Future directions for vaccine discovery 2

Published on May 28, 2015   25 min

Other Talks in the Series: Vaccines

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Now, let me ask the question, can the same principles, somewhat complex, that I've just walk you through that we've used to create an HIV vaccine be applied to produce a vaccine to prevent the acquisition or transmission of sound falciparum malaria, the most virulent and lethal form of malaria. This disease is transmitted by the bite of mosquitoes that contain infectious parasites. The problem, then, is infection with Plasmodium falciparum, the proper name of the falciparum malaria parasite, can induce immunity to the red cell stage of the disease, reducing its severity. But that infection does not prevent infection or transmission. In other words, just like for HIV, we have to have a vaccine that is better than natural infection at inducing protection. That is, the challenge to prevent infection or transmission of the infection to others is that the vaccine must be more protective than natural infection. It must induce an unnatural form of immunity to relatively invariant pre red cells stages of the parasite, or stages of the parasite called gametocytes that are transmitted into other mosquitoes, and are then ultimately in that mosquito turned into new parasites that can affect another individual. And those antigens are not targets of natural immunity in infection.
So in order to induce a pre-erythrocytic vaccine for malaria, we need a vaccine that's better than natural infection. What do we have that gives us hope and optimism that this is achievable? Well, we have a great advantage here over situations such as in HIV. It's actually possible to challenge humans with malaria and then to treat them if they become infected so that we can ask, can we give an individual a vaccine, intentionally infect them with malaria through mosquito bites, and determine if that vaccine has protected them. This challenge model has allowed the iterative testing, de-risking, and advancement of vaccine candidates. Moreover, using such a model, more than 30 years ago it was shown that protection can be achieved. Initially, that was achieved by having volunteers who would be challenged bitten by more than 1,000 malaria-infected mosquitoes. And that type of vaccine, containing irradiated parasites within the mosquito so that they could not produce disease, provided greater than 80% sterile protection. That is, protection from infection, whereas natural infection provides no such protection. Moreover, more recently, a similar degree of protection has been achieved with five intravenous injections of 100,000 irradiated sporozoites, or with as little as 45 bites from infected mosquitoes followed immediately by treatment to prevent red cell stage parasitemia from occurring. Unfortunately, neither of these whole parasite approaches is practicable or scalable for use in research limited settings. However, there is a potential practical vaccine candidate on the horizon. A vaccine known as RTS,S which is composed of a circumsporozoite protein, abbreviated here as CSP, has been developed through a committed partnership between academics, US military, and industrial partners who've worked together for more than 20 years on this project. That vaccine has been shown in field trials in Africa to provide 30% and 50% protection from clinical and severe malaria in infants and young children, respectively. However, the problem is that we'd really like a vaccine that was more than 80% effective and provided durable protection in individuals at risk. How might we achieve that?