Malaria Vaccines: Pvs230D1-EPA and PvCSP

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

The major challenges facing Pvs230D1-based TBV development are 1) preparation and successful filing of an Investigational New Drug application with the FDA, 2) demonstrating in a first-in-human study that Pvs230D1 is a suitable antigenic target to generate transmission-blocking antibodies, using a safe formulation that induces sustained high antibody responses, 3) developing the P. vivax blood stage challenge model at the NIH Clinical Trial Center including the successful filing of an IND application for use of the Australian P. vivax challenge agent and to produce two NIH P.vivax master cell banks, 4) COVID-19-related disruption to clinical center facility availability for bank manufacture and 5) demonstration of reliable mosquito transmission in bank validation clinical trials to permit assessment of transmission-blocking endpoints as part of PvTBV development. Using our chemical conjugation platform, Pvs230D1M has been chemically conjugated to EPA and the conjugated nanoparticle enhanced immunogenicity compared to the monomer in mice. The conjugated Pvs230D1M-EPA enhanced the antibody titers compared to the monomeric form. The antibodies raised against the conjugate reduced transmission of P. vivax to mosquitoes in the ex vivo membrane feeding assay. In FY18, a manufacturing campaign was initiated for the cGMP production of a Pvs230D1-EPA chemically conjugated vaccine for phase 1 human trials, with funds provided by OD, NIAID. The technical transfer process and cGMP manufacturing has been completed according to project timelines. In Q1 2021 approximately 2000 vials were filled and have been evaluated for identify, strength, quality and purity. The conjugated Pvs230D1M-EPA vials passed all regulated tests in accordance with prespecified parameters. The bulk drug substance, conjugated Pvs230D1M-EPA, has been shown to be stable under its current storage conditions. Preclinical development has been initiated using Matrix-MTM (Novavax, Gaithersburg, MD), a saponin based adjuvant. A GLP rabbit toxicology study was completed in Q2 2021 with conjugated Pvs230D1M-EPA/Matrix-M; no safety concerns were observed. Pooled antiserum obtained from the rabbit toxicology study was shown to have transmission reducing activity in the ex vivo membrane feeding assay using P. vivax gametocytes obtained from a Saimiri monkey infected with P. vivax. An agreement with Novavax to use Matrix-M adjuvant for the phase 1 clinical trial is anticipated. Phase 1 safety and immunogenicity trials in the US will include a P. vivax blood stage challenge to produce gametocytes that will facilitate assessment of preliminary transmission-blocking endpoints and accelerate product development prior to field studies. We report no publications in FY2022. Our unpublished progress during this reporting period includes the following advances: In FY22, LMIV launched its first clinical study to establish a P. vivax blood stage challenge model at the NIH Clinical Center, using a P. vivax challenge agent manufactured in Australia. The cGMP manufacture of two NIH P. vivax inoculum master cell banks derived from the Australian challenge agent has now been completed, using units of blood from two human volunteers who were successfully infected with the Australian P. vivax agent. Testing of the two blood banks for any agents has thus far been satisfactory, and a Drug Master File will be submitted for the NIH P. vivax master cell banks.