Thèse Médecine Paris 1877 numéro 78.

Background: Poor demand for vaccines has long been recognized as a threat to the realization of public and global health objectives. Consequently, over time a range of interventions have been researched, proposed, and implemented in an attempt to improve the acceptability of vaccines and overcome vaccine resistance. However, much of the contemporary research concentrates disproportionately on individual-level determinants as viable targets for interventions. This disparate focus on individual-level factors has seemingly been at the expense of research into fundamental contextual influences. As a result, the primary aim of this thesis is to explore and develop a greater understanding of the contextual determinants of vaccine acceptability and their evolution over time and across different global contexts. Furthermore, emerging themes will be analyzed in an effort to explore how different contextual determinants work together or separately to influence vaccine acceptability. Methodology: The methodological approach adopted for this thesis concentrated on enabling and conducting an in-depth literature review of the contextual determinants of vaccine acceptability. To begin, a concept analysis was conducted to inform the design, focus, and implementation of a literature review. Subsequently, an in-depth literature review of research derived from the Global Health database was conducted using relevant papers published between 1910 and 2022. Data related to publication and content characteristics were extracted to support the analysis process and discussion. Ultimately themes related to the seven contextual determinants categories were identified, extracted, and analyzed. Results: Through the final analysis, 32, often interrelated themes were identified across the seven contextual determinant categories. The determinant category of Politics & Policy was found to be relevant in 70.5% (n=98) of articles included in this literature review. Religious, Social & Cultural determinants were relevant in 53.24% (n=74) of articles, followed by Communication & Media Environment at 43.16% (n=60), Influential Leaders at 41.37% (n=58), History & Historical Factors at 38.13% (n=53), Pharmaceutical Influences at 24.46% (n=34), and Geographic Influences at 18.7% (n=26). Conclusion: The acceptability of vaccines is undoubtedly influenced by the broader factors that shape the contexts in which vaccines are delivered. Additionally, these contextual determinants are likely to interact with, or influence the many commonly referenced putative individual-level determinants of vaccine acceptability. As a result, the complex nature of any relevant contextual determinants should be considered in the design of efforts aimed at promoting or improving demand for vaccines. / Thesis / Master of Science (MSc) / The contextual determinants of vaccine acceptability have been seemingly under- researched relative to other individual-level factors. As a result, this thesis aims to explore and develop a greater understanding of the contextual determinants of vaccine acceptability and their evolution over time and across different global contexts. To achieve this objective, an in-depth literature review of 139 identified articles was conducted in an effort to explore and identify themes related to the contextual determinant of vaccine acceptability. Ultimately, through this review 32 themes across the seven contextual determinant categories were identified and discussed. These findings helped elucidate the complex and fundamental role that contextual determinants have in shaping demand for vaccines.

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Historical data suggests that prolonged survival of Brucella vaccine organisms in the target host enhances immune protection. Recent research has focused upon the development of rough vaccine strains to avoid interference with standard diagnostic tests. Rough organisms are rapidly cleared from the host, however. In an effort to develop improved vaccine strains, we have screened signature tagged mutagenesis banks to identify mutants with varying survival characteristics. We hypothesize that in order for a vaccine to be efficacious, it must survive in the host. In order to test this, we constructed marked and unmarked deletion mutants of B. abortus and B. melitensis in genes previously demonstrated by transposon mutagenesis to attenuate in vivo and in vitro virulence. Survival and efficacy of these novel deletion mutants were then evaluated in the mouse model. The asp24 mutants, which persist for extended periods in vivo, appear superior as a vaccine candidate compared to approved vaccine strains S19 and Rev1 in the mouse model against either homologous or heterologous challenges. Once enhanced protection against infection was demonstrated in the mouse, components of immune function that appeared to be most important were identified to correlate the immune response with the observed protection. We demonstrated that the most persistent mutant, delta-asp24, affords the greatest protection in mice against virulent challenge. In order to evaluate safety of the novel vaccine strains as well as protection against infection and abortion, we tested selected B. melitensis unmarked deletion mutants in a natural host, the goat. The delta-asp24 mutant was shown to be safe in pregnant goats while providing significant protection against infection and abortion.

published_or_final_version / Public Health / Master / Master of Public Health

Background Pneumococcal disease, caused by Streptococcus pneumoniae (S. pneumoniae), leads to a great burden of morbidity and mortality globally, especially in developing countries. World Health Organization (WHO) estimated that 476,000 out of 8.8 million global annual deaths in children under 5 years old in 2008 were due to pneumococcal infection. Currently there are 2 second generation pneumococcal conjugate vaccines (PCVs) targeted at children, the 10-valent pneumococcal conjugate vaccine (PCV-10) and 13-valent pneumococcal conjugate vaccine (PCV-13) available in the market for the prevention of pneumococcal disease. Nowadays, about half of the countries already included PCVs into their National Immunization Programme (NIP) and around one-fourth are planning the introduction. The objective of this systematic review is to evaluate the cost-effectiveness of PCV-10 and PCV-13 so that the results could inform policy decisions of including PCVs into the NIP. Methods A systematic review was conducted by searching from 2 databases (PubMed and Medline) for the economic evaluation studies of the PCV-10 and PCV-13. Information of the design and characteristics of studies, burden of pneumococcal disease assumption, and baseline vaccine efficacy assumptions were extracted and results were presented in incremental cost-effectiveness ratio (ICER). Results Eleven studies were included, with 4 studies done in Europe, 3 in South America, 2 in Africa, 1 in Asia and 1 across North America and Europe. The results varied greatly among studies, with 5 of them reporting PCV-10 to be more cost-effective and/or cost-saving, while 4 of them reporting PCV-13 to be more cost-effective and/or cost-saving, and 2 of them concluded in a different way: PCV-10 was more cost-effective and cost-saving, however PCV-13 would lead to higher life-years gained (LYG) and/or disability-adjusted life years (DALYs) averted. Conclusion Due to the uncertainties in the clinical and epidemiological parameters, the unavailability of the data of local disease burden, and the analytical choices about endpoints which could significantly affect the input data, the results of the studies reviewed were contrasting from each other. Therefore, there was not enough evidence to show whether PCV-10 or PCV-13 was more cost-effective to be included into the NIP of children. Further research should be done on the sensitive variables of the cost-effectiveness ratio, as well as the local serotype distribution and disease burden should also be taken into account when planning the inclusion of PCVs into the NIP. / published_or_final_version / Public Health / Master / Master of Public Health

Background Chickenpox is a common infectious disease among children. Ever since a live attenuated vaccine was developed in 1970s, different countries have adopted different vaccination program against chickenpox. Hong Kong recently has commenced a routine childhood varicella vaccination program. The objective of this study is to evaluate whether routine childhood varicella vaccination is cost effective and the implications to Hong Kong. Methodology Literature search was done on electronic databases: Medline and Embase for articles relevant to the topic. A total of 9 articles were retrieved for this systemic review. All 9 studies focus on the cost effectiveness of childhood varicella vaccination with comparison to no vaccination or other interventions. Findings Routine childhood varicella vaccination program is cost effective especially from the societal perspective. The longer the vaccination program takes place, the more cost effective it would be. The cost effectiveness ratio is most sensitive to the coverage rate and the vaccine price. Conclusion It remains unclear whether the routine childhood varicella vaccination program in Hong Kong would be cost effective or not. As the Hong Kong program has adopted the most recent recommendations towards varicella vaccines that the review articles were not included. / published_or_final_version / Public Health / Master / Master of Public Health

BACKGROUND: Despite the current recommendation by the Centre for Health Protection (CHP)of Hong Kong for adults aged 65 years or above to receive 23-valent pneumococcal polysaccharide vaccine (PPV23), pneumococcal disease(PD) has become the second leading causes of death in Hong Kong. A relatively new pneumococcal vaccine –13-valent pneumococcal conjugate vaccine (PCV13) was approved by the US Food and Drug Administration (FDA) in December 2011 and the European Medicines Agency (EMA) in July 2013 for the prevention of invasive disease caused by S. pneumoniae for older adults aged 50 years or above. It was shown to overcome some of the limitations of PPV23and potentially confer benefits to older adults in the prevention of PD. OBJECTIVES: To systematically review available literatures to examine whether PCV13 is superior to PPV23 or no vaccination in terms of the cost-effectiveness in the prevention of PD in older adults aged 50 years or above. METHODS: Two databases, PubMed and ISI Web of Science, were used to search for published journals. The year range of search in these databases was confined to10 years. RESULTS: A total of 318studies were identified initially and 10studies were included in this systematic review. Studies were conducted in the US, Colombia and European Union (EU) countries e.g. Italy, Germany, Netherlands and Spain. Different perspectives including societal, payer and health system were considered. The use of PCV13 was compared to either PPV23 or no vaccination in older adults aged 50 years or above. The coverage of PCV13 ranged from 42.4% to 70%, conferring an efficacy between 58% and 93.9%. The cost-effectiveness of PCV13 was expressed through the number of avoided cases/deaths for PD including invasive pneumococcal disease(IPD), inpatient and outpatient community-acquired pneumonia (CAP) as well as the incremental cost-effectiveness ratios (ICERs),either in cost per quality-adjusted life-year (QALY) gained or cost per life-year gained (LYG).Overall, PCV13 is shown to avoid more pneumococcal cases compared to PPV23 or no vaccination and is cost-effective in older adults aged 50 years of above. CONCLUSION: PCV13 is considered to be more cost-effective in older adults compared to PPV23 or no vaccination based on the current systematic review. Randomized controlled trials and cost-effectiveness evaluations are suggested to be conducted in Hong Kong and Asia-specific regions in order to obtain clinical and economic data of PCV13 in the Asian population. Policy-makers should also consider the effects of serotype replacement on the change in serotype distribution in local setting from time to time so that vaccines with appropriate serotype formulations could be researched. / published_or_final_version / Public Health / Master / Master of Public Health