Reprogramming T cells for disease tolerance in falciparum malaria (BIO-004)

Malaria is an infectious disease caused by the Plasmodium parasite and is a major public health problem in many parts of the world. Malaria is spread by the bite of an infected mosquito. There are five species of the Plasmodium parasite that are known to cause malaria in humans. Of these five species, Plasmodium falciparum causes the most sickness and death globally, with an estimated 241 million cases of malaria and 619,000 deaths worldwide in 2021. Plasmodium vivax accounts for more than half of all malaria cases in the Americas and Southeast Asia; globally, around 14 million annual cases present a significant clinical and economic burden. Most of the deaths from malaria occur in children under five living in Africa, with infants under 1 year being at the highest risk. A significant study conducted in Tanzania showed that while the number of malaria parasites in the blood remained constant over the first few malaria infections of life, the risk of severe disease and hospitalisation decreased significantly with each infection. This study concluded that rather than killing the malaria parasite, the immune system developed the ability to ‘tolerate’ the presence of the parasite in the body, which reduced the damage caused during repeated infections. This was an important finding, however, the way that the immune system tolerates the malaria parasite remains unknown. In order to better understand how the immune system adapts to tolerate the malaria parasite after repeated infections, this study will recruit participants to undergo three malaria challenges. In a ‘malaria challenge’, study participants will be injected with a small amount of malaria-infected blood under carefully regulated conditions to cause malaria infection. This is important as the exact moment of infection will be known making it possible to track the immune response that follows. This is difficult to do when studying infections that occur naturally. This study will assess: 1. Changes in the immune (T-cell) response after three infections with P. falciparum malaria (Group 1 only) 2. Changes in the immune (T-cell) response after two infections with P. falciparum malaria followed by one infection with a different species of malaria, P. vivax (Group 2 only) 3. Changes in the bone marrow following the first malaria infection (Group 2 only) compared to the third malaria infection (Group 1 only) (we will do this by taking samples of bone marrow through a procedure called a ‘bone marrow test’) 4. Whether the immune (T-cell) response to vaccination is changed by repeated malaria infection – we will use the yellow fever vaccine to answer this question as this vaccine is known to stimulate a T-cell response. While the main aim of our study is to improve malaria survival among children in areas of the world where malaria is common, there are a number of reasons why this study was undertaken in healthy adults in the UK. Firstly, in areas of the world where malaria is common, it would be difficult to find adults who have not had malaria before. This is important to understand the difference in the immune response to the first-ever malaria infection and malaria infections that occur afterwards. Additionally, this type of research could not be conducted in infants as it would not be possible or ethical to take the amount of blood needed for the laboratory tests from young children. It is hoped that the results of this study will help inform strategies to reduce the frequency of severe disease and death among children in parts of the world where the burden of malaria is high. Who can participate? Healthy adults aged 18–45 years old What does the study involve? Participants will enrol into either Group 1 or Group 2 Group 1: Participants will undergo three malaria challenges, approximately 5 months apart. After the third (and last) malaria challenge, they will be asked to drink a small amount of a substance called heavy water daily for between 2-3 weeks. They will also undergo a bone marrow test. They will then receive the yellow fever vaccination and complete their follow-up visits. The total study time will be around 20 months (plus 2 later optional visits occurring 3 and 15 months later) Group 2: Participants will receive the yellow fever vaccination first and then undergo three malaria challenges, approximately 5 months apart. After the first malaria challenge, they will be asked to drink a small amount of a substance called heavy water daily for between 2–3 weeks. They will also undergo a bone marrow test.

Study type: Interventional

Enrollment: 22 participant

Primary purpose: Other

Allocation: Non-Randomized

Trial number:  ISRCTN85988131

Project details

P. vivax
Vaccines (Immune Correlates)

Mar 2022 — Nov 2027

United Kingdom