Optimizing parasite transmission to laboratory-reared mosquitoes following controlled human malaria infection with Plasmodium vivax asexual blood stage parasites in malaria-naïve healthy volunteers in the Netherlands

Plasmodium vivax is the second-most important malaria parasite (following P.
falciparum) and has a significant, although difficult to measure, disease
burden, particularly in South and Southeast Asia as well as in South America.
In parts of Africa, P. vivax infection also results in a significant health
burden. The World Health Organization has therefore included the development of
vaccines to prevent P. vivax malaria and transmission into its updated Malaria
Vaccine Technology Roadmap. In order to assess the efficacy of malaria vaccine
candidates, controlled human malaria infections (CHMI) play a pivotal role.
This validated tool allows down-selection of vaccine candidates very early in
clinical development based on the most relevant criterion - protective efficacy
- with a minimal number of healthy and non-vulnerable participants. The gain in
statistical power is achieved through highly controlled experimental conditions
with regards to the sample (e.g. similar background immunity, age and health
status) and an inoculum that consistently leads to infection with similar
kinetics. CHMI with P. falciparum is well established in the development
pipeline for pre-erythrocytic, asexual blood stage and, since recently, also
transmission-blocking vaccine candidates.
Today, P. falciparum CHMI is one of the most-used experimental models for
vaccine development. In the past, intentional inoculation of humans with P.
vivax were much more common. They have been used extensively in the first half
of the 20th century for the treatment of late-stage syphilis (malariotherapy).
It was considered a standard therapy and was experimentally used for other
conditions; some until the second half of the 20th century. It is one of the
first immune-therapies (the malaria-induced systemic inflammatory reaction was
the therapeutic principle), had an estimated efficacy around 50% and was used
in tens of thousands of patients (Snounou and Pérignon 2013). Until today, P.
vivax CHMI plays a role in testing interventions, although the lack of
standardised procedures and isolates as well as the scarcity of new
interventions for P. vivax and difficulties in accessing well-defined challenge
agents make them an underused technology.

In RaViCHMI1, a protocol for reproducibly infecting laboratory-reared
mosquitoes following inoculation of healthy, adult, malaria-naïve participants
with asexual blood stage parasites of the PvW1 clone of P. vivax will be
established. This model will be used to 1) assess interventions that inhibit
transmission to mosquitoes (e.g. transmission-blocking vaccines) and to 2)
produce infected mosquitoes to assess interventions targeting the sporozoite
and hepatic stages of the parasite life cycle.

Main objective: Develop a protocol to reproducibly infect mosquitoes with blood
from human study participants undergoing asexual blood stage CHMI with the P.
vivax clone PvW1.
Secondary objectives: Maximize mosquito infection rate with PvW1 by I) using ex
vivo gametocyte concentration techniques, and II) antimalarial treatment that
minimizes malaria-associated symptoms and adverse events due to asexual
parasitaemia while not affecting gametocyte viability during CHMI.

Single centre, sequential, non-controlled, non-randomized transmission study

All participants undergo Controlled Human Malaria Iinfection with PvW1 and
receive gametocyte-sparing and end-of-study antimalarial treatment.

Inoculum: Participants will undergo CHMI using a cryopreserved blood inoculum
of the P. vivax clone PvW1. The inoculum 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, so far.
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. Nevertheless, there is a significant disease burden
including complications and death, which are associated with chronic and
relapsing infections, pregnancy, and co-morbidities. As a blood inoculum is
used, there is no risk of P. vivax relapse. The antimalarial treatment is
curative, therefore no complications of chronic or recurrent malaria may occur.
Antimalarial treatment: Participants will receive gametocyte-sparing
antimalarial treatment with piperaquine or mepacrine as well as end-of-study
treatment with atovaquone-proguanil or artemether-lumefantrine. All
antimalarials have been given in millions of doses and their safety profile is
well described. Piperaquine, mepacrine and lumefantrine can prolong the QT
interval. Therefore, an electrocardiogram is part of screening. Potential
participants with ECG abnormalities will be excluded.
Mosquito bites: Mosquito bites can cause local discomfort. Mild local
inflammation and pruritus typically accompanies the bite of the insect. In
contrast to other insect bites (e.g., bees) anaphylaxis after mosquito bites is
extremely rare and has never been reported in CHMI studies.
Phlebotomy: Up to 40 phlebotomies will be done during the study: at screening,
before inoculation, daily until treatment completion and at two late follow up
visits. During CHMI, daily monitoring of parasitaemia will be done to initiate
treatment and reduce potential symptoms of malaria. Phlebotomies will be
performed by qualified nurses and physicians and sites of sampling will be
frequently inspected. For blood sampling in short intervals an intravenous
catheter may be used. No more than 500 mL of blood (the equivalent of one blood
donation) will be sampled over the trial period.
Other burden and risks: Wild Anopheles mosquitoes may be infected by a
participant. The risk is well below the background (imported infections from
endemic areas) as gametocytes will circulate only shortly and at very low
numbers. In addition, there are very few competent Anopheles species in the
study area.
Benefits: There is no direct benefit for study subjects from participation in
the trial. Subjects may indirectly benefit from general medical evaluation and
health screening procedures. The group benefit of the study is mainly for
people at risk for malaria; mostly in malaria-endemic regions but also
travellers as RaViCHMI1 is intended to accelerate development of antimalarial
interventions.