A clinical study to assess the safety and feasibility of relapsing P. vivax controlled human malaria infection through experimental sporozoite infection of healthy malaria-naïve UK adults, and to characterise parasite growth and immune responses to primary and relapsing P. vivax infection

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

All participants undergo CHMI with P.vivax infected Anopheles mosquitoes. They
also receive Malarone or Riamet as treatment against the blood stage of
malaria. They receive this after CHMI and after recurrent infections. At the
end of the study, they are treated with Primaquine.

-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).