The overarching objective of this thesis was to investigate the phenomenon of vaccine hesitancy in Canada and examine relationships among vaccine beliefs, socio-demographic characteristics, and seasonal influenza immunization. Quantitative findings were derived from a national health risk perception survey administered to adults across Canada (N = 1,125). Respondents were asked to provide their level of agreement (1 = do not agree at all to 5 = agree completely) with 2 vaccine-related behaviour statements and 21 vaccine-related beliefs statements. A principal components analysis was performed to reduce the number of belief statements into meaningful components. Two components were retained and reflected negative beliefs about ‘vaccine safety’ and positive beliefs about ‘vaccine regulation and benefits’. Descriptive results presented in the first study indicated a heightened uncertainty about the long-term side effects of vaccination, particularly with respect to the purported link between the Measles-Mumps-Rubella vaccine and the development of autism, among survey respondents. Multivariate analyses identified differences in the endorsement of numerous vaccine beliefs according to age and educational attainment. Findings revealed that older respondents and respondents without a university education demonstrated more negative attitudes towards vaccination, whereas younger respondents and respondents with a university education demonstrated more positive vaccine attitudes, respectively. Finally, both components of vaccine beliefs were significant predictors of vaccine-related behaviours, including discussing information about vaccines with others and reported receipt of the seasonal influenza vaccine. The second study investigated interrelationships among components of vaccine beliefs, socio-demographic characteristics, and reported receipt of the seasonal influenza vaccine. A mediation analysis revealed that higher levels of agreement with the statement ‘I usually get the seasonal flu vaccine’ among older adults was associated with lower levels of agreement with negative beliefs about vaccine safety in conjunction with higher levels of agreement with positive beliefs about the regulation and benefits of vaccines, whereas the opposite was true for younger adults. Also, a significant moderation analysis revealed that among respondents with greater concern about vaccine safety, those with higher educational attainment reported lower levels of agreement with the statement ‘I usually get the seasonal flu vaccine’ compared to those with lower educational attainment. Recognizing the limitations of quantitative findings, a qualitative investigation was undertaken to provide more in-depth insight on the factors driving influenza immunization among healthy adults. A thematic analysis was performed on transcripts from 6 semi-structured focus group discussions with a total of 18 participants residing in Ottawa, Ontario. Findings identified 7 themes and 8 sub-themes related to contextual, vaccine specific, and individual determinants of vaccine hesitancy. Participants predominantly discussed themes related to individual determinants of vaccine hesitancy (perceived severity, susceptibility, and likelihood of contracting the influenza virus; personal interests; interactions with healthcare professionals). The perceived novelty, severity and effectiveness of the influenza vaccine, as well as a lack of information and discontent with communication by government health authorities and the media were also discussed. Overall, findings identified salient themes informing vaccine decision-making and behaviours among a sample of educated adults, which can inform subsequent studies investigating influenza immunization in a more representative sample of Canadian adults.

Background: International analyses suggest that routine maternal vaccination with seasonal trivalent influenza vaccine is cost-effective, but few studies have been done in middle- to low- income countries. Method: A decision-tree analysis was modelled for the South African public healthcare setting over one year from a payer's perspective. Direct medical costs and consequences were obtained from published literature. Incremental cost effectiveness ratios (ICERs) and univariate sensitivity analyses were then measured. Discounting was excluded due to the seasonality of influenza, limiting the time horizon to a one year period. Findings: The model predicted that to avert influenza-associated hospitalisations amongst pregnant women and their infants less than six months of age, vaccination of pregnant women was not cost-effective. This was irrespective of whether the universal vaccination or HIV-targeted approach was used. A base model simulating 100% vaccine uptake predicted that seasonal vaccination of 100,000 pregnant women results in an estimated net cost of R69,118,114.05 per neonatal influenza-associated hospitalisation averted. Similarly, the model suggested that vaccinating 100,000 pregnant women would cost R1,197,779.79 per maternal hospitalisation averted. Univariate sensitivity analyses reinforced that influenza vaccination of pregnant women was not cost-effective, except when lower incidence of maternal influenzaassociated hospitalisations associated with antenatal influenza vaccination were simulated where the targeted approach became dominant. The latter analysis predicted savings of R770,530.86 per maternal influenza-associated hospitalisation averted. Interpretation: The ICERs suggest that influenza vaccination amongst pregnant women is not cost-effective in the South African public healthcare sector compared to no vaccination, with respect to averting influenza-associated hospitalisations amongst pregnant women and their infants less than six months of age. However, these estimates should be re-evaluated, pending vaccine effectiveness studies of higher methodological quality for low- and middle- income countries and using cost inputs relevant to South African public healthcare setting. This analysis may provide preliminary information regarding the upscaling of influenza vaccination amongst pregnant women as a priority in the constraints of a limited healthcare budget and careful consideration is required regarding vaccine mobilisation amongst pregnant women. / Dissertation (MSc)--University of Pretoria, 2016. / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

Seasonal influenza produces substantial disease within the United States every year. Despite the availability of safe and effective vaccines for influenza, millions of individuals go unvaccinated each flu season, with notable differences across racial/ethnic groups. Using the Behavioral Risk Factor Surveillance System (BRFSS), I examine vaccination rates among non-Hispanic whites and Hispanics during the 2000-2009 influenza seasons. After developing a new method that addresses shortcomings of BRFSS vaccination measures, I find that non-Hispanic whites exhibit higher vaccination rates than Hispanics. Through a series of logistic regression models I show that the disparities between non-Hispanic whites and Hispanics narrow after controlling for healthcare coverage and socioeconomic characteristics. This suggests that seasonal influenza vaccination may be improved among U.S. Hispanics by addressing structural barriers in receiving the vaccine, especially access to health care.

The seasonal influenza (flu) vaccine has been shown to prevent flu outbreaks that can cause debilitating effects on the body and even death. Underserved members of Black communities are more likely to refuse the flu vaccine than are persons of other ethnicities. The purpose of the project was to determine from a needs assessment the reasons for flu vaccine refusal in the Black population of an inner city clinic in order to develop tailored communication and nursing actions that promote awareness of the flu vaccine's importance and safety. The health belief model constructs (perceived susceptibility, perceived severity, perceived benefits, and perceived barriers) were used to guide the project. A survey based on the constructs of the health belief model was administered to a convenience sample of 40 adult patients in an inner city clinic who completed the anonymous survey while they waited for the physician. Descriptive statistics showed that adults ages 18 to 36, who were the largest group of respondents (n = 33), agreed to be vaccinated and believed the flu to be a serious disease for their age group. Reported barriers to vaccination included finding time to get vaccinated and the belief that the vaccine causes the flu. The findings supported development of an annual seasonal flu vaccine campaign that included verbal and written education, informational posters, social media messages, and a standing order to offer and administer the injection to all adults served by the practice. Social change implications are expected to include decreased morbidity and mortality from flu among the Black inner city patients and closer alignment of the clinic with the Healthy People 2020 vaccination goals.

A pandemic subtype of influenza A sometimes replaces (e.g., in 1918, 1957, 1968) but sometimes coexists (e.g., in 1977) with the previous seasonal subtype. This research aims to determine a condition for replacement or coexistence of influenza subtypes. We formulate a hybrid model for the dynamics of influenza A epidemics taking into account cross-immunity of influenza strains depending on the most recent seasonal infection. A combination of theoretical and numerical analyses shows that for very strong cross-immunity between seasonal and pandemic subtypes, the pandemic cannot invade, whereas for strong and weak cross-immunity there is coexistence, and for intermediate levels of cross-immunity the pandemic may replace the seasonal subtype. Cross-immunity between seasonal strains is also a key factor of our model because it has a major influence on the final size of seasonal epidemics, and on the distribution of susceptibility in the population. To determine this cross-immunity, we design a novel statistical method, which uses a theoretical model and clinical data on attack rates and vaccine efficacy among school children for two seasons after the 1968 A/H3N2 pandemic. This model incorporates the distribution of susceptibility and the dependence of cross-immunity on the antigenic distance of drifted strains. We find that the cross-immunity between an influenza strain and the mutant that causes the next epidemic is 88%. Our method also gives an estimated value 2.15 for the basic reproduction number of the 1968 pandemic influenza. Our hybrid model agrees qualitatively with the observed subtype replacement or coexistence in 1957, 1968 and 1977. However, our model with the homogeneous mixing assumption significantly over estimates the pandemic attack rate. Thus, we modify the model to incorporate heterogeneity in the contact rate of individuals. Using the determined values of cross-immunity and the basic reproduction number, this modification lowers the pandemic attack rate slightly, but it is still higher than the observed attack rates. / Graduate

INTRODUÇÃO: A vacinação anual é recomendada como a medida mais efetiva contra a influenza sazonal. O Instituto Butantan (IB) realizou, anualmente, estudos clínicos das vacinas influenza sazonais trivalentes (fragmentada e inativada), produzidas em2013, 2014 e 2015. MÉTODO: Estudos de coorte prospectivos para descrever a imunogenicidade e a segurança da vacina influenza produzida pelo IB nos anos de 2013, 2014 e 2015 em participantes adultos saudáveis e idosos. Após assinatura do TCLE os participantes foram submetidos à coleta de sangue e receberam uma dose da vacina. Nos dias 1, 2 e 3 após a vacinação foram contatados para avaliação da segurança (reações adversas solicitadas locais e sistêmicas e não solicitadas). No dia 21(+7) pósvacinação retornaram ao centro de pesquisa para nova checagem da segurança e para a coleta de sangue para a avaliação da imunogenicidade pós-vacinação. As análises de imunogenicidade foram feitas através do método inibição de hemaglutinação (IH). Os desfechos de imunogenicidade foram: porcentagem de soroconversão (SC), porcentagem de soroproteção (SP) e razão da média geométrica dos títulos (RMGT) de anticorpos inibidores da hemaglutinação. O estudo de 2013 foi conduzido no Centro de Referência para Imunobiológicos Especiais (CRIE) e no Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, os estudos de 2014 e 2015 foram realizados apenas no CRIE. As composições das vacinas utilizadas nos estudos em 2013, 2014 e 2015 seguiram as recomendações da OMS para vacina influenza sazonal do hemisfério sul. RESULTADOS: No ano de 2013, foram incluídos no estudo 47 adultos e 13 idosos, em 2014, 60 adultos e 60 idosos e em 2015, 62 adultos e 57 idosos. Nos estudos de 2013, 2014 e 2015, dor foi a reação adversa local mais frequente e cefaleia a sistêmica mais relatada. Todas as reações adversas observadas foram classificadas como leves ou moderadas e nenhuma como grave. Porcentagens de SP > 70% e >60% foram demonstradas para adultos e idosos, respectivamente, para os três vírus vacinais, nos estudos de 2013, 2014 e 2015. Porcentagem de SC > 40% foi demonstrada para os adultos, para os três vírus vacinais, apenas no estudo de 2014 e porcentagem de SC >30% foi demonstrada nos idosos, para os três vírus vacinais, apenas nos estudos de 2013 e 2014. RMGT > 2.5 nos adultos para os três vírus vacinais foi demonstrada apenas no estudo de 2013 e RMGT > 2 nos idosos, para os três vírus vacinais, foi demonstrada nos estudos de 2013, 2014 e 2015. CONCLUSÃO: As vacinas influenza sazonal de 2013, 2014 e 2015, produzidas integralmente pelo Instituto Butantan, foram seguras e imunogênicas segundo os parâmetros de imunogenicidade definidos pela EMA / INTRODUCTION: Annual vaccination is most effective way to prevent seasonal influenza illness. Instituto Butantan (IB) performed clinical studies with its 2013, 2014 and 2015 seasonal trivalent influenza vaccines (split-virion and inactivated) METHODS: Prospective cohort studies to describe the safety and immunogenicity of Instituto Butantan influenza vaccine, in healthy adults and elderly, from 2013 to 2015. Soon after the informed consent was signed, participants underwent blood collection followed by vaccination. On study days 1, 2 and 3 post vaccination participants were contacted by the stuffy to evaluate the occurrence of solicited (local and systemic) and non-solicited adverse reactions. On study day 21(+7) subjects returned to the clinical site for final safety assessments and blood collection for the immunogenicity evaluation post vaccination. The immunogenicity analyses were performed by means of haemagglutination inhibition assay (HI). The immunogenicity endpoints were: seroprotection (SPR) and seroconversion (SCR) rates and the geometric mean HI antibody titer ratio (GMTR). The 2013 study The Centro de Referência para Imunobiológicos Especiais (CRIE) and at the Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas of Medical School of University of São Paulo and the 2014 and 2015 studies were conducted at CRIE. The vaccine composition followed the WHO recommendation for the southern hemisphere seasonal influenza vaccine RESULTS: 47 healthy adults and 13 elderly participated in the 2013 study, 60 healthy adults and 60 elderly in the 2014 study, and 62 healthy adults and 57 elderly in the 2015 study. In the 2013, 2014 and 2015 studies, pain was the most frequent local adverse reaction and headache the most frequent systemic adverse reaction. All observed adverse reactions were classified as mild or moderate and none as severe. SPR > 70% and SPR > 60% were observed in adults and elderly, respectively, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. SCR > 40% was observed in adults, for the three vaccine viruses, only in the 2014 study and SCR > 30% was observed in elderly, for the three vaccine viruses, only in the 2013 and 2014 studies. GMTR >2.5 among adults, for the three vaccine viruses was only observed in the 2013 study and GMTR > 2.0 was observed among elderly, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. CONCLUSION: The 2013, 2014 and 2015 seasonal influenza vaccines produced by Instituto Butantan were safe and immunogenic according to the immunogenicity criteria defined by EMA

INTRODUÇÃO: A vacinação anual é recomendada como a medida mais efetiva contra a influenza sazonal. O Instituto Butantan (IB) realizou, anualmente, estudos clínicos das vacinas influenza sazonais trivalentes (fragmentada e inativada), produzidas em2013, 2014 e 2015. MÉTODO: Estudos de coorte prospectivos para descrever a imunogenicidade e a segurança da vacina influenza produzida pelo IB nos anos de 2013, 2014 e 2015 em participantes adultos saudáveis e idosos. Após assinatura do TCLE os participantes foram submetidos à coleta de sangue e receberam uma dose da vacina. Nos dias 1, 2 e 3 após a vacinação foram contatados para avaliação da segurança (reações adversas solicitadas locais e sistêmicas e não solicitadas). No dia 21(+7) pósvacinação retornaram ao centro de pesquisa para nova checagem da segurança e para a coleta de sangue para a avaliação da imunogenicidade pós-vacinação. As análises de imunogenicidade foram feitas através do método inibição de hemaglutinação (IH). Os desfechos de imunogenicidade foram: porcentagem de soroconversão (SC), porcentagem de soroproteção (SP) e razão da média geométrica dos títulos (RMGT) de anticorpos inibidores da hemaglutinação. O estudo de 2013 foi conduzido no Centro de Referência para Imunobiológicos Especiais (CRIE) e no Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, os estudos de 2014 e 2015 foram realizados apenas no CRIE. As composições das vacinas utilizadas nos estudos em 2013, 2014 e 2015 seguiram as recomendações da OMS para vacina influenza sazonal do hemisfério sul. RESULTADOS: No ano de 2013, foram incluídos no estudo 47 adultos e 13 idosos, em 2014, 60 adultos e 60 idosos e em 2015, 62 adultos e 57 idosos. Nos estudos de 2013, 2014 e 2015, dor foi a reação adversa local mais frequente e cefaleia a sistêmica mais relatada. Todas as reações adversas observadas foram classificadas como leves ou moderadas e nenhuma como grave. Porcentagens de SP > 70% e >60% foram demonstradas para adultos e idosos, respectivamente, para os três vírus vacinais, nos estudos de 2013, 2014 e 2015. Porcentagem de SC > 40% foi demonstrada para os adultos, para os três vírus vacinais, apenas no estudo de 2014 e porcentagem de SC >30% foi demonstrada nos idosos, para os três vírus vacinais, apenas nos estudos de 2013 e 2014. RMGT > 2.5 nos adultos para os três vírus vacinais foi demonstrada apenas no estudo de 2013 e RMGT > 2 nos idosos, para os três vírus vacinais, foi demonstrada nos estudos de 2013, 2014 e 2015. CONCLUSÃO: As vacinas influenza sazonal de 2013, 2014 e 2015, produzidas integralmente pelo Instituto Butantan, foram seguras e imunogênicas segundo os parâmetros de imunogenicidade definidos pela EMA / INTRODUCTION: Annual vaccination is most effective way to prevent seasonal influenza illness. Instituto Butantan (IB) performed clinical studies with its 2013, 2014 and 2015 seasonal trivalent influenza vaccines (split-virion and inactivated) METHODS: Prospective cohort studies to describe the safety and immunogenicity of Instituto Butantan influenza vaccine, in healthy adults and elderly, from 2013 to 2015. Soon after the informed consent was signed, participants underwent blood collection followed by vaccination. On study days 1, 2 and 3 post vaccination participants were contacted by the stuffy to evaluate the occurrence of solicited (local and systemic) and non-solicited adverse reactions. On study day 21(+7) subjects returned to the clinical site for final safety assessments and blood collection for the immunogenicity evaluation post vaccination. The immunogenicity analyses were performed by means of haemagglutination inhibition assay (HI). The immunogenicity endpoints were: seroprotection (SPR) and seroconversion (SCR) rates and the geometric mean HI antibody titer ratio (GMTR). The 2013 study The Centro de Referência para Imunobiológicos Especiais (CRIE) and at the Centro de Pesquisa Clínica do Instituto da Criança, Hospital das Clínicas of Medical School of University of São Paulo and the 2014 and 2015 studies were conducted at CRIE. The vaccine composition followed the WHO recommendation for the southern hemisphere seasonal influenza vaccine RESULTS: 47 healthy adults and 13 elderly participated in the 2013 study, 60 healthy adults and 60 elderly in the 2014 study, and 62 healthy adults and 57 elderly in the 2015 study. In the 2013, 2014 and 2015 studies, pain was the most frequent local adverse reaction and headache the most frequent systemic adverse reaction. All observed adverse reactions were classified as mild or moderate and none as severe. SPR > 70% and SPR > 60% were observed in adults and elderly, respectively, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. SCR > 40% was observed in adults, for the three vaccine viruses, only in the 2014 study and SCR > 30% was observed in elderly, for the three vaccine viruses, only in the 2013 and 2014 studies. GMTR >2.5 among adults, for the three vaccine viruses was only observed in the 2013 study and GMTR > 2.0 was observed among elderly, for the three vaccine viruses, in the 2013, 2014 and 2015 studies. CONCLUSION: The 2013, 2014 and 2015 seasonal influenza vaccines produced by Instituto Butantan were safe and immunogenic according to the immunogenicity criteria defined by EMA

La grippe saisonnière et ses complications associées peuvent avoir des conséquences de morbimortalité importantes notamment pour les personnes à risque. Les taux de couverture vaccinale (TCV) restent toutefois faibles, dans la plupart des pays européens, et ce malgré l'existence de recommandations vaccinales. À ce jour, peu de travaux permettant d'expliquer ce phénomène ont été réalisés. L'asymétrie d'information entre les groupes cibles, les vaccinateurs et les autorités de santé peut éventuellement expliquer le faible TCV. Outre l'évaluation du fardeau économique de la grippe saisonnière en France, cette thèse explore le processus d'élaboration des recommandations vaccinales et les variables (financières ou non) impactant la propension des médecins généralistes (MGs) à vacciner. Une enquête prospective conduite sur la base des cas de grippe confirmés en laboratoire a estimé l'impact économique de la grippe pour l'assurance maladie à 193 millions d'Euros pour l'année 2010/2011 en France. Les entretiens avec des acteurs clés, impliqués dans l'élaboration des recommandations vaccinales en France et aux Pays-Bas, ont mis en lumière le processus de décision et l'influence notamment des évaluations économiques. L'utilisation systématique d'un classement du niveau de preuve des informations n'a cependant pas été observée, alors qu'elles étaient considérées plutôt comme de faible qualité. Des informations similaires ont été utilisées dans les deux pays ; on observe néanmoins des différences entre les groupes cibles ; le jugement des experts étant crucial pour le processus de décision. Une étude pilote, conduite auprès des MGs en France, a identifié les incitations financières et non-monétaires à vacciner les groupes cibles. Cette étude a permis de mettre en exergue le poids des incitations non-monétaires dans la promotion de la vaccination contre la grippe saisonnière en France : niveau de preuves scientifiques sur l'efficacité du vaccin, transparence des recommandations vaccinales, nouvelles modalités organisationnelles. / Seasonal influenza complications may cause hospitalization and even death. Despite the existence of vaccination recommendations to risk-groups, the vaccination coverage rates (VCR) in most European countries are low. Currently, few studies have been undertaken to explain this phenomenon. Information asymmetry between target groups, vaccinators and health authorities may possibly explain the low VCR. This thesis aimed at investigating (1) the economic burden of seasonal influenza in France, (2) the decision-making process for developing seasonal vaccination recommendations and (3) the incentives that would motivate general practitioners (GPs) to promote vaccination. A prospective survey conducted with laboratory-confirmed cases of influenza has shown the important economic impact of influenza under the perspective of the French Health Insurance. The main cost drivers are hospitalizations and daily allowances. Interviews with key actors, in France and in the Netherlands, involved in the development of vaccination recommendations explored their perceptions about the decision-making process and the influence of economic evaluations and other information on decisions. No systematic grading of the evidence was observed, whereas it was considered of low quality. Similar information was used in both countries, but as experts’ judgement was crucial for the process, differences about the target groups for vaccination were observed. Financial incentives to Dutch vaccinators were associated with their higher VCR. A pilot-study web-surveyed GPs, major vaccinators in France, about the influence of existing financial and non-monetary incentives. GPs were more likely to promote vaccination under non-monetary incentives. Probably because they were generally in favour of vaccinations, including the influenza vaccine; but they seek evidence proving the effectiveness of the vaccine and transparency of vaccination recommendations.