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NHMRC Centre of Research Excellence for Pneumococcal Disease Control in the Asia-Pacific

The National Health and Medical Research Council (NHMRC) Centre of Research Excellence on Asia-Pacific Pneumococcal Disease Control in the PCV Era (CRE-PDC), aims to address two outstanding research gaps for pneumococcal conjugate vaccine (PCV) use in the Asia-Pacific region:

  • country decisions regarding reduced dose PCV schedules (1+1);
  • and understanding serotype replacement following vaccine introduction.

The program will generate new evidence to support decisions regarding the sustainability of national immunisation PCV programs. In addition the program will forge partnerships with key end-users to ensure research translation, establish new international linkages to enable broader dissemination and develop the next generation of nationally competitive researchers; with provision of capacity building and early career development opportunities and collaboration. The CRE-PDC is funded by the NHMRC for five years (2021-2025).

What is pneumococcal disease?

Pneumococcal disease is an infection caused by the bacteria, Streptococcus pneumoniae (the pneumococcus). The pneumococcus commonly resides in the back of the nose without causing symptoms, but may sometimes spread to the lungs, brain, and other organs causing serious diseases such as pneumonia, meningitis or septicaemia (invasive pneumococcal disease).

Why is pneumococcal disease important?

According to the World Health Organization, pneumonia is the single biggest killer of children globally, accounting for the deaths of approximately 1.4 million children aged under five years each year. Pneumonia is more common in South Asia and sub-Saharan Africa.

Why is it important to do surveillance for pneumococcal disease?

Surveillance for pneumococcal disease is important to describe disease trends, monitor changes in the frequency of antimicrobial resistant strains, describe changes in pneumococcal serotypes (strains), monitor the impact of vaccines on disease, advise on future vaccine development and the optimal schedule needed to control the disease.

Impact of pneumococcal conjugate vaccines

Surveillance for pneumococcal disease has shown that PCV introduction has resulted in a decline in both carriage and invasive pneumococcal disease due to serotypes covered by the vaccine. However, serotypes not contained in the vaccine have increased (so called replacement) and the extent to which this occurs is not known in the Asia-Pacific region.

Reduced dose pneumococcal conjugate vaccine schedules

To optimise a schedule, reduce the number of injections, and make space for other vaccines, reducing the schedule from a 3-dose to a 2-dose schedule in countries that have “mature” PCV programs and have pneumococcal vaccine-type disease controlled, could potentially improve the vaccine’s financial sustainability. This strategy is being pursued as part of a global PCV research agenda. The success of this approach relies on this schedule being able to maintain vaccine-type pneumococcal carriage control, and thereby continue generating herd protection. It is important to identify immunological markers which demonstrate that the reduced schedule is likely to be successful and to provide economic evidence for countries regarding the use of reduced schedules for health policy decision making.  


Related MCRI research

Theme: Infection and Immunity

Groups:


Image credits: Direct Relief/2003 under CC BY-NC-ND 2.0 license

Chief Investigators

Professor Fiona RussellProfessor Fiona Russell is the Asia-Pacific Health Research Group Leader at MCRI and the Director of the Child and Adolescent PhD Program at the University of Melbourne. Prof Russell is the Principal investigator on PCV impact evaluations and surveillance studies in Fiji, Laos, Mongolia and PNG (funded by BMGF, Gavi, WHO and the Department of Foreign Affairs and Trade (DFAT)) in partnership with senior government officials (Directors of Public Health, Communicable Diseases and National Immunisation Programs) and WHO.
Associate Professor Paul LicciardiAssociate Professor Paul Licciardi is an immunologist and Senior Research Fellow at MCRI with expertise in the evaluation of vaccine immune responses in animal models and humans. He is the Immunology Team Leader within the New Vaccines Research Group at MCRI. A/Prof Licciardi has honorary appointments at the University of Melbourne, Menzies School of Health Research and is a Scientific Consultant at Singapore Polytechnic. He leads the immunology work on PCV reduced dose schedules in Vietnam and has established B and T cell assays at MCRI and in Vietnam.
Associate Professor Catherine SatzkeAssociate Professor Catherine Satzke is the Translational Microbiology Group Leader at MCRI. A/Prof Satzke has established gold-standard approaches for pneumococcal carriage studies, including leading the WHO guideline for pneumococcal carriage, the authoritative standard in the field. She leads the microbiology for 10 PCV studies in the Asia/Pacific and oversees a laboratory training and capacity-building program in the Asia/Pacific and leads an experimental research program investigating the biology of pneumococcal carriage and disease.
Professor Kim MulhollandProfessor Kim Mulholland is the New Vaccines Group Leader at MCRI, and has a joint appointment at the London School of Hygiene and Tropical Medicine. Prof Mulholland is a pre-eminent world leader in pneumococcal vaccinology and has been a leading figure in advising on the international pneumococcal research agenda for WHO. He currently leads PCV impact evaluations in Mongolia and reduced dose schedules in Vietnam (funded by BMGF and Gavi, in partnership with senior government officials and WHO) and is co-investigator on PCV impact studies in Laos Fiji and PNG.
Professor Mark JitProfessor Mark Jit is a Professor of vaccine epidemiology at the London School of Hygiene and Tropical Medicine and is currently a visiting professor (10% FTE) at the University of Hong Kong, School of Public Health. Prof Jit is a world leading health economist whose research on vaccine economics has helped inform immunisation policy on a range of vaccines, including PCV, in LMICs.
Professor Sarath RanganathanProfessor Sarath Ranganathan is Director of Respiratory and Sleep Medicine at the Royal Children’s Hospital in Melbourne, Group leader at the Murdoch Children’s Research Institute and Professor, Head of Department, Melbourne University Department of Paediatrics. He has extensive experience in the area of detection and monitoring of lung disease. He holds leadership roles within paediatric respiratory medicine internationally and provides clinical leadership internationally, including the Asia-Pacific region. His research findings have translated into UK and Australian national guidelines.
Professor Peter McIntyreProfessor Peter McIntyre has more than 20 years of experience as a medical epidemiologist with a clinical background in paediatric infectious diseases working in a broad range of research related to vaccines and vaccine-preventable diseases. He was Deputy-Director (1997-2004) and Director (2004-17) of the Australian National Centre for Immunisation Research and Surveillance (NCIRS), now Senior Professorial Fellow. He has a current role as the WHO Western Pacific regional representative on the WHO Special Advisory Group of Experts (SAGE) in Immunisation.
Dr Natalie CarvalhoDr Natalie Carvalho is a health economist and Senior Research Fellow at the University of Melbourne. She sits within the Centre for Health Policy (Health Economics Unit) and the Global Burden of Disease Group at Melbourne School of Population and Global Health. She also has an honorary appointment at MCRI. Dr Carvalho’s research career has successfully intertwined health policy and global health, with a focus on the use of economic evidence for decision-making in health policy. Dr Carvalho recently assessed the cost-effectiveness of three new childhood vaccines (rotavirus, pneumococcal conjugate, human papillomavirus) in four Pacific Island countries (funded by Asian Development Bank).
Professor Yin Bun CheungProfessor Yin Bun Cheung is a Professor at Duke-NUS Medical School, Singapore, and Adjunct Professor at Tampere University, Finland. Prior to joining Duke-NUS in 2012, he served as a biostatistician at the National Cancer Center Singapore, a senior lecturer at the London School of Hygiene & Tropical Medicine, and Chief Scientific Officer at the Singapore Clinical Research Institute. He received his degrees in social science, medical demography, statistics and paediatric epidemiology from institutions in Hong Kong, Singapore, and the United Kingdom. He has broad interest in the studies of child health, statistical methodology, and health and quality of life outcomes. As of 2020, he is the Principal Investigator of a study to improve statistical methodology for analysis of recurrent events in vaccine research (funded by the National Medical Research Council, Singapore), and the Co-Principal Investigator of a cluster randomized trial to evaluate the impact of periodic mass administration of azithromycin to infants in a high-mortality setting (funded by the Bill & Melinda Gates Foundation).
Dr Cattram NguyenDr Cattram Nguyen is a biostatistician/senior research fellow at MCRI, with an honorary appointment with the University of Melbourne. She is also a post-doctoral researcher at the Victorian Centre for Biostatistics. Her research portfolio spans statistical methodology and applied research in maternal and child health. She is the statistician on PCV impact studies in the Asia-Pacific and 6 RCTs, including pneumococcal vaccine trials in Vietnam and The Gambia. Dr Nguyen has contributed to translation of statistical knowledge through her teaching activities in Australia and internationally, as well as through her statistical research on multiple imputation, a method for handling missing data.

Associate Investigators

Dr Toan NguyenDr Toan Nguyen is a medical doctor with a public health, epidemiology and vaccinology background who is currently Head of Clinical Research Center of Pasteur Institute, Ho Chi Minh City, Vietnam. He has extensive experience in ethical clinical trial review, clinical trial operation, technical writing, training and evaluation of health programs and is involved in giving technical support to National Immunization Program members and been an investigator on more than 17 clinical vaccine trials since 2009. He has been involved in developing guidelines such as the National Vaccine Trial Guidelines for the Vietnam MoH and is currently establishing a clinical trial centre at Pasteur Institute.
Professor Mayfong MayxayProfessor Mayfong Mayxay is the Head of the Field Research of Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU) and Vice-President of the Lao National University of Health Sciences, Ministry of Health. He has also been a Visiting Professor in Tropical Medicine at University of Oxford since March 2020. Prof Mayxay is one of the key founders of LOMWRU, Lao Medical Journal and he is also the founder of the Ethical Committee for Health in the University of Health Sciences, Laos. His particular research interests include antimalarial drug resistance, AMR, causes of fever, dengue, rickettsial infections, Japanese Encephalitis virus infection and infantile beri-beri.
Staff memberDr Eric Rafai is a Public Health Physician and Head of the Health Information Unit and International Projects in the Fiji Ministry of Health. Formerly he was the Deputy Secretary of Public Health in the Ministry of Health & Medical Services, Fiji. His post graduate training includes a Master of Public Health from Queensland University of Technology and a Masters of Infectious Disease from the University of Western Australia. He has at least 19 years’ experience in public health research in Fiji and the Region, representing the MoH in International & Regional Public Health Initiatives, forums and Expert meetings. Dr Rafai has research interest in AMR, Climate Change & Health and infectious diseases. Dr Rafai provides local advisory capacity of the Ministry’s participation in the projects.
Dr Tuya Mungan is a paediatrician who has been working in maternal and child health and development areas for 30 years in Mongolia and throughout Asia, both with the Mongolian government and with UNICEF. During her career she has contributed to research and programs focused on reducing child morbidity and mortality in LMICs in Asia. This involved the introduction of low cost- high impact interventions such as immunisation, child growth and safe motherhood and prevention of micronutrient deficiency as well as nutrition. Dr Mungun currently leads a Gavi funded PCV impact evaluation in Mongolia in cooperation with the Mongolian MoH, MCRI and WHO.
Professor Kulkanya ChokephaibulkitProfessor Kulkanya Chokephaibulkit is a Professor of Pediatrics at Mahidol University. Her research focuses on paediatric infectious disease, vaccine responses, and HIV infection. She has extensive experience in clinical research, with over 220 peer-reviewed publications. She has been an advisory board member of Thai National Immunization Program, and an Executive Board member of the National Vaccine Institute. She founded the Pneumococcal Laboratory Network to study pneumococcal serotypes in IPD in children in central Thailand in 2005, and her team continue to monitor the pneumococcal serotypes in the area. She is one of the leading paediatric infectious diseases paediatricians in Asia. Prof Chokephaibulkit is currently the Director of SICRES (Siriraj Institute of Clinical Research) in Bangkok, Thailand.
Staff memberProfessor Anna Lisa T. Ong-Lim is an Associate Professor and attending paediatrician at the Department of Paediatrics, College of Medicine, Philippine General Hospital, University of the Philippines, Manila. Prof Ong-Lim is a member of many professional organisations, societies and committees. She is a Fellow of the Philippine Pediatric Society and a member of its Board of Trustees. In addition, she is a Fellow of the Pediatric Infectious Disease Society of the Philippines and serves as its current President. Prof Ong-Lim has been clinical research coordinator, co-investigator and principal investigator in several clinical trials, in particular vaccine-related trials. She has contributed to both local and international clinical guidelines on paediatric infectious diseases.
Professor Stephen D. BentleyProfessor Stephen D. Bentley is a molecular microbiologist and a global leader of bacterial genomics. He is a Principal Staff Scientist and team leader at the Wellcome Sanger Institute, Cambridge, UK. Prof Bentley is Director of the Global Pneumococcal Sequencing project which sequenced more than 25,000 pneumococcal genomes from more than 50 countries to survey the evolutionary impact of pneumococcal vaccine implementation. The findings have been employed by the Bill & Melinda Gates Foundation and other stakeholders in the selection of antigens to be included in next-generation pneumococcal vaccines with direct contribution to reducing mortality in the foreseeable future. His study to sequence the capsular biosynthesis genes for all known serotypes of S. pneumoniae enabled molecular methods for determining serotype which have brought important new understanding of pneumococcal colonisation and transmission. Since the development of high throughput sequencing his research has focussed on population genomics with pioneering papers on MRSA (2010) and the pneumococcus (2011) revealing patterns of international spread, vaccine escape and the acquisition of antimicrobial resistance. Prof Bentley has honorary professorships at the Universities of Cambridge and Liverpool.

Project 1: Evaluating novel markers of pneumococcal vaccine immunity

A key question related to the use of pneumococcal vaccines, particularly to alternative PCV schedules, is the duration of immunity and whether novel markers of PCV immunity, such as B-cell and T-cell responses are important for protection against vaccine-type pneumococcal carriage. Using stored PBMC samples collected from infants in the Vietnam Pneumococcal Project, the Project will evaluate whether pneumococcal-specific memory B cells and Th17 cells persist into the second year of life following PCV use in infants.

Project 2: Determining immune correlates of protection against pneumococcal carriage.

Defining a correlate of protection against vaccine-type pneumococcal carriage remains an unmet goal in PCV research. This Project will investigate different immunological parameters (IgG, OPA, memory B cells) to determine an immune correlate of protection against vaccine-type carriage. This is of particular importance in the context of reduced-dose PCV schedules, where more sensitive measures of pneumococcal immunity, such as the memory B cell response may be required to maintain protection.

Project 3: Undertake health economic assessments of 1+1 PCV in Asia-Pacific countries

This Project will assess value for money of a 1+1 PCV schedule through a cost-effectiveness analysis and evaluate the financial impact on the government’s immunisation budget through a budget impact analysis in three Asia-Pacific countries. Other countries will also be invited to join the Project. The data will be supplemented with key informant interviews to estimate the economic and financial costs of delivering vaccines from a government and international partner perspective.

Project 4: Impact of pneumonia on the health and economic wellbeing of the household

Laos is one of the poorest countries in South-East Asia. High out-of-pocket payments for health can lead to catastrophic health expenditure, resulting in impoverishment for vulnerable groups. Oxygen supplementation can be prohibitively expensive, with many families unable to afford treatment. This Project aims to describe the health and economic impact of a pneumonia health shock on the household and will include children admitted to hospital with a catastrophic pneumonia event (severe pneumonia and either ventilated, require oxygen or referral).

Project 5: Evaluate the broader health, financial and equity impacts of alternative financing arrangements for PCV through extended cost-effectiveness analysis

Given the cost of PCV introduction and recurring costs of routine vaccine dose and delivery once introduced, the added costs of PCV introduction is likely to represent a large portion of a national health budget in low- and middle-income countries (LMICs). Understanding all funding options as well as the expected economic and budgetary impact of the various options, alongside the effect on health, financial risk protection and equity, is necessary for policy-makers to adequately inform decision-making surrounding these options. This Project aims to compare the budget impact, cost-effectiveness and extended cost-effectiveness (including quantifying the impact on household impoverishment and catastrophic expenditure) of different financing options for PCV introduction.

Project 6: Serotype replacement in empyema

Empyema is a severe form of pneumonia where pus accumulates in the pleural cavity. It is important to monitor the causative empyema pneumococcal serotypes. However, obtaining a suitable sample from pneumonia patients for testing is challenging. Although ~60% of the world’s population live in Asia, there is little information on the serotypes causing disease from the region, particularly from LMICs. The likely impact of PCVs and replacement in Asia cannot be inferred from other settings, because the epidemiology, antibiotic use and social interactions vary. We will overcome this challenge by examining replacement in empyema. Empyema is caused by a number of different bacteria, including pneumococci. This Project aims to employ molecular methods to determine the aetiology of empyema in hospitalised children in five countries (Mongolia, Indonesia, Thailand, Philippines and Hong Kong) and monitor serotype replacement.

Project 7: Is the detection of minor pneumococcal serotypes important?

We have been undertaking carriage and pneumonia surveillance in Laos, Fiji, Mongolia and PNG for 3-5 years. We will use these stored carriage samples with multiserotype carriage rates ranging from <1 to 54%, to explore whether the rate of multiserotype carriage influences the vaccine-type carriage rate ratios pre/post-PCV, and thereby estimates of PCV impact. The Project will determine whether microarray serotyping adds information value to traditional culture-based serotyping methods, using stored carriage samples from the Asia-Pacific region.

Project 8: Identifying replacement serotypes

PCV introduction leads to substantial changes to the pneumococcal population, including the emergence of non-vaccine serotypes (serotype replacement). There is a paucity of data on the pneumococcal capsule genes and population biology from the Asia-Pacific. Using carriage isolates sourced from children in six countries (Vietnam, Laos, Fiji, Mongolia, PNG and Indonesia), we will use whole-genome sequencing to understand the organisation of capsule genes, and apply widely used phenotypic and molecular serotyping methods to identify mistyping. We will determine if antibodies induced by vaccination or infection are still effective against these variants. To assess the virulence of replacing lineages, we will use animal models of carriage, transmission and pneumonia.

Project 9: Association between non-vaccine type carriage and severe pneumonia

This Project aims to determine whether non-vaccine carriage (replacement) is associated with severe pneumonia following five years of PCV use.

We will use data from our PCV evaluation programmes in Laos, Mongolia and PNG where carriage surveillance has been established in children admitted to hospital with pneumonia, and detailed social contact information and potential confounders for carriage were collected.

Project 10: Extension of PNEUmococcal CArriage in Pneumonia To Investigate Vaccine Effects (PneuCAPTIVE) study in PNG

The PneuCAPTIVE study aims to (1) investigate the relationship between PCV13 coverage and pneumococcal vaccine-type carriage among undervaccinated children (indirect effects) aged 2–59 months with an acute respiratory infection in three sites including PNG; (2) describe monthly trends in vaccine-type carriage prevalence among cases and contacts; (3) investigate the relationship between PCV13 coverage and VT carriage among undervaccinated contacts (indirect effects) and caregivers living in the community; and (4) compare the PCV13 coverage required to demonstrate indirect effects of PCV13 by site

This extension Project will test nasopharyngeal samples collected from caregivers to determine changes in vaccine-type carriage in the community and to examine indirect effects in the adult age group.


Image credits: Direct Relief/2013 under CC BY-NC-ND 2.0 license

Useful websites

CRE Training Lab podcasts
Aimed at early to mid career researchers and PhD students for topics such as preparing grant applications and conducting systematic reviews
https://www.predict.org.au/podcasts/

MCRI Clinical Research Development Office (CRDO)
Guidance, procedures and templates to help you plan and conduct your trials
https://www.mcri.edu.au/research/training-and-resources/launching-pad

MCRI Clinical Epidemiology & Biostatistics Unit (CEBU)
Short courses and training on statistical methods, data management and software packages
https://www.mcri.edu.au/research/facilities-resources-and-training/cebu-...

TeachEpi
A resource for learning and teaching epidemiology
https://www.teachepi.org/


Image credits: UN Women Asia and the Pacific/2015 under CC BY-NC-ND 2.0 license