Human Papilloma Viruses (HPVs) are a large family of viruses with a capsid constituted by the L1 and L2 proteins, which bind to receptors of the basal epithelial cells, thus promoting virus entry. The majority of sexually active people become exposed to HPV, which is the most common cause of cervical cancer affecting more than 600.000 women every year. Moreover, every year more than 13.000 new cases of HPV-related cancers, including anal, penile and head and neck cancers, are diagnosed in men. Three vaccines are available based on the L1 capsid protein, which self-assembles and forms virus-like particles (VLPs) when expressed in yeast and insect cells. Although very effective, these vaccines are HPV type-restricted, and their costs limit broad vaccination campaigns, especially in low- and middle- income countries. Recently, vaccine candidates based on the conserved L2 epitope from serotypes 16, 18, 31, 33, 35, 6, 51 and 59 were shown to elicit broadly neutralizing anti-HPV antibodies, reaching a protection around 90% against all the HPV serotypes. During my research activity, we have tested whether E. coli Outer Membrane Vesicles (OMVs) could be successfully decorated with L2 polytopes and whether the engineered OMVs could induce neutralizing antibodies. OMVs represent an attractive vaccine platform for their intrinsic adjuvanticity and their low production costs. We show that strings of L2 epitopes could be efficiently expressed on the surface of the OMVs and a polypeptide constituted by the L2 epitopes from serotypes 18, 33, 35 and 59 provided broad cross-protective activity against a large panel of HPV serotypes as judged by the in vitro pseudovirus neutralization assay. In order to better characterize the vesicle and in perspective of future clinical studies of our HPV candidate vaccine, we also worked on the setting-up of a simple and reproducible production process at laboratory scale ready to be transferred at industrial level.Moreover, we focused our attention on the strategy used for the engineering of the OMVs with the L2 epitopes and in particular on the carrier used for the delivery of the fusion construct in the surface of the vesicle. More in detail, since part of the carrier is a human cancer epitope, we tested whether a similar scaffold, with less homologies to the human gene could maintain the same properties in terms of: i) expression level of the fused epitopes in the OMVs, ii) localization on the surface of the vesicle and iii) 9 immunogenicity and efficiency to stimulate the immune system in order to produce anti L2 antibodies. Considering all the results described in this work combined with the points of strength of the OMV-based vaccine platform, as the simplicity of the production process, the yields of vaccine doses and the low cost/dose, our data provide a very promising prototype of universal anti-HPV vaccine.

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Human rotavirus (HRV) and human norovirus (HuNoV) are the most common causative agents of acute gastroenteritis- (AGE) related morbidity and mortality around the world. Gnotobiotic (Gn) pigs are the ideal large-animal model that allows for accurate, and precise, preclinical evaluation of vaccine efficacy. Similarities in gastrointestinal anatomy, physiology, and immune system allows for direct translation of results from Gn pigs to humans. Commercially available HRV vaccines perform significantly poorer in low- and middle- income countries as compared with developed countries. Non-replicating rotavirus vaccines (NRRVs) have been proposed as a viable solution to the problems facing currently available live-, attenuated oral vaccines and evaluation of a NRRV was the first research project in this dissertation. Three doses of a novel parenterally administered nanoparticle-based RV vaccine, P24-VP8*, adjuvanted with Al(OH)3 adjuvant, was able to prime VP8*-specific mucosal and systemic T cell responses (IFN-γ producing CD4+ and CD8+ T cells), and to induce strong systemic B cell responses (IgA, IgG and serum neutralizing antibodies). A significant reduction in the mean diarrhea duration, fecal virus shedding titers, and significantly lower fecal cumulative consistency scores was observed among vaccinated pigs demonstrating the efficacy of the vaccine against RV infection and diarrhea. Next, we determined the median infectious dose (ID50) and median diarrhea dose (DD50) of the GII.4/2003 Cin-1 variant of HuNoV in Gn pigs to better standardize the pig model for HuNoV vaccine evaluation. Gn pigs were inoculated with 7 different doses of Cin-1 at 33-34 days of age. Pigs were monitored daily from post-inoculation day (PID) 1 to 7, for fecal virus shedding and fecal consistency to evaluate the virus infectiousness and associated diarrhea. The Log10 ID50 and DD50 were determined based on various mathematical models to be between 3.11 to 3.76, and 3.37 to 4.87 RNA copies, respectively. The Beta-Poisson was identified to be the best-fitting statistical model for estimating both the ID50 and DD50 of Cin-1. Determining the ID50 of the challenge virus strain is crucial for identifying the true infectiousness of HuNoVs and for accurate evaluation of protective efficacies in pre-clinical studies of therapeutics, vaccines and other prophylactics using this reliable animal model. The lack of an easily reproducible cell culture model for HuNoV has significantly delayed the development of effective vaccines. There is still no HuNoV vaccine available. Currently, the vaccine development efforts are mostly based on genetically engineered virus-like particles (VLPs) comprised of the major HuNoV capsid protein VP1. We tested the immunogenicity of a novel tetravalent VLP vaccine containing 4 major HuNoV genotypes (GI.1, GII.3, GII.4 and GII.17) using Gn pigs and evaluated its protective efficacy when challenged with GII.4 Cin-1 HuNoV. Three doses of the VLP vaccine with Al(OH)3 adjuvant administered to Gn pigs intramuscularly (IM), induced high levels of VLP-specific serum IgA and IgG antibody and hemagglutination inhibition antibody responses in the vaccinated pigs. VLP-specific IFN-γ producing CD4+ and CD8+ T cells were also elevated among vaccinated pigs at post-challenge day (PCD) 7 in the spleen and blood, but not in the ileum. However, the vaccinated pigs were not protected from infection and diarrhea when challenged with any one of the three different doses (2 x 105, 8 x 104, and 2 x 104 genome RNA copies) of Cin-1 HuNoV. These results indicated that the IM tetravalent VLP vaccine was highly immunogenic, but the presence of high levels of immune effectors induced by the vaccine were not sufficient for protecting the Gn pigs from Cin-1 challenge. Amino acid (aa) sequence analysis showed that the GII.4 Sydney 2012 strain which was included in the VLP vaccine, had 23 aa substitutions in the major receptor binding domain (P2) compared to the Cin-1, a GII.4 Farmington Hills 2002 strain. Our findings, for the first time, provided in vivo experimental evidence for the total lack of cross-genogroup, cross-genotype and cross-variant protection among HuNoV. This finding has importance implications for HuNoV vaccine development. HuNoV vaccines have to include multiple variants and have to be routinely updated in order to ensure sustained protection among the population. Together these three studies in this dissertation demonstrate the versatility of Gn pigs as a reliable large animal model for studying the pathogenesis and immunity of enteric viruses and the evaluation of immunogenicity and protective efficacy of novel enteric viral vaccines. / Doctor of Philosophy / People of all age groups are susceptible to acute gastroenteritis (AGE), a condition characterized by sudden onset of diarrhea, nausea and abdominal cramps. The two most important viral pathogens responsible for causing AGE are rotavirus (RV) and norovirus (NoV). Gnotobiotic (Gn) pigs have been valuable in helping us understand the mechanism of infection, pathogenesis, immunity and have played a key role in the expediting development of novel vaccines and therapeutics against both of these viruses. Live oral RV vaccines are available but they are not very effective in low income countries where the vaccines are needed the most. Next generation parenteral vaccines are proposed to improve the RV vaccine efficacy. Our first study showed that a nanoparticle-based intramuscular (IM) RV vaccine effectively reduced the duration and severity of human RV infection and diarrhea in Gn pigs. Secondly, we examined in detail the infectivity of HuNoV and identified accurately using different mathematical models on how much virus would be required to infect and cause diarrhea in naïve Gn pigs. This knowledge would greatly help in the accurate assessment of the efficacy of NoV vaccines. Third, we evaluated the immunogenicity and protective efficacy of a tetravalent IM NoV vaccine in Gn pigs. Although the vaccine was highly immunogenic, it did not confer any protection against infection and diarrhea upon challenge with the NoV at different doses. NoVs are so diverse that one year we might be infected with one strain and a few years later, we might be infected again with another strain, even though they belong to the same genotype, and experience the same symptoms. This is because, changes brought about due to mutation in the virus capsid protein allow the viruses to hide from neutralizing antibodies induced by previous infection or vaccination as we have revealed in this study. NoV diversity and lack of cross protection need to be taken into consideration during vaccine development. This thesis shows how Gn pigs can be used to study these components in order to further maximize our ability to understand and combat enteric viral diseases.

Flaviviruses are a genus of vector-transmitted viruses that are nearly globally distributed, and flavivirus infections can result in life threatening diseases. Many flaviviruses such as Dengue, West Nile, yellow fever and Zika viruses are globally distributed. Zika virus (ZIKV) is a single strand positive-sense RNA virus, and its disease has been linked to Guillain Barré Syndrome (i.e., a debilitating autoimmune disorder that affects the nerves) in adults and congenital birth defects including microcephaly (i.e., a neurodevelopmental disorder due to impaired neural cell proliferation) in newborns. Insect-specific flaviviruses (ISFVs) are understudied given their apathogenic characteristics to humans and animals. However, given their close genetic relationship to vertebrate infectious flaviviruses, ISFVs can serve as a delivery system (i.e., vector) for flavivirus antigenic proteins. Aripo virus (ARPV) is a recently discovered ISFV isolated in Trinidad. We developed a chimeric Zika vaccine, Aripo-Zika, by substituting the pre-membrane and envelope genes of ZIKV into the ARPV genome. Here, we explored (i) the efficacy of Aripo-Zika (AZ) vaccination by evaluating passive transfer of maternal antibodies, (ii) the optimal dosage regimen, (iii) anti-vector immunity to the ARPV backbone, and (iv) the effects of boosters on vaccine efficacy. We also evaluated AZ safety via a co-infection study. Our results show a near linear relationship between increased dose and immunogenicity, with 1011 genome copies being the most effective minimum dose administered. Inclusion of boosters further increased the immunogenicity of AZ. Additionally, prior immunization with AZ showed minimal effects on subsequent immunization with an ARPV-West Nile virus (AWN) vaccine candidate, confirming the applicability of the ARPV backbone to multiple flavivirus vaccine candidates. In vitro co-infection of ZIKV with ARPV, and ZIKV with AZ in African green monkey kidney cells (i.e., Vero-76) indicated ARPV and AZ remain incapable of replication in vertebrate cells, even in the presence of active ZIKV replication. Altogether, our data suggests that the ARPV platform is a safe and effective strategy for the development of flavivirus vaccines. / Master of Science in Life Sciences / Vaccines are one of the best tools available since their initial conception. Vaccines have collectively increased human lifespan and reduced the burden of disease in humans and animals worldwide. Vaccine research aims to create vaccines that have a perfect balance of safety and efficacy. The goal is to produce a vaccine that can generate a strong immune response against the virus(es) of interest, while causing the least harm or side effects from the vaccine. Insect-specific viruses are viruses that infect insect cells, but are unable to replicate in humans or other vertebrate cells. The Auguste Lab has created a chimeric vaccine using the genome of an insect-specific virus called Aripo-Zika virus (AZ) that is genetically related to Zika virus. A person vaccinated with AZ is expected to develop an immune response against Zika but would not have any disease or side effects associated with a Zika infection or virus replication. In order to determine if this vaccine would be safe and effective enough to advance to clinical trials in humans, we must first determine if it is safe in smaller animal models. My studies have five central aims. First, determine the lowest dose of AZ that can be given and still be protective against Zika disease in mouse models. Second, determine if boosters are necessary and if they increase protection. Third, determine if immunity derived from vaccination can be passed down from mother to pups. Fourth, determine if Zika virus and AZ can co-exist in the same cell line without AZ replication occurring. Lastly, determine if mice can be vaccinated with AZ and subsequently with another similar Aripo virus-based vaccine (i.e., Aripo-West Nile) without changing the effectiveness of the subsequent immunization. Our results showed that AZ is able to be passed from mother to pup, 1011 genome copies is the minimum protective dose, and boosters can increase the effectiveness of AZ. We also found that AZ does not replicate in vertebrate cells when it co-exists with ZIKV and subsequent vaccination with Aripo-West Nile does not seem affect the effectiveness of either vaccine.

Human papillomavirus (HPV) is widespread in the population and an important concern for public health. HPV-associated benign and cancerous disease is vaccine preventable yet vaccine uptake has been suboptimal. Adolescents are the primary target for vaccination yet their perspective has been inadequately examined. Ontario provides population-based preventive HPV vaccination to adolescent girls yet in the program’s first 2 years only approximately half of eligible girls received it. Effective strategies to improve vaccine uptake are needed. This thesis proposes a theory and ethics-based model to guide health promotion planning for HPV vaccination. Adopting an adolescent perspective, the model is applied and comprises: 1) a systematic review to identify barriers and facilitators to HPV vaccination from the viewpoint of young females; 2) GIS uses for communicating geospatial health information regarding vaccination; and 3) a roadmap for the future including recommendations for guiding principles, research, intervention development, and health policy.

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

Human papillomavirus (HPV) is widespread in the population and an important concern for public health. HPV-associated benign and cancerous disease is vaccine preventable yet vaccine uptake has been suboptimal. Adolescents are the primary target for vaccination yet their perspective has been inadequately examined. Ontario provides population-based preventive HPV vaccination to adolescent girls yet in the program’s first 2 years only approximately half of eligible girls received it. Effective strategies to improve vaccine uptake are needed. This thesis proposes a theory and ethics-based model to guide health promotion planning for HPV vaccination. Adopting an adolescent perspective, the model is applied and comprises: 1) a systematic review to identify barriers and facilitators to HPV vaccination from the viewpoint of young females; 2) GIS uses for communicating geospatial health information regarding vaccination; and 3) a roadmap for the future including recommendations for guiding principles, research, intervention development, and health policy.

Human papillomavirus (HPV) is widespread in the population and an important concern for public health. HPV-associated benign and cancerous disease is vaccine preventable yet vaccine uptake has been suboptimal. Adolescents are the primary target for vaccination yet their perspective has been inadequately examined. Ontario provides population-based preventive HPV vaccination to adolescent girls yet in the program’s first 2 years only approximately half of eligible girls received it. Effective strategies to improve vaccine uptake are needed. This thesis proposes a theory and ethics-based model to guide health promotion planning for HPV vaccination. Adopting an adolescent perspective, the model is applied and comprises: 1) a systematic review to identify barriers and facilitators to HPV vaccination from the viewpoint of young females; 2) GIS uses for communicating geospatial health information regarding vaccination; and 3) a roadmap for the future including recommendations for guiding principles, research, intervention development, and health policy.