Elsevier

Vaccine

Volume 27, Issue 42, 25 September 2009, Pages 5719-5725
Vaccine

Conference report
Report 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

https://doi.org/10.1016/j.vaccine.2009.07.049Get rights and content

Abstract

Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing pre-erythrocytic stage vaccines, some researchers believe that the sporozoite challenge model is less appropriate for testing blood stage vaccines. Here we report a consultation, co-sponsored by PATH MVI, USAID, EMVI and WHO, where scientists from all institutions globally that have conducted such clinical challenges in recent years and representatives from regulatory agencies and funding agencies met to discuss clinical malaria challenge models. Participants discussed strengthening and harmonizing the sporozoite challenge model and considered the pros and cons of further developing a blood stage challenge possibly better suited for evaluating the efficacy of blood stage vaccines. This report summarizes major findings and recommendations, including an update on the Plasmodium vivax clinical challenge model, the prospects for performing experimental challenge trials in malaria endemic countries and an update on clinical safety data. While the focus of the meeting was on the optimization of clinical challenge models for evaluation of blood stage candidate malaria vaccines, many of the considerations are relevant for the application of challenge trials to other purposes.

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

References (24)

  • B. Genton et al.

    Asexual blood-stage malaria vaccine development: facing the challenges

    Curr Opin Infect Dis

    (2007)
  • J.D. Chulay et al.

    Malaria transmitted to humans by mosquitoes infected from cultured Plasmodium falciparum

    Am J Trop Med Hyg

    (1986)
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