Induced Blood-Stage Malaria in Healthy Malaria-Naive Adults to Assess the Safety and Infectivity of Plasmodium Vivax Challenge Agent and Evaluate Transmission in Mosquito Feeding Assays

Description

Study Description: Single-center, open-label, phase 1 study to characterize the safety and infectivity of Plasmodium vivax (P. vivax) challenge agent for induced blood-stage malaria (IBSM) in malaria-naive participants at the NIH Clinical Center (NIHCC). Challenge agent derived from 2 cell banks of cryopreserved blood-stage P. vivax (PvHMB-CCE001 and PvHMB-CCE002) will be administered intravenously. A minimum of 2 participants per bank will undergo IBSM to establish the safety and infectivity of the challenge agent. Additional participants, with a ceiling of 16 per bank undergoing IBSM, will be enrolled to further develop the model including to evaluate transmission to mosquitoes using feeding assays and assess the host response to P. vivax infection. All participants who receive challenge agent will undergo antimalarial treatment. Qualification of the IBSM model in transmission assays is a requisite goal in supporting future studies of transmission-blocking vaccines (TBVs).

Challenge agent derived from each of the 2 banks (PvHMB-CCE001and PvHMB-CCE002) will be assessed first in a pilot group of at least 2 participants, then subsequently in a main group with participants receiving inoculations in cohorts of up to 10 individuals based on logistical considerations including the capacity of clinic resources. The dose of the challenge agent may be adjusted if needed to generate reliable IBSM.

Objectives:

* Primary Objective

–To assess the safety of the P. vivax IBSM model following inoculation of healthy participants.
* Secondary Objectives

* To establish an appropriate challenge agent dose for use in P. vivax IBSM studies.
* To evaluate transmission of P. vivax to vector mosquitoes in the IBSM model by mosquito feeding assays.
* To establish a dataset that may be used as a historical control in future interventional IBSM transmission studies.
* Exploratory Objectives

* To further characterize blood and sexual stage parasite growth profiles following blood-stage P. vivax challenge and treatment.
* To assess the immune responses to P. vivax IBSM.
* To optimize mosquito infectivity in feeding assays including the generation of mosquito stages of the parasite lifecycle.

Endpoints:

* Primary Endpoint

–Incidence and severity of local and systemic adverse events (AEs) or serious adverse events (SAEs).
* Secondary Endpoints

* A suitable dose of challenge agent that generates parasitemia in a reliable and timely manner as determined by the investigator.
* Transmission of P. vivax to Anopheles spp. using mosquito feeding assays including direct feeding assays and/or membrane feeding assays as determined by the detection of oocysts following midgut dissection. Additional optional measures may include salivary gland dissection or detection by molecular methods.
* Demonstration of transmission in mosquito feeding assays among a requisite number of participants.
* Exploratory Endpoints

* Asexual blood-stage and sexual stage parasite growth profiles by quantitative polymerase chain reaction (qPCR) and/or microscopy.
* Antibody responses: Antibody levels elicited following IBSM as measured by enzyme-linked immunosorbent assay (ELISA) (e.g., antibodies against Pvs230, Pvs25, Pvs44/45 sexual stage antigens, or PvMSP3, MSP9, and AMA1 asexual stage antigens), cellular immune responses, and transcriptional profiling at various timepoints.
* Collection of gametocyte-containing blood and study in mosquito transmission assays.