Malaria Vaccines: Pvs230D1-EPA and PvCSP

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The major objectives for our Pvs230D1-based TBV development program include 1) preparation and successful filing of an Investigational New Drug application with the FDA, and 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. Development of a P. vivax blood stage challenge model at the NIH is underway, with pre-IND submission for use of a P. vivax challenge agent manufactured in Australia completed in FY20, and an IND submission completed in Q3 2021. The cGMP manufacture of two NIH P. vivax inoculum master cell banks derived from the Australian challenge agent is planned for Q4 2021. This protocol has completed NIH scientific and regulatory review in Q2 FY21 and was submitted to the FDA in Q3 2021. It is anticipated that a Drug Master File will be submitted for the NIH P. vivax master cell banks. A further IND submission is planned for the NIH master cell bank validation studies in FY22 to confirm safety and infectivity of the NIH P. vivax cell banks and establish the P. vivax blood stage challenge model. In Q4 22, an IND will be submitted for the phase 1/2 safety and immunogenicity of the Pvs230D1M-EPA/Matrix-M vaccine followed by P. vivax challenge and drug treatment to assess transmission reducing activity following direct skin feeds. We report no publications in 2021. Our unpublished progress during this reporting period includes the following advances: In FY2021, completed manufacturing and release of the filled sterile vials with Pvs230D1M-EPA drug substance intermediate. Materials are now part of an ongoing stability program. In FY2021, identified Novavax as a collaborator and commercial source of a robust adjuvant, Matrix-M for formulating with Pvs230D1M-EPA and have shown the Pvs230D1M-EPA/Matrix-M formulation is safe in a rabbit toxicology study. In FY2021, in collaboration with Drs. David Stroncek and Steven Highfill from the Department of Transfusion Medicine have qualified the parameters for using the Australian P. vivax challenge agent for human inoculation to yield a NIH master cell bank(s). The process qualification and appropriate documentation will support the Q3 IND submission.