Publications

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

EDCTP portfolio: Malaria

The PfTBV study is accelerating the development of vaccines that interfere with the transmission of malaria via mosquitoes.

Prevention of malaria transmission

Blood-sucking mosquitoes are responsible for transmitting malaria parasites from an infected individual to a new host. Parasites are taken up by mosquitoes at a particular stage in their life cycle, the gametocyte, and develop further in the mosquito into a form that can re-infect people. Vaccination against gametocyte antigens could prevent parasites completing their life cycle in the mosquito.

Hence, although transmission-blocking vaccines would not protect an individual from being infected, they could prevent parasites being transmitted to others.

The challenge

Some progress has been made in the development of transmission-blocking malaria vaccines. However, progress has been slow, in part because most studies investigate single vaccine options in a step-wise fashion. The PfTBV study aims to accelerate development by comparing multiple options, and multiple adjuvants, and focusing on those showing most promise.   

It will focus on three gametocyte antigens: Pfs230D1M, a well-advanced candidate; R0.6C (a fusion of two antigens, GLURP and Pfs48/45), which has yet to be tested in humans; and Pfs230-6C, a novel fusion antigen combining Pfs230 and Pfs48/45. Initial studies will focus on how well these candidates elicit transmission-blocking antibodies, when used with a range of different adjuvants. The safety and efficacy of Pfs230D1M will also be assessed in children over the age of 5 years.

The project will also make use of ‘controlled human malaria infection’ facilities established in Africa, to determine whether vaccination reduces the ability of mosquitoes to transmit parasites. Following these preparatory studies, the most suitable candidate will be evaluated in a phase II field trial in adults.

The PfTBV project also aims to identify features of immune responses associated with vaccine efficacy. In addition, it will build malaria vaccine research capacity in Africa and establish a biobank of African samples for future study. 

The project

Transmission-blocking vaccines have the potential to break the cycle of malaria transmission. They could be used in combination with existing malaria vaccines, such as RTS,S/AS01 or its successors, which would provide protection against infection. In particular, by reducing the ‘reservoir’ of infective parasites, transmission-blocking vaccines have been identified as critical to malaria elimination and eradication.

Impact


crucial in

widening African

children’s access

to antiretrovirals

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

Blood-sucking mosquitoes are responsible for transmitting malaria parasites from an infected individual to a new host. Parasites are taken up by mosquitoes at a particular stage in their life cycle, the gametocyte, and develop further in the mosquito into a form that can re-infect people. Vaccination against gametocyte antigens could prevent parasites completing their life cycle in the mosquito.

Hence, although transmission-blocking vaccines would not protect an individual from being infected, they could prevent parasites being transmitted to others.

Some progress has been made in the development of transmission-blocking malaria vaccines. However, progress has been slow, in part because most studies investigate single vaccine options in a step-wise fashion. The PfTBV study aims to accelerate development by comparing multiple options, and multiple adjuvants, and focusing on those showing most promise.   

It will focus on three gametocyte antigens: Pfs230D1M, a well-advanced candidate; R0.6C (a fusion of two antigens, GLURP and Pfs48/45), which has yet to be tested in humans; and Pfs230-6C, a novel fusion antigen combining Pfs230 and Pfs48/45. Initial studies will focus on how well these candidates elicit transmission-blocking antibodies, when used with a range of different adjuvants. The safety and efficacy of Pfs230D1M will also be assessed in children over the age of 5 years.

The project will also make use of ‘controlled human malaria infection’ facilities established in Africa, to determine whether vaccination reduces the ability of mosquitoes to transmit parasites. Following these preparatory studies, the most suitable candidate will be evaluated in a phase II field trial in adults.

The PfTBV project also aims to identify features of immune responses associated with vaccine efficacy. In addition, it will build malaria vaccine research capacity in Africa and establish a biobank of African samples for future study. 

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.

Transmission-blocking vaccines have the potential to break the cycle of malaria transmission. They could be used in combination with existing malaria vaccines, such as RTS,S/AS01 or its successors, which would provide protection against infection. In particular, by reducing the ‘reservoir’ of infective parasites, transmission-blocking vaccines have been identified as critical to malaria elimination and eradication.

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