Developing malaria vaccines: Investing in the tools of the trade
Progress in developing highly efficacious malaria vaccines relies on scientists' ability to efficiently evaluate the potential of different approaches. Such progress would be accelerated with increased investments in technologies that can produce comparable data and maximize learning within the community.
With this in mind, the scientific community has set as a priority the development of a standard set of immunological tests or assays with uniform procedures to enable the malaria vaccine community to compare experimental results and evaluate vaccine-induced immune responses across studies of similar vaccines.
This priority is one of several laid out in the Malaria Vaccine Technology Roadmap, the community’s blueprint for accelerating the pace of malaria vaccine development. In direct response to the Roadmap and to address the need for fully comparable data for portfolio decisions, the PATH Malaria Vaccine Initiative (MVI) has made investments in malaria vaccine evaluation technologies a top priority.
"Our investments in improving the quality and availability of evaluation technologies may be among our greatest contributions to the fight against this complex disease," said David C. Kaslow, MD, director of MVI. "We certainly need to know more about the enemy we are fighting and since resources are limited, we need to be able to compare data to help drive transparent and objective decisions as we manage our portfolio of vaccine projects, and as we decide which vaccine approaches warrant the investments of millions of dollars required to conduct a clinical trial."
MVI is supporting evaluation technologies that can accelerate the development of different vaccine approaches—those against P. falciparum, those against the less deadly but still burdensome P. vivax, and those that could disrupt the transmission of both parasites.
Evaluating Immune Response in the Lab and in Humans
The vaccine evaluation tools that malaria scientists need today can be broken down into two basic categories, and MVI is committed to supporting both.
Researchers need reliable, standardized laboratory tools that provide consistent results, test after test, so that early in the process, scientists can obtain preliminary evidence of how different formulations elicit malaria-fighting antibodies or how they prompt human cells to resist a parasite invasion. MVI is developing such tools through partnerships with the Walter Reed Army Institute of Research, the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health; and the International AIDS Vaccine Initiative. (See Sidebar: Finding Common Cause with AIDS Vaccine Effort.
Malaria vaccine researchers also need challenge models. Given that P. falciparum malaria does not naturally infect commonly used laboratory animals, developing a challenge model for the malaria parasite has required special centers where human volunteers are deliberately infected or “challenged” with malaria to observe whether a candidate vaccine can prevent or delay an infection. In this regard, MVI is supporting the Malaria Clinical Trials Center at the Seattle Biomedical Research Institute, one of only half a dozen facilities of its kind worldwide. (See Sidebar: MVI Invests in Human Challenge Center).
MVI also is supporting the work of researchers at Johns Hopkins University to develop models in which rodents are challenged with an artificially engineered rodent malaria parasite containing fragments of P. falciparum.
In addition, MVI is embarking on an effort to shore up antibody tests that evaluate the ability of antibodies to block infection by the parasite. These tests would look at whether antibodies can interfere with the parasite’s ability to invade and develop in liver cells. With the planned investment in these tests, MVI will increase the number of tools that can be used for malaria vaccine development.
“We are closer than ever to achieving the malaria community’s goal of a first-generation malaria vaccine that protects against disease at least half the time,” Kaslow said. “But even so, questions remain about how the vaccine approach may be providing immunity. As we focus on developing next-generation vaccines that is significantly more effective, we need to move quickly to equip our scientists with the evaluation technologies that will allow them to more thoroughly understand the secrets of malaria immunity and defeat a parasite that has plagued humanity for thousands of years.”
Vaccines can provide immunity by prompting the body to produce disease-specific antibodies that attack invading pathogens, and MVI has undertaken various collaborations to help scientists consistently measure antibody responses to malaria vaccine candidates. But in afflictions like AIDS and malaria, the disease can hide out in cells where it is virtually invisible to antibodies, thus requiring the development of vaccines that can battle the disease on its own turf—through cell-mediated immunity.
One obstacle to comparing the cell-mediated immunity elicited by different malaria vaccine candidates has been the lack of uniform techniques and processes for conducting such tests. Several years ago, the same dilemma arose for AIDS vaccine developers. The International AIDS Vaccine Initiative (IAVI) responded by refining specific tests or assays that measure vaccine-induced, cell-mediated immunity. MVI is now partnering with IAVI and Imperial College London to develop a standard set of such tests for malaria vaccine researchers. (See: PATH Malaria Vaccine Initiative (MVI) Creates New Central "Reference" Lab, Standardizing Ability to Measure Performance of Malaria Vaccine Formulations).
Once a malaria vaccine candidate has been tested for safety in a small number of healthy adult volunteers, some candidates may undergo a “challenge” phase of testing. Under this model, volunteers vaccinated with a malaria vaccine candidate are deliberately “challenged” with malaria through the bites of malaria-infected mosquitoes to assess whether or not the candidate vaccine can prevent or delay malaria infection.
This human challenge phase of malaria vaccine development can provide researchers with valuable information to decide whether or not to move a vaccine candidate forward for testing on a larger scale, including testing in malaria-endemic regions of the world. MVI has collaborated with the Seattle Biomedical Research Institute (Seattle BioMed) to establish a center devoted to testing the safety and efficacy of malaria vaccine candidates in humans. The Malaria Clinical Trials Center at Seattle BioMed is one of only a handful of facilities of its kind worldwide.