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Infectious Diseases

The research of the Infectious Diseases Group focuses on improving the diagnosis, treatment and prevention of infectious diseases in children. It comprises both clinical and laboratory-based research studies. The clinical research aspect includes randomised controlled trials, observational studies and systematic reviews of best practice. Our laboratory research encompasses basic and applied medical microbiology, as well as immunological studies to explore the mechanisms by which pathogens cause disease and their interaction with the host immune response.

We have a particular interest in infections that are important to child health worldwide such as tuberculosis and other respiratory infections, diarrhoeal illnesses and neonatal sepsis. A key focus of our current work is the investigation of the heterologous effects of BCG vaccination. The team are investigating the hypothesis that the immunomodulatory effects of BCG influence the development of infant immunity to enhance protection against infections and reduce susceptibility to allergic disease.

BCG vaccination to Reduce the impact of COVID-19 in Australian healthcare workers following Coronavirus Exposure (BRACE) Trial

MIS BAIR - BCG for allergy and infection reduction study

Group Leaders: 
Team Leaders: 
Kaya Gardiner
Role: 
Group Program Coordinator
Dr Laure Pettite
Role: 
Clinician Post-doctoral Researcher
Susie Germano
Role: 
Senior research assistant
Dr Samantha Bannister
Role: 
PhD Student
Dr Lianne Cox
Role: 
PhD Student
Dr Bridget Freyne
Role: 
PhD Student
Dr Freya Harewood
Role: 
PhD Student
Dr Eva Sudbury
Role: 
Research Officer
Dr Paola Villanueva
Role: 
PhD Student
Dr Petra Zimmermann
Role: 
PhD Student
Dr Amanda Wilkins
Role: 
Masters Student
Frances Oppedisano
Role: 
Laboratory Manager
Hannah Elborough
Role: 
Research Nurse
Simone Hamilton
Role: 
Research Nurse
Veronica Abruzzo
Role: 
Data Manager
Casey Goodall
Role: 
Study Assistant
Dr Vanessa Clifford
Role: 
Honorary Fellow

Our research uses a combination of basic, clinical and epidemiology research to investigate a wide range of topics including:

The BRACE trial 
BCG vaccination to Reduce the impact of COVID-19 in Australian healthcare workers following Coronavirus Exposure

Summary

In addition to protecting against its target disease, tuberculosis, BCG vaccine has beneficial off-target (‘heterologous’ or ‘non-specific’) effects on the immune system that provide protection against a diverse range of pathogens, including viral infections 1,2. The ability of BCG vaccination to enhance the immune response could be exploited to provide protection against COVID-19.

 

The Challenge
 

  • It is almost inevitable that the COVID-19 pandemic (caused by SARS-CoV-2) will dramatically worsen placing a great strain on hospital resources. In the Southern hemisphere, this is likely to coincide with the influenza season.
  • Health care worker absenteeism due to COVID-19 and other respiratory infections will exacerbate the pressure on the health care system.
  • There are currently no vaccines or other prophylactic therapeutic interventions available to protect health care workers at the frontline exposed to SARS-CoV-2.

Rationale
 

  • BCG vaccination induces changes in the innate immune system that lead to a stronger response to subsequent infections - this relatively new finding has been termed ‘trained immunity’ 3
  • In a human challenge model, BCG vaccination reduced viraemia by over 70% and improved anti-viral responses using the yellow fever vaccine virus as an experimental viral infection. This virus is a single-stranded, positive-sense RNA virus like SARS-CoV-2 4.
  • In animal models, BCG protects against mortality from a range of viral infections, including single-stranded, positive sense RNA viruses 5,6
  • In two randomised trials in adults (one in the elderly), BCG reduced the incidence of acute upper respiratory tract infections by 70-80% 7,8.
  • Two epidemiological studies (including a 25-year study of over 150,000 children from 33 countries) reported a ~40% lower risk of acute lower respiratory tract infections in BCG-vaccinated children 9,10.
  • BCG vaccination has been associated with increased immune responses to subsequent infant vaccines 11,12.
  • In high-mortality settings, BCG vaccination reduces all-cause infant mortality by more than a third and protection is observed within 7 days of vaccination 13
  • A recent WHO-commissioned systematic review concluded that BCG vaccine had beneficial off-target effects. WHO subsequently recommended further randomised trials to provide more information about these effects 14.


Relevance & Significance 
If BCG vaccination protects against COVID-19, this has implications beyond the effect on the individual, by potentially reducing spread of the virus and the burden on healthcare costs and resources. It has clear global significance, as this is a readily available and cheap intervention that could be used in future pandemics before a disease-specific vaccine is developed.

Hypothesis
Enhanced immunity induced by BCG vaccination will provide protection against COVID-19 (symptomatic disease or severity of illness).

Primary Objective (over 6 months)
To determine whether, in HCW in Australia exposed to SARS-CoV-2 (Participants), does BCG vaccination (Intervention) compared with no BCG vaccination (Comparator) reduce the prevalence and severity (hospitalisation or death) of COVID-19 (Outcome) measured over the 6 months following randomisation (Time).
 

Trial Design
 

  • A multi-centre randomised controlled trial in HCW in Australia at risk of SARS-CoV-2 exposure.
  • Outcomes collected and measured by the following:
    • Self-reported online-based questionnaires
    • Regular telephone/SMS follow-up
    • Healthcare records
    • Biospecimens for confirmation of SARS-CoV-2 infection.
  • Immunological sub-study.


Safety of BCG and Revaccination         
BCG vaccination in immunocompetent adults is considered safe even if they have previously been vaccinated with BCG or have previously been exposed to tuberculosis 7,15,16
BCG adverse effects (e.g. injection site abscess) are rare; >120 million doses given each year worldwide.
A repeat dose of BCG vaccine improves off-target protection.

 

For more information visit the BRACE Trial webpage.

 

Heterologous effects of vaccines 

Bacillus Calmette–Guérin (BCG) vaccine which is given to over 80% of infants worldwide to protect against TB, has an additional substantial effect on all-cause infant mortality in high-mortality settings by providing ‘heterologous’ or ‘non-specific’ protection against other infections. It is believed that this results from the well-established immunomodulatory effects of BCG. These beneficial non-specific effects of BCG may also include reducing susceptibility to allergic disease such as food allergy, eczema and asthma.

The MIS BAIR randomised controlled trial
The Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) is an Australian NHMRC-funded randomised controlled trial (RCT) that will assess the effect of neonatal BCG vaccination on clinical allergy and infection outcomes in infants in Melbourne. Over 1200 infants were randomised to BCG or no BCG at birth and will be followed up for five-years.

Clinical Outcomes
Using three-six monthly online questionnaires together with clinial test to determine the prevalence of allergy to food and other allergens, MIS BAIR will determine if BCG vaccination leads to a reduction the following clinical outcomes by one and five years of age

  • food sensitisation
  • eczema
  • lower respiratory tract infection
  • asthma (5 years only)

Non-specific immunological effects
Our unique cohort of BCG vaccinated and BCG naïve infants who are being followed up longitudinally from birth in the MIS BAIR study provides us with the unparalleled opportunity to investigate the immunological and molecular mechanisms by which BCG mediates beneficial heterologous protective immunity.
To this end, in addition to the clinical allergy and infection outcomes, we are collecting a large number of biosamples, for immunological and studies.  These include the following:

  • venous blood at seven days, six months, one year and five years of age
  • stool samples daily for the first seven days of life and at one year of age for microbiome analyses

The BabyBAIR study
In this cohort study we are investigating how BCG vaccination modifies the immune response to subsequent (in vitro) challenge with viral and bacterial pathogens unrelated to TB in healthy children and young adults.

ELVIS (Early Life Vaccine Immunity Study)
This is a randomised controlled trial to determine the heterologous effects of BCG and Hepatitis B vaccination at birth on neonatal immune responses.
It is designed to investigate the possible interaction between these two vaccines on the innate and adaptive immune response in the first 7 days of life.

Childhood tuberculosis

Approximately 1.3 million new cases of active TB occur in children under 15 years of age and TB claims the lives of over half a million children annually, despite TB being a treatable disease. Our TB research focuses on creating new techniques for the diagnosis of childhood TB, and understanding the immune response and adverse events of BCG (the current TB vaccine). We have a number of clinical and epidemiological projects.

Current studies

Biomarkers for immunodiagnosis and monitoring of TB
We have identified novel Mycobacterium tuberculosis (MTB)-specific cytokine response biomarkers in blood that have the potential to improve the immune-based diagnosis of TB and, critically, distinguish between active TB and latent TB infection (LTBI).
Our current studies assess the validity of these biomarkers, TST and IGRA in children in both high and low TB prevalence settings.
This NHMRC funded study recruited 149 children and found a number of novel cytokine responses that can distinguish between TB-uninfected and TB-infected children. In addition, some of these cytokines have the ability to distinguish between latent TB infection and active TB.
Further participants are currently being recruited to validate these findings in children in Melbourne children. Also, the TB biomarkers identified in this project are currently undergoing further investigation in two further studies (VIDA and the Peru project) in adults and children. These studies will assess the performance of the biomarkers in different age-groups and settings (low and high TB prevalence), a key step in the development of a novel TB test for clinical use. 

Peru childhood TB diagnosis project
This NHMRC funded study will recruit children in Lima, Peru, to determine sensitivity and specificity of our novel biomarkers in children in a high TB prevalence setting. This validation is a critical step in the development of a new generation of low cost, point-of-care immunodiagnostic assays for TB. In this prospective cohort study, we are enrolling over 400 children children aged 0-14 years which suspected active TB or who are household contacts of adult TB patients and thus at high risk of latent TB infection or TB disease.

    Epidemiology of childhood TB in Victoria

    • Epidemiology of active TB in Victoria
    • Study of the management of child contacts of adults with TB in Victoria

    Mycobacterial-specific response to BCG
    In addition to investigating the non-specific effects of BCG we are also  investigating the mycobacterial-specific response to BCG immunisation. These studies are investigating the immune response to BCG and the influence of vaccine strain, age of administration (birth vs 2 months, and child vs adult) and maternal vaccination on response to BCG.  Further studies will be undertaken as part of the MIS BAIR and BabyBAIR studies

    Clinical infectious diseases

    Research is conducted in close collaboration with the clinical infections diseases team at The Royal Children’s Hospital. We have a large number of ongoing projects on a wide range of topics including the following.

    Current studies

    • VANC trial: RCT of continuous versus intermittent dosing of vancomycin in neonates
    • Antibiotic penetration of CSF
    • Staphylococcus aureus bacteraemia in children
    • Candida study
    • Stethocloud project

    E. coli diarrhoeal disease research

    Current studies:

    Understanding how Escherichia coli causes diarrhoea
    We are studying E. coli to discover how certain types are able to cause diarrhoea and other diseases. The aim of this research is to develop tools that will allow us to distinguish pathogenic from harmless E. coli varieties and to develop interventions to treat and prevent infections with these bacteria.

    Prevention of infections with enterotoxigenic Escherichia coli
    Enterotoxin-producing strains of E. coli are an important cause of diarrhoea and death in children in developing countries, and the commonest cause of travellers' diarrhoea worldwide. As no effective vaccines are available for these infections, we are investigating a novel technique for vaccine delivery to develop one. We are also working on strategies to prevent travellers' diarrhoea that do not require immunisation.

    References

    1.         Pollard AJ, Finn A, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102(11): 1077-81.
    2.         Higgins JP, Soares-Weiser K, Lopez-Lopez JA, Kakourou A, Chaplin K, Christensen H, Martin NK, Sterne JA, Reingold AL. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ (Clinical research ed) 2016; 355: i5170.
    3.         Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, Jacobs C, van Loenhout J, de Jong D, Stunnenberg HG, Xavier RJ, van der Meer JW, van Crevel R, Netea MG. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012; 109(43): 17537-42.
    4.         Arts RJW, Moorlag S, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken C, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, Netea MG. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe 2018; 23(1): 89-100 e5.
    5.         Freyne B, Marchant A, Curtis N. BCG-associated heterologous immunity, a historical perspective: intervention studies in animal models of infectious diseases. Trans R Soc Trop Med Hyg 2015; 109(4): 287.
    6.         Moorlag S, Arts RJW, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect 2019; 25(12): 1473-8.
    7.         Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, Mulenga H, Hanekom WA, Self SG, Bekker LG, Ryall R, Gurunathan S, DiazGranados CA, Andersen P, Kromann I, Evans T, Ellis RD, Landry B, Hokey DA, Hopkins R, Ginsberg AM, Scriba TJ, Hatherill M, Team CS. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med 2018; 379(2): 138-49.
    8.         Wardhana, Datau EA, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones 2011; 43(3): 185-90.
    9.         Hollm-Delgado MG, Stuart EA, Black RE. Acute lower respiratory infection among Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics 2014; 133(1): e73-81.
    10.       de Castro MJ, Pardo-Seco J, Martinon-Torres F. Nonspecific (Heterologous) Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection and Sepsis. Clin Infect Dis 2015; 60(11): 1611-9.
    11.       Zimmermann P, Curtis N. The influence of BCG on vaccine responses - a systematic review. Expert Rev Vaccines 2018; 17(6): 547-54.
    12.       Messina NL, Zimmermann P, Curtis N. The impact of vaccines on heterologous adaptive immunity. Clin Microbiol Infect 2019; 25(12): 1484-93.
    13.       Shann F. Nonspecific effects of vaccines and the reduction of mortality in children. Clin Ther 2013; 35(2): 109-14.
    14.       SAGE Working Group on BCG Vaccines and WHO Secretariat. Report on BCG vaccine use for protection against mycobacterial infections including tuberculosis, leprosy, and other nontuberculous mycobacteria (NTM) infections. Geneva: World Health Organization, 2017.
    15.       Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, Hoft DF, Boom WH, Hanekom WA, Johnson JL. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine 2014; 32(31): 3982-8.
    16.       World Health Organization. Recommendations to assure the quality, safety and efficacy of BCG vaccines. In: WHO Expert Committee on Biological Standardization, editor. Geneva: World Health Organization; 2011. p. 1-48.

    Collaborations: 
    • Centre of Research Excellence on Tuberculosis Control
    • Radboud University Nijmegen Medical Centre
    • University of Oxford
    • University College London
    • Instituto de Medicina Tropical Alexander von Humboldt Cayetano Heredia University
    • University of Melbourne
    • Hudson Institute of Medical Research
    • Groningen University Nijmegen Medical Centre
    • Microbiological Diagnostic Unit Public Health Laboratory
    • Victorian Infectious Diseases Reference Laboratory