An effector memory T cell-inducing subunit vaccine against malaria

An effector memory T cell-inducing subunit vaccine against malaria

Objectives

  • To use cytomegalovirus as a novel tool to immediately intersect incoming parasites at the liver stage, thus preventing blood infection and disease.
  • To determine whether the RhCMV/Pk4 vaccine is protective by challenging with P. knowlesi sporozoites
  • To know whether a TEM-inducing vaccine can improve the level and duration of sterilising immunity induced by subunit vaccines against malaria parasites.

PI Institution(s)

Principal Investigator (PI)

Funding source(s)

Abstract

The ultimate goal of this project is to develop a sterilising vaccine against malaria. The specific hypothesis tested in this proposal is that sterilising immunity against malaria can be achieved by induction of a lasting effector memory T cell (TEM) response targeting the liver stage of Plasmodium parasites. Repeated immunisations with live or irradiated sporozoites are known to protect vaccinated individuals against malaria challenge. Recent evidence suggests that this protection correlated with the presence of frequent pluripotent TEM, suggesting that permanent sterilising immunity against malaria requires the induction of high levels of long-lived TEM by vaccination. To test this hypothesis, we propose to use recombinant cytomegalovirus (CMV) as a vaccine vector because CMV is the prototypical virus inducing long-lived TEM that do not show signs of T cell exhaustion. This unique capability of CMV-vectors was recently applied to induce long-lived TEM against simian immunodeficiency virus, resulting in protection against SIV-challenge that was by far superior to conventional heterologous prime/boost vaccines with respect to efficacy and duration. Since sterilising protection against Plasmodium knowlesi parasites was only partial and shortlived when heterologous prime/boost vaccines were used, we will examine whether CMV-derived vaccine vectors will similarly confer lasting and efficacious immunity against challenge with Plasmodium knowlesi (Pk) sporozoites. We propose to generate recombinant RhCMV expressing four Pk antigens previously used for heterologous prime-boost vaccination: the circumsporozoite protein (CSP), the sporozoite surface protein 2 or thrombospondin-related adhesion protein (SSP2 or TRAP), the apical merozoite antigen-1 (AMA1) and the C-terminus of the merozoite surface protein 1 (MSP1c). We will inoculate animals with this panel of four recombinant RhCMV/Pk vectors and monitor the development of TEM in blood, lung and liver.

https://goo.gl/al1ccv

Key facts

  • Dates
    Feb 2013 to Jan 2016
    Funding amount
    $455,000
    Country
    • United States

MESA tags

  • Methodology
    Product development & clinical research
    Theme(s)
    Tools for elimination