Bacterial vaginosis among women at high risk for HIV in East Africa: the role of behaviour, host immunity, genetics

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Around 25 million people are infected with the human immunodeficiency virus (HIV) in sub-Saharan Africa - roughly two-thirds of the worldwide total. The greatest burden is shouldered by 13.3 million African women, who make up 60% of the epidemic in this region. A risk factor for HIV, bacterial vaginosis (BV) is a highly prevalent, reproductive tract infection affecting women. We do not understand the causes of BV or how to control it long-term.

By further investigating behaviour, genetics, and immunological responses to BV, as well as the bacteria that are associated with BV, we hope to further understand the role of these factors in BV and develop a framework that would help researchers to design interventions to respond to this infection. Though research has shown that some types of behaviour are risk factors for BV, notably intravaginal cleansing and sexual behaviour (e.g. new sex partners, frequency of sexual intercourse without condoms), it seems that behaviour does not completely explain the following questions: why some populations have consistently higher prevalence of BV than others; why some women have recurrent BV and others do not; and why some women have symptoms and others do not. We hope to find answers to these questions that will guide future research on BV with the aim of reducing reproductive health burden and HIV transmission.

Technical Summary

Aims:
1) To investigate the role of behavioural, genetic and immunological risk factors for bacterial vaginosis as well as BV-associated bacteria in a population of women at high-risk for HIV in Tanzania.
2) To develop a comprehensive framework for further research related to BV that would include each of the above factors and their interactions, and contribute to the development of interventions against BV.

Objectives:
1) To investigate the prevalence of BV in two large observational cohorts, and to identify social and behavioural factors related to BV, symptomatic infection and recurrence
2) To describe the vaginal flora in women with and without BV
3) To investigate the immunological response and gene expression in women with and without BV
4) To finalise a conceptual framework to inform future epidemiological studies investigating BV

Design: Secondary analyses of data from three observational cohorts and the testing and analysis of stored specimens.

Methodology: This work will exploit the data previously collected from several studies in North-West Tanzania including the EDCTP-funded Women‘s Health Project (WHP), the MRC-funded Inflammation Sub-study, and MDP 301 feasibility study. With these data, we will be able to do in-depth analyses of the correlates of BV and recurrence, description and correlates of BV-specific bacteria, and description of immune responses associated with BV or BV-specific bacteria.

In addition, the WHP has preserved 230 CVL cell pellets from participants attending for their 12 month (final) visit. Samples will be sequenced for selected bacteria using semi-quantitative methods, and then tested for human gene expression.

With the outputs from the above analyses, I will employ advanced epidemiological methods including causal inference and infectious disease modelling to develop a conceptual framework for future research on BV.

Scientific and medical opportunities: Detailed research on BV has not been carried t previously among women at high risk for HIV in sub-Saharan Africa. This research would take advantage of previously collected data to analyse correlates of BV and recurrent BV, identify BV-associated bacteria and obtain detailed data on vaginal mucosal immunity. In addition, we will be able to carry out human genome-wide expression studies that will provide a comprehensive picture of the genes and immune pathways activated during BV. With the outputs from these analyses, I will be able to develop future strategies for research projects including intervention studies on the treatment or prevention of BV with the aim of reducing reproductive health burden and HIV transmission.

Publications

10 25 50

 
Description Advances in approaches to optimise testing for sexually transmitted infections
Amount € 45,000 (EUR)
Organisation European Centre for Disease Prevention and Control (ECDC) 
Sector Public
Country European Union (EU)
Start 05/2018 
End 03/2019
 
Description EDCTP Strategic Primer Grant (Preparing for clinical trials of interventions to improve the reproductive health of adolescent girls in sub-Saharan Africa)
Amount € 1,138,625 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 10/2012 
End 09/2014
 
Description MRC Public Health Intervention Development Scheme (Menstrual Hygiene and Safe Male Circumcision Promotion in Ugandan Schools [MENISCUS]: Feasibility and preparatory phase for a cluster randomised trial)
Amount £150,000 (GBP)
Funding ID MC_PC_14098 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 10/2016
 
Description MRC/DfID/Wellcome Global Health Trials Development
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 09/2018
 
Description New Investigator Research Grant
Amount £800,000 (GBP)
Funding ID MR/N023692/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 06/2019
 
Title HC-HIV IPD Database 
Description The HC-HIV IPD database 18 HIV prevention studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. 
Type Of Material Database/Collection of data 
Year Produced 2015 
Provided To Others? Yes  
Impact Impact on WHO policy on medical eligibility of contraceptive use among women at high risk for HIV infection 
 
Title STIMA Database 
Description Revised database from HC-HIV database that included 18 HIV prevention studies (cohort studies and randomized controlled trials; conducted during 1993±2011), representing >37,000 women, that tested participants for >1 selected STIs or BV at baseline. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Not yet - just published last week. 
 
Title VMB Dataset 
Description We have combined data from 16SrRNA sequencing of the vaginal microbiota, NMR metabolomics and 33 immune protein targets from 221 women at high risk for HIV in Tanzania 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact We are analyzing these data. 
 
Description HAYA 
Organisation Healthy Adolescents & Young Adults (HAYA) Research Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution I am leading on a study to access the feasibility and acceptability of carrying out an survey on reproductive tract infections (including bacterial vaginosis) among young women and men in a demographic surveillance site in Kwa-Zulu Natal, South Africa. We will be collecting samples for testing bacterial vaginosis and storage for future 16SrRNA sequencing. This is the first time to my knowledge that this has been done as a part of a population-based household survey. This is a pilot to apply for future funding to assess physiological risk of HIV infection among young people.
Collaborator Contribution My collaborators are co-investigators on this project, contributing intellectual input and field work at the site in Kwa-Zulu Natal.
Impact Francis SC, Mthiyane TN, Baisley K, Mchunu SL, Ferguson J, Smit T, Gareta D, Dlamini S, Mutevedzi T, Seeley J, Pillay D, McGrath N, Shahmanesh M. Prevalence of Sexually Transmitted Infections among Young People in South Africa: A Nested Survey in a Health and Demographic Surveillance Site. PLOS Medicine, 2018; 15(2):e1002512. We are submitting and ethics application to carry out 16SrRNA sequencing for the vaginal microbiome
Start Year 2015
 
Description HC-HIV IPD 
Organisation FHI 360
Country United States 
Sector Charity/Non Profit 
PI Contribution We have contributed data to a individual participants data meta-analysis that is investigating the association between hormonal contraception and HIV acquisition in sub-Saharan Africa.
Collaborator Contribution FHI 360 is analysing the data and leading on the collaboration
Impact Oral presentation at AIDS 2014 (Melbourne, Australia) "Hormonal contraception and HIV infection: results from a large individual participant data meta-analysis" No.THAC0503. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook A, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JHHM, Stalter R, Low N. Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis. PLoS Med. 2015 Jan 22;12(1):e1001778.
Start Year 2012
 
Description Imperial College - Luminex testing 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided samples
Collaborator Contribution Robin Shattock's group will be carrying out targeted immune profiling using Luminex of the supernatant of the 215 samples sent to the Sanger for 16S rRNA testing.
Impact We are writing a paper together
Start Year 2014
 
Description MENISCUS I 
Organisation MRC/UVRI Uganda Research Unit on AIDS
Country Uganda 
Sector Public 
PI Contribution MENISCUS is a study investigating the feasibility of conducting a cluster randomized controlled trial to investigate the effect of improved menstrual hygiene management on school attendance among secondary school students in Entebbe, Uganda. A secondary outcome of the planned trial is to investigate the effect of improved menstrual hygiene management on reproductive tract infections. I am leading a sub-study that will investigate the acceptability of vaginal swab sampling among girls in a school setting. We will test the samples for bacterial vaginosis and store samples for future 16SrRNA sequencing.
Collaborator Contribution My partners are co-investigators and have provided intellectual input as well as field based research at the MRC site in Entebbe.
Impact Miiro G, Rutakumwa R, Nakiyingi-Miiro J, Nakuya K, Musoke S, Namakula J, Francis SC, Torondel B, Gibson LJ, Ross DA, Weiss H. Menstrual health and school absenteeism among adolescent girls in Uganda (MENISCUS): A feasibility study. BMC Women's Health (2018) 18:4. Miiro G, DeCelles J, Rutakumwa R, Nakiyingi-Miiro J, Muzira P, Ssembajjwe W, Musoke S, Gibson LJ, Hershow RB, Francis SC, Torondel B, Ross DA, Weiss HA. Soccer-based promotion of safe medical male circumcision: A mixed-methods feasibility study with secondary students in Uganda. PLOS ONE, 2017 Oct 9;12(10):e0185929
Start Year 2014
 
Description RHASA Collaboration 
Organisation Institute of Tropical Medicine Antwerp
Department Unit of Epidemiology and Control of HIV/ STD
Country Belgium 
Sector Academic/University 
PI Contribution Expertise in the vaginal microbiome; intravaginal practices and research with young women.
Collaborator Contribution ITM is leading the project
Impact We are writing several papers together
Start Year 2012
 
Description STI IPD 
Organisation World Health Organization (WHO)
Country Global 
Sector Public 
PI Contribution We are providing data for an individual participant data meta-analysis to investigate the prevalence and incidence of STIs in sub-Saharan Africa. Suzanna Francis is on the coordinating group
Collaborator Contribution The WHO will lead on this research.
Impact Torrone E, Morrison C, Kwok C, Chen PL, Looker K, Francis SC, Hayes R, Low N, McCormack S, McGrath N, van de Wijgert J, Watson-Jones D, Gottlieb S, STIMA working group. Prevalence of Sexually Transmitted Infections and Bacterial Vaginosis among Women in Sub-Saharan Africa: An Individual Participant Data Meta-Analysis of 18 HIV Prevention Studies. PLOS Medicine, 2018; 15(2):e1002511
Start Year 2014
 
Description The Sanger - 16S sequencing 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are providing 215 samples from the last visit from a cohort of women at increased risk for HIV in North-west Tanzania (funded partially by MRC G0701039). We have extensively piloted the v-regions to find the best regions for sequencing vaginal microbiota. We have now sent 215 DNA extracts for sequencing by Julian Parkhill's group.
Collaborator Contribution Alan Walker, post-doc from the Parkhill Group piloted 15 samples on the Roche 454 platform. The Sanger changed platforms to Illumina MiSeq and and 8 samples were piloted comparing different V-regions of the 16S rRNA gene. This piloting worked ended in September 2014 and we have now sent 215 samples for sequencing of the V1-V2 variable regions. Alan Walker has now moved the University of Aberdeen, and we are now collaborating with Josef Wagner.
Impact We are writing a paper together
Start Year 2013
 
Description U Reading - Metabolomics 
Organisation University of Reading
Country United Kingdom 
Sector Academic/University 
PI Contribution We will be providing samples
Collaborator Contribution Dr Swann will be using nuclear magnetic resonance to obtain a metabolomic profile of 215 samples that have been 16S rRNA sequenced and immune profiling by Luminex.
Impact We are writing up a paper together
Start Year 2014
 
Description iGugu Radio Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Radio interview about the publication of the paper Francis SC, Mthiyane TN, Baisley K, Mchunu SL, Ferguson J, Smit T, Gareta D, Dlamini S, Mutevedzi T, Seeley J, Pillay D, McGrath N, Shahmanesh M. Prevalence of Sexually Transmitted Infections among Young People in South Africa: A Nested Survey in a Health and Demographic Surveillance Site. PLOS Medicine, 2018; 15(2):e1002512
Year(s) Of Engagement Activity 2018