EDCTP portfolio: Senior Fellowships
index
Dr Ally Olutu is introducing controlled human infection with blood-stage malaria parasites into Africa.
Malaria prevention in school-age controlled blood-stage malaria infection
The malaria parasite has a complex life cycle. In humans, it first invades and multiplies in liver cells, before infecting red blood cells; gametocytes released from erythrocytes are taken up when mosquitoes bite, and develop into the forms that can establish new human infections.
Controlled human infection studies, in which malaria parasites are introduced into volunteers in highly controlled settings and then treated with drugs before serious symptoms develop, have generated a wealth of information on the mechanisms of infection. They are also increasingly key to new vaccine development, providing a highly efficient way to test and compare candidate vaccines for further evaluation. Controlled human infection models have been introduced in several African countries, but have to date focused on the first stage of malaria infection.
The challenge
Dr Ally Olutu has played a key role in the evaluation of the most advanced malaria vaccine, RTS,S/AS01, which is undergoing pilot implementation studies in three African countries. His work has also covered the relationship between vaccine efficacy and past exposure to malaria and immunological markers of vaccine-induced and natural post-infection immunity.
In his Senior Fellowship, Dr Olutu is introducing a new type of controlled human infection model into Tanzania, focusing on the bloodstream stage of infection. This model has been used in Australia and Europe but not so far in Africa.
Work on the bloodstream stage will provide important information on parasite multiplication and factors affecting transmission to mosquitoes. It is also essential for testing transmission-blocking vaccines, which target the bloodstream (gametocyte) form of Plasmodium and are designed to break the cycle of malaria transmission. Establishment of the model in Africa is essential to ensure that findings are directly relevant to affected populations.
Having established the model, Dr Olutu plans to investigate factors affecting the efficiency of transmission to mosquitoes, including immune responses to different parasite antigens, parasite loads, and the sex ratio of male and female gametocytes.
The project
Dr Olutu’s project will extend the range of controlled human infection models being used in Africa. It will generate new insights into a key stage in the parasite life cycle that drives transmission. It will facilitate studies on candidate transmission-blocking vaccines, efficiently identifying those showing greatest promise so that expensive phase III trials are only carried out on those with the greatest likelihood of being effective.
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
The malaria parasite has a complex life cycle. In humans, it first invades and multiplies in liver cells, before infecting red blood cells; gametocytes released from erythrocytes are taken up when mosquitoes bite, and develop into the forms that can establish new human infections.
Controlled human infection studies, in which malaria parasites are introduced into volunteers in highly controlled settings and then treated with drugs before serious symptoms develop, have generated a wealth of information on the mechanisms of infection. They are also increasingly key to new vaccine development, providing a highly efficient way to test and compare candidate vaccines for further evaluation. Controlled human infection models have been introduced in several African countries, but have to date focused on the first stage of malaria infection.
Dr Ally Olutu has played a key role in the evaluation of the most advanced malaria vaccine, RTS,S/AS01, which is undergoing pilot implementation studies in three African countries. His work has also covered the relationship between vaccine efficacy and past exposure to malaria and immunological markers of vaccine-induced and natural post-infection immunity.
In his Senior Fellowship, Dr Olutu is introducing a new type of controlled human infection model into Tanzania, focusing on the bloodstream stage of infection. This model has been used in Australia and Europe but not so far in Africa.
Work on the bloodstream stage will provide important information on parasite multiplication and factors affecting transmission to mosquitoes. It is also essential for testing transmission-blocking vaccines, which target the bloodstream (gametocyte) form of Plasmodium and are designed to break the cycle of malaria transmission. Establishment of the model in Africa is essential to ensure that findings are directly relevant to affected populations.
Having established the model, Dr Olutu plans to investigate factors affecting the efficiency of transmission to mosquitoes, including immune responses to different parasite antigens, parasite loads, and the sex ratio of male and female gametocytes.
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 Olutu’s project will extend the range of controlled human infection models being used in Africa. It will generate new insights into a key stage in the parasite life cycle that drives transmission. It will facilitate studies on candidate transmission-blocking vaccines, efficiently identifying those showing greatest promise so that expensive phase III trials are only carried out on those with the greatest likelihood of being effective.
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