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Background Information and Scientific Rationale Alternative Pneumococcal Vaccination Schedules for Infants in Fiji and Pneumococcal Epidemiology Dr Fiona Mary Russell Submitted in total fulfillment of the requirements of the degree of Doctor of Philosophy 11th October, 2010 Department of Paediatrics Faculty of Medicine, Dentistry, and Health Sciences The University of Melbourne i ABSTRACT This thesis documents the pneumococcal disease burden and the results of a Phase II pneumococcal vaccine trial in the low middle income country, Fiji. The overall objective was to gather sufficient evidence for the Fiji Ministry of Health to decide whether to introduce the pneumococcal vaccination into its national schedule and define an appropriate and affordable vaccination strategy. The nasopharynx is the main reservoir for pneumococci and plays an important role in the spread of the organism. Studies of nasopharyngeal carriage offer insights into the pneumococcal disease burden in a community, particularly for potential serotypes which may cause pneumonia, and are a convenient way of determining the level of antibiotic resistance among pneumococcal isolates circulating in a population. The first study, a cross- sectional pneumococcal nasopharyngeal carriage survey of healthy children aged 3–13 months, was undertaken to document the prevalence of pneumococcal nasopharyngeal carriage, risk factors for carriage, serotypes and antimicrobial susceptibility patterns of carried pneumococci in healthy young children in Fiji (Chapter 3). Pneumococcal nasopharyngeal carriage was common in Fijian children. Penicillin resistance was documented for the first time, and, as a result, first-line treatment for meningitis was altered. A low proportion of carriage serotypes were included in the 7-valent pneumococcal conjugate vaccine. Invasive pneumococcal disease is an important cause of morbidity and mortality, particularly in the very young and the elderly. The introduction of the 7-valent pneumococcal conjugate vaccine in the national immunisation schedule in the USA has resulted in an impressive reduction in infant invasive pneumococcal disease. In addition, the vaccine has had a more than expected herd immunity effect on invasive pneumococcal disease in the elderly and other age groups. Chapter 4 reports on a study that aimed to document age-specific burden of invasive pneumococcal disease including clinical syndromes, underlying conditions, serotype distribution, and the potential protection against invasive pneumococcal disease and chest X-ray confirmed pneumonia by 7-valent pneumococcal conjugate vaccine in Fiji. The annual invasive pneumococcal disease incidence was comparable to countries of similar socioeconomic status. Being indigenous Fijian was an independent risk factor for disease. Underlying conditions were common and the case fatality rate was high particularly in the elderly population. For every 1,930 and 128 infants vaccinated, one death and one case ii respectively, would be prevented in those <5 years, by introduction of universal immunisation with the 7-valent conjugate vaccine. A Phase II vaccine trial was undertaken to document the safety, immunogenicity and impact on pneumococcal carriage of various pneumococcal vaccination regimens combining one, 2, or 3 doses of 7-valent pneumococcal conjugate vaccine in infancy (Chapters 5 to 10). In order to broaden the serotype coverage, the additional benefit of a booster of 23-valent pneumococcal polysaccharide vaccine at 12 months of age was also assessed. To address the theoretical concerns of hyporesponsiveness to 23-valent pneumococcal polysaccharide vaccine following re-challenge, the immunological responses at 17 months of age to a small challenge dose of 20% of 23-valent pneumococcal polysaccharide vaccine (mPPS) in children who had or had not received the 23-valent pneumococcal polysaccharide vaccine at 12 months of age was undertaken. The immunogenicity following a 2 or 3 dose 7-valent pneumococcal conjugate vaccine primary series was similar for many serotypes. A single 7-valent pneumococcal conjugate vaccine dose would offer protection in the first 12 months of life for many serotypes. The one or 2 dose 7-valent pneumococcal conjugate vaccine schedules induced immunologic memory, with memory responses following 23-valent pneumococcal polysaccharide vaccine being most profound for children who had received only a single dose of 7-valent pneumococcal conjugate vaccine previously, compared with the 2 or 3 dose groups. Following the 23-valent pneumococcal polysaccharide vaccine booster, there were significant responses for all 23 serotypes which persisted for at least 5 months following vaccination. However despite higher antibody concentrations at 17 months in children who had received 23-valent pneumococcal polysaccharide vaccine at 12 months, the response to a re-challenge was poor to all 23 serotypes compared to children who did not receive the 12 month 23-valent pneumococcal polysaccharide vaccine. This indicates immunological hyporesponsiveness or non-responsiveness. This effect occurred regardless of pre-mPPS antibody levels and prior 7-valent pneumococcal conjugate vaccine exposure. The addition of 23-valent pneumococcal polysaccharide vaccine at 12 months had no impact on carriage, despite the substantial boosts in antibody levels observed and despite significantly higher opsonophagocytic activity and antibody avidity comparing pre- and post-levels. In summary, a substantial burden of pneumococcal disease in Fiji was found. The 7-valent pneumococcal conjugate vaccine would provide limited coverage of invasive disease compared to its use in affluent countries. Two doses of 7-valent pneumococcal conjugate iii vaccine have similar immunogenicity as 3 doses although a single dose still provides some protection. The 23-valent polysaccharide vaccine booster was found to be immunogenic but re-challenge resulted in hyporesponsiveness. Further research evaluating the potential of reduced dose schedules using the newer conjugate vaccines with an early conjugate booster would be recommended. iv DECLARATION This is to certify that 1. the thesis comprises only my original work towards the PhD except where indicated in the Preface, 2. due acknowledgement has been made in the text to all other materials used, 3. the thesis is less than 100,000 words in length, exclusive of tables, maps, bibliographies, and appendices. Name: Fiona Russell Signature: Date: 11th October, 2010 v PREFACE Abstract: This chapter is entirely my work under the supervision of Prof Kim Mulholland and Prof Jonathan Carapetis. Chapter 1: Literature Review This chapter is entirely my work under the supervision of Prof Kim Mulholland and Prof Jonathan Carapetis. Chapter 2: Extended Materials and Methods section I was responsible for writing the bulk of this chapter under the supervision of Prof Kim Mulholland and Prof Jonathan Carapetis. Prof Kim Mulholland outlined the initial concept of the design of the study. Expert advice was sought from Porter Anderson, Brian Greenwood, George Siber, and DMID NIH personnel for various aspects of the study. The fieldwork SOPs were written by Sam Colquhoun, Jane Nelson, and Vanessa Johnson, under my direction and supervision. The laboratory ELISA and avidity SOPs and methods were written by Anne Balloch and Paul Licciardi. The OPA methods were written by Rob Burton and Moon Nahm, University of Alabama at Birmingham, Birmingham, Alabama, USA. The microbiology laboratory SOPs were written by Chris Pearce (formerly from the Royal Children’s Hospital, Melbourne) and Shirley Warren (Westmead Hospital). The statistics section, including sample size calculations were written by Graham Byrnes. Chapter 3: Pneumococcal nasopharyngeal carriage and patterns of penicillin resistance in young children in Fiji I was responsible for the design of the study under the supervision of Prof Kim Mulholland and Prof Jonathan Carapetis. I wrote the protocol, submitted the study to the ethics committee for approval, and supervised the fieldwork. Senibua Ketawai, the laboratory technician, processed the specimens. Dr Viema Kunabuli and Mabel Taoi collected the specimens. Sharon Biribo and Anna Seduadua performed the serotyping. I analysed the data, wrote the first draft of the manuscript with input from the co-authors on the published paper: JR Carapetis, S Ketawai, V Kunabuli, M Taoi, S Biribo, A Seduadua, EK Mulholland. vi Chapter 4: Epidemiology of Invasive Pneumococcal Disease in Fiji: the potential impact of pneumococcal conjugate vaccine I was responsible for the design of the study under the supervision of Prof Kim Mulholland and Prof Jonathan Carapetis. I wrote the protocol, submitted the study to the ethics committee for approval, and reviewed all the medical records. Anna Seduadua and Reginald Chand processed and stored the isolates. Catherine Satzke processed the isolates for shipment for serotyping. Shahin Oftadeh and Prof Lyn Gilbert were responsible for serotyping the isolates. I analysed the data, wrote the first draft of the manuscript with input from the co-authors on the published paper: JR Carapetis, L Tikoduadua, R Chandra, A Seduadua, C Satzke, J Pryor, E Buadromo, L Waqatakirewa, EK Mulholland. Chapter 5: Immunogenicity Following One, Two, or Three Doses of the 7-valent Pneumococcal Conjugate Vaccine Chapter 6: Safety and Immunogenicity of the 23-Valent Pneumococcal Polysaccharide Vaccine at 12 months of age, following One, Two, or Threes Doses of the 7-valent Pneumococcal Conjugate Vaccine in Infancy Chapter 7: Hyporesponsiveness
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