VMP001 Q&A with Ashley Birkett
The director of the PATH Malaria Vaccine Initiative, Dr. Ashley Birkett, tells us about recently completed work on a novel vaccine approach against the “other malaria parasite,” Plasmodium vivax, and gives us a behind-the-scenes look at some unique hurdles to testing the approach in human volunteers.
1. Why do we need a vaccine for Plasmodium vivax?
There are multiple species of the parasite that causes malaria. Plasmodium falciparum is the most deadly, and the most prevalent in sub-Saharan Africa–the region that shoulders the majority of the burden of this disease. However, Plasmodium vivax is the most widespread malaria-causing parasite in humans, and is prevalent across Asia and Latin America. Unlike falciparum malaria, it causes relapse infections. That means that once you become infected with vivax, you may get sick and recover, but then the infection can go into a dormant stage in your liver. You can then relapse months or even years later as the parasites emerge from the liver and grow again in your blood. Therein lies the additional challenge in treating vivax, as well as eliminating and eventually eradicating it. To eradicate malaria, we will need to develop tools, like vaccines, for both falciparum and vivax.
2. MVI worked with the Walter Reed Army Institute of Research (WRAIR) to conduct a Phase 1 clinical trial with a vaccine called VMP001. What is this vaccine, and what were the results?
VMP001 is a vaccine candidate developed by WRAIR. It was designed to elicit an antibody response against a section of the vivax parasite’s surface. We funded that clinical trial, and, as we do in such partnerships, we also provided support through expertise in study design, analysis of immune responses, and project management.
This study involved 30 volunteers in the United States who were given 3 doses of VMP001 and then “challenged” with vivax malaria parasites delivered through the bite of infected mosquitoes. This process is known as controlled human malaria infection (CHMI) or, more simply, a human challenge trial. It was the first in-human challenge trial of a vivax vaccine candidate.
In this human challenge trial, we were looking for the vaccine to provide protection from P. vivax malaria infection, but we didn’t see evidence for this in any of the volunteers. All ultimately became infected from the mosquito bites, but there was evidence suggesting that the antibody responses had impeded the growth of the parasite—just not sufficiently to prevent people from getting infected.
This isn’t enough for us to be able to move the candidate forward into the field but certainly it gives us something to build on in the future.
3. Where do you find vivax-infected mosquitoes to bite the volunteers?
It’s difficult to do vivax research with parasites in non-endemic areas such as the United States because we can’t grow the parasites in the lab. This is one of the key differences between vivax and falciparum. Scientists know how to replicate the life cycle of falciparum parasites, which makes it relatively easy to grow them for use in studies. If we want to do a challenge study, we can pull a vial of frozen falciparum parasites out of the freezer, and we use that to infect mosquitoes also maintained in the lab. We can’t do that with vivax because scientists haven’t yet figured out how to replicate its life cycle in the lab.
So for this study, we had to go to a country where vivax malaria is endemic, in this case, Thailand, and infect mosquitoes with vivax parasites. This was undertaken by WRAIR. They drew blood containing vivax parasites from an individual with malaria, then used the blood to infect mosquitoes.
Afterward, those mosquitoes were packaged up and shipped in the passenger cabin of an airplane (they wouldn’t survive in the belly of the plane) from Thailand to the United States to be used to infect the volunteers in the study.
4. What were the logistical and ethical challenges associated with infecting and then transporting mosquitoes from Thailand?
This required a huge amount of logistical organization at WRAIR, which included obtaining various permits needed in order to get those mosquitoes legally into the United States, as well as work to screen the blood of the donor—the individual who provided the blood to infect the mosquitoes, to ensure it didn’t contain any transmissible pathogens, other than P. vivax.
WRAIR did test runs with dummy shipments in order to find the best way to transport the mosquitoes on airplanes so as to maximize their survival and viability. You need a lot of highly infectious mosquitoes for a challenge study.
There were a lot of questions from the US Food and Drug Administration in terms of the health status of the donor volunteer. The same guidelines applied to this person as would be applied to someone in the US who wanted to donate blood to the Red Cross (banked blood is infected in the lab, and fed to mosquitoes, to generate infectious mosquitoes for P.falciparum challenge trials). Although there is no evidence that diseases like HIV or hepatitis B can be transmitted by mosquitoes, we wanted to be sure that the volunteer was not infected with any additional infectious agents. The bar was understandably very high.
5. Why was the decision made to transport the mosquitoes to the US instead of doing the trial at the WRAIR facility in Thailand?
WRAIR looked into conducting the trial in Thailand, however, Thai authorities wanted to see data from other challenge studies before they felt comfortable having Thai nationals involved. Because this was the first time a challenge study was to be conducted in humans to support testing of a vaccine candidate to combat vivax malaria, there wasn’t much data to point to. We therefore needed to further establish the model elsewhere before it could be considered for use in Thailand.
6. Why is P. vivax vaccine research still in such early stages, as compared to that for malaria caused by P. falciparum?
There are probably a couple of reasons. First is a lack of funding for vivax research and development—vivax malaria is often seen as a lower priority compared to falciparum malaria, which is associated with higher mortality.
Over the last five years, however, more data have emerged that suggest that infection with vivax parasites is not as benign as we thought. It may not kill as many people as falciparum but it’s still a pretty devastating disease and is more widespread than its deadlier counterpart. In order to eliminate and eradicate malaria, we will need to tackle P. vivax in a concerted way. We can’t talk about eradication of human malaria without thinking about both falciparum and vivax parasites.
Secondly, vivax is more difficult to work with. It’s a very different parasite from falciparum and we can’t just take what we’ve learned from one parasite species and apply it to the other. With falciparum, we can replicate the whole parasite’s life cycle in the lab—something we can’t yet do with vivax. Instead, we have to study the vivax parasite by taking it directly from infected people, which means much of the work needs to be done in endemic areas.
We need dedicated investments in research and development to help us better understand the vivax parasite and to develop new tools against it.
7. What are the next steps for this vaccine approach, or for vivax malaria vaccine research generally?
While there isn’t much funding out there for research and development of vivax vaccines, we do have a little. The most cost-effective approach, in such a resource-constrained environment, is to apply the most promising results from approaches targeting falciparum malaria. Last year, in partnership with GSK and WRAIR, we reported 87% efficacy (26/30 protected in CHMI) for a P. falciparum vaccine approach. We plan to use our limited P. vivax resources to evaluate a similar vaccine approach. This is exciting and we’re eager to test the hypothesis; a relatively modest investment in manufacturing and clinical trials could have a tremendous impact. However, we and the other institutions working on this problem definitely don’t have the resources we need to give vivax the attention it requires or to take a vaccine approach across the development finish line. We will need more help.
22 Jun 2016