Unconventional T-Cell immunity and tolerance to malaria

Malaria is caused by the parasitic pathogen Plasmodium, of which there are five known species that infect humans, with P. falciparum the deadliest. Plasmodium is a complex pathogen existing in two host organisms, mosquitos and humans. The World Health Organization (WHO) reported that in 2019 there were 229 million malaria cases and 409,000 deaths; however, due to sustained research activity, development of anti-mosquito countermeasures, improved frontline anti-malaria drugs and investment in healthcare systems, there has been a decline in the burden of disease since 2000 (WHO Malaria Report, 2020). However, in the last 5 years this decline has reached a plateau and is facing a major tipping point, with the increase in global warming having the potential to increase the spread of malaria and the worsening prevalence of drug-resistant strains of Plasmodium, sources for major global health concern. The need for an effective vaccine for malaria is now critical. Vaccination strategies have revolutionized human health by limiting the transmission or eradicating some of the deadliest communicable diseases, such as polio and measles. Malaria is one of world’s most prevalent global pathogens that does not have an effective vaccine. Currently, only one malaria vaccine has been approved (RTS,S) for use, and it confers <30% protection. The WHO has mandated that next-generation malaria vaccines require >50% protection. A major hurdle in developing vaccines to malaria has been a lack of understanding of the human immune response that contribute to natural protection from malaria. Clinical immunity (asymptomatic infection) to malaria is frequently achieved in people living in areas of world with high incidences of malaria. The immune system has co-evolved alongside malaria and is the major target for vaccine strategies. The majority of current malaria vaccines target the induction of sterilizing antibody responses or induce antimalarial T lymphocytes (T cells) to limit the liver stages of Plasmodium infection. However, these approaches have not struck the right balance to generate an effective vaccine against malaria.

There is access to human challenge samples from (1) adult volunteers that have been repeatedly infected with P. falciparum in a highly controlled clinical study or (2) volunteers protected from malaria by an experimental liver-stage vaccine. The project will explore these concepts using world-leading and innovative techniques to look at the gamma delta TCR landscape in extraordinary detail. The plan is to uncover how these TCRs change and may shape the subsequent immune response after P. falciparum infection and experimental vaccination. Understanding these details of host-pathogen interaction will allow us to understand how P. falciparum drives the gamma delta T cell response in protection from malaria. Together, these studies will provide detailed information on an often overlooked immune network in malaria. This work will firmly establish our ability to design new strategies to manipulate this immune response. This research and the new therapies it will lead to will help to limit the impact and damage of malaria. In the future, this innovative research will help to improve the quality of life for Service Members and populations living in malaria endemic regions.

Basic Science
Vaccines (Immune Correlates)

Oct 2020 — Sep 2021

$216,733

United Kingdom