Publications

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

EDCTP portfolio: Career Development Fellowships

Dr Virginie Rozot aims to understand NK and B cell determinants of immunity to Mycobacterium tuberculosis in humans.

Understanding progression to active TB

Tuberculosis (TB) is the major human killer from a single infectious agent. A better understanding of the immunopathogenesis of Mycobacterium tuberculosis (Mtb) infection and disease is critical for the rational development of improved interventions needed to control and eradicate TB. The mechanisms that govern how humans control infection with Mtb are not understood. Recent studies have shown that CD4 T cell responses are necessary but not sufficient for immunological protection against TB.

The challenge

Dr Rozot proposes that NK and B cells participate alongside antigen-specific Th1 responses in the successful immune response to Mtb and are dysregulated in persons who progress to active disease. She aims to identify new NK and B cell subsets involved in tuberculosis progression.

First, the study aims to re-analyse a longitudinal mass cytometry CyTOF dataset of 37 progressors who transitioned from Mtb infection to incident TB disease, and 37 matched Mtb-infected controls who remained asymptomatic during 2 years of follow-up. This complex dataset was generated to primarily study T cell response correlates of TB disease risk. Re-analysis will now allow us to characterise changes in NK and B cell phenotypes and functions in the context of the Mtb-specific T cell response using 16 NK-specific and 17 B-cell specific markers.

Secondly, she and her team will investigate the mechanisms of activation of NK cells whether they are directly activated by the pathogen or through nonspecific cytokine stimulations. Further, the relevance of the findings made in the peripheral blood will be defined by analysing post-mortem tissue samples from the site of Mtb-infection from TB patients and healthy Mtb-infected individuals who died from trauma/accidents. A new 40 marker mass cytometry antibody panel will be defined to deeply decipher phenotype and functions of NK and B cells at the site of infection in humans after stimulation with Mtb. The role of NK cells in IL-22 production will be defined as well as the memory profile and cytokine production capabilities of B cells and their contribution to the milieu at the site of infection.

The project

The study will uncover new potential targets for host-directed therapies, early diagnosis and vaccine design and will provide the fellow with the opportunity to expand her knowledge and technical capacities as well as her international network of collaborations, essential skills to become a research leader in the field of infectious diseases and particularly tuberculosis in South Africa.

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

Tuberculosis (TB) is the major human killer from a single infectious agent. A better understanding of the immunopathogenesis of Mycobacterium tuberculosis (Mtb) infection and disease is critical for the rational development of improved interventions needed to control and eradicate TB. The mechanisms that govern how humans control infection with Mtb are not understood. Recent studies have shown that CD4 T cell responses are necessary but not sufficient for immunological protection against TB.

Dr Rozot proposes that NK and B cells participate alongside antigen-specific Th1 responses in the successful immune response to Mtb and are dysregulated in persons who progress to active disease. She aims to identify new NK and B cell subsets involved in tuberculosis progression.

First, the study aims to re-analyse a longitudinal mass cytometry CyTOF dataset of 37 progressors who transitioned from Mtb infection to incident TB disease, and 37 matched Mtb-infected controls who remained asymptomatic during 2 years of follow-up. This complex dataset was generated to primarily study T cell response correlates of TB disease risk. Re-analysis will now allow us to characterise changes in NK and B cell phenotypes and functions in the context of the Mtb-specific T cell response using 16 NK-specific and 17 B-cell specific markers.

Secondly, she and her team will investigate the mechanisms of activation of NK cells whether they are directly activated by the pathogen or through nonspecific cytokine stimulations. Further, the relevance of the findings made in the peripheral blood will be defined by analysing post-mortem tissue samples from the site of Mtb-infection from TB patients and healthy Mtb-infected individuals who died from trauma/accidents. A new 40 marker mass cytometry antibody panel will be defined to deeply decipher phenotype and functions of NK and B cells at the site of infection in humans after stimulation with Mtb. The role of NK cells in IL-22 production will be defined as well as the memory profile and cytokine production capabilities of B cells and their contribution to the milieu at the site of infection.

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.

The study will uncover new potential targets for host-directed therapies, early diagnosis and vaccine design and will provide the fellow with the opportunity to expand her knowledge and technical capacities as well as her international network of collaborations, essential skills to become a research leader in the field of infectious diseases and particularly tuberculosis in South Africa.

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