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: 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

Streptococcus pneumoniae is one of the leading causes of morbidity and mortality in children under 5. Low-income countries are disproportionally affected and data in these settings are lacking. Effective strategies to control disease include infant immunisation with pneumococcal protein-polysaccharide conjugate vaccines. However, ongoing surveillance of carriage and disease are important to understand the impact of vaccination within communities. This thesis evaluated nasopharyngeal (NP) carriage in 3 generations, following introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the UK. NP carriage was also compared between rural and urban Nepalese children and a novel method of delayed culture and transport was assessed. Finally, the immunogenicity of a 10-valent pneumococcal conjugate vaccine administered in a 2-dose priming schedule without a booster was compared to a 3-dose priming schedule with a booster in Nepalese infants. Key findings include carriage rates in UK children being similar to pre-PCV7 (7 valent pneumococcal conjugate vaccine) carriage rates at 47% with low carriage rates in seen in adults. PCV7 serotypes accounted for 1.5% of carriage isolates in children, 0% in parents and 15.4% in older adults. In Nepalese children carriage was higher in a rural (69.2%) compared to an urban setting (40.9%) and delayed culture and transport using silica desiccant packets (SDP) provided a reliable, albeit underestimated, estimate of carriage. Finally this author demonstrated that following primary immunisation and boosting, there was no difference in immune responses to serotypes 1, 5 and 14 with a 2 dose priming schedule compared to a 3-dose schedule. At 2-4 years of age a significantly higher proportion of vaccinees in the 2+1 group had ≥0·2µg/mL IgG for serotypes 1, 5, 6B and 18C compared to vaccinees in the 3+0 group.

Pneumonia is one of the top causes of deaths in children younger than 5 years of age. According to WHO estimation, globally there are nearly 2 millions young children who die from pneumonia every year, and more than 70% of these deaths occurred in Africa and Southeast Asia. Pneumonia caused by Streptococcus pneumoniae (also called pneumococcus) is a vaccine preventable disease, accounting for 39% of community-acquired pneumonia. There are two types of pneumococcal vaccines that are pneumococcal polysaccharide vaccine (PPV) and pneumococcal conjugate vaccines (PCV). The latter one is routinely advised for children younger than five years. The aims of this paper are to review the global disease burden caused by Streptococcus pneumoniae in children younger than 5 years and to gather vaccine program information globally. For narrative review and policy analysis, WHO websites, other websites of health organizations or institutions, and literatures from Pubmed were reviewed, using key words “children pneumonia”, “Streptococcus pneumoniae”, “pneumonia vaccine”, “pneumococcal conjugate vaccine ”, “PCV-7”, “7-valent PCV”, “PCV-13”, “13-valent PCV”. Numerous literatures have reported that obvious incidence decrease of invasive pneumococcal diseases (IPD) in young children after PCV vaccination. In July 2000 PCV-7 (“7-valent pneumococcal conjugate vaccine”) was incorporated into National Immunization Program (NIP) in United States. Although since then the incidence of IPD caused by vaccine-covered serotypes markedly decreased, those caused by non-vaccine-covered serotypes were found substantially increased. In February 2010, PCV-13 (“13-valent pneumococcal conjugate vaccine”) replaced PCV-7 in NIP in United States. With a wider range of serotypes, PCV-13 was expected to be more effective than PCV-7 in children under 5. Using modeling method, many scholars estimated that PCV-13 was likely to be more cost-effective in reported settings when herd immunity was taken into consideration. Schedule of vaccine was another issue that needs to be investigated. There are three schedules commonly adopted by health authorities: 2 primary doses with 1 booster dose (2p+1), and 3 primary doses with 1 booster (3p+1) or without 1 booster dose (3p+0). In individual report, it seems three schedules were all effective. From result of systematic review, more evidence supported to use 3p+0 schedule (and 3p+1 schedule). However, emerging evidences are in support of 2p+1 schedule tool. WHO recommended both 3p+0 and 2p+1 schedule. If the country with high incidence rate in young infant (less than 32 weeks) 2p+1 schedule may not provide adequate protection for special individual serotype. In addition 2p+1 schedule may also lead to lower antibody level between the second primary dose and the booster dose, but the booster dose could induce higher antibody level, which is important for protecting certain serotypes. Countries should consider local factors and choose suitable vaccine schedule accordingly. In terms of global PCV programs, around 80 countries have already added PCV into their NIP, 58 countries (30%) were planning to introduce the program; nevertheless remaining 51 countries (26%) of countries have no schedule to introduce it yet. Most countries that have implemented PCV programs were western industrialized countries. With support from Global Alliance for Vaccines and Immunization (GAVI), 15 eligible African countries have had routine PCV programs. Comparatively, in Asia, India and China, two countries with the largest population and largest number of IPD cases in the world, have no PCV program to the children. Even industrialized economies like Japan and Taiwan have not implemented yet. Asia was lagging behind for decades. PCV program needs to be prioritized in Asian countries. Asian governments should consider investing more in PCV programs (high-income countries) and/or cooperating with other organizations such as GAVI (low-income countries) to increase the coverage of PCVs in children under 5 and to protect them from pneumococcal diseases. / published_or_final_version / Public Health / Master / Master of Public Health

Objectives: By summarizing and comparing the pattern of invasive pneumococcal disease (IPD) in the 4 areas (namely Hong Kong, other parts of China, United States and Thailand) at different stages of implementation of universal pneumococcal vaccination, a snapshot picture could be obtained to visualize how pneumococcal vaccination has impacted upon various important measures, including the burden of IPD, prevalent serotypes, antimicrobial resistance, risk factors of IPD, to guide us on the next step to optimize our ability to combat against IPD. Methods: To achieve the objective, a systematic search through PubMed, Medline, Cochrane Library, EmBase, CINAHL, and the China Journal Net (for Chinese journal articles to obtain a more comprehensive data for “other parts of mainland) has been performed. Articles were selected according to the inclusion and exclusion criteria, and in straight accordance to the literature search and article retrieval steps as described in the methodology. The quality of the articles was assessed by the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) checklists. Results: In general, there was decline in IPD incidence after PCV vaccination, but the problem of serotype replacement and antimicrobial resistance was still an ongoing problem, which differs geographically. Conclusion: From the above data, we could see the significant impact on PCV on reduction of incidence in IPD as shown in United States, however, it was also very clear that unless development of non-serotype specific vaccine become available to us, we are still facing the problem of serotype replacement and that we need to have regular surveillance, as in the case of United States, to supply the data for timely replacement of new PCV combating the emerging serotypes, such that we would still be in the safe ground. In Hong Kong, the statutory reporting of IPD to Centre for Health and Protection (CHP) has been effective since 2/1/201443, after the start of universal immunization since October 2008, followed by PCV10 in 2009 and PCV13 in December 2011, we seems lacking behind on the surveillance. With the surveillance started by CHP, we hope to understand the Hong Kong situation better and with more published data for our local burden and serotype pattern of IPD. It is interesting to note that the antimicrobial pattern does vary geographically, even in US with universal immunization. This suggests that while PCV was helping us to reduce the penicillin resistant strain, another more important factor – the practice of use of antibiotics- is still operating to effect on the overall antibiotic resistance. The pattern that rural Thailand was having much much less penicillin resistance as compared to urban Bangkok, where antibiotic is more readily available, also supports this explanation. / published_or_final_version / Public Health / Master / Master of Public Health

Influenza (IV) and pneumococcal polysaccharide vaccination (PPV) may reduce hospitalization and mortality but the effectiveness of these vaccines in older adults (≥65 years) is controversial. This thesis includes seven parts with a total of ten studies studying different aspects regarding IV and PPV in institutionalized older adults - the group with the highest infection-related morbidity and mortality. 　　 　　In Part I, we presented the controversies about effectiveness of influenza and pneumococcal vaccination in institutionalized older adults. 　　 　　In Part II, we studied a retrospective cohort of 1737 older adults showing that nursing home residence is independent risk factor of infection-related mortality and hospitalization. 　　 　　In Part III, the second and third studies were systematic reviews showing that IV and PPV could reduce pneumonia and death.. 　　 　　In Part IV, we evaluated the effectivenss of IV and PPV through prospective cohorts. The fourth study was a prospective cohort study of 1859 institutionalized older adults showing that IV significantly reduced mortality and hospitalization. The fifth study was a prospective cohort study of 532 institutionalized older adults showing that when the IV strain does not match the circulating strain, PPV provided additional protection in reducing mortality. 　　 　　In Part V, the sixth study was a randomized controlled trial of 100 institutionalized older adults showing that intradermal IV has better immunogenicity than intramuscular vaccination without compromising safety. 　　 　　In Part VI, we identified factors that may affect clinical effectiveness of IV. The seventh and eighth studies were prospective cohort studies of 711 institutionalized older adults showing that vaccine efficacy declined with increasing impaired functional status and renal function. 　　 　　In Part VII, we identified determinants of receiving IV and PPV in institutionalized older adults. The ninth study was a cross-sectional study of 155 institutionalized older adults showing that encouragement from nHCWs was a major facilitator of receiving vaccination. The tenth study was a cross-sectional study of 1300 nHCWs showing that 40.2% of nHCWs had encouraged residents to receive vaccination. 　　 　　In conclusion, ten studies from this thesis demonstrated that IV and PPV are effective in preventing hospitalization and reducing mortality in institutionalized older adults. Different strategies in improving its effectivenss and acceptance were suggested. / published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (M.Med.(Paediatrics), Faculty of Health Sciences, University of the Witwatersrand, 2009 / Background In settings with a high burden of tuberculosis, children with unrecognised culture-confirmed pulmonary tuberculosis (PTB) may be discharged from hospital before mycobacterial culture results are available; in these cases clinical improvement may have been due to successful treatment of an intercurrent viral or bacterial co-infection. Aim To estimate the burden of tuberculosis in children who were enrolled in a double-blind, placebo-controlled pneumococcal conjugate vaccine (PCV) trial, and to probe for the presence of pneumococcal co-infection in trial participants who had a hospital-based diagnosis of PTB. Methods A retrospective case-finding strategy was adopted in order to define the tuberculosis case load amongst 39 836 children that had been enrolled in a PCV efficacy trial in Soweto, Gauteng Province. The trial follow-up period was 5.3 years. Children with a hospital-based diagnosis of tuberculosis were categorised by strength of evidence for the disease, HIV status and PCV vaccination status. Incidence rates and risk ratio assessments were conducted using standard statistical methods. Results Four-hundred and ninety-two episodes of tuberculosis arose amongst 425 of the 39 836 PCV Study participants. Tuberculosis incidence was 1067 per 100 000 children (95% Confidence Interval [CI], 968 – 1173), with the greatest burden observed amongst HIV-infected children (10 633 per 100 000 children [95% CI, 9411 – 11 969]; Risk Ratio [RR] 27.5 [95% CI, 22.6 – 33.5], P<0.001). The burden of PTB in the cohort was 982 cases per 100 000 children (95% CI, 887 – 1084): 9895 per 100 000 (95% CI, 8718 – 11 187) in the HIV-infected children and 352 per 100 000 (95% CI 294 – 417) in the HIV-uninfected children (RR 28.1; 95% CI, 22.9 – 34.6), P<0.001. PCV recipients exhibited a 44 percent (95% CI, 11 – 65), P=0.010, reduction in incident culture-confirmed PTB compared to placebo recipients; this apparent reduction was demonstrated chiefly in PCV-vaccinated HIV-infected children (RR 0.53; 95% CI, 0.31 – 0.90) compared to HIV-infected placebo recipients, P=0.017. Conclusions A high burden of tuberculosis is carried by children under 5.3 years in the study setting, with HIV-infected children bearing the brunt of the morbidity. Pneumococcal co-infections are common in the context of hospitalised PTB in the study setting.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Comparison of Post-licensure safety surveillance of 13-Valent Pneumococcal Conjugate vaccine and 7-Valent Pneumococcal Conjugate vaccine: Data from the Vaccine Adverse Event Reporting System (VAERS). Background: On February 24, 2010, Food and Drug Administration (FDA) licensed a 13-valent pneumococcal conjugate vaccine (Prevnar 13®, [PCV13]) for use among children aged 6 weeks--71 months. The Advisory Committee on Immunization Practices (ACIP) recommended PCV13 routine vaccination of all children aged 2--59 months, children aged 60--71 months with underlying medical conditions, with PCV13 replacing PCV7 for all doses. Methods: We searched case reports to the Vaccine Adverse Event Reporting System (VAERS), a US passive surveillance system, for adverse events (AEs) reported after immunization with PCV13 vaccine from February 24, 2010 through February 24, 2011 for persons vaccinated from February 24, 2010 through December 31, 2010 and compared them with AEs reported by persons who were vaccinated with PCV7. Results: VAERS received 1503 reports of AEs after PCV13; multiple vaccines were given in 79.0% of reports. One hundred eighty (11.9%) were coded as serious, including nineteen reports of death. The most frequently reported symptoms were injection site reactions, fever, irritability and vomiting. Seven hundred fifty-eight (50.4%) reports comprised males. Most reports (37.7%) were from children 1-2 years. Total number of reports received for PCV13 was very similar to those received after vaccination with PCV7. Conclusions: AEs reported to VAERS following 13-valent pneumococcal conjugate vaccine were consistent with AEs previously observed in pre-licensure trials. We did not identify any major safety concerns or outcomes.