Publications

Funding for clinical research |drugs, vaccines, microbicides, diagnostics | HIV/AIDS, tuberculosis, malaria, other infectious diseases |sub-Saharan Africa

Dr Francis Ndungu

Kenya

EDCTP portfolio: Senior Fellowships

Dr Francis Ndungu is studying individuals who are seemingly resistant to malaria infection, to identify immune responses correlating with protection against infection.

Understanding natural immunity to malaria

Malaria still has a major impact on the health and economic wellbeing of people in sub-Saharan Africa. Half the population live in areas affected by malaria.

Although the first effective malaria vaccine, RTS,S/AS01, is beginning to be rolled out, it is only partially protective and alternatives are urgently needed. However, a major challenge in malaria vaccine development is that it is still unclear which specific immune responses are most important in conferring protection against infection.

The challenge

Dr Francis Ndungu has been involved in numerous studies exploring naturally acquired immunity to malaria, as well as trials of the RTS,S/AS01 vaccine and follow up of vaccinated children. Recently, he has also worked on ‘controlled human infection’ studies, a newly introduced approach in Africa in which individuals are deliberately infected with malaria parasites. This approach provides a great opportunity to understand more about the immune responses to malaria parasites and their association with infection and protection.  

In his EDCTP Senior Fellowship, Dr Ndungu will follow up on an intriguing preliminary finding that about one in 10 people previously exposed to malaria parasites do not develop blood-stage infections when injected with sporozoites – the parasite stage transmitted to people by mosquitoes. This suggests that these individuals mount immune responses that stop parasites from invading and multiplying within red blood cells (so-called pre-erythrocytic immunity).

RTS,S/AS01 also induces pre-erythrocytic immunity. However, most studies of naturally acquired immunity have focused on responses to erythrocytic rather than pre-erythrocytic stages. Hence, the current understanding of naturally acquired immunity may not be a useful guide to the design of pre-erythrocytic vaccines. Using the controlled human infection model, Dr Ndungu will be able to gain a detailed understanding of the mechanisms and antibody responses associated with pre-erythrocytic immunity in individuals that do not develop blood-stage infections after exposure to sporozoites.

The project

Dr Ndungu’s Senior Fellowship project will provide important data on the association between specific immune responses and outcomes of infection. By identifying parasite antigens eliciting protective immune responses that prevent red blood cell infection, it will provide important input into the prioritisation of targets for pre-erythrocytic vaccine development.

Impact


test the safety and efficacy of this new formulation in young children

Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

EDCTP portfolio: HIV & HIV-associated infections

The challenge

Malaria still has a major impact on the health and economic wellbeing of people in sub-Saharan Africa. Half the population live in areas affected by malaria.

Although the first effective malaria vaccine, RTS,S/AS01, is beginning to be rolled out, it is only partially protective and alternatives are urgently needed. However, a major challenge in malaria vaccine development is that it is still unclear which specific immune responses are most important in conferring protection against infection.

Dr Francis Ndungu has been involved in numerous studies exploring naturally acquired immunity to malaria, as well as trials of the RTS,S/AS01 vaccine and follow up of vaccinated children. Recently, he has also worked on ‘controlled human infection’ studies, a newly introduced approach in Africa in which individuals are deliberately infected with malaria parasites. This approach provides a great opportunity to understand more about the immune responses to malaria parasites and their association with infection and protection.  

In his EDCTP Senior Fellowship, Dr Ndungu will follow up on an intriguing preliminary finding that about one in 10 people previously exposed to malaria parasites do not develop blood-stage infections when injected with sporozoites – the parasite stage transmitted to people by mosquitoes. This suggests that these individuals mount immune responses that stop parasites from invading and multiplying within red blood cells (so-called pre-erythrocytic immunity).

RTS,S/AS01 also induces pre-erythrocytic immunity. However, most studies of naturally acquired immunity have focused on responses to erythrocytic rather than pre-erythrocytic stages. Hence, the current understanding of naturally acquired immunity may not be a useful guide to the design of pre-erythrocytic vaccines. Using the controlled human infection model, Dr Ndungu will be able to gain a detailed understanding of the mechanisms and antibody responses associated with pre-erythrocytic immunity in individuals that do not develop blood-stage infections after exposure to sporozoites.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Dr Ndungu’s Senior Fellowship project will provide important data on the association between specific immune responses and outcomes of infection. By identifying parasite antigens eliciting protective immune responses that prevent red blood cell infection, it will provide important input into the prioritisation of targets for pre-erythrocytic vaccine development.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact

L’homme RF et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. 2008;22(5):557–65.

Mulenga V et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIVinfected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169–79.

WHO. Guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2010.

WHO. Consolidated guidelines on the use of antiretroviral drugs
for treating and preventing

HIV infection: Recommendations for a public health approach
(second edition). 2016

Projects: Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS): CHAPAS-1 and -3

Project lead: Professor Chifumbe Chintu, University Teaching Hospital, Zambia (CHAPAS-1); Dr Veronica Mulenga, University Teaching Hospital, Zambia (CHAPAS-3)

Target population(s): Children with HIV

Sample size: 71 (CHAPAS-1); 480 (CHAPAS-3)

Countries involved: Ireland, the Netherlands, the UK, the USA, Zambia (CHAPAS-1); Uganda, Zambia (CHAPAS-3)

Project duration: 2005–2009 (CHAPAS-1); 2010 –2011 (CHAPAS-3)

EDCTP funding: €1.2M (CHAPAS-1); €4.6M (CHAPAS-3)

Total project funding: €1.2M (CHAPAS-1); €5.0M