An international non-profit organization, PATH is a leader in malaria vaccine development. RTS,S, the most advanced vaccine candidate, has been developed by PATH Malaria Vaccine Initiative (MVI) in association with GlaxoSmithKline. Dr. Ashley Birkett, Director of PATH MVI, shares his views on the current status of the malaria vaccine pipeline, recent technological advances as well as issues that delay the development of an effective vaccine against malaria. Edited excerpts:
What are the potential malarial vaccine candidates under PATH MVI and at what stages of development are they?
We are pursuing a diverse portfolio of vaccine projects aligned with the goal of accelerating malaria (parasite) elimination. These projects share a common goal of trying to induce immune responses to block parasite transmission between humans and mosquitoes.
The RTS,S vaccine will be introduced into three countries in Africa through a pilot introduction being coordinated by the WHO. We also have a research programme looking at a vaccine regimen using a fractional, delayed third dose of the RTS,S vaccine. There is an ongoing phase 2b clinical trial evaluating this regimen in young children at two clinical research centres in Africa. We also have a number of early clinical projects looking at transmission blocking vaccine approaches, as well as a whole parasite approach.
A critical attribute of next-generation vaccines will be improved durability of protection, compared to RTS,S, to minimize the requirement for repeat administration.
To block transmission, we are targeting ‘bottlenecks’ in the parasite life-cycle, when it circulates in relatively low numbers. These bottlenecks occur as the parasite transitions between its two hosts: humans and female Anopheline mosquitoes.
Some of these approaches would prevent mosquitoes that feed on infected humans from passing along malaria-causing parasites to new victims, while others would prevent the parasites from maturing and causing illness inside the human body and prevent onward transmission via mosquitoes.
Can you briefly explain the mechanism of PATH’s mAb-based vaccines and how they are different?
PATH has pioneered the testing of mAbs as interventions against infection by malaria parasite P. falciparum. Delivery of a mAb should be considered quite different from a conventional vaccine. With a conventional vaccine, the human immune system is trained to produce antibodies to prevent infection. With PATH’s mAb programmes, the antibody is delivered fully formed into the person.
Would the mAb vaccines be therapeutic or preventive?
PATH’s mAb programmes are directed at the prevention of infection and the prevention of transmission of the parasite. So, in this sense, they are inherently prophylactic. These mAbs would not be used to diminish the severity of an existing infection the way standard malaria drugs are used.
RTS,S vaccine (or perhaps its enhanced version) was supposed to undergo extensive phase 3 clinical studies starting from 2018. What is its current status?
A large-scale safety and efficacy trial for the RTS,S vaccine was completed in 2014. That study involved nearly 15,500 infants and young children across 11 clinical research centres in seven African countries.
This year, the vaccine will be introduced through national immunization programmes in parts of three African countries; Ghana, Kenya and Malawi will provide the malaria vaccine to young children in selected areas of high malaria transmission.
This pilot introduction is a country-led, WHO-coordinated initiative. It’s a collaborative effort with Ministries of Health in the three countries and a range of partners, including PATH and GSK, the manufacturer of the vaccine.
The pilot introduction will address several outstanding questions related to the use of the vaccine in real life settings, including how best to deliver the required four doses of RTS,S, the vaccine’s potential role in reducing childhood deaths, and its safety in the context of routine use. About a million children will receive this vaccine across the three countries. The pilot introduction will provide information to allow for a decision on possible wider use of the vaccine across Africa.
Apart from CSP protein, is PATH exploring other potential vaccine targets in the malarial parasite?
Yes, PATH has actively supported identification of new vaccine targets intended to induce immunity that blocks infection and/or transmission. Circumsporozoite protein (CSP) remains the most effective target of anti-infective immunity. We are actively pursuing several promising targets for inducing immunity to block parasite transmission, namely Pfs48/45, Pfs25 and Pfs230.
A vaccine offering lasting immunity against malaria still looks a bit far off. What are the major hurdles that come in the way of developing an effective vaccine against malaria?
We’re learning that the magnitude of the immune response needed to protect against malaria is higher than is typical for gaining immunity against bacteria, for example. A related challenge is the induction of durably protective responses. Vaccine induced immunity [in malaria] wanes over time, falling below the (very high) protective threshold more rapidly than observed with typical pathogens, resulting in renewed susceptibility. We need to understand how we can induce very high, or more potent, immune responses that can persist and provide protective immunity over the long term.