The Pneumococcal Research Group, led by Professor Kim Mulholland, works across three distinct but closely-related sub-groups to develop, evaluate and enhance vaccination strategies worldwide:
- Clinical and Epidemiology
The group is currently conducting a vaccine clinical trial in Ho Chi Minh City, whole cell vaccine studies in Bandung and vaccine impact studies in Mongolia, Lao PDR, and Papua New Guinea. In Fiji the group is conducting a program of work evaluating the introduction of Pneumococcal, Rotavirus and Human papillomavirus vaccines.
In 2012 the group was awarded a Centre of Excellence grant from the National Health and Medical Research Council (NHMRC).
The pneumococcal research program covers four main areas:
The only way to study pneumococcal population biology, and the impact of vaccines on it, is to study nasopharyngeal carriage of pneumococci. It is known that children frequently carry two or more serotypes, and that density of carriage is important for the likelihood of disease and transmission. Yet all major studies have relied on simple microbiology, sampling only a few pneumococcal colonies from the agar plate. In 2006, Murdoch Children's secured a small sub-grant from the Helsinki-based PneumoCarr mathematical modelling consortium to address this. With support from the Bill and Melinda Gates Foundation this grew to be a global program (PneuCarriage project), led by Dr Catherine Satzke, which brought together field sites from Asia and Africa, along with 15 leading pneumococcal research groups around the world. This has established the most appropriate methodology that is now being used in major field sites.
With the support of the Australian National Health and Medical Research Council (NHMRC), the team has established a major research program in Ho Chi Minh City, in partnership with Menzies School of Health Research and the Pasteur Institute. The main trial, which compares various schedules of Pneumococcal Conjugate Vaccines (PCV10 and PCV13) with co-administered Infanrix-Hexa, uses the full range of pneumococcal immunological tests, along with a novel new B-cell assay developed in Fiji, and the microbiology technology developed as part of the PneuCarriage project, to evaluate the vaccines and schedules. Already the most detailed and comprehensive pneumococcal vaccine trial, it is now being developed further and extended, with a grant from the Bill and Melinda Gates Foundation.
Vaccine Impact in Asia
There are two components to this issue: the burden of pneumonia in Asia, and the contribution of pneumococcus to that burden. To contribute to the first component we are undertaking, in partnership with Menzies School of Health Research in Darwin and the Pasteur Institute of Ho Chi Minh City, a study of the pneumonia burden in Ho Chi Minh City. Vaccine impact is the only way to accurately determine how much of the pneumonia burden is vaccine preventable. We are currently leading studies in Fiji, Laos and Mongolia to evaluate the impact of pneumococcal vaccine introduction on pneumonia incidence and pneumococcal carriage. Most countries are unable to show evidence of vaccine impact. The Bill and Melinda Gates Foundation is funding a study to demonstrate how carriage surveillance in children with pneumonia can be used to estimate the pneumococcal conjugate vaccine coverage required to show evidence of herd immunity, and monitor the vaccine’s impact on carriage, and thereby provide information for national planners to maximize the effectiveness of their immunization programs. This is led by Associate Professor Fiona Russell.
New pneumococcal vaccines
The leading non-capsular pneumococcal vaccine under development is a non-encapsulated whole cell vaccine developed in Boston. With support from the Bill and Melinda Gates Foundation, Program for Appropriate Technology in Health (PATH) is now developing this vaccine, which will be produced in Indonesia by the Biofarma Indonesia company. MCRI is currently leading preparatory studies in collaboration with Professor Cissy Kartasasmita at Universitas Padjadjaran (UNPAD) in Bandung, Indonesia and we will lead the forthcoming trials in Bandung and Lombok.
Current Projects are listed below. All projects involve a combination of team members from clinical epidemiology, microbiology and immunology:
Pneumococcal Vaccine Research and Development
Led by Professor Mulholland and funded by the Australian National Health and Medical Research Council. The trial is designed to answer the remaining questions needed to implement a 2+1 schedule on a global scale. These include:
- Evaluation of the immunogenicity of the two new-generation conjugate vaccines (PCV10 and PCV13) in a 2+1 schedule, in comparison with existing recommended schedules;
- Evaluation of the impact on carriage of the two new-generation conjugate vaccines (PCV10 and PCV13) in a 2+1 schedule, in comparison with existing recommended schedules and an unvaccinated control group;
- The immunogenicity of co-administered Hib containing combination vaccines in a 2+1 schedule;
- Evaluation of the immunogenicity and impact on carriage of PCV10 in an experimental 1+1 schedule (2 and 6 months).
Vietnam study extension funded by Bill and Melinda Gates Foundation
The add-on study proposes to fully evaluate the 0+1 and 1+1 schedules for both the existing PCVs and to extend the length of follow up of the existing trial to strengthen its power to address the key questions.
B. Mongolia pneumococcal vaccine impact evaluation
Principal Investigator Professor Mulholland in collaboration with WHO and Mongolia Ministry of Health. Funded by the GAVI Alliance. The primary objective is to evaluate the impact of PCV introduction on the incidence of radiological pneumonia among under-5 children in four large districts of Ulaanbaatar.
C. Nasopharyngeal carriage surveillance (PneuCAPTIVE Project)
Principal Investigator Associate Professor Fiona Russell. Collaborating with WHO Western Pacific Regional Office, Lao Ministry of Health, Lao-Oxford- Mahosot Hospital-Wellcome Trust-Research Unit (LOMWRU), the University of Western Australia, the Institute of Medical Research, PNG and Mongolia Ministry of Health, and St George’s Hospital, UK. This project aims to estimate the PCV coverage required to show direct and indirect immunity, by using innovative methods suitable for low- and middle-income countries.
D. Lao PDR pneumococcal vaccine impact evaluation
This project, funded by the GAVI Alliance, is co-led by Associate Professor Fiona Russell and Professor Kim Mulholland in collaboration with the World Health Organization (WHO) and the Lao Ministry of Health, and will provide information on the impact of the newly introduced pneumococcal conjugate vaccine on childhood pneumonia and carriage. The study’s design was presented by A/Prof Russell at the WHO Expert consultation on PCV Impact Evaluation meeting, Geneva, in 2013
E. Fiji new vaccine evaluation project
This project is a collaboration between Murdoch Children's and the Fiji Ministry of Health. It is co-led by Associate Professor Fiona Russell and Professor Kim Mulholland, and funded by Australian Aid. The NVEP aims to improve surveillance at the Fiji government’s public health laboratory and evaluate the impact of pneumococcal conjugate vaccine, rotavirus vaccine, and human papillomavirus vaccines which the government recently introduced. The team will evaluate the pneumococcal conjugate vaccine’s impact on carriage and disease, and we are transferring technology from MCRI to the Fiji Ministry of Health to support meningitis surveillance. The NVEP is measuring the impact of rotavirus vaccine on diarrhoea in Fiji; monitoring for intussusception; and providing support for surveillance. In addition, the NVEP is evaluating reduced dose HPV schedules, and will establish surveillance for human papillomavirus infection in Fiji.
F. Typhoid project (Fiji)
Assessment project funded by Australian Aid and led by Prof Mulholland. While typhoid has long been recognized as a problem for Fiji and other Pacific nations, that dramatic increase in cases since 2007 has now placed Fiji in the highest category of typhoid endemic countries, along with countries like Nepal and Pakistan. The reasons for this are unknown.
Following the perceived failure of a vaccination program initiated by WHO and CDC in 2010, the Fijian Ministry of Health requested Murdoch Children's to help them to find a solution. In 2012, the Institute convened a meeting of leading typhoid specialists in Fiji to address the issue. The paradoxes of typhoid in Fiji and the lack of objective epidemiological, clinical and microbiological information were highlighted in the meeting.
This led to an AusAID (now Australian Aid) funded project to implement the recommendations of the meeting and get to the bottom of the problem. Murdoch Children's is now leading a project in collaboration with Melbourne University (Prof Strugnell), University of Otago (Prof Crump), Oxford University Vietnam (Dr Baker) and the Sanger Institute UK (Prof Dougan) to address this.
G. Modelling the effect of social contact (Fiji)
Associate Professor Fiona Russell is the Prinicipal Investiagtro on this Bill and Melinda Gates Foundation funded project in Fiji. The project aims to show whether the frequency and intensity of social contact effects pneumococcal carriage rates and density, and if so, whether PCV10 is able to overcome the effects of social contact on the carriage of PCV10 serotypes. This study will contribute to the understanding of why there are ethnic and regional pneumococcal disease burden differences and help to elucidate whether the perceived lower pneumococcal disease burden in India, and more broadly in Asia, in comparison with Africa, may be partly explained by the effect social behaviour has on pneumococcal carriage.
H. Bandung Pneumococcal Project
Pneumococcal carriage in Indonesian infants ahead of the Streptococcus pneumoniae whole cell vaccine efficacy trial. Principal Investigator Prof Mulholland, in collaboration with Universitas Padjadjaran. Funded by PATH.
Currently, the only pneumococcal vaccines licenced for use in children are pneumococcal conjugate vaccines (PCVs). Although PCVs are successful at reducing pneumococcal disease overall, they are expensive to produce and they only protect against a subset of pneumococcal serotypes, so their use can lead to increased carriage and disease caused by non-vaccine serotypes (serotype replacement).
S. pneumoniae whole cell vaccine (PATH-wSP) has been developed as a low-cost alternative to pneumococcal conjugate vaccines (PCVs), which could deliver broad protection against the pneumococcus. PATH-wSP has undergone safety testing (Phase I clinical trials) in healthy adults, and the first clinical trials in children are planned to take place in Kenya and Indonesia.
Indonesia is the world’s fourth most populous country and there are no plans to introduce PCVs to the Indonesian National Immunization Program.
In collaboration with Professor Cissy Kartasasmita of Universitas Padjadjaran (UNPAD) in Indonesia, we are leading a new research project to acquire baseline information on pneumococcal carriage that will help inform the design of (PATH-wSP) efficacy trials.
The research will also provide additional evidence that the pneumococcus is an important and common pathogen in Indonesian infants. Understanding nasopharyngeal carriage of the pneumococcus, in both urban and rural populations, will be essential for evaluating the vaccine’s true impact.
The baseline carriage study will have two components:
a longitudinal study to investigate pneumococcal carriage dynamics including serotype-specific acquisition and clearance in the first year of life, and
a cross-sectional study to generate pan-Indonesian data on the carriage rates of pneumococci and other important colonizing pathogens.
I. PneuCarriage follow-up study
‘Monitoring pneumococcal carriage and vaccine impact’. Co-principal Investigators Dr Catherine Satzke and Prof Kim Mulholland. This project is funded by Bill and Melinda Gates Foundation to establish appropriate serotyping methods for the investigation of pneumococcal carriage in the context of measuring pneumococcal conjugate vaccine impact in low-income countries.
Centre of Research Excellence in Pneumococcal Vaccinology
Project led by Prof Mulholland and funded by National Health and Medical Research Council.
- Case-control vaccine effectiveness studies: Data collection, analysis and reporting results. 2017
- Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls. 2017
- Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study. 2017
- Clinical development strategy for a candidate group A streptococcal vaccine. 2017
- Cost-effectiveness of 13-valent pneumococcal conjugate vaccination in Mongolia. 2017
- Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity. 2017
- Repeat pneumococcal polysaccharide vaccine in Indigenous Australian adults is associated with decreased immune responsiveness. 2017
- Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites. 2017
- Standardized Interpretation of Chest Radiographs in Cases of Pediatric Pneumonia From the PERCH Study. 2017
- The cause-specific morbidity and mortality, and referral patterns of all neonates admitted to a tertiary referral hospital in the northern provinces of Vietnam over a one year period. 2017
- The contrasting roles of Th17 immunity in human health and disease. 2017
- Tuberculosis in adolescents and young adults: epidemiology and treatment outcomes in the Western Cape. 2017
- Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection. 2016
- Early gut colonization by Bifidobacterium breve and B. catenulatum differentially modulates eczema risk in children at high risk of developing allergic disease. 2016
- Effect of the introduction of pneumococcal conjugate vaccination on invasive pneumococcal disease in The Gambia: a population-based surveillance study. 2016
- Health at the Sub-catchment Scale: Typhoid and Its Environmental Determinants in Central Division, Fiji. 2016
- Identification of Pif1 helicases with novel accessory domains in various amoebae. 2016
- Investigation of Streptococcus salivarius-mediated inhibition of pneumococcal adherence to pharyngeal epithelial cells. 2016
- Morbidity and Mortality Due to Bordetella pertussis: A Significant Pathogen in West Africa? 2016
- No long-term evidence of hyporesponsiveness after use of pneumococcal conjugate vaccine in children previously immunized with pneumococcal polysaccharide vaccine. 2016
- Real-time qPCR improves meningitis pathogen detection in invasive bacterial-vaccine preventable disease surveillance in Fiji. 2016
- Respiratory Syncytial Virus and Other Viral Infections among Children under Two Years Old in Southern Vietnam 2009-2010: Clinical Characteristics and Disease Severity. 2016
- Status of research and development of vaccines for Streptococcus pyogenes. 2016
- Sustained antibody responses six years following one, two, or three doses of quadrivalent HPV vaccine in adolescent Fijian girls, and subsequent responses to a single dose of bivalent HPV vaccine: a prospective cohort study. 2016
- The economic burden of childhood pneumococcal diseases in The Gambia. 2016
- The large contribution of twins to neonatal and post-neonatal mortality in The Gambia, a 5-year prospective study. 2016
- The scenario approach for countries considering the addition of oral cholera vaccination in cholera preparedness and control plans. 2016
- Acute respiratory infection and bacteraemia as causes of non-malarial febrile illness in African children: a narrative review. 2015
- Antibiotic trials for community-acquired pneumonia - Authors' reply. 2015
- Characterization of 19A-like 19F pneumococcal isolates from Papua New Guinea and Fiji. 2015
- Child Mortality after Discharge from a Health Facility following Suspected Pneumonia, Meningitis or Septicaemia in Rural Gambia: A Cohort Study. 2015
- Deconstructing the differences: a comparison of GBD 2010 and CHERG's approach to estimating the mortality burden of diarrhea, pneumonia, and their etiologies. 2015
- Foot Length, Chest Circumference, and Mid Upper Arm Circumference Are Good Predictors of Low Birth Weight and Prematurity in Ethnic Minority Newborns in Vietnam: A Hospital-Based Observational Study. 2015
- Increased disease due to Haemophilus influenzae type b: population-based surveillance in eastern Gambia, 2008-2013. 2015
- Long-term impact of pneumococcal polysaccharide vaccination on nasopharyngeal carriage in children following a reduced dose pneumococcal conjugate vaccine primary series in infancy. 2015
- Oral cholera vaccines in endemic countries. 2015
- Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events. 2015
- Pneumococcal carriage in rural Gambia prior to the introduction of pneumococcal conjugate vaccine: a population-based survey. 2015
- Pneumococcal conjugate vaccines PREVenar13 and SynflorIX in sequence or alone in high-risk Indigenous infants (PREV-IX_COMBO): protocol of a randomised controlled trial. 2015
- Pneumococcal vaccination and childhood pneumonia in South Africa. 2015
- PneuMum: Impact from a randomised controlled trial of maternal 23-valent pneumococcal polysaccharide vaccination on middle ear disease amongst Indigenous infants, Northern Territory, Australia. 2015
- Reduced dose human papillomavirus vaccination: An update of the current state-of-the-art. 2015
- Reduced IL-17A Secretion Is Associated with High Levels of Pneumococcal Nasopharyngeal Carriage in Fijian Children. 2015
- Single-plex quantitative assays for the detection and quantification of most pneumococcal serotypes. 2015
- Spatial analysis of under-5 mortality and potential risk factors in the Basse Health and Demographic Surveillance System, the Gambia. 2015
- The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods for Examining Pneumococcal Carriage in Vaccine Evaluation Studies. 2015
- The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods for Examining Pneumococcal Carriage in Vaccine Evaluation Studies. 2015
- A prospective study of the prevalence of tuberculosis and bacteraemia in Bangladeshi children with severe malnutrition and pneumonia including an evaluation of Xpert MTB/RIF assay. 2014
- Antibodies against Haemophilus influenzae type b in The Gambia: investigating the extent of protection across age groups. 2014
- Capsular Serotyping of Streptococcus pneumoniae by latex agglutination. 2014
- Comparison of Anti-Pneumococcal Antibodies in Cord Blood from Australian Indigenous and Gambian Neonates and the Implications for Otitis Media 2014
- Impaired serotype-specific immune function following pneumococcal vaccination in infants with prior carriage. 2014
- Investigating the effects of probiotics on pneumococcal colonization using an in vitro adherence assay. 2014
- Placebo use in vaccine trials: recommendations of a WHO expert panel. 2014
- Colonisation endpoints in Streptococcus pneumoniae vaccine trials 2013
- Design questions for Streptococcus pneumoniae vaccine trials with a colonisation endpoint. 2013
- Detection of group a streptococcal pharyngitis by quantitative PCR. 2013
- Does a 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine prevent respiratory exacerbations in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: protocol for a randomised controlled trial. 2013
- Emergence of Streptococcus pneumoniae serotype 15A after the introduction of the conjugate vaccine in Victoria. 2013
- In vitro growth of pneumococcal isolates representing 23 different serotypes. 2013
- Inhibition of Streptococcus pneumoniae adherence to human epithelial cells in vitro by the probiotic Lactobacillus rhamnosus GG. 2013
- Nasopharyngeal microbial interactions in the era of pneumococcal conjugate vaccination. 2013
- Otitis media among high-risk populations: can probiotics inhibit Streptococcus pneumoniae colonisation and the risk of disease? 2013
- Production of latex agglutination reagents for pneumococcal serotyping. 2013
- Silica desiccant packets for storage and transport of Streptococcus pneumoniae and other clinically relevant species. 2013
- Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: updated recommendations from the World Health Organization, Pneumococcal Carriage Working Group 2013
- Supporting local planning and budgeting for maternal, neonatal and child health in the Philippines. 2013
- The high burden of cervical cancer in Fiji, 2004-07. 2013
- Effect of pneumococcal vaccination on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Fijian children. 2012
- Measles in the 21st century. 2012
- Meningitis in children in Fiji: etiology, epidemiology, and neurological sequelae. 2012
- Molecular surveillance of true nontypeable Haemophilus influenzae: an evaluation of PCR screening assays. 2012
- Pneumococcal polysaccharide vaccine at 12 months of age produces functional immune responses 2012
- Protecting against Pneumococcal Disease: Critical Interactions between Probiotics and the Airway Microbiome. 2012
- Serotype replacement after pneumococcal vaccination. 2012
- The cost of outpatient pneumonia in children 2012
- Human papillomavirus genotype prevalence in cervical biopsies from women diagnosed with cervical intraepithelial neoplasia or cervical cancer in Fiji 2011
- Laboratory-based diagnosis of pneumococcal pneumonia: state of the art and unmet needs 2011
- Multilocus Sequence Typing of Streptococcus pneumoniae by Use of Mass Spectrometry. 2011
- Pneumococcal glycoconjugate vaccines produce antibody responses that strongly correlate with function 2011
- Reduction in Rotavirus-associated Acute Gastroenteritis Following Introduction of Rotavirus Vaccine Into Australia's National Childhood Vaccine Schedule 2011
- Serotype-specific avidity is achieved following a single dose of the 7-valent pneumococcal conjugate vaccine, and is enhanced by 23-valent pneumococcal polysaccharide booster at 12 months 2011
- Australian Aid
- Bill and Melinda Gates Foundation
- GAVI Alliance
- National Health and Medical Research Council
- Centre for International Child Health, The University of Melbourne
- Charles Darwin University
- Edith Cowan University
- Emory University, Atlanta, USA
- John Hopkins University, Baltimore, USA
- Lao PDR Ministry of Health
- Laos Oxford Mahosot Wellcome Research Unit
- London School of Hygiene and Tropical Medicine
- Medical Research Council (MRC)
- Menzies School of Health Research
- Ministry of Health, Fiji
- Mongolian Ministry of Health
- Otago University, Dunedin, NZ
- Papua New Guinea Institute of Medical Research
- Pasteur Institute, Vietnam
- The Respiratory and Meningeal Pathogens Research Unit (RMPRU) /Wits, Johannesburg, South Africa
- St George’s Hospital, London, UK
- St George’s, University of London (SGUL), UK
- Telethon Kids
- Universitas Padjadjaran (UNPAD), Bandung, Indonesia
- University of Idaho, Moscow, USA
- University of Oxford, UK
- University of Western Australia
- University of Witswatersrand, Johannesburg, South Africa
- World Health Organization (WHO), Western Pacific Regional Office
- World Health Organization (WHO) HPV Reference Laboratory, The Women’s Hospital
- World Health Organization (WHO) Rotavirus Regional Reference Laboratory, MCRI
- Women’s Centre for Infectious Diseases, University of Melbourne