2024-25 Project (Chico & Khalil)

Preventing growth restriction and preterm birth in countries with a high infectious disease burden

SUPERVISORY TEAM

Supervisor

Dr Matthew Chico at LSHTM
Email: matthew.chico@lshtm.ac.uk

Co-Supervisor

Professor Asma Khalil at SGUL
Email: akhalil@sgul.ac.uk

PROJECT SUMMARY

Project Summary

Title:   Preventing growth restriction and preterm birth in countries with a high infectious disease burden    Description:   LSHTM and SGUL are seeking applicants for the MRC LID Doctoral Training Programme to conduct novel research that will involve characterising the pathological mechanisms that lead to poor fetal growth and pregnancy outcomes in two large phase-3 double-blind randomised, partly placebo-controlled trials (RCTs) of East and Southern Africa (N=10,116).  The two RCTs involved the monthly administration of intermittent preventive treatment in pregnancy (IPTp) during the second and third trimesters using the standard of care recommended by the World Health Organization (WHO), sulfadoxine–pyrimethamine (SP) and alternative regimens chosen for their potential to provide superior protection against malaria and curable sexually transmitted and reproductive tract infections (STIs/RTIs) in pregnancy.      The MRC LID PhD student will develop quantitative skills to analyse changes in the vaginal and intestinal microbiomes, and maternal inflammatory markers, and relate these laboratory findings to clinical outcomes observed in the two RCTs that involved more than 10,000 women.  We offer a unique package of learning and welcome inquiries.

Project Key Words

Microbiome, Immunology, Bioinformatics, Infections in Pregnancy

MRC LID Themes

  • Global Health = Yes
  • Health Data Science = No
  • Infectious Disease = Yes
  • Translational and Implementation Research = Yes

Skills

MRC Core Skills

  • Quantitative skills = Yes
  • Interdisciplinary skills = Yes
  • Whole organism physiology = Yes

Skills we expect a student to develop/acquire whilst pursuing this project

The PhD student will learn nanopore metagenomic sequencing methods for full-genome sequencing, identification of inflammatory biomarkers and growth factors, and statistical skills necessary to relate laboratory findings with clinical outcomes.

Routes

Which route/s is this project available for?

  • 1+4 = No
  • +4 = Yes

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? No

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • LSHTM’s standard institutional eligibility criteria for doctoral study.
  • Applicants should have an MSc in Clinical Infectious Diseases or related course with a solid grounding in laboratory sciences.

Other useful information

  • Potential CASE conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

1.       Project Objectives 
The MRC LID PhD student will investigate the mechanism(s) involved in the observed protection conferred by SP against preterm birth and low birthweight among pregnant women who received IPTp in the ASPIRE and IMPROVE trials.  The PhD student will explore intervention effects on a reduced burden of infection in pregnancy, inflammation and/or the modulation of microbiomes to improve nutrient uptake (intestinal) and/or reduce diversity (vaginal).     

2. Techniques to be used 
Experiments will involve use of next generation sequencing and PCR to characterise microbial pathogens and mucosal microbiomes. Immunological markers will be assessed using flow cytometry and multiplexed protein detection. Modelling of the interaction between microbes and human cells will be done with in vitro culture systems.  Hypothesis testing will be conducted using standard statistical methods that will relate laboratory observations to clinical outcomes.   

In the first year of the PhD, the student will conduct whole genome sequencing on DNA isolated from stool samples. Analysis will focus on pathways in the metagenome involved in starch degradation and release of energy and whether increases in bacterial families with these genes can account for the improved growth in the SP group.  In second year, the student will focus on the on the vaginal microbiome and its co-variance with the gut microbiome under the influence of SP versus other regimens administered. The student will also look at systemic inflammation and growth factor levels in plasma samples using enzyme linked immunosorbent assay (ELISA) and the Meso Scale Discovery multiplex platform. With these experiments, the student will be able to demonstrate that growth factors are inversely related to systemic inflammation, which is in turn related to infection with malaria and/or sexually transmitted infections.   

3.     Confirmed availability of any required databases or specialist materials 
At the close of the two MRC-funded RCTs, ASPIRE and IMPROVE, vaginal swabs and stool samples were shipped to the bio-bank in London where they await analyses.  Plasma samples from the IMPROVE trial await shipment from Tanzania.  The necessary material transfer agreement is already in place.  Data from both RCTs are securely stored at LSHTM will be made available to the PhD student to design the laboratory studies based on treatment group and clinical outcomes.     

4.          Potential risks to the project and plans for their mitigation 
Risks to the project are low because all vaginal swabs and stool samples have already been transferred and are awaiting the PhD student.  Data from the two RCTs are also readily available.  We still need to transfer plasma samples from Tanzania and plan to do so without delay so as to reduce the risk of potential power outages at the Mwanza laboratory.

Further reading

(Relevant preprints and/or open access articles)

  • 10.1016/S0140-6736(22)02535-1
  • 10.1016/j.ijid.2023.07.012

Additional information from the supervisory team

  • The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.
    Chico-Khalil Recording
  • Chico-Khalil Slides
  • Biological and pathological mechanisms leading to the birth of a small vulnerable newborn. The Lancet (2023) 401 (10389), 1720-1732 10.1016/S0140-6736(23)00573-1.

MRC LID LINKS