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.
"For malaria, consensus was reached that the term 'controlled human malaria infection' (CHMI) should be used for all future studies. CHMI trials have involved more than 1,500 volunteers since the late 1980s    "
[Show abstract][Hide abstract] ABSTRACT: The deployment of a safe and effective malaria vaccine will be an important tool for the control of malaria and the reduction in malaria deaths. With the launch of the 2030 Malaria Vaccine Technology Roadmap, the malaria community has updated the goals and priorities for the development of such a vaccine and is now paving the way for a second phase of malaria vaccine development. During a workshop in Brussels in November 2014, hosted by the European Vaccine Initiative, key players from the European, North American and African malaria vaccine community discussed European strategies for future malaria vaccine development in the global context. The recommendations of the European malaria community should guide researchers, policy makers and funders of global health research and development in fulfilling the ambitious goals set in the updated Malaria Vaccine Technology Roadmap.
"This has been shown to vary from centre to centre, between trials at the same centre, and even between individuals in the same trial at the same centre . Although it has been suggested that the use of vialed sporozoites administered by needle and syringe for challenge could reduce these variations [3,20], it is important to be cautious since this is not a natural route of sporozoite infection and will undoubtedly have immune response implications . In addition, it will not address the issues of variation in parasite fitness and innate host variability. "
[Show abstract][Hide abstract] ABSTRACT: Background
The use of quantitative real-time PCR (qPCR) has allowed for precise quantification of parasites in the prepatent period and greatly improved the reproducibility and statistical power of controlled human malaria infection (CHMI) trials. Parasitological data presented here are from non-immunized, control-challenged subjects who participated in two CHMI trials conducted at the Walter Reed Army Institute of Research (WRAIR).
Standardized sporozoite challenge was achieved through the bite of five Anopheles stephensi mosquitoes infected with the 3D7clone of the NF54 strain of Plasmodium falciparum. Blood smears were scored positive when two unambiguous parasites were found. Analysis of parasitological PCR data was performed on log-transformed data using an independent sample t-test when comparing the two studies. The multiplication rate of blood-stage parasites was estimated using the linear model.
On average, parasites were detected 4.91 days (95% CI = 4.190 to 5.627) before smears. The earliest parasites were detected within 120 hours (5.01 days) after challenge. Parasite densities showed consistent cyclic patterns of blood-stage parasite growth in all volunteers. The parasite multiplication rates for both studies was 8.18 (95% CI = 6.162 to 10.20). Data showed that at low parasite densities, a combination of sequestration and stochastic effects of low copy number DNA may impact qPCR detection and the parasite detection limit.
Smear positive is an endpoint which antimalarial rescue is imperative whereas early detection of parasitological data by qPCR can allow for better anticipation of the endpoint. This would allow for early treatment to reduce clinical illness and risk for study participants. To use qPCR as the primary endpoint in CHMI trials, an algorithm of two positives by qPCR where one of the positives must have parasite density of at least 2 parasites/μL is proposed.
"As an alternative to sporozoites, parasitized erythrocytes can be used to challenge vaccinated individuals . They may have advantages over sporozoite challenge for testing the efficacy of blood-stage vaccines since they allow use of a standardized and low dose challenge and, consequently, a longer period for assessment of induced blood stage immunity before parasites are detected and treatment is required. "
[Show abstract][Hide abstract] ABSTRACT: The WHO Malaria Advisory Committee (MALVAC) provides advice to WHO on strategic priorities, activities and technical issues related to global efforts to develop vaccines against malaria. MALVAC convened a series of meetings to obtain expert, impartial consensus views on the priorities and best practice for vaccine-related research and development strategies. The technical areas covered during these consultations included: guidance on clinical trial design for candidate sporozoite and asexual blood stage vaccines; measures of efficacy of malaria vaccines in Phase IIb and Phase III trials; standardization of immunoassays; the challenges of developing assays and designing trials for interventions against malaria transmission; modelling impact of anti-malarial interventions; whole organism malaria vaccines, and Plasmodium vivax vaccine-related research and evaluation. These informed discussions and opinions are summarized here to provide guidance on harmonization of strategies to help ensure high standards of practice and comparability between centres and the outcome of vaccine trials.
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