subsequent infections, they often harbor parasites and transmit them to mosquitoes, which in turn infect other people. To accelerate future elimination and eradication efforts, vaccines are needed that induce immunity to prevent humans from becoming infected and to shrink the human parasite reservoir.
MVI's two-pronged strategy is to develop vaccines that prevent people from becoming infected after being bitten by infected mosquitoes (anti-infection vaccines, or AIVs) and that prevent mosquitoes from becoming infected, even after feeding on an infected person (transmission-blocking vaccines, or TBVs). Vaccines that combine these two attributes will be of particular focus.
Progress against malaria, which still kills more than 600,000 people annually, is threatened by growing resistance to the drugs and insecticides responsible for recent gains against the disease.
"This new grant for the MVI program will help ensure that PATH can continue its effort to implement an organization-wide strategy aimed at supporting control, then elimination and ultimately eradication of malaria," said Steve Davis, PATH's president and CEO. "We think that malaria vaccines are key to success against malaria and I am deeply appreciative of the Gates Foundation's confidence in our ability to make a contribution in this area."
"At MVI, we think it's time to turn the tables on this disease and to rid the world of it entirely," said Ashley Birkett, Ph.D., director of MVI. "To do this, however, will require new and improved tools. Vaccines are likely to provide the best opportunity to complement drugs and vector-control measures in reducing transmission to zero, and they are the single most important intervention for preventing reintroduction. We know from history that vaccine-induced community immunity can eliminate or significantly reduce the threat of infectious diseases—just look at smallpox, polio, measles, mumps and more recently meningitis A."
Birkett pointed to a particular strength of vaccines: they do not require a change in behavior to provide the benefit. The protection provided by an immunization travels with the recipient, and it works independently of the recipient's behavior. "Malaria vaccines are not the whole answer, but they are part of the answer," she said.
MVI's near-term goal is to advance at least one malaria vaccine candidate through early-stage field trials and have the evidence to declare a candidate for product development as early as the end of 2017. This ambitious goal will be achieved by building on MVI's ongoing work to target the bottlenecks in the parasite's life cycle, where it is most vulnerable.
The parasites are at their lowest numbers—before they multiply from tens into billions—at the points in the life cycle when they are transitioning between the two necessary hosts: humans and female Anopheles mosquitoes. Further, natural immunity does not appear to be a significant factor in targeting these stages of the life cycle, so MVI will be aiming to develop vaccines that induce an unnatural immunity—something that the parasite has never had to deal with before.
Identifying new targets (antigens or proteins) for vaccine development is essential to MVI's strategy. Since malaria infection is fully curable if caught early, researchers have the advantage of using a "challenge model" to evaluate potential vaccines: healthy adult volunteers who receive a new vaccine are then exposed to drug-sensitive malaria parasites (from infected mosquitoes) under controlled laboratory conditions. If a volunteer is not protected, the infection can be treated.
This parasite "challenge" can be used to demonstrate the efficacy of a new vaccine or drug for malaria prior to advancing it into much larger and more expensive field trials. The effective use of these challenge trials, and other evaluation technologies, will enable MVI and its partners to generate the evidence needed, in an accelerated, cost-effective manner, to ensure that MVI advances only the most promising candidates to field studies. This critically reduces the potential for costly vaccine failures in late-stage development. MVI has used the challenge model to assess more than a dozen vaccine approaches since being established as a program of PATH in 1999.
An additional approach MVI will deploy is to use monoclonal antibodies to validate, in controlled malaria challenge trials, target antigens that hold promise for preventing infection and transmission—part of a field-wide "shift to left" trend in malaria vaccine research and development (R&D) to diversify and reinvigorate the vaccine pipeline by allocating resources to earlier stage research. Normally, researchers use a prototype vaccine to induce antibodies in a person and thereby evaluate new targets, which typically leads to inconclusive outcomes relative to the true potential of the target.
"This approach should enable us to assess a greater number of new targets, generate more conclusive outcomes as to their true potential, and accelerate the subsequent design and development of associated vaccines," said Birkett, who noted MVI already has initiated work on several dozen new targets.
"As we approach implementation of this ambitious strategy, we are conscious of our role in an emerging malaria eradication ecosystem," she said. "We are not working in isolation; rather, we are thinking of how interventions such as vaccines will be implemented, together with other interventions such as drugs, even before they're developed."
In all, MVI currently is supporting more than two dozen feasibility studies and the clinical evaluation of six vaccine projects. MVI's more than 50 partners (and 70 collaboration agreements) include academic and nonprofit research groups, biotech and pharmaceutical companies and U.S. government agencies.
MVI was first established to accelerate malaria vaccine development, focused primarily on developing a vaccine for use in children in Africa—the population and the region most at risk of the deadliest form of the disease. In early 2008, MVI began focusing more attention on development of vaccines that interrupt transmission of the malaria parasite to support eradication, making its first investments in transmission-blocking vaccine approaches later that year. MVI's portfolio—one of the largest in the field—currently includes approaches that take aim at every stage of the parasite's life cycle.