Enhanced production of yellow fever virus through tailored culture media optimization.

In the present study, an initial screening was conducted using 12 types of cell culture media, and four media with the best performance were selected for further study. The optimization of four media blend for YFV production was evaluated using an Augmented simplex centroid mixture design. Among all the different models that were investigated, the quadratic model was found to be the most appropriate model for exploring mixture design. It was found that M10 exhibited the greatest impact on YFV production, followed by M9, M4, and M1. The utilization of M1 and M4 media individually yielded higher compared to their blends with other media. The YFV titers were reduced when M1 media was combined with other media. The utilization of M9 and M10 media in combination resulted a higher viral yield compared to their respective concentrations. The optimal ratio for achieving a higher titer of YFV from primary CEFs was found to be approximately 38:62, with M9 and M10 being the most favorable media blend. The use of a media mixture led to a significant increase of virus titer up to 2.6 × 108 PFU/ml or 2 log titer yield, which is equivalent to 1.92 × 105 doses, without any changes to growth conditions or other process factors. This study concluded that the utilization of a mixture design could be efficiently employed to choose the optimal combination of media blends for enhanced viral production from cell culture.

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.

YF17D-based vaccines - standing on the shoulders of a giant.

Live-attenuated yellow fever vaccine (YF17D) was developed in the 1930s as the first ever empirically derived human vaccine. Ninety years later, it is still a benchmark for vaccines made today. YF17D triggers a particularly broad and polyfunctional response engaging multiple arms of innate, humoral and cellular immunity. This unique immunogenicity translates into an extraordinary vaccine efficacy and outstanding longevity of protection, possibly by single-dose immunization. More recently, progress in molecular virology and synthetic biology allowed engineering of YF17D as a powerful vector and promising platform for the development of novel recombinant live vaccines, including two licensed vaccines against Japanese encephalitis and dengue, even in paediatric use. Likewise, numerous chimeric and transgenic preclinical candidates have been described. These include prophylactic vaccines against emerging viral infections (e.g. Lassa, Zika and SARS-CoV-2) and parasitic diseases (e.g. malaria), as well as therapeutic applications targeting persistent infections (e.g. HIV and chronic hepatitis), and cancer. Efforts to overcome historical safety concerns and manufacturing challenges are ongoing and pave the way for wider use of YF17D-based vaccines. In this review, we summarize recent insights regarding YF17D as vaccine platform, and how YF17D-based vaccines may complement as well as differentiate from other emerging modalities in response to unmet medical needs and for pandemic preparedness.

Yellow fever neutralizing antibody seroprevalence proportion and titers in previously vaccinated adults with chronic kidney disease.

Studies on yellow fever vaccine (YF) in chronic kidney disease (CKD) patients are scarce. This cross-sectional study aimed to evaluate YF neutralizing antibody seroprevalence and titers in previously vaccinated adults with CKD, on dialysis (D-CKD) or not (ND-CKD), compared to healthy persons. The micro Plaque Reduction Neutralization-Horseradish Peroxidase (µPRN-HP) test was used. Antibody titers were expressed as the reciprocal of the highest dilution that neutralized the challenge virus by 50 % (µPRN50). Seropositivity cut-off was set at ≥ 1:100. We included 153 participants: 46 ND-CKD, 50 D-CKD and 57 healthy adults. Median ages were 58.3, 55 and 52.2 years, respectively. Median time since YF vaccination was 22.3, 18.5 and 48.3 months respectively. There were no statistically significant differences in YF seroprevalence and neutralizing antibodies titers among groups: 100 % of ND-CKD; 96 % of D-CKD and 100 % of healthy participants were seropositive. Geometric mean titers (GMT) were 818.5, 683.0 and 665.5, respectively (p = 0.289).

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.

Characterization of "Off-Target" Immune Modulation Induced by Live Attenuated Yellow Fever Vaccine.

BACKGROUND: Live attenuated vaccines alter immune functions and are associated with beneficial outcomes. We previously demonstrated that live attenuated yellow fever virus (YFV) vaccine (LA-YF-Vax) dampens T-cell receptor (TCR) signaling in vitro via an RNA-based mechanism. We examined study participants before and after LA-YF-Vax to assess TCR-mediated functions in vivo. METHODS: Serum samples and peripheral blood mononuclear cells (PBMCs) were obtained before and after LA-YF-Vax (with or without additional vaccines) or quadrivalent influenza vaccine. TCR-mediated activation was determined by interleukin 2 release or phosphorylation of the lymphocyte-specific Src kinase. TCR-regulating phosphatase (protein tyrosine phosphatase receptor type E [PTPRE]) expression was also measured. RESULTS: Compared with prevaccination findings, LA-YF-Vax recipient PBMCs demonstrated transient reduction in interleukin 2 release after TCR stimulation and PTPRE levels, unlike in control participants who received quadrivalent influenza vaccine. YFV was detected in 8 of 14 participants after LA-YF-Vax. After incubation of healthy donor PBMCs in serum-derived extracellular vesicles prepared from LA-YF-Vax recipients, TCR signaling and PTPRE levels were reduced after vaccination, even in participants without detectable YFV RNA. CONCLUSIONS: LA-YF-Vax reduces TCR functions and PTPRE levels after vaccination. Extracellular vesicles from serum recapitulated this effect in healthy cells. This likely contributes to the reduced immunogenicity for heterologous vaccines after LA-YF-Vax administration. Identification of specific immune mechanisms related to vaccines should contribute to understanding of the "off-target," beneficial effects of live vaccines.

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.

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.

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.

Phenotypic and genetic characterization of a next generation live-attenuated yellow fever vaccine candidate.

We assessed the genetic and phenotypic characteristics of a yellow fever vaccine candidate, which was cloned from a YF-VAX substrain selected for growth in Vero cells (vYF-247), during the manufacturing process from the master seed lot (MSL) and working seed lot (WSL) through to the drug substance (DS) stage. There were nine minor nucleotide variants observed from the MSL to the DS stage, of which five led to amino acid changes. The variant positions were, however, not known risks for any virulence modification. vYF-247 exhibits a homogenous plaque size profile (as expected for a cloned vaccine candidate) composed of small plaques (<1 mm) that remained consistent throughout the manufacturing process. In addition, there was no change in the viral replication rate. Of note, the DS sequences across the two manufacturing campaigns (2018 and 2019) were very similar suggesting a high batch-to-batch consistency. All MSL, WSL and DS batches exhibited similar neurovirulence profiles in mice and had a more attenuated neurovirulence phenotype than the YF-VAX (egg-based vaccine) comparator. Overall, the neurovirulence phenotype of vYF-247 does not change from MSL, WSL to DS. These data collectively support the safety and genetic stability of vYF-247 during the production process.

Live-attenuated YF17D-vectored COVID-19 vaccine protects from lethal yellow fever virus infection in mouse and hamster models.

BACKGROUND: The live-attenuated yellow fever vaccine YF17D holds great promise as alternative viral vector vaccine platform, showcased by our previously presented potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate YF-S0. Besides protection from SARS-CoV-2, YF-S0 also induced strong yellow fever virus (YFV)-specific immunity, suggestive for full dual activity. A vaccine concomitantly protecting from SARS-CoV-2 and YFV would be of great benefit for those living in YFV-endemic areas with limited access to current SARS-CoV-2 vaccines. However, for broader applicability, pre-existing vector immunity should not impact the potency of such YF17D-vectored vaccines. METHODS: The immunogenicity and efficacy of YF-S0 against YFV and SARS-CoV-2 in the presence of strong pre-existing YFV immunity were evaluated in mouse and hamster challenge models. FINDINGS: Here, we show that a single dose of YF-S0 is sufficient to induce strong humoral and cellular immunity against YFV as well as SARS-CoV-2 in mice and hamsters; resulting in full protection from vigorous YFV challenge in either model; in mice against lethal intracranial YF17D challenge, and in hamsters against viscerotropic infection and liver disease following challenge with highly pathogenic hamster-adapted YFV-Asibi strain. Importantly, strong pre-existing immunity against the YF17D vector did not interfere with subsequent YF-S0 vaccination in mice or hamsters; nor with protection conferred against SARS-CoV-2 strain B1.1.7 (Alpha variant) infection in hamsters. INTERPRETATION: Our findings warrant the development of YF-S0 as dual SARS-CoV-2 and YFV vaccine. Contrary to other viral vaccine platforms, use of YF17D does not suffer from pre-existing vector immunity. FUNDING: Stated in the acknowledgments.

Duration of Protection After Vaccination Against Yellow Fever: A Systematic Review and Meta-Analysis.

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination.

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.