Infection & Immunity Research

About the project

Rationale: A study to determine the safety and immunogenicity of pneumococcal conjugate vaccines PCV10 (Synflorix™) and PCV13(Prevenar13™) in PNG infants for the serotypes in the respective vaccines.

Design: This randomized control trial investigated the safety and immunogenicity of PCV10 and PCV13 in 200 children.  100 children received PCV10 and 100 received PCV13. At 9 months, 50 children in each PCV arm received booster doses of PPV23 (Pnemovax™)while the remaining 50 in each PCV arm received only the scheduled measles vaccine. At 23 months all children received a challenge dose (0.1mg/ml) of PPV23, to determine the role of hyporesponsiveness to PPV23 at 9 months. Blood and nasopharyngeal swabs were collected at 1,4,9,10,23 and 24 months. Vaccine reaction was measured 24-48 hour post vaccination and all serious adverse events were reported to a data safety monitoring board.

Progress: This study was successfully concluded mid-2016 in terms of participant recruitment, follow-ups and specimen collections.  As of January 2017, completion of 23 & 24 month visit nasopharyngeal swab culturing, serotyping and sensitivity remained outstanding.  Culture, serotyping and the bulk of sensitivity testing had been completed by mid-2017.  A few sensitivity testing remained and was reliant on the procurement of some reagents.  This has now been completed, and the results have been compiled and the database has been updated.  The most recent manuscript relating to this study was accepted and published in February of this year.

Significance: This study helped to inform the National Department of Health (NDoH) about the safety and immunogenicity of PCV10 and PCV13 given with EPI schedules at 1,2, and 3 months.  PCV13 was successfully introduced in PNG in 2014 into the national immunization schedule through support from the Global Alliance for Vaccines and Immunisation (GAVI).  The results from this study should also help to inform the NDoH about whether PCV10 andPCV13 areinterchangeable should global demand exceed supply. In addition, PCV10 contains an important component of Haemophilus influenzae, which could reduce nontypeable Haemophilus influenzae, an important bacteria commonly isolated from lung aspirates of children with pneumonia.  Furthermore, this study has shown that a booster given of PPV23, which provides broader coverage than the conjugate vaccines, may play an important role in preventing deaths due to pneumococcal infection in PNG.

Contributors

Investigators: William Pomat, Andrew Greenhill,Vela Solomon, Peter Richmond, DeborahLehmann, Megan Passey, Anita Van Den Biggelaar, Lea-Ann Kirkham, PeterJacoby, Peter Siba,William Lagani, Rebecca Ford.

Collaborating centres: PNG Institute of MedicalResearch; National Department of Health, PNG;University of Western Australia, Telethon Institutefor Child Health, Sydney University.

Publications related to this project

van den Biggelaar AHJ et al. (2019) Immunogenicity and Immune Memory after a Pneumococcal Polysaccharide Vaccine Booster in a High-Risk Population Primed with 10-Valent or 13-Valent Pneumococcal Conjugate Vaccine: A Randomized Controlled Trial in Papua New Guinean Children.Vaccines7(1).pii: E17. doi: 10.3390/vaccines7010017.

Pomat WS et al. (2018) Safety and immunogenicity of pneumococcal conjugate vaccines in a high-risk population: a randomised controlled trial of 10-valent and 13-valent PCV in Papua New Guinean infants. Clin Infect Dis. doi: 10.1093/cid/ciy743.

Lehmann et al. (2017) Rationale and methods of a randomized controlled trial of immunogenicity, safety and impact on carriage of pneumococcal conjugate and polysaccharide vaccines in infants in Papua New Guinea. Pneumonia 9:20. DOI 10.1186/s41479-017-0044-z.

Conference presentations:

Impact of 10 valent and 13 valent pneumococcal conjugate vaccines on pneumococcal carriage among Papua New Guinean infants.Orami T, Ford R, Michael A, Yoannes M, Nagepu B, Solomon V, Masiria G, Saleu G, Dreyam M, Nivio B, Siba P, Passey M, Jacoby P, Richmond P, Kirkham LA, Lehmann D and Pomat W.  Poster presentation, 11^th International Symposium on Pneumococci & Pneumococcal Diseases, Melbourne, Australia, 15-19 April 2018; and oral presentation, 54^th Annual Symposium of the Medical Society of Papua New Guinea, Madang, Papua New Guinea, 2-7 Sept 2018.

About the project

Rationale: Pneumonia and meningitis are common and serious diseases of childhood, with significant admissions and deaths in children under five years of age.  Studies conducted in EHP have repeatedly shown Haemophilus influenza and Streptococcus pneumoniae to be frequently isolated from sterile sites of sick children. However, these studies were performed more than 20 years ago, and there is a lack of data on what pathogens are currently causing diseases with the introduction of Hib vaccine into the EPI in 2008. This study aims to determine the causes of pneumonia and meningitis in hospitalised children and investigate antibiotic susceptibility in these children.

Design: 1000 children under 5 years of age attending outpatient at Eastern Highlands Provincial Hospital with moderate or severe pneumonia or meningitis were asked to take part in the study.Samples including blood, CSF and urine were collected for laboratory testing.  Children were followed up a month after discharge from the hospital for further investigation. Another 800-1000 healthy children from communities of thesick children were also recruited into the study.Nasopharyngeal swabs were collected from these children.

Progress: The study was essentially completed in January 2016 in terms of recruitment, follow-ups and specimen collections.  As of early this year, some viral and bacterial PCR work remained outstanding, which had been temporarily halted while awaiting the arrival of some essential reagents.  The viral PCR work has now been completed and the bacterial PCR work has resumed, with completion anticipated by mid-year.  An initial draft of a clinical paper for this study has been drafted and is anticipated to be completed and submitted for publication by the end of the year.  A separate virology paper from this study is also being prepared.

Significance: This study will provide information on bacterial and viral pathogens currently circulating in sick and healthy children to guide treatment.

Contributorsntributors

Investigators: Chris Blyth, William Pomat, Andrew Greenhill, Illomo Hwaihwanje, Deborah Lehmann, Celestine Aho, Audrey Michael, Trevor Duke, Joyceline Sapura, Elizabeth Williams, Geraldine Masiria, Rebecca Fordollaborating centres: PNG Institute of Medical Research, Eastern Highlands Provincial Hospital, Universityof Western Australia, Telethon Institute for Child Health Research, Murdoch Children Research Institute

Publications related to this project

Blyth, CC et al. (2017). Childhood pneumonia and meningitis in the Eastern Highlands Province, Papua New Guinea in the era of conjugate vaccines: study methods and challenges. Pneumonia 9:5. DOI 10.1186/s41479-017-0029-y.

An initial draft of a clinical paper for this study has been drafted.

About the project

Rationale:  With the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in PNG in 2014 against the bacteria that causes serious pneumonia in the population, this study aims to determine the level of PCV13 coverage required to achieve a sustained decline in the carriage of PCV13 serotypes in vaccinated and unvaccinated children hospitalised with acute lower respiratory illness in the Eastern Highlands Province.

Design:  The study is being conducted at the Eastern Highlands Provincial Hospital, nearby clinics, PNGIMR, and Goroka township area within 1 hour’s drive of the hospital.  Three groups are invited to participate.  The first group (cases) are hospitalised children <5 years with serious pneumonia or meningitis.  Blood samples, nasopharyngeal swabs, and if necessary, cerebrospinal fluid will be taken from these children for bacterial and viral detection.  The second group (contact participants) are children <5 years who have slept or played with the sick children.  If parents agree, questions about the risk factors for pneumococcal disease will be asked, a nasopharyngeal swab taken, and vaccine information from child health books taken.  The third group are adults who look after the cases and contact participants.  They will also be asked questions about the risk factors for pneumococcal disease, and one nasopharyngeal swab taken.  In addition, community surveys will collect data on as many children <5 years from the communities of the cases from which vaccination information only is obtained and recorded.  Target case recruitment is 1200, with up to 1200 contacts and caregivers enrolled as well.

Progress:  This was initially a 3 year study which started in April 2016, but has now been extended to the end of this year.  As of the end of March 2019, 2127 cases, 2123 caregivers, and around 750 contacts had been recruited; and around 3800 community surveys conducted.  Case recruitment of 40 per month continues to be up and down due to:polio vaccination round implementations, closure of North clinic and COPD due to water issues and staffing problems within the clinics themselves, as well as access to vehicles.  Contact swab collection has continued to improve, with an overall average of 20 per month for the study so far.  Blood culture contamination has continued to remain lower than previously (20%) to about 13%.  638 case swabs have been serotyped by microarray analysis. 

Significance: Implementation of the PCV program has resulted in more than half of children being vaccinated.  It is anticipated that as PCV13 coverage increases, there will be a corresponding decline in PCV13 serotype carriage in both vaccinated and unvaccinated individuals.  However, PNG children in the highlands have diverse pneumococcal carriage from early infancy, which may limit the effectiveness of the vaccine.  Continued surveillance for vaccine preventable diseases is very important and needed to help guide vaccine policies and recommendations.

Contributors

Investigators: Fiona Russell, Chris Blyth, William Pomat, Deborah Lehmann, Peter Siba, Jocelyn Chan, Rebecca Ford, Catherine Satzke, Eileen Dunne, Jana Lai, Trevor Duke, Yazid Abdad, Amanda Lang, Peter Richmond, Kim Muholland

Collaborating centres: PNG Institute of Medical Research, Eastern Highlands Provincial Hospital, University of Western Australia, Telethon Kids Institute, Murdoch Children’s Research Institute

Publications related to this project

Chan et al. (2018). Determining the pneumococcal conjugate vaccine coverage required for indirect protection against vaccine-type pneumococcal carriage in low and middle-income countries: a protocol for a prospective observational study. BMJ Open 8:e021512. DOI: 10.1136/bmjopen-2018-021512.

Conference presentations:

PneuCaptive Study: 13-valent pneumococcal conjugate vaccine coverage in hospitalised children with pneumonia from the Eastern Highlands Province, Papua New Guinea. Kave J, Sapura J, Nivio B, Akunaii Z, Dreyam M, Ford RL, Kirarock W, Chan J, Muholland EK, Lehmann D, Pomat WS, Blyth CC and Russell FM. Poster presentation, 11^th International Symposium on Pneumococci & Pneumococcal Diseases, Melbourne, Australia, 15-19 April 2018; and oral presentation, 54^th Annual Symposium of the Medical Society of Papua New Guinea, Madang, Papua New Guinea, 2-7 Sept 2018.

High rates of multiple serotype carriage detected by micro array in hospitalised children with pneumonia in the Eastern Highlands of Papua New Guinea. Ford RL, Dunne EM, Satzke C, Chan J, Yuasi L, Yoannes M, Nation ML, Pell CL, Ortika BD, Alamrousi A, Hinds J, Sapura J, Nivio B, Akunaii Z, Muholland EK, Lehmann D, Pomat WS, Blyth CC and Russell FM. Poster presentation, 11^th International Symposium on Pneumococci & Pneumococcal Diseases, Melbourne, Australia, 15-19 April 2018; and oral presentation, 54^th Annual Symposium of the Medical Society of Papua New Guinea, Madang, Papua New Guinea, 2-7 Sept 2018.

Direct and indirect effects of 13-valent pneumococcal conjugate vaccine in hospitalised children with pneumonia. Ford R, Sapura J, Kave J, Yuasi L, Yoannes M, Chan J, Dunne E, Satzke C, Lehmann D, Pomat WS, Blyth CC and Russell FM. Oral presentation, 53^rdAnnualSymposium of the Medical Society of Papua New Guinea, Port Moresby, Papua New Guinea, 3-6 Sept 2017.

About the project

Rationale:  To better understand the microbial communities in the digestive tract of children in early childhood.  These communities of microbes are referred to as the gut microbiota, and in recent years have been closely associated with human health.  As yet, no studies have looked into the role the gut microbiota might play in preventing infectious diseases in young children.

Design:  Up to 40 infant participants, and up to 60 adult participants will be asked to participate through both the antenatal clinic and through community engagement from the Goroka and Asaro districts of the Eastern Highlands Province.  Infant participants will be followed through the first 12-15 months of their life.  A stool sample will be collected from a soiled diaper each month (up to 12 samples per participant), and a small volume of blood (3ml) will be collected at 6 and 12 months.  For adult participants, up to 3 stool samples and 2 blood samples (up to 10ml) will be collected.  If mothers of some participating babies are enrolled, up to 3 samples of breast milk (up to 5ml each sample) will be collected in addition.

Progress:A total of 38 general adults, 37 infants, and 36 mothers of participating infantshave been enrolled and recruited into the study.  All general adult samples have been collected for visits 1& 2.  All maternal participant samples have been collected for visit 1; with 15 having been seen through to visit 2. All infant participants enrolled have been seen through their 1 month visit; 26 babies have completed their 2 month visit; 20 babies have completed their 3 month visit; 11 babies have been seen through their 4 month visit; and 2 babies have completed their 5month visit.Immunisation/vaccination status for all infant participants are up-to-date.  All samples collected have been processed and currently stored appropriately for future analysis.

Significance:  Through this study it is hoped that protective “good” germs will be identified that potentially could be administered to help protect infants against diarrhoea.

Contributors

Investigators:  Andrew Greenhill, William Pomat, Rebecca Ford, Jessica Schneider, Jens Walter, Paul Horwood, Peter Siba, Moses Laman, Severine Navarro, Jason Norman, Elisheba Malau.

Collaborating Centres:  PNG Institute of Medical Research, Eastern Highlands Provincial Hospital, Federation University, Vedanta Biosciences, James Cook University.

About the project

Rationale:  Despite pneumonia continuing to remain a leading cause of childhood morbidity and mortality worldwide, little is known about host immune determinants that may predispose some children to developing severe pneumococcal pneumonia.  In an earlier investigation, saliva samples collected from severe childhood pneumonia cases as part of the Aetiology of pneumonia and meningitis study, revealed a novel single nucleotide variant (SNV) in the gene coenzyme Q6 that was unique to PNG children.  Using a mouse model, this gene variant was subsequently found to increase susceptibility to pneumococcal lung infection, suggesting that SNV may be a contributing factor to increased disease burden in PNG children.  To verify that this genetic variant is disease-associated, a larger cohort is required.

Design:  Over the next 3 years, up to 300 children less than 5 years of age with ALRI, and up to 300 biological relatives and 320 unrelated population controls will be asked to participate through the Eastern Highlands Provincial Hospital, nearby clinics, PNGIMR, and through community engagement from the Goroka township area.  A saliva sample will be collected from all participants, from which DNA will be extracted for genetic analysis of the COQ6 variant, as well as some demographic information.

Progress: An ethics application for this study has recently been submitted, reviewed and accepted by the IMR IRB and MRAC ethics committee.  Consent and saliva sample collection has already commenced as part of the ongoing Aetiology-PneuCaptive study and through a previous ethics application submitted for the initial cohort from where the genetic variant was initially identified; with 300 ALRI samples having already been collected.

Significance: Through this study the frequency of occurrence of the COQ6 variant in the Goroka population will be determined; and whether or not this variant is associated with paediatric pneumonia.

Contributors

Investigators: Celeste Morley, William Pomat, Sarah Javati, Todd Druley, Barak Cohen, James Kazura, Chris Blyth, Deborah Lehmann.

Collaborating Centres:  PNG Institute of Medical Research, Eastern Highlands Provincial Hospital, Washington University, Case Western Reserve University, The University of Western Australia, Telethon Kids Institute.