Monoclonal antibodies (mAbs) to fight malaria: A conversation with Dr Carolina Barillas-Mury
Dr Carolina Barillas-Mury with almost 20 years experience in the malaria vector field, has a focus on transmission-blocking strategies. Part of this work has involved researching mAbs with transmission-blocking activity, that prevents mosquitoes from becoming infected.
Q: Could you tell us a little bit about you and your research interests?
Carolina Barillas-Mury (CBM): We are interested in understanding the interactions between Plasmodium parasites and the mosquito immune system that affect malaria transmission. We also would like to understand how a previous Plasmodium infection affects the way the mosquito immune system responds to a subsequent infection. Our long-term goal is to develop new strategies to prevent malaria by disrupting mosquitoes transmission.
Q: Why do you think mAbs should be part of the therapeutic arsenal against malaria? Benefits?
CBM: I think mAbs could be very useful in some situations, such as when trying to disrupt transmission for several months for those travelling or working temporarily in malaria-endemic areas. As well they could also be useful during eradication efforts, to prevent re-introduction of the parasite in the boundary of areas where it has been eliminated.
Chronic infection with Plasmodium causes a modulation of the immune system that reduces antibody responses to vaccines. In general, the immune response to anti-malarial vaccines is much better in healthy naïve individuals than in those chronically infected with Plasmodium. Therefore passive administration of mAbs overcomes this limitation since they are functional antibodies conferring protection. Moreover, they can be administered at a dose that is effective and which is similar in all individuals. However, I would be concerned about eliciting anti-antibody immune responses if antibodies are administered multiple times, and there could also be unexpected off-target effects.
Q: Could you explain to us which challenges you think are the main ones when trying to implement mAbs in the malaria field?
CBM: A major limitation of passive immunization with mAbs is that by definition a mAb is “transient, passive, and leaves” and therefore it does not contribute to a long-term benefit. Nevertheless, with a vaccine, the immune system “learns” to recognize protective antigens and every “boost” enhances the immune memory.
The administration is also an issue as, in my opinion, intravenous administration is not practical for massive vaccination campaigns. It can also be administered subcutaneously, but I am not sure what is the largest volume that can be reasonably administered that would result in a level of discomfort acceptable to the population.
Q: Could you explain why did you choose to focus your research on mAbs against mosquito stages?
CBM: A few years ago, we identified a protein on the parasite’s surface called Pfs47, that allows the parasite to evade the mosquito immune system and is also involved in fertilization. We used mAbs to map the region of the protein where antibody binding disrupted malaria transmission and identified mAbs that blocked Plasmodium development in the mosquito. Plasmodium parasite undergoes major loses during the early stages of infection in mosquitoes, resulting in a natural bottleneck in which usually less than five parasites reach the oocyst stage. Parasites are also extracellular during these early stages, making them accessible to effectors such as immune cells, antibodies and complement from the vertebrate host that are ingested with the blood meal, as well as effectors of the mosquito immune system. This makes mosquito stages an attractive target to disrupt disease transmission.
Q: How can mAbs facilitate the development of a malaria vaccine?
CBM: Recent studies indicate that one of the strategies used by the parasite to escape the host immune system is to present highly immunogenic epitopes on its surface that elicit a strong antibody response. However, the location of the binding site does not harm the parasite. For example, Pfs47 has three domains. Therefore if you immunize with the full-length protein which elicits a strong antibody response to domains 1 and 3 this does not confer protection because only antibodies binding to the specific region of the domain 2 results in a strong transmission-blocking activity. Consequently, we used a combination of mAbs and protein deletions to map the region of the protein that confers protection.
Q: In your opinion, should a high efficacy malaria vaccine contain antigens from different stages of the parasite? Why?
CBM: Yes, I think it could be best to combine different antigens because by targeting different developmental stages or surface proteins one could achieve a synergistic effect that would make the vaccine much more efficient. It would also make it less likely that the parasite would develop resistance to multiple targets at the same time.
Q: You had been in this field for around 20 years. How do you see the implementation of mAbs in this sickness? Are the results positive so far?
CBM: I think that the technology for mass production of mAbs is evolving quickly and more data on safety will be available as the use mAbs for other chronic diseases, such as autoimmune therapy, becomes more common and the effects of long-term are better known. The price of mass production is going down, and the half-life has been extended by introducing specific mutations. Several mAbs that confer strong protection from infection with the sporozoite stage, the stage injected by mosquitoes that infect humans, have been identified and shown to be highly efficient. Strategies to screen for new mAbs are also evolving fast.
Q: In your opinion, when will it be available a high efficacy vaccine against malaria?
CBM: Transmission blocking vaccines that prevent infection of mosquitoes when they bite an infected host are looking very promising. The detailed mapping of protective epitopes with mAbs also could make it possible to develop vaccines that present critical regions of different vaccine targets at the same time. Eliciting a “focused” immune response, to circumvent the distraction of presenting highly immunogenic regions where antibody binding does not confer protection.
Dr Carolina Barillas-Mury became a senior investigator of the Laboratory of Malaria and Vector by 2010 and now she is the Chief of the Mosquito Immunity and Vector Competence Section Research at the National Institute of Allergy and Infectious Diseases (NIH) in the USA.
