EDCTP portfolio: Emerging diseases

The NIFTY trial will determine whether smaller doses of yellow fever vaccine stimulate protective immune responses – which could enable more people to benefit from a vaccine in limited supply.

Making yellow fever vaccine go further

Yellow fever has shown a resurgence in recent years. It affects 34 countries in Africa, causing up to 170,000 cases and 60,000 deaths a year. A safe and highly effective vaccine is available, but it is difficult to manufacture and shortages in supply contribute to limited routine immunisation and inadequate stockpiles to deal with major outbreaks.

To address supply shortage, WHO recently recommended the use of ‘fractional dosing’ – using one fifth of the standard vaccine dose – in emergency outbreak situations. This is thought to be appropriate as studies have shown that even fractional doses stimulate immune responses in excess of those thought to provide protection from infection. However, the shortage of data (including the absence of data from Africa) prevented WHO from recommending wider use of fractional dosing.

The challenge

The NIFTY trial will generate key data on fractional dosing of yellow fever vaccine in adults and children to guide policymaking. Immune responses will be monitored in nearly 2000 adults vaccinated with the full dose and three fractional doses of decreasing volume. The lowest fractional dose generating protective responses in adults will then be compared with the full dose in 700 children. Immune responses will be evaluated after a month and a year.

The project

In 2015, UNICEF estimated that global demand for yellow fever vaccine was more than 40% higher than supply. Fractional dosing could enable more individuals to receive a potentially life-saving vaccine but it will be important to ensure that this does not compromise vaccine effectiveness – and the NIFTY trial will generate key data to answer this question.

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

Yellow fever has shown a resurgence in recent years. It affects 34 countries in Africa, causing up to 170,000 cases and 60,000 deaths a year. A safe and highly effective vaccine is available, but it is difficult to manufacture and shortages in supply contribute to limited routine immunisation and inadequate stockpiles to deal with major outbreaks.

To address supply shortage, WHO recently recommended the use of ‘fractional dosing’ – using one fifth of the standard vaccine dose – in emergency outbreak situations. This is thought to be appropriate as studies have shown that even fractional doses stimulate immune responses in excess of those thought to provide protection from infection. However, the shortage of data (including the absence of data from Africa) prevented WHO from recommending wider use of fractional dosing.

The NIFTY trial will generate key data on fractional dosing of yellow fever vaccine in adults and children to guide policymaking. Immune responses will be monitored in nearly 2000 adults vaccinated with the full dose and three fractional doses of decreasing volume. The lowest fractional dose generating protective responses in adults will then be compared with the full dose in 700 children. Immune responses will be evaluated after a month and a year.

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.

In 2015, UNICEF estimated that global demand for yellow fever vaccine was more than 40% higher than supply. Fractional dosing could enable more individuals to receive a potentially life-saving vaccine but it will be important to ensure that this does not compromise vaccine effectiveness – and the NIFTY trial will generate key data to answer this question.

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

About us

The European & Developing Countries Clinical Trials Partnership (EDCTP) is a public–public partnership between 14 European and 16 African countries, supported by the European Union. EDCTP’s vision is to reduce the individual, social and economic burden of poverty-related infectious diseases by affecting sub-Saharan Africa. EDCTP’s mission is to accelerate the development of new or improved medicinal products for the identification, treatment and prevention of infectious diseases, including emerging and re-emerging diseases, through pre- and postregistration clinical studies, with emphasis on phase II and III clinical trials. Our approach integrates conduct of research with development of African clinical research capacity and networking. The second EDCTP programme is implemented by the EDCTP Association supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation.

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