Conference reportReport of a Consultation on the Optimization of Clinical Challenge Trials for Evaluation of Candidate Blood Stage Malaria Vaccines, 18–19 March 2009, Bethesda, MD, USA☆
Section snippets
Background
Pre-erythrocytic malaria vaccine development has benefited enormously from the existence of a clinical sporozoite challenge model. Plasmodium falciparum circumsporozoite antigen based vaccines have been iteratively improved using the efficacy readout from this model [1], [2], [3], [4] to the point where a first generation malaria vaccine consistently shown to provide sterile protection in a proportion of volunteers has been successfully optimized with regard to formulation and transitioned to
Sporozoite challenge trials for evaluation of blood stage malaria vaccines
The challenge trial procedure established in the 1980s, primarily at the US Military Malaria Vaccine Program, involved culture of well characterized strains of P. falciparum and infection of Anopheles stephensi mosquitoes. Volunteers were infected by the bites of 5 mosquitoes, whose infectivity was subsequently confirmed by microscopic visualization of malaria sporozoites in mosquito salivary glands [9]. The bites of two infected mosquitoes were not sufficient to reliably infect [10].
Blood stage challenge trials for evaluation of blood stage vaccines
Many researchers have had doubts as to whether the relatively short period of blood stage parasitaemia, and the relatively high liver-to-blood inoculum after experimental sporozoite challenge are appropriate to allow a blood stage vaccine to exert its protective effect. These two considerations, the potential to inoculate very low doses of merozoites and the possibility of a longer period to allow action of blood stage immunity, led some researchers to develop a protocol for inoculation of low
P. vivax clinical challenge
The meeting reviewed major progress in P. vivax clinical challenge. A presentation outlined the work that has been performed on clinical P. vivax challenge in Colombia using Anopheles albimanus mosquitoes infected from the blood of carefully screened P. vivax infected patients identified in a P. vivax endemic area of Colombia. Several cohorts have successfully undergone clinical challenge with both reproducible pre-patent periods and confirmation of protection from blood stage infection in
Clinical challenge trials in malaria endemic countries
The Colombian work represents one example of challenge trials which have already occurred, successfully and to high ethical and scientific standards in a malaria endemic country. A presentation at the meeting discussed the possibility of conducting challenge trials in sub-Saharan Africa. African investigators in several research centres in this region are articulating an interest in leading such an activity.
Scientifically there are no data to indicate that sporozoite challenges would not be
Clinical safety of the malaria challenge model
Three groups from the USA, UK and The Netherlands gave summary presentations on their clinical challenge experience to date. The modern era of experimental challenge in which mosquitoes are infected by feeding on cultures of P. falciparum began in 1985. Since then more than 1300 volunteers have been challenged by the bite of P. falciparum-infected mosquitoes at these 3 centres. 983 volunteers have been challenged with P. falciparum at the US Military Malaria Vaccine Program since 1985; of these
Recommendations
Above we outline the discussions held at the meeting on applying the challenge model to blood stage vaccines. The group was confident that, in the medium term, the testing of well-designed candidate blood stage malaria vaccines, appropriately formulated and delivered for optimal immunogenicity in blood stage and sporozoite clinical challenge models will enhance the possibility of identifying vaccines, which can impact the host–parasite relationship. Once the community has reached this stage,
Conclusions
The clinical malaria challenge model is amenable to producing sufficiently robust and reproducible results to enable decision-making for pre-erythrocytic malaria vaccines. Establishment of this challenge model at the US Military Malaria Vaccine Program has made a very substantial contribution to malaria vaccine development and has been essential to the development of the RTS,S/AS01 malaria vaccine candidate entering pivotal phase 3 evaluation, and critical to generating the data [24] that have
Acknowledgements
PATH MVI, USAID, EMVI and WHO Initiative for Vaccine Research organized the meeting collaboratively with joint decision-making on the technical content and final participant list. Travel and meeting logistics costs were met by USAID. PATH MVI provided administrative support. WHO Initiative for Vaccine Research acknowledges the contribution of funding support from Fondazione Monte dei Paschi di Siena for the organisation of the meeting.
We acknowledge the technical contribution of all the
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Co-sponsored by PATH MVI, USAID, EMVI and WHO Initiative for Vaccine Research.