Impact of HIV-Related Immune Impairment of Yellow Fever Vaccine Immunogenicity in People Living with HIV-ANRS 12403.

The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited due to safety concerns and a lack of consensus regarding decreased immunogenicity and long-lasting protection for this population. The mechanisms associated with impaired YF vaccine immunogenicity in PLWH are not fully understood, but the general immune deregulation during HIV infection may play an important role. To assess if HIV infection impacts YF vaccine immunogenicity and if markers of immune deregulation could predict lower immunogenicity, we evaluated the association of YF neutralization antibody (NAb) titers with the pre-vaccination frequency of activated and exhausted T cells, levels of pro-inflammatory cytokines, and frequency of T cells, B cells, and monocyte subsets in PLWH and HIV-negative controls. We observed impaired YF vaccine immunogenicity in PLWH with lower titers of YF-NAbs 30 days after vaccination, mainly in individuals with CD4 count <350 cells/mm3. At the baseline, those individuals were characterized by having a higher frequency of activated and exhausted T cells and tissue-like memory B cells. Elevated levels of those markers were also observed in individuals with CD4 count between 500 and 350 cells/mm3. We observed a negative correlation between the pre-vaccination level of CD8+ T cell exhaustion and CD4+ T cell activation with YF-NAb titers at D365 and the pre-vaccination level of IP-10 with YF-NAb titers at D30 and D365. Our results emphasize the impact of immune activation, exhaustion, and inflammation in YF vaccine immunogenicity in PLWH.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics.

BACKGROUND: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. METHODS: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. RESULTS: A total of 202 PLWH with CD4 ≥ 200 cells/µL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. CONCLUSIONS: 17DD was safe and well-tolerated in PLWH with CD4 ≥ 200 cells/µL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Egg allergy and yellow fever vaccination.

OBJECTIVE: Evaluate biomarkers capable of safely guiding Yellow fever vaccine (YFV) vaccination among individuals suspicious of hen's egg allergy, and identify factors associated with a higher risk for adverse events after immunization (AEAI). METHODS: Patients underwent skin prick test (SPT) for standardized allergens: whole egg, egg white, egg yolk; YFV (1:10 dilution; Biomanguinhos-Fiocruz), and intradermal test (IDT; YFV 0.02 mL, 1:100 dilution) and positive and negative controls. Serum levels of specific IgE (sIgE) for a whole egg, egg white, egg yolk, egg albumin, ovomucoid, lysozyme, and conalbumin (ImmunoCap®; ThermoFisher®) were obtained. Patients sensitized to YFV were submitted to YFV desensitization, and those negatives received YFV (0.5mL) and remained under surveillance for at least one hour. RESULTS: 103 patients were enrolled, 95% under 12 years old. 71% (81/103) of patients had reactions: 80% immediate, 11% mixed, and 9% delayed. There was an association between positive skin test results with YFV and the severity of the reaction (OR:7.64; 95%CI:1.61-36.32; p = 0,011). Only the presence of sIgE to ovomucoid was associated with clinical symptoms (p = 0,025). Thirty patients underwent the YFV desensitization protocol. CONCLUSION: There is a relationship between the positivity of the egg's components and the severity of the clinical reaction. Furthermore, the relationship between the positivity of the tests with the YFV and egg's components may show a tendency to look at ovomucoid and conalbumin, but it is not a certainty. Therefore, further studies are needed to confirm these associations, and for now, the authors still recommend using the vaccine for testing when necessary.

Egg allergy and yellow fever vaccination

Abstract Objective Evaluate biomarkers capable of safely guiding Yellow fever vaccine (YFV) vaccination among individuals suspicious of hen's egg allergy, and identify factors associated with a higher risk for adverse events after immunization (AEAI). Methods Patients underwent skin prick test (SPT) for standardized allergens: whole egg, egg white, egg yolk; YFV (1:10 dilution; Biomanguinhos-Fiocruz), and intradermal test (IDT; YFV 0.02 mL, 1:100 dilution) and positive and negative controls. Serum levels of specific IgE (sIgE) for a whole egg, egg white, egg yolk, egg albumin, ovomucoid, lysozyme, and conalbumin (ImmunoCap®; ThermoFisher®) were obtained. Patients sensitized to YFV were submitted to YFV desensitization, and those negatives received YFV (0.5mL) and remained under surveillance for at least one hour. Results 103 patients were enrolled, 95% under 12 years old. 71% (81/103) of patients had reactions: 80% immediate, 11% mixed, and 9% delayed. There was an association between positive skin test results with YFV and the severity of the reaction (OR:7.64; 95%CI:1.61-36.32; p =0,011). Only the presence of sIgE to ovomucoid was associated with clinical symptoms (p =0,025). Thirty patients underwent the YFV desensitization protocol. Conclusion There is a relationship between the positivity of the egg's components and the severity of the clinical reaction. Furthermore, the relationship between the positivity of the tests with the YFV and egg's components may show a tendency to look at ovomucoid and conalbumin, but it is not a certainty. Therefore, further studies are needed to confirm these associations, and for now, the authors still recommend using the vaccine for testing when necessary.

Safety of the yellow fever vaccine in people living with HIV: a longitudinal study exploring post-vaccination viremia and hematological and liver kinetics

ABSTRACT Background: Safety data on the yellow fever vaccine 17DD in People Living with HIV (PLWH) are limited. This study explored the occurrence of post-vaccination 17DD viremia and the kinetics of hematological and liver laboratorial parameters in PLWH and HIV-uninfected participants [HIV(-) controls]. Methods: We conducted a secondary analysis of a longitudinal interventional trial (NCT03132311) study that enrolled PLWH and HIV(-) controls to receive a single 17DD dose and were followed at 5, 30 and 365 days after vaccination in Rio de Janeiro, Brazil. 17DD viremia (obtained throughreal-time PCR and plaque forming units' assays), hematological (neutrophils, lymphocytes and platelets counts) and liver enzymes (ALT and AST) results were assessed at baseline and Days 5 and 30 post-vaccination. Logistic regression models explored factors associated with the odds of having positive 17DD viremia. Linear regression models explored variables associated with hematological and liver enzymes results at Day 5. Results: A total of 202 PLWH with CD4 > 200 cells/μL and 68 HIV(-) controls were included in the analyses. 17DD viremia was found in 20.0 % of the participants and was twice more frequent in PLWH than in HIV(-) controls (22.8% vs. 11.8 %, p-value < 0.001). Neutrophils, lymphocytes and platelets counts dropped at Day 5 and returned to baseline values at Day 30. 17DD viremia was associated with lower nadir of lymphocytes and platelets at Day 5. ALT levels did not increase post-vaccination and were not associated with 17DD viremia. Conclusions: 17DD was safe and well-tolerated in PLWH with CD4 > 200 cells/μL. Post-vaccination viremia was more frequent in PLWH than in controls. Transient and self-limited decreases in lymphocytes and neutrophils occurred early after vaccination. 17DD viremia was associated with lower lymphocytes and platelets nadir after vaccination. We did not observe elevations in ALT after 17DD vaccination.

Differential gene expression of cytokines, receptors, and miRNAs in individuals living with HIV-1 and vaccinated against yellow fever.

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-ß, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RTqPCR. TCD4+ cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4+ cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4+ counts. Furthermore, we identified the downregulation of CD19 and TGF-ß, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination.

Hesitação da vacina da febre amarela e sua relação com influências contextuais, individuais ou de grupo e questões específicas da vacina: uma revisão de escopo / Yellow fever vaccine hesitancy and its relationship with contextual, individual, or group influences and vaccine-specific issues: a scoping review

Resumo A hesitação vacinal é um fenômeno com potencial para reduzir as taxas de cobertura vacinal, como observado na vacina contra febre amarela (VFA), propiciar epidemias e a reintrodução de doenças imunopreveníveis controladas. O objetivo deste estudo é mapear junto à literatura científica a relação entre a falta de informação, a segurança da vacina e os eventos adversos e a hesitação vacinal da VFA. Foi realizada uma revisão de escopo nas bases Biblioteca Virtual em Saúde (BVS), National Library of Medicine (PubMed), SCOPUS, Embase e Web of Science utilizando descritores controlados (DeCS/MeSH) e não controlados. Foram selecionados 11 artigos publicados nos idiomas inglês, espanhol e português, sem delimitação de tempo e que atenderam aos critérios de inclusão. Estiveram relacionados à hesitação vacinal da VFA informações falsas, conhecimento inadequado sobre o imunizante, falta de tempo para se vacinar, aceitação da vacina, insegurança na vacina e medo dos eventos adversos. Este estudo reforça a importância do acesso a informações adequadas, orientações sobre a segurança e os eventos adversos da VFA e pode auxiliar na elaboração de estratégias de saúde pública para mitigar a hesitação vacinal.

Abstract Vaccine hesitancy is a phenomenon with the potential to reduce vaccination coverage rates, as observed with the yellow fever vaccine (YFV), leading to epidemics and the reintroduction of controlled immunopreventable diseases. This study, together with the scientific literature, aims to map the relationship among the lack of information, vaccine safety and adverse events, and vaccine hesitancy concerning YFV. A scoping review was conducted in the Virtual Health Library (VHL), National Library of Medicine (PubMed), SCOPUS, Embase, and Web of Science databases, using controlled (DeCS/MeSH) and uncontrolled descriptors. In this work, we selected eleven articles, published in English, Spanish, and Portuguese, with no time limits, which met the inclusion criteria. False information, inadequate knowledge about the immunizer, lack of time to take a vaccination, acceptance of the vaccine, vaccine safety, and fear of adverse events were related to vaccine hesitancy. This study reinforces the importance of access to adequate information, provides guidance on YFV safety and adverse events, and can aid in the development of public health strategies to mitigate hesitancy.

Enhanced safety surveillance of STAMARIL® yellow fever vaccine provided under the expanded access investigational new drug program in the USA.

BACKGROUND: YF-VAX® (Sanofi, Swiftwater, PA), a live, attenuated vaccine based on the yellow fever (YF) substrain 17D-204, is the only YF vaccine licensed in the USA. Manufacturing disruption of YF-VAX and anticipated depletion of the US supply by mid-2017 led to the importation of another YF vaccine, STAMARIL® (Sanofi, France), into the USA under an expanded access investigational new drug program (EAP) to fulfil the public health need for YF vaccination. As part of this program, Sanofi collected enhanced safety surveillance data following vaccination with STAMARIL. Here, we report the results of the enhanced safety surveillance. METHODS: STAMARIL vaccine was offered to those aged ≥9 months at high risk of YF. Vaccine recipients (or parents/guardians) were instructed to report suspected adverse reactions, any serious adverse events (SAEs) including adverse events of special interest [AESI] occurring after vaccination regardless of suspected relationship, and any inadvertent exposure in pregnancy or breastfeeding within 14 days of vaccination. The AESIs monitored were anaphylaxis, neurotropic disease (YEL-AND) and viscerotropic disease (YEL-AVD). RESULTS: Overall, 627 079 individuals received STAMARIL from May 2017 through June 2021; of these, 1308 (0.2%) reported at least one AE, of which 122 reported at least one SAE. There were seven cases of YEL-AND and three cases of YEL-AVD reported, for reporting rates of 1.1 and 0.5 per 100 000 vaccine recipients, respectively. One vaccine recipient developed an anaphylactic reaction (reporting rate: 0.16 per 100 000). No safety concerns were identified from inadvertent vaccine exposure during pregnancy (41 pregnant women) or potential neonatal exposure via breast milk (four exposed infants). CONCLUSIONS: This study supports the utility of STAMARIL in the EAP as an alternative solution for the YF vaccine shortage in the USA. SAEs were very rare and consistent with the known safety profile of STAMARIL.

Yellow Fever Vaccine-Associated Viscerotropic Disease among Siblings, São Paulo State, Brazil.

We describe 5 cases of yellow fever vaccine-associated viscerotropic disease (YEL-AVD) in 2 familial clusters during the 2017-2018 yellow fever (YF) vaccination campaign in São Paulo state, Brazil. The first case was that of a 40-year-old white man who died of icterohemorrhagic syndrome, which was confirmed to be YEL-AVD by using real-time reverse transcription PCR to detect 17DD YF vaccine in the liver. Ten years previously, his brother died of a clinically similar disease without a confirmed diagnosis 9 days after YF vaccination. The second cluster included 3 of 9 siblings in whom hepatitis developed in the first week after receiving fractionated doses of YF vaccine. Two of them died of hemorrhagic diathesis and renal and respiratory failure, and 17DD-YF vaccine was detected in serum samples from all patients and in the liver in 1 case. Genetic factors might play a substantial role in the incidence of YEL-AVD.

Yellow fever vaccine safety in immunocompromised individuals: a systematic review and meta-analysis.

BACKGROUND: Yellow fever (YF) is an arbovirus with variable severity, including severe forms with high mortality. The vaccination is the most effective measure to protect against the disease. Non-serious and serious adverse events have been described in immunocompromised individuals, but previous studies have failed to demonstrate this association. This systematic review assessed the risk of adverse events after YF vaccination in immunocompromised individuals compared with its use in non-immunocompromised individuals. METHODS: A search was conducted in the MEDLINE, LILACS, EMBASE, SCOPUS, DARE, Toxiline, Web of Science and grey literature databases for publications until February 2021. Randomized and quasi-randomized clinical trials and observational studies that included immunocompromised participants (individuals with HIV infection, organ transplants, with cancer, who used immunosuppressive drugs for rheumatologic diseases and those on immunosuppressive therapy for other diseases) were selected. The methodological quality of observational or non-randomized studies was assessed by the ROBINS-I tool. Two meta-analyses were performed, proportion and risk factor analyses, to identify the summary measure of relative risk (RR) in the studies that had variables suitable for combination. RESULTS: Twenty-five studies were included, most with risk of bias classified as critical. Thirteen studies had enough data to carry out the proposed meta-analyses. Seven studies without a comparator group had their results aggregated in the proportion meta-analysis, identifying an 8.5% [95% confidence interval (CI) 0.07-21.8] risk of immunocompromised individuals presenting adverse events after vaccination. Six cohort studies were combined, with an RR of 1.00 (95% CI 0.78-1.29). Subgroup analysis was performed according to the aetiology of immunosuppression and was also unable to identify an increased risk of adverse events following vaccination. CONCLUSIONS: It is not possible to affirm that immunocompromised individuals, regardless of aetiology, have a higher risk of adverse events after receiving the YF vaccine.

Eventos adversos imediatos à vacina febre amarela em crianças alérgicas ao ovo / Immediate adverse events to the yellow fever vaccine in egg-allergic children

Introdução: A vacina contra a febre amarela é cultivada em ovos embrionados de galinha e por isso pode estar contraindicada em indivíduos alérgicos ao ovo. Quando indicada, deve ser aplicada com cautela, após atendimento especializado para avaliação de testes e necessidade de dessensibilização. Sua segurança nos alérgicos ao ovo ainda é pouco estudada. Objetivo: Descrever uma população pediátrica encaminhada por alergia ao ovo, com ou sem diagnóstico comprovado, e os casos de eventos adversos do tipo imediata à vacina contra a febre amarela em um centro de referência para imunobiológicos especiais (CRIE). Material e métodos: Estudo transversal realizado com coleta de dados retrospectivos de crianças entre 9 meses e 12 anos de idade, vacinadas contra a febre amarela com história de alergia ao ovo, no período de 2018 a 2019. Resultados: Dentre as 829 crianças, com diagnóstico presumido de alergia ao ovo, foi identificada uma maior prevalência de sintomáticos após exposição ao ovo, com IgE específica detectável para ovo, clara de ovo e/ou ovoalbumina. Testes para vacina febre amarela foram realizados em 25 crianças com suspeita de alergia grave ou anafilaxia ao ovo, sendo 15 (60%) positivos com a vacina aplicada após dessensibilização. Foram evidenciados apenas 11 (1,3%) casos de evento adverso imediato à vacina, todos classificados como evento adverso não grave e com acometimento especial da pele (reação local e exantema ou urticária). A maioria dos eventos ocorreu em menores de 2 anos, nos sintomáticos após ingesta de ovo e naqueles com altos valores de IgE específica para clara de ovo. Conclusão: Este estudo evidencia que a vacina contra a febre amarela pode ser aplicada em crianças alérgicas ao ovo, de forma segura, inclusive naquelas com história de anafilaxia, desde que em ambiente adequado e com profissionais especializados.

Introduction: The yellow fever vaccine is grown in embryonated chicken eggs and may be contraindicated for egg-allergic individuals. When indicated, it should be applied with caution, after testing and desensitization. Its safety in egg-allergic patients is still poorly studied. Objective: To describe a pediatric population referred for egg allergy, with or without a confirmed diagnosis, and cases of immediate-type adverse events to the yellow fever vaccine at a reference center for special immunobiologicals. Material and methods: This cross-sectional study collected retrospective data from children between 9 months and 12 years of age who were vaccinated for yellow fever between 2018 and 2019 and had a history of egg allergy. Results: In the 829 children diagnosed with presumed egg allergy, a higher prevalence of symptoms was identified after egg exposure, with detectable specific IgE for egg, egg white, and/ or egg albumin. Yellow fever vaccine tests were performed in 25 children suspected of severe allergy or anaphylaxis to eggs, and 15 (60%) tested positive to the vaccine after desensitization. Only 11 (1.3%) cases of immediate adverse events to the vaccine occurred, all classified as non-serious events that especially involved the skin (local reaction and rash or urticaria). Most events occurred in children under 2 years of age, those symptomatic after egg ingestion, and those with high levels of specific IgE to egg white. Conclusion: This study demonstrated that the yellow fever vaccine can be safely administered to egg-allergic children, including those with a history of anaphylaxis, in an appropriate environment and with specialized professionals.

Previous biological therapy and impairment of the IFN-γ/IL-10 axis are associated with low immune response to 17DD-YF vaccination in patients with spondyloarthritis.

Yellow fever (YF) vaccination is known to induce a suboptimal response in patients with autoimmune diseases (AIDs). To date, few studies have focused on the performance of 17DD-YF vaccination in patients with spondyloarthritis (SpA). In general, patients with SpA are young and have less comorbidities than other patients with AIDs, and frequently receive biological disease-modifying antirheumatic drugs (DMARDs) that may impact their response to vaccines. Taking this background information, the present study aimed to investigate whether the use of biological DMARDs, even after planned washout, or disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), would impact the overall performance of planned 17DD-YF primary vaccination in patients with SpA. For this purpose, 74 subjects were enrolled in a prospective study, including adult patients with SpA (SpA; n = 51) and a healthy control (HC; n = 23) group. Analysis of YF specific neutralizing antibodies test (PRNT), along with YF viremia and the levels of serum chemokines, cytokines, and growth factors were performed at distinct time points (D0, D3, D4, D5, D6, D7, D14, and D28). The BASDAI scores were evaluated at D0 and D180. Data demonstrated that overall, the SpA group presented lower PRNT titers and seropositivity rates as compared to the HC group (GeoMean = 112 vs. 440; 73% vs. 96%, respectively). In SpA subgroup analyses, previous biological DMARDs (BIO-IT) led to a lower PRNT titers (BIO-IT 79, 95% CI [39-150] vs. without biological DMARDs [non-BIO-IT] 159, 95% CI [94-267], p < 0.001). The non-BIO-IT group achieved a response similar to the HC group (81% vs. 96%, p = 0.112), whereas the BIO-IT group had a lower seroconversion rate (64% vs. 96% HC, p = 0.007). The BASDAI was not associated with PRNT levels and did not change after 6 months of follow-up. No differences in YF viremia were observed amongst subgroups. Higher baseline levels of serum biomarkers were observed in the BIO-IT group vs. the non-BIO-IT group, as well as in those with a BASDAI ≥ 4 vs. those with a BASDAI < 4. Increasing levels of several biomarkers were observed in SpA, especially in the BIO-IT and BASDAI ≥ 4 subgroups throughout the timeline kinetics, with impairment/disturbance in the IFN-γ/IL-10 axis around the peak of viremia (D5). Altogether, these findings suggested that the use of biological DMARDs impacts the response to the 17DD-YF vaccine, even after planned washout. Therefore, previous biological DMARD therapy, the inflammatory status prior vaccination, and impairment of the IFN-γ/IL-10 axis at the peak of viremia may determine the immunogenicity of 17DD-YF vaccination in patients with SpA.

A Systematic Review and a Meta-Analysis of the Yellow Fever Vaccine in the Elderly Population.

We conducted a systematic review and a meta-analysis to assess the risk of serious adverse events in the elderly after yellow fever vaccination compared to the non-elderly population. We searched multiple databases and grey literature, and we selected research without language and publication date restrictions. Studies were analyzed in a descriptive way and meta-analyzed and expressed in terms of prevalence ratio and risk ratio with a 95% confidence interval, depending on the degree of heterogeneity found. A total of 18 studies were included and 11 were meta-analyzed. The results obtained through the meta-analysis showed a risk of serious adverse events after yellow fever vaccination three times higher for the elderly when compared to the non-elderly population and five times higher for persons > 70 years. In relation to adverse event types, viscerotropic disease associated with the yellow fever vaccine had a risk that was six times higher when compared to the population < 60 years. The evidence found supports that the vaccine indication in individuals > 60 years of age should be based on a careful analysis of individual benefit-risk assessments. The results found suggest a higher risk of events for individuals > 70 years, especially for viscerotropic and neurotropic disease associated with YFV contraindicating the use of the YFV in this age group.

Yellow fever vaccination before and during the covid-19 pandemic in Brazil

ABSTRACT OBJECTIVE To analyze the number of yellow fever vaccine doses administered before and during the covid-19 pandemic in Brazil. METHODS This is an ecological, time series study based on data from the National Immunization Program. Differences between the median number of yellow fever vaccine doses administered in Brazil and in its regions before (from April/2019 to March/2020) and after (from April/2020 to March/2021) the implementation of social distancing measures in the country were assessed via the Mann-Whitney test. Prais-Winsten regression models were used for time series analyses. RESULTS We found a reduction in the median number of yellow fever vaccine doses administered in Brazil and in its regions: North (-34.71%), Midwest (-21.72%), South (-63.50%), and Southeast (-34.42%) (p < 0.05). Series showed stationary behavior in Brazil and in its five regions during the covid-19 pandemic (p > 0.05). Brazilian states also showed stationary trends, except for two states which recorded an increasing trend in the number of administered yellow fever vaccine doses, namely: Alagoas State (before: β = 64, p = 0.081; after: β = 897, p = 0.039), which became a yellow fever vaccine recommendation zone, and Roraima State (before: β = 68, p = 0.724; after: β = 150, p = 0.000), which intensified yellow fever vaccinations due to a yellow fever case confirmation in a Venezuelan State in 2020. CONCLUSION The reduced number of yellow fever vaccine doses administered during the covid-19 pandemic in Brazil may favor the reemergence of urban yellow fever cases in the country.

Prevenção e controle da febre amarela: avaliação de ações de vigilância em área indene no Brasil / Yellow fever prevention and control: assessment of surveillance activities in a previously unaffected area in Brazil / Prevención y control de la fiebre amarilla: evaluación de acciones de vigilancia en un área indemne de Brasil

A partir da reemergência da febre amarela em 2014/2015, o Brasil registrou nos anos sequentes sua maior epidemia de febre amarela das últimas décadas, atingindo principalmente a região sudeste. A febre amarela, doença viral hemorrágica, é causada por um flavivírus, transmitido por mosquitos silvestres (Haemagogus; Sabethes). Na ocorrência do ciclo urbano, erradicado no Brasil desde 1942, a transmissão se dá pelo Aedes aegypti. Primatas não humanos são os principais hospedeiros do vírus e constituem "sentinelas" na vigilância da febre amarela. Este artigo descreve as ações de controle e prevenção desencadeadas durante a epidemia de febre amarela no Estado do Espírito Santo, Brasil, e a implementação da vacinação por meio de um estudo ecológico com abordagem espacial. O estudo evidenciou a falha na detecção de epizootias em primatas não humanos pelos serviços de vigilância do Espírito Santo, sendo simultânea à detecção em humanos. Apresentou a evolução das ações de vacinação, com alcance de 85% de cobertura vacinal geral para o estado em seis meses, sendo heterogênea entre os municípios (de 59% a 122%). Destaca-se que 55% dos municípios com ações de imunização em tempo oportuno, considerando o intervalo adotado para este estudo, não apresentaram casos em humanos. A intensificação das ações de vigilância, interlocução entre as áreas e equipes multidisciplinares na condução da epidemia otimizou a detecção e o diagnóstico dos casos em humanos e viabilizou o controle da epidemia. Foi possível reconhecer avanços, apontar algumas medidas tardias e lacunas na vigilância que necessitam melhorias.

Following the reemergence of yellow fever in 2014/2015, Brazil recorded its largest yellow fever epidemic in recent decades, mainly affecting the country's Southeast region. Yellow fever is a hemorrhagic viral disease caused by a flavivirus transmitted by sylvatic mosquitos (Haemagogus; Sabethes). In the urban cycle, eradicated in Brazil since 1942, the virus is transmitted by Aedes aegypti. Nonhuman primates are the principal hosts of the virus and constitute "sentinels" in yellow fever surveillance. This article describes the control and prevention activities launched during the yellow fever epidemic in the State of Espírito Santo, Brazil, and the implementation of vaccination, through an ecological study with a spatial approach. The study revealed the lack of detection of epizootics in nonhuman primates by surveillance services in Espírito Santo, with simultaneous detection in humans. The study presented the evolution of vaccination activities, reaching 85% overall coverage for the state in six months, varying widely, from 59% to 122%, between municipalities (counties). Importantly, 55% of the municipalities with timely immunization, considering the interval adopted for this study, did not present human cases. The intensification of surveillance activities, communication between areas, and multidisciplinary teams in managing the epidemic optimized the detection and diagnosis of human cases and allowed control of the epidemic. The study identifies progress and points to some late measures and gaps in surveillance that require improvements.

A partir del resurgimiento de la fiebre amarilla en 2014/2015, Brasil registró los años siguientes su mayor epidemia de fiebre amarilla de las últimas décadas, alcanzando principalmente la región sudeste. La fiebre amarilla, enfermedad viral hemorrágica, es causada por un flavivirus, transmitido por mosquitos silvestres (Haemagogus; Sabethes). Respecto a la ocurrencia del ciclo urbano, erradicado en Brasil desde 1942, la transmisión se produce por el Aedes aegypti. Primates no humanos son los principales huéspedes del virus, y constituyen "centinelas" en la vigilancia de la fiebre amarilla. Este artículo describe las acciones de control y prevención desencadenadas durante la epidemia de fiebre amarilla en el Estado de Espírito Santo, Brasil, y la implementación de la vacunación mediante un estudio ecológico con abordaje espacial. El estudio evidenció el fallo en la detección de epizootias en primates no humanos por los servicios de vigilancia de Espírito Santo, siendo simultánea a la detección en humanos. Presentó la evolución de las acciones de vacunación, con alcance de un 85% de cobertura en la vacunación general para el estado en seis meses, siendo heterogénea entre los municipios (de 59% a 122%). Se destaca que un 55% de los municipios con acciones de inmunización en tiempo oportuno, considerando el intervalo adoptado para este estudio, no presentaron casos humanos. La intensificación de las acciones de vigilancia, interlocución entre las áreas y equipos multidisciplinarios en la gestión de la epidemia optimizó la detección y diagnóstico de los casos humanos y viabilizó el control de la epidemia. Fue posible reconocer avances, apuntar algunas medidas tardías y lagunas en la vigilancia que necesitan mejorías.

Testing the genomic stability of the Brazilian yellow fever vaccine strain using next-generation sequencing data.

The live attenuated yellow fever (YF) vaccine was developed in the 1930s. Currently, the 17D and 17DD attenuated substrains are used for vaccine production. The 17D strain is used for vaccine production by several countries, while the 17DD strain is used exclusively in Brazil. The cell passages carried out through the seed-lot system of vaccine production influence the presence of quasispecies causing changes in the stability and immunogenicity of attenuated genotypes by increasing attenuation or virulence. Using next-generation sequencing, we carried out genomic characterization and genetic diversity analysis between vaccine lots of the Brazilian YF vaccine, produced by BioManguinhos-Fiocruz, and used during 11 years of vaccination in Brazil. We present 20 assembled and annotated genomes from the Brazilian 17DD vaccine strain, eight single nucleotide polymorphisms and the quasispecies spectrum reconstruction for the 17DD vaccine, through a pipeline here introduced. The V2IDA pipeline provided a relationship between low genetic diversity, maintained through the seed lot system, and the confirmation of genetic stability of lots of the Brazilian vaccine against YF. Our study sets precedents for use of V2IDA in genetic diversity analysis and in silico stability investigation of attenuated viral vaccines, facilitating genetic surveillance during the vaccine production process.

Next generation live-attenuated yellow fever vaccine candidate: Safety and immuno-efficacy in small animal models.

Yellow fever (YF) remains a threat to human health in tropical regions of Africa and South America. Live-attenuated YF-17D vaccines have proven to be safe and effective in protecting travellers and populations in endemic regions against YF, despite very rare severe reactions following vaccination - YF vaccine-associated viscerotropic disease (YEL-AVD) and neurological disease (YEL-AND). We describe the generation and selection of a live-attenuated YF-17D vaccine candidate and present its preclinical profile. Initially, 24 YF-17D vaccine candidate sub-strains from the Stamaril® and YF-VAX® lineage were created through transfection of viral genomic RNA into Vero cells cultured in serum-free media to produce seed lots. The clone with the 'optimal' preclinical profile, i.e. the lowest neurovirulence, neurotropism and viscerotropism, and immunogenicity at least comparable with Stamaril and YF-VAX in relevant animal models, was selected as the vaccine candidate and taken forward for assessment at various production stages. The 'optimal' vaccine candidate was obtained from the YF-VAX lineage (hence named vYF-247) and had five nucleotide differences relative to its parent, with only two changes that resulted in amino acid changes at position 480 of the envelope protein (E) (valine to leucine), and position 65 of the non-structural protein 2A (NS2A) (methionine to valine). vYF-247 was less neurovirulent in mice than Stamaril and YF-VAX irrespective of production stage. Its attenuation profile in terms of neurotropism and viscerotropism was similar to YF-VAX in A129 mice, a 'worst case' animal model lacking type-I IFN receptors required to initiate viral clearance. Thus, vYF-247 would not be expected to have higher rates of YEL-AVD or YEL-AND than Stamaril and YF-VAX. In hamsters, vYF-247 was immunogenic and protected against high viremia and death induced by a lethal challenge with the hamster-adapted Jimenez P10 YF virus strain. Our data suggests that vYF-247 would provide robust protection against YF disease in humans, similar to currently marketed YF vaccines.

Activation of an Effective Immune Response after Yellow Fever Vaccination Is Associated with the Genetic Background and Early Response of IFN-γ and CLEC5A.

The yellow fever vaccine (YF17DD) is highly effective with a single injection conferring protection for at least 10 years. The YF17DD induces polyvalent responses, with a TH1/TH2 CD4+ profile, robust T CD8+ responses, and synthesis of interferon-gamma (IFN-γ), culminating in high titers of neutralizing antibodies. Furthermore, C-type lectin domain containing 5A (CLEC5A) has been implicated in innate outcomes in other flaviviral infections. Here, we conducted a follow-up study in volunteers immunized with YF17DD, investigating the humoral response, cellular phenotypes, gene expression, and single nucleotide polymorphisms (SNPs) of IFNG and CLEC5A, to clarify the role of these factors in early response after vaccination. Activation of CLEC5A+ monocytes occurred five days after vaccination (DAV). Following, seven DAV data showed activation of CD4+ and CD8+T cells together with early positive correlations between type II IFN and genes of innate antiviral response (STAT1, STAT2, IRF7, IRF9, OAS1, and RNASEL) as well as antibody levels. Furthermore, individuals with genotypes rs2430561 AT/AA, rs2069718 AG/AA (IFNG), and rs13237944 AC/AA (CLEC5A), exhibited higher expression of IFNG and CLEC5A, respectively. Together, we demonstrated that early IFN-γ and CLEC5A responses, associated with rs2430561, rs2069718, and rs13237944 genotypes, may be key mechanisms in the long-lasting immunity elicited by YF17DD.

Vogt-Koyanagi-Harada-like Disease following Yellow Fever Vaccination.

Purpose: To report the manifestation of Vogt-Koyanagi-Harada-like disease (VKH) following yellow fever vaccination.Methods: Case report.Results: A 34-year-old immunocompetent male had tinnitus, headache, and decreased vision after a booster dose of yellow fever vaccine. Visual acuity was 20/100 in the right eye and 20/80 in the left, with serous retinal detachment (SRD) and choroidal thickening identified on clinical examination and multimodal imaging. Lumbar puncture revealed pleocytosis and an increased protein content, but extensive investigations ruled out infectious/neurological diseases. Pulse intravenous methylprednisolone was given, followed by a tapering regimen of high-dose oral prednisone. Azathioprine was started early, 3 weeks after initiation of oral steroids. Intraocular inflammation and SRD rapidly resolved, with visual acuity reaching 20/20 in both eyes, after 3 weeks. No recurrence of intraocular inflammation or sign of depigmentation was so far noticed, at 2 years of follow-up.Conclusion: Yellow fever vaccine may be a possible trigger for VKH.

Planned Yellow Fever Primary Vaccination Is Safe and Immunogenic in Patients With Autoimmune Diseases: A Prospective Non-interventional Study.

Yellow Fever (YF) vaccination is suggested to induce a large number of adverse events (AE) and suboptimal responses in patients with autoimmune diseases (AID); however, there have been no studies on 17DD-YF primary vaccination performance in patients with AID. This prospective non-interventional study conducted between March and July, 2017 assessed the safety and immunogenicity of planned 17DD-YF primary vaccination in patients with AID. Adult patients with AID (both sexes) were enrolled, along with healthy controls, at a single hospital (Vitória, Brazil). Included patients were referred for planned vaccination by a rheumatologist; in remission, or with low disease activity; and had low level immunosuppression or the attending physician advised interruption of immunosuppression for safety reasons. The occurrence of AE, neutralizing antibody kinetics, seropositivity rates, and 17DD-YF viremia were evaluated at various time points (day 0 (D0), D3, D4, D5, D6, D14, and D28). Individuals evaluated (n = 278), including patients with rheumatoid arthritis (RA; 79), spondyloarthritis (SpA; 59), systemic sclerosis (8), systemic lupus erythematosus (SLE; 27), primary Sjögren's syndrome (SS; 54), and healthy controls (HC; 51). Only mild AE were reported. The frequency of local and systemic AE in patients with AID and HC did not differ significantly (8 vs. 10% and 21 vs. 32%; p = 1.00 and 0.18, respectively). Patients with AID presented late seroconversion profiles according to kinetic timelines of the plaque reduction neutralization test (PRNT). PRNT-determined virus titers (copies/mL) [181 (95% confidence interval (CI), 144-228) vs. 440 (95% CI, 291-665), p = 0.004] and seropositivity rate (78 vs. 96%, p = 0.01) were lower in patients with AID after 28 days, particularly those with SpA (73%) and SLE (73%), relative to HC. The YF viremia peak (RNAnemia) was 5-6 days after vaccination in all groups. In conclusion, consistent seroconversion rates were observed in patients with AID and our findings support that planned 17DD-YF primary vaccination is safe and immunogenic in patients with AID.