Remdesivir efficacy against yellow fever in a hamster model.

Yellow fever virus (YFV) continues to cause periodic outbreaks of severe disease throughout tropical regions of South America and Africa despite the availability of an effective vaccine. Despite efforts to control this virus for the last century, no antivirals have been approved for the treatment of YFV. The purpose of this study was to evaluate the broadly active antiviral compound remdesivir (RDV) in a hamster model of disease. Yellow fever (YF) disease in hamsters was prevented when treatment with RDV was initiated just prior to virus challenge, which was confirmed in a second study. Disease parameters including viremia, serum ALT and weight loss were significantly improved with RDV treatment in a dose-dependent manner. RDV was also effective when treatment was initiated as late as 4 days post-virus infection (dpi). These results demonstrate therapeutic efficacy of RDV in the treatment of YF in a relevant animal model of disease.

Vaccines for International Pediatric Travelers.

The pretravel management of the international pediatric traveler is based on provision of preventive education, chemoprophylaxis against malaria and traveler's diarrhea, as well as travel vaccinations. Immunization requirements are determined based on the traveler's pretravel immunization status, age, medical history, and destination. Immunization needs also vary depending on the exposures during the trip. Potential exposure to water, insects, or animals as well as duration of travel will help tailor risk avoidance education and travel immunizations. This review provides clinicians an overview of vaccines recommended for children traveling internationally.

Impact of COVID-19-related disruptions to measles, meningococcal A, and yellow fever vaccination in 10 countries.

Background: Childhood immunisation services have been disrupted by the COVID-19 pandemic. WHO recommends considering outbreak risk using epidemiological criteria when deciding whether to conduct preventive vaccination campaigns during the pandemic. Methods: We used two to three models per infection to estimate the health impact of 50% reduced routine vaccination coverage in 2020 and delay of campaign vaccination from 2020 to 2021 for measles vaccination in Bangladesh, Chad, Ethiopia, Kenya, Nigeria, and South Sudan, for meningococcal A vaccination in Burkina Faso, Chad, Niger, and Nigeria, and for yellow fever vaccination in the Democratic Republic of Congo, Ghana, and Nigeria. Our counterfactual comparative scenario was sustaining immunisation services at coverage projections made prior to COVID-19 (i.e. without any disruption). Results: Reduced routine vaccination coverage in 2020 without catch-up vaccination may lead to an increase in measles and yellow fever disease burden in the modelled countries. Delaying planned campaigns in Ethiopia and Nigeria by a year may significantly increase the risk of measles outbreaks (both countries did complete their supplementary immunisation activities (SIAs) planned for 2020). For yellow fever vaccination, delay in campaigns leads to a potential disease burden rise of >1 death per 100,000 people per year until the campaigns are implemented. For meningococcal A vaccination, short-term disruptions in 2020 are unlikely to have a significant impact due to the persistence of direct and indirect benefits from past introductory campaigns of the 1- to 29-year-old population, bolstered by inclusion of the vaccine into the routine immunisation schedule accompanied by further catch-up campaigns. Conclusions: The impact of COVID-19-related disruption to vaccination programs varies between infections and countries. Planning and implementation of campaigns should consider country and infection-specific epidemiological factors and local immunity gaps worsened by the COVID-19 pandemic when prioritising vaccines and strategies for catch-up vaccination. Funding: Bill and Melinda Gates Foundation and Gavi, the Vaccine Alliance.

The global burden of yellow fever.

Yellow fever (YF) is a viral, vector-borne, haemorrhagic fever endemic in tropical regions of Africa and South America. The vaccine for YF is considered safe and effective, but intervention strategies need to be optimised; one of the tools for this is mathematical modelling. We refine and expand an existing modelling framework for Africa to account for transmission in South America. We fit to YF occurrence and serology data. We then estimate the subnational forces of infection for the entire endemic region. Finally, using demographic and vaccination data, we examine the impact of vaccination activities. We estimate that there were 109,000 (95% credible interval [CrI] [67,000-173,000]) severe infections and 51,000 (95% CrI [31,000-82,000]) deaths due to YF in Africa and South America in 2018. We find that mass vaccination activities in Africa reduced deaths by 47% (95% CrI [10%-77%]). This methodology allows us to evaluate the effectiveness of vaccination and illustrates the need for continued vigilance and surveillance of YF.

Serological Protection 5-6 Years Post Vaccination Against Yellow Fever in African Infants Vaccinated in Routine Programmes.

Introduction: Although effective live attenuated yellow fever (YF) vaccines have been available for over 9 decades sporadic outbreaks continue to occur in endemic regions. These may be linked to several factors including epidemiological factors such as vector and intermediate host distribution or vaccine coverage and efficacy. The World Health Organization's research priorities include gathering systematic evidence around the potential need for booster vaccination with YF vaccine whether this follows full or fractional doses in children. Knowledge on the longevity of response to YF vaccine and the implications of this response needs to be consolidated to guide future vaccination policy. Methods: We measured anti-YF IgG by microneutralization assay in a group of 481 African infants who had received YF vaccine as part of routine EPI programmes, to explore serological protection from YF 5-6 years post YF vaccination, as well as the effect of co variates. Findings: Notably, 22.2% of the cohort had undetectable antibody concentrations, with another 7.5% revealing concentrations below the threshold of seropositivity of 0.5 IU/mL. Sex, season, country and time since vaccination did not affect the longevity of antibody concentration or having antibody concentrations above a defined threshold. Conclusion: Roughly 30% of children in this cohort did not demonstrate anti-yellow fever antibody concentrations above the defined threshold of protection, with 20% having no demonstrable antibody. Knowledge on the longevity of response to YF vaccine and the implications needs to be consolidated to guide future vaccination policy.

Measurement of Cellular Immune Response to Viral Infection and Vaccination.

Combined cellular and humoral host immune response determine the clinical course of a viral infection and effectiveness of vaccination, but currently the cellular immune response cannot be measured on simple blood samples. As functional activity of immune cells is determined by coordinated activity of signaling pathways, we developed mRNA-based JAK-STAT signaling pathway activity assays to quantitatively measure the cellular immune response on Affymetrix expression microarray data of various types of blood samples from virally infected patients (influenza, RSV, dengue, yellow fever, rotavirus) or vaccinated individuals, and to determine vaccine immunogenicity. JAK-STAT1/2 pathway activity was increased in blood samples of patients with viral, but not bacterial, infection and was higher in influenza compared to RSV-infected patients, reflecting known differences in immunogenicity. High JAK-STAT3 pathway activity was associated with more severe RSV infection. In contrast to inactivated influenza virus vaccine, live yellow fever vaccine did induce JAK-STAT1/2 pathway activity in blood samples, indicating superior immunogenicity. Normal (healthy) JAK-STAT1/2 pathway activity was established, enabling assay interpretation without the need for a reference sample. The JAK-STAT pathway assays enable measurement of cellular immune response for prognosis, therapy stratification, vaccine development, and clinical testing.

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.

Awareness of Inadvertent Use of Yellow Fever Vaccine Among Recipients of Renal Transplant.

Yellow fever (YF) is a vaccine-preventable disease, but live attenuated YF vaccine (YFV) is contraindicated in immunosuppressed patients due to the risk of life-threatening YFV-associated side effects. This study aimed to evaluate 1. the knowledge of renal transplant recipients (RTRs) about the contraindication and risks of YFV; 2. the prevalence of inadvertent vaccination of RTRs against YF; and 3. the outcome of these patients. A cross-sectional telephone contact study was conducted with 200 RTRs selected from the outpatient clinic of our transplantation unit. There were 116 successful telephone contacts (58%). A total of 11 vaccinated patients were identified: 5 received YFV in the pretransplant period and 6 in the post-transplant period. All patients received the full dose of the vaccine. Among those vaccinated after transplant, only 1 reported a mild adverse event (nausea) after receiving the vaccine. All vaccinated patients who were post-transplant did not know about vaccine contraindications as a result of their clinical condition. Among the unvaccinated patients, this rate was 12.4%. YFV is the main tool for disease prevention and control as there is no specific antiviral treatment for YF. Our results confirm the evidence that transplant recipients tolerate YFV well. However, data are not strong enough to recommend this vaccine in transplant recipients. Counseling RTRs on the contraindications of YFV is important to prevent inadvertent use of this vaccine in this population.

A chimeric yellow fever-Zika virus vaccine candidate fully protects against yellow fever virus infection in mice.

The recent Zika virus (ZIKV) epidemic in the Americas, followed by the yellow fever virus (YFV) outbreaks in Angola and Brazil highlight the urgent need for safe and efficient vaccines against the ZIKV as well as much greater production capacity for the YFV-17D vaccine. Given that the ZIKV and the YFV are largely prevalent in the same geographical areas, vaccines that would provide dual protection against both pathogens may obviously offer a significant benefit. We have recently engineered a chimeric vaccine candidate (YF-ZIKprM/E) by swapping the sequences encoding the YFV-17D surface glycoproteins prM/E by the corresponding sequences of the ZIKV. A single vaccine dose of YF-ZIKprM/E conferred complete protection against a lethal challenge with wild-type ZIKV strains. Surprisingly, this vaccine candidate also efficiently protected against lethal YFV challenge in various mouse models. We demonstrate that CD8+ but not CD4+ T cells, nor ZIKV neutralizing antibodies are required to confer protection against YFV. The chimeric YF-ZIKprM/E vaccine may thus be considered as a dual vaccine candidate efficiently protecting mice against both the ZIKV and the YFV, and this following a single dose immunization. Our finding may be particularly important in the rational design of vaccination strategies against flaviviruses, in particular in areas where YFV and ZIKV co-circulate.

Repurposing the yellow fever vaccine for intratumoral immunotherapy.

Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild-type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non-transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T-cell-dependent manner. In mice bearing bilateral tumors in which only one is intratumorally injected, contralateral therapeutic effects are observed consistent with more prominent CD8 T-cell infiltrates and a treatment-related reduction of Tregs. Additive efficacy effects were observed upon co-treatment with intratumoral 17D and systemic anti-CD137 and anti-PD-1 immunostimulatory monoclonal antibodies. Importantly, when mice were preimmunized with 17D, intratumoral 17D treatment achieved better local and distant antitumor immunity. Such beneficial effects of prevaccination are in part explained by the potentiation of CD4 and CD8 T-cell infiltration in the treated tumor. The repurposed use of a GMP-grade vaccine to be given via the intratumoral route in prevaccinated patients constitutes a clinically feasible and safe immunotherapy approach.

Análise das características epidemiológicas da febre amarela em um estado da Região Sudeste do Brasil / Análisis de las características epidemiológicas de la fiebre amarilla en un estado del sureste de Brasil / Analysis of the epidemiological characteristics of yellow fever in a state of southeastern Brazil

Resumo O objetivo do estudo foi analisar o perfil epidemiológico da febre amarela (FA) em Minas Gerais, região sudeste do Brasil. Trata-se de estudo transversal, do tipo série de casos, analisando as notificações de FA entre 03 de janeiro de 2016 a 08 de julho de 2017. Foram notificados 1.677 casos, sendo 427 confirmados e 133 óbitos; com taxa de letalidade de 31,3%. A maioria dos casos foi em homens, adultos jovens, ocupação rural e baixa escolaridade. Em 2016, 28 municípios notificaram epizootias e 1 confirmou morte de macaco por FA. Em 2017, 182 municípios notificaram e 142 confirmaram. No período analisado, a cobertura vacinal média foi inferior a 90% em 96% das Unidades Regionais de Saúde. Destacam-se elevadas porcentagens de campos não preenchidos. Constatou-se elevado número de casos no período analisado. Considerar o perfil epidemiológico da doença no Estado é importante para direcionar as ações de controle, movendo esforços para os grupos mais vulneráveis.

Resumen El objetivo de este estudio fue analizar el perfil epidemiológico de la fiebre amarilla (FA) en Minas Gerais, sureste de Brasil. Se planteó un estudio transversal, de tipo serie de casos, con análisis de las notificaciones entre 03 de enero de 2016 a 08 de julio de 2017. Se notificaron 1.677 casos, siendo 427 confirmados y 133 muertos; con tasa de letalidad de 31,3%. Ocurrió más en hombres jóvenes, con ocupación rural y baja educación. En 2016, 28 municipios tienen epizootias y fue confirmada una muerte de mono por FA. En 2017, se han notificado a 182 municipios y 142 confirmados. La cobertura de vacunación promedio fue inferior al 90% en 96% de las Unidades Regionales de Salud. Incluyen altos porcentajes de campos sin llenar. Tiene alto número de casos en el período analizado. Se concluye que es importante considerar el perfil epidemiológico de la enfermedad en el estado para dirigir las acciones de control, hacia los grupos más vulnerables.

Abstract The objective of this study was to analyze the epidemiological profile of yellow fever (YF) in Minas Gerais, southeastern Brazil. A cross-sectional study was raised, of type series of cases, with analysis of the notifications of between January 03, 2016 to July 08, 2017. 1,677 cases were reported, with 427 confirmed and 133 dead; with a lethality rate of 31,3%. It happened more in young men, rural occupation and low education. In 2016, 28 municipalities have epizootics and one confirmed death of monkey by YF. In 2017, 182 municipalities have notified and 142 confirmed. In the analysis period, the average vaccination coverage was less than 90% in 96% of Regional Health Units. High percentages of unfilled fields were found. It has a high number of cases in the period analyzed. It is concluded that it is important to consider the epidemiological profile of the disease in the State is important to direct the actions of control, moving efforts to the most vulnerable groups.

The Public Health Benefits and Economic Value of Routine Yellow Fever Vaccination in Colombia.

OBJECTIVES: To evaluate the public health benefits and economic value of live-attenuated yellow fever (YF) 17D vaccine in Colombia. METHODS: A decision tree model was used to assess the theoretical impact of routine YF vaccination of 1-year-olds (no "catch-up") during the interepidemic period from 1980 to 2002, avoiding capturing the impact of YF vaccine introduction in 2003. The vaccine was assumed to be 99% effective, to provide lifetime protection, and to cover 85% of the target population. Costs per disability-adjusted life-year (DALY) averted were computed from payer and societal perspectives. Univariate sensitivity analyses were performed. RESULTS: During the interepidemic period, routine YF vaccination would have averted 2223 nonfatal cases of YF and 65 deaths, leading to an overall reduction of 1365 DALYs. The net cost of this vaccination would have been $25 964 813 (payer's perspective) and $16 535 465 (societal perspective). Cost per DALY averted was $19 022 and $12 114 from payer and societal perspectives, respectively (all costs in 2015 US dollars). Vaccination was considered cost-effective from both perspectives (ie, between 1- and 3-fold the gross domestic product per capita, $7158) and remains so if price per dose was $2.75 or less and $4.66 from payer and societal perspectives, respectively. Underreporting had the largest impact on the results. CONCLUSIONS: Routine toddler YF vaccination in Colombia would have been considered cost-effective in the prevaccination era. This study provides insights on the value of vaccination in an upper middle-income country.

Clinical evidence for the immunogenicity and immune persistence of vaccination with yellow fever virus strain 17D in Chinese peacekeepers deployed to Africa.

Yellow fever is a serious disease caused by infection with the yellow fever virus (YFV). A live-attenuated YFV vaccine strain, 17D (YFV-17D) is the only virus strain available for the production of the YFV vaccine. This study evaluated the immunogenicity and immune persistence of vaccination with YFV-17D and identified their influencing factors in Chinese peacekeepers deployed to Africa. Serum specimens were collected before and ≥21 days after primary vaccination with YFV-17D in 349 Chinese peacekeepers who were subsequently deployed to Africa for the first time from 2016 to 2017 (population 1). Serum specimens were collected from 1 to 11 years after vaccination with YFV-17D in 2062 returned Chinese peacekeepers who were deployed to Africa from 2005 to 2015 (population 2). We found that YFV-17D exhibited an excellent protective effect in the Chinese peacekeepers deployed to Africa early following vaccination. In the Chinese peacekeepers one year after vaccination, the serum antibody titer against YFV increased with increasing age at vaccination; in those two or more years after vaccination, the serum antibody titer against YFV decreased over years and was similar to but greater than the minimum protective level 11 years after vaccination. The number of peacekeeping missions exhibited an almost negligible influence on the serum antibody titer against YFV. (This study has been registered at International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/) under registration Nos. ChiCTR1800017024.).

A qualitatively validated mathematical-computational model of the immune response to the yellow fever vaccine.

BACKGROUND: Although a safe and effective yellow fever vaccine was developed more than 80 years ago, several issues regarding its use remain unclear. For example, what is the minimum dose that can provide immunity against the disease? A useful tool that can help researchers answer this and other related questions is a computational simulator that implements a mathematical model describing the human immune response to vaccination against yellow fever. METHODS: This work uses a system of ten ordinary differential equations to represent a few important populations in the response process generated by the body after vaccination. The main populations include viruses, APCs, CD8+ T cells, short-lived and long-lived plasma cells, B cells and antibodies. RESULTS: In order to qualitatively validate our model, four experiments were carried out, and their computational results were compared to experimental data obtained from the literature. The four experiments were: a) simulation of a scenario in which an individual was vaccinated against yellow fever for the first time; b) simulation of a booster dose ten years after the first dose; c) simulation of the immune response to the yellow fever vaccine in individuals with different levels of naïve CD8+ T cells; and d) simulation of the immune response to distinct doses of the yellow fever vaccine. CONCLUSIONS: This work shows that the simulator was able to qualitatively reproduce some of the experimental results reported in the literature, such as the amount of antibodies and viremia throughout time, as well as to reproduce other behaviors of the immune response reported in the literature, such as those that occur after a booster dose of the vaccine.

Estimating the number of unvaccinated Chinese workers against yellow fever in Angola.

BACKGROUND: A yellow fever epidemic occurred in Angola in 2016 with 884 laboratory confirmed cases and 373 deaths. Eleven unvaccinated Chinese nationals working in Angola were also infected and imported the disease to China, thereby presenting the first importation of yellow fever into Asia. In Angola, there are about 259,000 Chinese foreign workers. The fact that 11 unvaccinated Chinese workers acquired yellow fever suggests that many more Chinese workers in Angola were not vaccinated. METHODS: We applied a previously developed model to back-calculate the number of unvaccinated Chinese workers in Angola in order to determine the extent of lack of vaccine coverage. RESULTS: Our models suggest that none of the 259,000 Chinese had been vaccinated, although yellow fever vaccination is mandated by the International Health Regulations. CONCLUSION: Governments around the world including China need to ensure that their citizens obtain YF vaccination when traveling to countries where such vaccines are required in order to prevent the international spread of yellow fever.

Febre Amarela: informação para todos, vacina para quem precisa

Febre Amarela: Portal do ministério da saúde informa, sobre sobre a Campanha de vacinação com dose fracionada nos estados de São Paulo, Rio de Janeiro e Bahia, tutorial para profissionais de saúde sobre a preparação da vacina fracionada, informações ao publico sobre, sintomas, transmissão, diagnostico e prevenção.

Newer Vaccines against Mosquito-borne Diseases.

Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum-adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases.

Plant-Produced Subunit Vaccine Candidates against Yellow Fever Induce Virus Neutralizing Antibodies and Confer Protection against Viral Challenge in Animal Models.

Yellow fever (YF) is a viral disease transmitted by mosquitoes and endemic mostly in South America and Africa with 20-50% fatality. All current licensed YF vaccines, including YF-Vax® (Sanofi-Pasteur, Lyon, France) and 17DD-YFV (Bio-Manguinhos, Rio de Janeiro, Brazil), are based on live attenuated virus produced in hens' eggs and have been widely used. The YF vaccines are considered safe and highly effective. However, a recent increase in demand for YF vaccines and reports of rare cases of YF vaccine-associated fatal adverse events have provoked interest in developing a safer YF vaccine that can be easily scaled up to meet this increased global demand. To this point, we have engineered the YF virus envelope protein (YFE) and transiently expressed it in Nicotiana benthamiana as a stand-alone protein (YFE) or as fusion to the bacterial enzyme lichenase (YFE-LicKM). Immunogenicity and challenge studies in mice demonstrated that both YFE and YFE-LicKM elicited virus neutralizing (VN) antibodies and protected over 70% of mice from lethal challenge infection. Furthermore, these two YFE-based vaccine candidates induced VN antibody responses with high serum avidity in nonhuman primates and these VN antibody responses were further enhanced after challenge infection with the 17DD strain of YF virus. These results demonstrate partial protective efficacy in mice of YFE-based subunit vaccines expressed in N. benthamiana. However, their efficacy is inferior to that of the live attenuated 17DD vaccine, indicating that formulation development, such as incorporating a more suitable adjuvant, may be required for product development.