BIO-006

Plasmodium vivax is the second-most important malaria parasite and has a significant disease and health burden. Relapse infections account for most cases of P. vivax malaria. The elimination of P. vivax hypnozoites is therefore an essential component in the pursuit of malaria eradication. However, the current drugs available are not fit for this purpose due to contraindications, polymorphisms associated with poor metabolism, and partial efficacy. Novel drug therapies against hypnozoites are required. In addition, P. vivax vaccine candidates must be able to demonstrate efficacy in preventing the development of hypnozoites in order to have a meaningful impact on P. vivax incidence and onwards transmission. Current in vitro strategies for investigating new drug and vaccines are hampered by an inability to produce a long-term culture of P. vivax parasite, while “real world” studies of relapsing P. vivax disease are confounded by an unquantifiable contribution from primary reinfections and heterologous relapses. We therefore need new controlled research methods to improve our understanding of homologous hypnozoite reactivation, and provide a platform for the development of novel therapies (curative or preventative) against relapsing P. vivax malaria.

Primary Objective
To assess the safety, feasibility and frequency of relapsing P. vivax PvW1 infection after experimental sporozoite-administered Controlled Human Malaria Infection (CHMI)

Secondary Objectives
To assess the immune response to primary and relapsing P. vivax PvW1 infection

non-randomized, open-label experimental study

Healthy, malaria-naïve adult male and female volunteers, 18 to 45 years old

-Mosquito bites: Participants will undergo CHMI by mosquito bites. Mosquito bites may cause local inflammatory reactions with redness, itching, swelling, scaling and/or tenderness. Topical anti-histamine cream for use twice daily for 3 days post-mosquito bite will be dispensed to both participants on the day of CHMI. Serious allergic reactions including anaphylaxis have not been seen in CHMI studies to date, but could theoretically occur. For this reason, participants will be inoculated in an area where Advanced Life Support trained physicians and defibrillator are immediately available.
-Phlebotomy: The approximate scheduled total blood volume drawn over the study period will be 477ml. Participants will never donate 470mL of blood in one sitting; the maximum volume they will donate in a single visit is 83mL so we would not expect them to report a high frequency of symptoms at the time of or just after blood donation. They will be closely monitored at all times of blood donation, and haemoglobin will be checked regularly, as described in the study procedures. Although the additional effect of malaria infection on potential anaemia is acknowledged, we are confident that the anticipated total blood volume should not compromise our participants.
Venepuncture: There may be minor bruising, local tenderness, pre-syncopal symptoms or syncope (rarely) associated with venepuncture or cannulation. To reduce these risks, venepuncture and cannulation will be performed by appropriately trained staff members.
-Risk of other infections: The challenge agent: PvW1 has been produced from a prospectively screened and infected donor with a universal blood group who passes all criteria for blood donation. All procedures related to producing the blood inoculum were done under strict quality assurance. The inoculum has been used safely in 37 malaria-naïve participants in the UK and in 8 participants in the Netherlands. The plasmosium infected mosquitoes will be created by the Radboud University Medical Center (RUMC) in Nijmegen, where healthy participants will be inoculated with PvW1. These participants will undergo similar stringent safety testing. This will include screening for blood borne infections (HIV, Hepatitis B and Hepatitis C), West Nile virus (a mosquito borne disease found in Western Europe) by PCR test, and other relevant mosquito borne diseases if indicated by travel history. The blood of these participants will then be fed to mosquitoes, which will have been reared under carefully controlled laboratory conditions. It is these laboratory-reared mosquitoes which will bite the participants in our study in order to infect them with PvW1. Due to this extensive repertoire of safety testing that has been performed the risk of transmission of any infections other than PvW1 to our participants is extremely low.
-P.vivax malaria: The main risk of P. vivax malaria are symptoms of systemic inflammation, such as fatigue, fever, headache, and myalgia. It is commonly characterized as “benign tertian malaria” because, in contrast to P. falciparum malaria, the risk of complications in healthy adults with a recently acquired infection is extremely low. Relapse infections may occur at any time during the study period and the exact number to be expected is unknown. This uncertainty will be emphasised to participants. They will be advised to contact the study team if they develop any symptoms of relapse malaria infection so that prompt treatment may be initiated.
-Relapsing P. vivax malaria following Primaquine treatment: Infection with P. vivax malaria carries a risk of ongoing relapsing disease if anti-hypnozoite treatment is suboptimal. This risk is minimised by giving participants a 14-day course of high-dose Primaquine treatment (30mg once daily) at the end of in-person follow-up. In addition we will screen participants for their ability to metabolise Primaquine effectively by checking CYP2D6 genotype. Only participants who demonstrate “high-metaboliser” status will be enrolled into the study. After completion of Primaquine treatment, participants will be followed up by email fortnightly until 1 year following CHMI and then annually thereafter until the End of Study (5 years following CHMI).