Malaria remains a major public health problem with up to half a billion-people infected with the parasite that causes the disease. In recent and ongoing studies, we have conducted controlled malaria infection in 189 Kenyan adults. By measuring malaria parasites in the blood, we have gained insights into the growth of parasites that will guide vaccine development. One other approach to vaccination is to target the transmitting stages of the malaria parasites such that mosquitoes feeding on the infected person would not become infected, thus breaking the life cycle of the parasite. There is a need to develop experimental methods to test the effect of candidate vaccines designed to interrupt transmission to mosquitoes so that vaccines showing evidence of efficacy can then be prioritized for large trials in the field. Furthermore, studying natural immunity in humans to the stages involved in malaria transmission will help characterize potential targets for new vaccines. 

We wish to develop a method to test the efficacy of vaccines and/or drugs designed to block transmission of malaria to mosquitoes and to identify the targets of transmission-blocking immunity to malaria.

The study will take place in Kilifi, Kenya. The study will involve the recruitment and screening of up to 250 individuals from Ahero and Kilifi to determine eligibility for participation and past exposure to malaria. This will be done after a programme of sensitisation and information giving about the study. The study will be conducted in two phases where individuals with moderate to high malaria exposure will be enrolled to participate in the following:

1. Phase A (N = 45): “dose-finding” of the dose of sporozoites given and optimisation of the dose of anti-malarial drug that will be used to promote development of transmission stages without clearing the infection completely (i.e. a “sub-curative dose”);
2. Phase B (N = 60): assessing infectivity of induced malaria transmission stages to mosquitoes.

For each of these phases, selection will be based on level of past malaria exposure and health status. To determine these, blood samples will be taken at the point of screening for each individual participant.

For screening, a blood sample of 21ml will be collected at the time of recruitment. A urine sample and medical history will also be obtained in addition to undergoing a clinical assessment and a test to check the functioning of the heart. For enrollment, a participant will need to have moderate to high malaria exposure and have no clinical disease. Those that meet this criteria, some will be enrolled into phase A and some into phase B (phase A will happen before phase B) for malaria infection studies and be required to stay at an in-patient facility in Kilifi near KEMRI-Kilifi. The participants will be asked to stay at the facility throughout the study so that they are closely monitored by the study staff. To transmit malaria to mosquitoes the human challenge model must first reliably induce infection and of a sufficient duration before being able to develop transmitting stages. We will:

1. For Phase A: Assign individuals to one of three groups to be given different doses of malaria by injection. These individuals will be further assigned to receive two different anti-malarial drugs (sub-curative treatment)
2. For Phase B: Based on results from Phase A, give individuals malaria infection by injection at the most successful dose and provide sub-curative treatment that promotes the most transmission stages. At peak time points of transmission stage induction (based on results from Phase A), mosquito feeding assays will be undertaken to determine infectivity to mosquitoes.

Multiple blood samples will be taken for those enrolled for malaria infections (both Phase A and B). For both phases, blood samples will be drawn as follows: a day before infection (40ml); at five days after infection (8ml); twice daily every day from seven days after infection until the day they will receive a sub-curative treatment (cumulative total of 185ml); and then once daily afterwards to twenty-one days after infection (cumulative total of 70ml); then every other day from day twenty-one until day forty-two (cumulative total of 71ml); once daily during curative treatment (cumulative total of 18ml);  and on day fifty-six after infection (40ml). In addition, for participants enrolled into Phase B, direct skin mosquito feeding and blood samples for mosquito membrane feeding assays will also be taken to assess mosquito infectivity (cumulative total of 28ml). The specific days for assessing mosquito infectivity will be dependent on the results from Phase A of the study. For the entire duration of the study (4-6months), a total of 465ml per participant of blood will be drawn for those enrolled in Phase A and a total of 493mls for those in Phase B. This total volume of blood is less than the volume taken during a blood donation. In addition to blood sampling, clinical assessments will be repeated a day before infection including collection of a urine sample and measurements of weights and heights. Observed sub-curative treatment for malaria will be administered on the day the parasites reach a set threshold and a curative dose on day forty-two after infection.

Controlled human malaria infection has been conducted in one hundred and eighty-nine (189) healthy adults in Kenya (Hodgson et al Front Microbiol. 2014 (Nairobi, N=28 volunteers, 2013) and KEMRI/SERU/CGMR-C/029/3190 (Kilifi, N=161 volunteers, 2016-2018)) and has been proven safe in these individuals. The risks relate to the possibility of developing an allergic reaction upon administration of the malaria infection. In addition, participants may develop signs and symptoms of malaria after infection which are unpleasant, may result in development of severe malaria due to the higher doses of sporozoites being given and may develop some side effects to the drugs used for treatment (sub-curative and curative doses). There are no direct benefits to individuals participating in this study other than information about their health. However, all participants will have their transport costs reimbursed and compensated for all out of pocket expenses for the entire duration of the study.

This work is necessary for enhancing our understanding of how malaria transmission stages develop, the immune targets involved and ability to test interventions such as vaccines in populations that have past exposure to malaria. The successful application of such interventions will benefit society by reducing malaria transmission, a major cause of illness, death and impediment to national development. An adaptation of the controlled human malaria infection provides a way of studying transmission of malaria in a very detailed way that is not possible using natural infections, and we believe that this step is now necessary to inform vaccine design and efficacy.

The study will start upon receipt of ethical clearance. Data collection, analysis and write up will take place over three years.

Malaria is a disease of major public health importance. The only vaccine available is partially effective and targets the pre-erythrocytic stages of the life cycle. Thus, there is a need to identify other potential vaccine targets as well as to develop models to test vaccine efficacy, especially that of transmission-blocking vaccines. Controlled human malaria infection (CHMI) has been shown to be an important tool for the assessment of the efficacy of novel malaria vaccines and drugs. CHMI also allows for the evaluation of immunity to malaria and monitoring of parasite growth rates in vivo. This is particularly useful in individuals from endemic areas with varying levels of exposure and immunity to malaria. Thus, CHMI in individuals with prior exposure to malaria has potential to accelerate malaria vaccine development. In this study, we aim to use CHMI in semi-immune adults to develop a model to assess transmissibility of malaria infection to mosquitoes, to study immune responses that are directed against sexual stages that might block transmission, and as a platform to test vaccines. To achieve this, the study will be carried out in two phases A (N=45 participants) and B (N=60 participants) over a period of 4-6months. We will vary the parasite dose in individuals enrolled for CHMI and use low-doses of anti-malarial drugs to promote the production of gametocytes in vivo (Phase A) and demonstrate transmissibility in mosquito feeding assays (Phase B). Thus, the main outcomes of the study will be: (1) optimisation of sporozoite dose for infections success in individuals with moderate-high malaria exposure; (2) use of sub-curative anti-malaria treatment for induction of gametocytes; and (3) infection of mosquitoes in mosquito feeding assays by induced gametocytes. To achieve this, we will screen up to 250 semi-immune adults who will be recruited from known areas of malaria endemicity in Kenya with varying exposure to malaria and enrol 105 individuals to conduct CHMI studies with serial quantitative polymerase chain reaction (PCR) to measure asexual parasite growth and induction of transmission stages in vivo. In addition, we will comprehensively characterize immunity and identify targets in relation to function assessed by various laboratory assays.