Recently, there has been an upsurge in mild and severe cases of diseases in the UK and other countries (see UKHSA report). Diseases caused by Strep A disproportionately impact the most vulnerable globally, and infection rates are higher in very young children and the elderly. However, many people can carry the bacteria but display no symptoms (asymptomatic infection). Despite the significant morbidity and mortality globally cause by this important pathogen, there is currently no licensed vaccine available.
In 2018, Dr Alice Halliday - was awarded an Early Career Fellowship from the Elizabeth Blackwell Institute, to investigate Streptococcus pyogenes bacteria with the help of vaccinologist Professor Adam Finn and his team in the School of Cellular and Molecular Medicine and the Bristol Vaccine Centre (Faculty of Life Sciences, University of Bristol). Dr Halliday had previously been working on immune diagnostics for Tuberculosis (TB) at Imperial College London.
“There are large gaps in our understanding of how Strep A causes different types of disease, as well as how different people respond to exposure, infection and post-infection syndromes,” Dr Halliday said. Dr Halliday’s fellowship project aimed to shed light on the host-bacterial interactions which occur at the site of infection in different states of infection, specifically comparing those with asymptomatic infection (no symptoms) to those with pharyngitis. The findings from this work could inform the design of new vaccines for Strep A diseases.
The importance of clinical samples
The success of this project was dependent on the availability of appropriate clinical samples. “Since early 2019 we have collected over 60 samples from children presenting with sore throat at the Children’s Emergency Department at Bristol’s Royal Hospital for Children through the use of the Bristol Biobank. I was also fortunate to obtain additional funding from HIC-Vac to collaborate with colleagues in Melbourne, Australia, who have set up a controlled infection model of a GAS strain and have transferred longitudinal throat swab samples from individuals challenged with GAS for use in this project.”
Due to the difficulty of extracting bacterial RNA from the samples, Dr Halliday and her team have initially focused more on the host immune response in the throat swab samples, and profiled changes in immune responses over time at the site of infection. However, work on the bacterial profiling is ongoing.
Preliminary findings from the fellowship
“Using NanoString technology, we have profiled the expression levels of 785 host response genes in over 120 samples from infected individuals. We found dynamic changes in gene expression profiles over time, suggesting recruitment of different immune cell types to the infection site after infection. In particular, those who developed symptoms had strong activation of multiple immune-related pathways and include profiles specific to neutrophils, indicating recruitment of these cells from the blood to the site of infection.”
COVID calling
In 2020, as Dr Halliday was due to return to her GAS research after taking maternity leave, another pathogen caused her to change research direction. The COVID-19 pandemic was a call to arms and as such, along with many other infectious disease researchers, Dr Halliday has spent a considerable amount of time working on COVID-19 since then.
Along with other colleagues in the University (as part of the UNCOVER network), Dr Halliday was supported by EBI to develop and evaluate novel serum and saliva antibody assays for detecting antibodies specific for SARS-CoV-2 (supported by EBI), which have since been deployed in multiple projects. These include a large UKRI-funded project called ‘COVID-19 Mapping and Mitigation in Schools (CoMMinS)’, investigating COVID-19 immune response profiling using samples from the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort, and determining the mucosal antibody response to vaccines from different vaccine cohorts.
As disruptive as the COVID-19 work was for the Group A Streptococcus research programme, the necessary pivot towards COVID has led to new avenues of research and multiple ongoing collaborations including new projects on GAS and other important respiratory pathogens.
A growing Strep A research programme in Bristol
The BVC immunology laboratories now have multiple ongoing areas of investigation, mostly around GAS and SARS-CoV-2. These include the study of survival/adaptation of pathogens during aerosol transmission, the development of novel antibody assays for evaluating mucosal and systemic antibody responses to GAS antigens of interest, and the use of novel tonsil organoid models to investigate mucosal T and B cell responses to candidate GAS antigens.
Unique support and flexible funding
“The Elizabeth Blackwell Institute fellowship has played an instrumental role in my academic career,” she continued. “It has enabled me to move to the University of Bristol to establish a new programme on group A streptococcal infections within Professor Finn’s group in partnership with Dr Anu Goenka (Clinical Lecturer). Since I started in Bristol, my role and the research group around me has changed considerably. I have moved labs and offices 3 times, and the group working in the field of mucosal immunology has grown from 1 staff member to 5 current staff members, with additional students and a clinical primer fellow along the way.”
“My initial funding period was planned to be 2 years,” she continued, “But I completed my fellowship after approximately 3.5 years, which is testament to the generosity and flexibility of Elizabeth Blackwell Institute to support me when faced with other events: most notably having my first child, but more recently by allowing me to shift my attention towards COVID-19 research.”
Dr Halliday now has a split role in School of Cellular and Molecular Medicine as a part time lecturer and part time researcher and is currently working towards expanding the GAS and mucosal immunology research programmes with other members of the BVC immunology group.