Centre of Research Excellence in Pneumococcal Vaccinology
The program of work of the Pneumococcal Centre of Research Excellence (CRE) recognises the similar importance of the three disciplines in this complex field of pneumococcal vaccine research namely, clinical epidemiology, immunology and microbiology. The major ongoing project as part of the CRE is a large Phase II trial in Vietnam, funded by NHMRC, examining different schedules of the two pneumococcal conjugate vaccines (PCVs). Clinical epidemiology forms the basis of this trial and will be supported by state-of-the-art immunology and microbiology developed and sustained by this CRE. Innovation in both areas will provide better tools for the ongoing evaluation of pneumococcal vaccines in all settings.
This work is expected to have regional and global implications for the use of pneumococcal vaccines in developing countries. The Phase II trial will guide developing countries all over the world as they struggle to introduce PCV. Improved microbiological and immunological assays undertaken with CRE will greatly enhance the interpretation and understanding of the information generated through this trial, enabling countries and international authorities to make better, evidence-informed choices. In addition, the molecular microbiology and mathematical modelling will provide the basis of tools to identify and monitor the impact of PCV introduction in all countries.
Professor Jonathan Rhys Carapetis
Telethon Institute, Perth
Professor Carapetis has been closely involved in the development of the pneumococcal research program since its inception in 2001. He provided co-supervision for A/Prof Russell’s PhD on the Fiji research program, and, as Director of the Menzies School of Health Research, personally oversaw the development of a strong pneumococcal vaccine research program amongst Indigenous children and adults in the Northern Territory. He is working on a global effort to accelerate the development of an effective Group A Streptococcal vaccine, a field with many similarities to the pneumococcal vaccine research field.
Associate Professor Amanda Leach
Menzies School of Health, Darwin
Dr Leach is an internationally recognized pneumococcal microbiologist. As the senior Australian microbiologist on the program, she is responsible for oversight of the microbiological aspects of the program. She is also the PI of a major new pneumococcal vaccine trial involving Indigenous children, and her involvement ensures that methods developed by the CRE members are used where appropriate for that study.
Associate Professor Dang Duc Anh
Head of Vietnam’s Expanded Programme on Immunisation
A/Prof Dang Duc Anh is the Deputy Director of the National Institute for Hygiene and Epidemiology in Vietnam. In that role he is the primary person responsible for advising the Government of Vietnam on the introduction of new vaccines. He is co-PI of the Phase 2 trial in Vietnam, and has been involved in detailed discussions with the PI on the role of a Phase 4 trial in Vietnam. He is a respected member of the global immunization community and a regional leader in the field of new vaccine introduction.
Associate Professor Lay Myint Yoshida
Nagasaki University, Japan
A/Prof Yoshida is a physician/molecular biologist from the University of Nagasaki in Japan. He is the leader of the Nagasaki University’s pneumonia research program in Nha Trang, on which the PI is a co-investigator. He is also an investigator on the Phase 2 trial in which he is responsible for overseeing the molecular biology undertaken in Vietnam. The Nha Trang demographic surveillance site, established by the group, is be an important part of the phase 4 trial.
Professor William Edmunds
London School of Hygiene and Tropical Medicine
Prof Edmunds heads the mathematical modelling team at the London School of Hygiene and Tropical Medicine. He is internationally recognised as a leader in the field of modelling vaccine effects on infectious diseases. His group will be responsible for the establishment of models to predict and understand the relationship between vaccine introduction, nasopharyngeal carriage of pneumococci and vaccine effectiveness. In particular we plan to develop models that will lead to the development of early warning systems to identify significant serotype replacement requiring policy adjustment.
Professor Andrew Pollard
University of Oxford, UK
Prof Pollard is the Professor of Paediatric Infection and Immunity at the University of Oxford. He is also Director of the Oxford Vaccine Group
Professor Keith Klugman
Head, Pneumonia, Bill and Melinda Gates Foundation
Prof Klugman is a global leader in the pneumococcal field. He is a major advisor to the United States, European and African regulatory authorities and to major industry partners. He is Chair of the Steering Committee for the PneuCarriage project lead by the PI and Dr Satzke. In his previous role he was as a sub-grantee on the project, as his group in South Africa are developing RT PCR assays for all 93 pneumococcal serotypes to act as a gold standard for the methods under evaluation.
The Centre of Research Excellence in Pneumococcal Vaccinology is a collaboration between experts from the following institutions:
- Murdoch Childrens Research Institute
- Telethon Kids Institute
- Menzies School of Health Research
- Vietnam’s Expanded Programme on Immunisation
- Nagasaki University, Japan
- London School of Hygiene and Tropical Medicine
- WHO, Expanded Programme on Immunization
- PATH, USA
- University of Oxford
- Bill and Melinda Gates Foundation
In Vietnam, we are conducting an NHMRC-funded Phase II trial evaluating alternative schedules of PCV10 and including the first head to head comparison of PCV10 and PCV13. The Phase II trial in Vietnam is designed around the remaining questions that need to be addressed for WHO to make a decision on whether to revise the basic EPI schedule to accommodate the particular characteristics of PCVs. Specifically, with regard to PCV, the study will evaluate:
- A reduction in the number of doses in the primary series to 2;
- The value of a booster dose at 9 months;
- The potential value of a schedule with 2 doses only; and
- The comparative value of the two available second generation PCVs (PCV10 and PCV13).
The study design is a six-armed open randomised trial of various schedules of PCV10 and PCV13. The sample size is based on two primary objectives, and the study is also powered to address key secondary objectives. The primary objectives are:
- To determine the optimal schedule for provision of EPI vaccines with the incorporation of PCV10; and
- To compare the responses to vaccination with PCV10 and PCV13.
With support from the CRE, we are expanding the range of methods used to analyse samples from the Phase II trial, in order to give the most complete picture of the performance of the vaccines under different schedules. For the purposes of sample size calculations we have carefully defined non-inferiority for the range of primary and secondary questions we are addressing. However, we do not see these questions as one-dimensional and we recognise that each of the vaccines and schedules may have advantages in some areas and disadvantages in others. For this reason we are proceeding with a full range of immunological and microbiological endpoints, with measurement of:
- Serotype-specific IgG by ELISA for each of the 13 serotypes in the vaccines;
- Opsonophagocytic antibody for the same serotypes;
- Memory B-cell responses to pneumococcal vaccination;
- Overall and vaccine-type pneumococci carriage using conventional and molecular means;
- H. influenzae carriage using conventional and molecular means; and
- The quantitative burden of pneumococci and H. influenzae.
An important part of the CRE is the development of new methodologies for the measurement of pneumococcal protein responses at MCRI (AIs Licciardi and Balloch), in collaboration with AI Alderson (currently Director of PATH’s Pneumococcal Protein Vaccine Project). Under this CRE, we plan to identify the best protein targets using cutting-edge technology used for the evaluation of
pneumococcal vaccine immunogenicity. Host immunity to novel pneumococcal protein candidates will be correlated with exposure to the organism, assessed by NP carriage. In addition, we are examining the memory response to pneumococcal proteins in the same way as that developed for the polysaccharide-specific B cell assay. We have demonstrated that memory B cells specific to other vaccine proteins such as tetanus and diphtheria can be measured in this way.
We are evaluating the immune response to (selected) pneumococcal proteins in a number of ways:
- Measurement of protein-specific IgG responses in the serum by ELISA;
- Assessment of antibody function by avidity measurement;
- Analysis of the T-lymphocyte response by proliferation assays;
- Enumeration of cytokine-secreting T-lymphocytes by ELISPOT; and
- Enumeration of the memory B cell response to novel pneumococcal proteins by ELISPOT.
We are establishing the best method to detect multiple serotype carriage, identified through the PneuCarriage Project, in our laboratories. We will apply the best method in the following settings:
- To examine pneumococcal carriage in participants of the Phase II trial in order to evaluate the extent of serotype replacement following immunisation and to identify possible differences between groups.
- To establish baseline data on carriage in the population through periodic cross-sectional analyses. This will provide the input into mathematical models to assist in monitoring the impact and process of serotype replacement at the individual and at the population level.
We are utilising qPCR to assess the effects of PCV10 and PCV13 on NP carriage of multiple bacterial species in Vietnamese children. We are expanding the qPCR protocol to quantify GAS and non-typhoid Salmonella spp., both of which are major causes of paediatric disease in developing countries. Overall, the microbiology techniques developed through the CRE will support our ongoing pneumococcal vaccine research work. Transferring the new technologies to our colleagues in Vietnam and elsewhere in the region will greatly assist with the introduction and evaluation of pneumococcal vaccines in the region.
The primary purpose of this program of work is to strengthen the evidence base for pneumococcal vaccine use, to identify the schedules most appropriate for their use in the developing world, and to develop a method of monitoring the population biology changes that result from their use. We constantly reassess our goals in the light of developing evidence from other groups and national programs.