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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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [All authors are employees of Sanofi Pasteur and may hold shares and/or stock options in the company.]., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: KG, AH, KJ, DG, LC, TG, NF No competing interests declared, (© 2021, Gaythorpe et al.)

Background: The United States military regularly deploys thousands of service members throughout areas of South America and Africa that are endemic for yellow fever (YF) virus. To determine if booster doses might be needed for service members who are repetitively or continually deployed to YF endemic areas, we evaluated seropositivity among US military personnel receiving a single dose of YF vaccine based on time post-vaccination., Methods: Serum antibodies were measured using a plaque reduction neutralization test with 50% cutoff in 682 military personnel at 5-39 years post-vaccination. We determined noninferiority of immune response by comparing the proportion seropositive among those vaccinated 10-14 years previously with those vaccinated 5-9 years previously. Noninferiority was supported if the lower-bound of the 2-tailed 95% CI for p 10-14years - p 5-9years was ≥-0.10. Additionally, the geometric mean antibody titer (GMT) at various timepoints following vaccination were compared to the GMT at 5-9 years., Results: The proportion of military service members with detectable neutralizing antibodies 10-14 years after a single dose of YF vaccine (95.8%, 95% CI 91.2-98.1%) was non-inferior to the proportion 5-9 years after vaccination (97.8%, 95% CI 93.7-99.3%). Additionally, GMT among vaccine recipients at 10-14 years post vaccination (99, 95% CI 82-121) was non-inferior to GMT in YF vaccine recipients at 5-9 years post vaccination (115, 95% CI 96-139). The proportion of vaccinees with neutralizing antibodies remained high, and non-inferior, among those vaccinated 15-19 years prior (98.5%, 95%CI 95.5-99.7%). Although the proportion seropositive decreased among vaccinees ≥ 20 years post vaccination, >90% remained seropositive., Conclusions: Neutralizing antibodies were present in > 95% of vaccine recipients for at least 19 years after vaccination, suggesting that booster doses every 10 years are not essential for most U.S. military personnel., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Yellow fever is still a current threat? Yellow fever is a mosquito-borne disease. Africa is the major endemic zone, although there have been epidemics of concern in South America in the last 3 years, especially in Brazil. The virus causes a febrile hepatitis, which can lead to hemorrhagic complications and death. Diagnosis is based on non-specific serological tests. There is no curative treatment. Prevention relies on protection against mosquito bites and on vaccination with a live attenuated vaccine. WHO recommends only one dose of vaccine but data from the literature about life-long protection are divergent on that point, and travel medicine French authorities still recommend a second dose in most at-risk situations., Competing Interests: E. Oliosi déclare n’avoir aucun lien d’intérêts. É. Caumes déclare des liens ponctuels avec Nukleus et Takeda. (vérif. au BAT)

Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated form, YFV-17D, remains one of the most potent vaccines ever developed. During the first half of the 20th century, vaccination combined with mosquito control eradicated YFV transmission in urban areas. However, the recent 2016-2018 outbreaks in areas with historically low or no YFV activity have raised serious concerns for an estimated 400-500 million unvaccinated people who now live in at-risk areas. Once a forgotten disease, we highlight here that YF still represents a very real threat to human health and economies. As many gaps remain in our understanding of how YFV interacts with the human host and causes disease, there is an urgent need to address these knowledge gaps and propel YFV research forward., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The purpose of this prospective, questionnaire-based study is to assess pre-travel vaccinations and malaria prophylaxis for long-term travellers who receive pre-travel advice in Greece. A total of 4721 travellers were studied from January 1, 2009 through December 31, 2012. Travellers sought pre-travel advice at a mean of 19.7 days (range: 0-349 days) before departure. Long-term travellers (≥ 1 month) accounted for 2205 (46.7%) of all travellers. Long-term travellers had a mean age of 34.5 years. The majority of them were men (79.8%). In terms of destinations, 84% were visiting malaria-endemic countries and sub-Saharan Africa was the most common destination (17.7%). Most long-term travellers pursued trips for work purposes (70%), visited urban areas (79.6%) and stayed in hotels (29.2%). Yellow fever, typhoid fever, hepatitis A and tetanus/diphtheria vaccines were administered to 1647 (74.7%), 741 (33.6%), 652 (29.5%), and 589 (26.7%) travellers, respectively. Yellow fever vaccine was administered to 339 (87%) and 132 (71%) of long-term travellers to sub-Saharan Africa and South America respectively, whereas typhoid vaccine to 119 (90.8%) and 330 (84.6%) of those travelling to the Indian subcontinent and sub-Saharan Africa respectively. Rabies vaccine was administered to 14 (0.6%) of them. Malaria prophylaxis was recommended to 446 (20%) of long-term travellers. Mefloquine was the most commonly (49%) prescribed agent, and was prescribed to 26.7% of long-term travellers to sub-Sahara Africa. In conclusion, this study revealed that recommendations for vaccine and malaria prophylaxis for long-term travellers to developing countries should be more selective, based on the assessment of all travellers' and travel characteristics, in order to provide adequate pre-travel preparation for this high risk group of travellers. More focused studies are suggested in order to understand the particular needs of long-term travellers. Increasing awareness of travellers and travel health consultants is very important., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In March 2013, the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunisation (SAGE) considered a number of issues in order to update the WHO Position Paper on Yellow Fever (2003). A key conclusion of this review was that a single dose of yellow fever (YF) vaccine appears to confer life-long protection against YF disease, and that a booster dose of YF vaccine is not needed to maintain immunity. While the efficacy of YF vaccine in the majority of vaccine recipients is not in doubt, the WHO announcement is somewhat surprising as there are some limitations in the evidence base, but more importantly, this announcement is not accompanied by any imminent change in the International Health Regulations 2005. The tension between what is considered best clinical practice and the law will be difficult to reconcile for many health professionals, travellers, and the travel industry, in an area of travel medicine that is already subject to debate and confusion. This commentary reviews the recent WHO announcement, and considers the practical implications for health professionals providing YF vaccine to international travellers., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The live, attenuated yellow fever (YF) 17D vaccine provides highly effective and durable immunity and is widely used for travelers to and residents of endemic areas of South America and Africa. Neurotropic and viscerotropic serious adverse events associated with these vaccines occur rarely, but YF 17D vaccine-associated viscerotropic disease (YEL-AVD) is notable for its lethality. There appear to be two distinct patterns of risk for YEL-AVD: the first in younger persons, particularly women, with defects in innate immunity, in whom the case-fatality rate is higher; and the second in elderly persons, particularly men with age-related immune senescence and a lower case-fatality rate. From 1990 to the present, the number of cases (n = 31) and deaths (n = 12) from YEL-AVD in travelers has exceeded the reports of YF (n = 6) acquired by natural infection, raising the question whether the risk of vaccination exceeds the benefit in travelers. To provide some guidance on this point, the rate of vaccine-related injury is compared with the rate of naturally acquired disease in a new analysis that estimates the immunologically susceptible denominator population in YF endemic and epidemic areas. For many years, the risk of vaccine-related illness and death was similar to the risk of illness and death from natural infection with YF in South America. Africa posed a substantially higher estimated risk of wild-type YF than vaccine-related injury. Multiple factors should be considered in making decisions about YF vaccination, including specific destination, season of the year, local evidence for YF transmission, likelihood of exposure to vector mosquitoes and individual risk factors for YEL-AVD, with the goal of increasing vaccine coverage for travel to high-risk areas and reducing unnecessary vaccination. Prospects for future, safer vaccines are also described.

Background: The number of international trips undertaken by French citizens is rising and we wished to assess the appropriateness of advices given to travelers in a vaccine and travel medicine center in France., Methods: We conducted a 3-month prospective study in one center in Paris where prescriptions and advice to travelers are given by trained physicians in travel medicine who have access to a computerized decision support system (Edisan). A questionnaire was used to record trip characteristics, patients' demographics, and prescriptions. Main outcome measure was the adequacy of prescriptions for malaria prophylaxis, yellow fever, and hepatitis A vaccines to French guidelines., Results: A total of 730 subjects were enrolled in this study, with a median age of 28 years. Travel destinations were sub-Saharan Africa (58%), Asia (21%), and South America (18%). Among the 608 patients (83%) traveling to malaria-endemic areas, malaria prophylaxis was in accordance with guidelines in 578/608 patients (95.1%, 95% CI: 93-96.5), and doxycycline was the regimen of choice (48%). Inappropriate malaria prophylaxis was given to eight patients, one of whom developed plasmodium falciparum malaria. All 413 patients (100%, 95% CI: 99-100) traveling to yellow fever-endemic areas who needed vaccination were correctly vaccinated. However, three patients received yellow fever vaccination without indication. Also, 442 of 454 patients (97.4%, 95% CI: 95.4-98.5) eligible to receive hepatitis A vaccination were immunized., Conclusion: Appropriate advice for malaria prophylaxis, yellow fever, and hepatitis A vaccinations was provided in a travel medicine and vaccine center where trained physicians used a computerized decision support system. Even in this setting, however, errors can occur and professional practices should be regularly assessed to improve health care., (© 2012 International Society of Travel Medicine.)

Yellow fever continues to occur in regions of Africa and South America, despite the availability of effective vaccines. Recently, some cases of severe neurologic disease and multiorgan system disease have been described in individuals who received yellow fever vaccine. These events have focused attention on the need to define criteria for judicious use of yellow fever vaccine and to describe the spectrum of adverse events that may be associated with yellow fever vaccine. Describing host factors that would increase risk of these events and identifying potential treatment modalities for yellow fever and yellow fever vaccine-associated adverse events are subjects of intense investigation.

Yellow fever virus (YFV) is the prototype member of the genus Flavivirus, a group of viruses that are transmitted between vertebrates by arthropod vectors. The virus is found in tropical regions of Africa and South America and is transmitted to primates by mosquitoes: Aedes spp. in Africa and Haemagogus and Sabethes spp. in South America. Despite the availability of an effective vaccine, yellow fever (YF) is considered a reemerging disease owing to its increased incidence in the past 25 years. Molecular epidemiologic data suggest there are seven genotypes of YFV that are geographically separated, and outbreaks of disease are more associated with particular genotypes. In addition, the risk of urban YF, owing to transmission of the virus by Aedes aegypti, is increasing in Africa, as is the potential of urban YF returning to South America. Both present serious potential public health problems to large population centers.

Yellow fever and dengue are old diseases, having caused major epidemics in centuries past. Both were effectively controlled in the mid 1900s, yellow fever in Francophone Africa by vaccination and yellow fever and dengue in the Americas by effective control of the principal urban vector of both viruses, Aedes aegypti. In the last 25 years of the 20th century, however, there was a resurgence of yellow fever in Africa, and of dengue worldwide. The factors responsible for this resurgence are discussed, as are current options for prevention and control.

Yellow fever is an acute life-threatening viral infection. In the case of the urban type, the virus is transmitted from one human to another by the Aedes mosquito vector. In particular travelers to Africa from non-endemic areas run a high risk of clinical disease in case of infection. For prophylaxis, a reliable live virus vaccine is available.

Yellow fever is a mosquito born viral illness that causes hemorrhagic fever in tropical Africa and South America. An estimated 200 000 people are still infected annually. There is no antiviral therapy available and vaccination is major strategy in the control yellow fever. From 60 years ago is available very safe and efficient vaccine. The vaccine is a live attenuated virus strain 17D. Recently identified vaccine associated viscerotropic diseases (YFV-AVD). This paper describes knowledge about yellow fever disease, vaccine associated adverse events and actually recommendation for vaccine use.

Yellow fever (YF) is a potentially lethal mosquito-borne viral hemorrhagic fever endemic in Africa and South America. Nine million tourists annually arrive in countries where YF is endemic, and fatal cases of YF have occurred recently in travelers. In this article, we review the risk factors for YF during travel and the use of YF 17D vaccine to prevent the disease. Although the vaccine is highly effective and has a long history of safe use, the occurrence of rare, fatal adverse events has raised new concerns. These events should not deter travelers to areas where YF is endemic from being immunized, because the risk of YF infection and illness may be high in rural areas and cannot be easily defined by existing surveillance. To avoid unnecessary vaccination, physicians should vaccinate persons at risk on the basis of knowledge of the epidemiology of the disease, reports of epidemic activity, season, and the likelihood of exposure to vector mosquitoes.

Since the 1980s, yellow fever has reemerged across Africa and in South America. The total of 18 735 yellow fever cases and 4522 deaths reported from 1987 to 1991 represents the greatest amount of yellow fever activity reported to the World Health Organization (WHO) for any 5-year period since 1948. There is an excellent vaccine against yellow fever. At present, a high proportion of travelers to at-risk areas are reported to be immunized, reflecting widespread knowledge about the International Health Regulations. In South America, yellow fever remains an occupational hazard for forest workers, who should be immunized. However, Aedes aegypti mosquitoes are now present in urban areas in the Americas (including southern parts of the United States), and there is concern that yellow fever could erupt in explosive outbreaks. In Africa, a large proportion of cases have occurred in children. The WHO, the United Nations Children's Fund (UNICEF), and the World Bank have recommended that 33 African countries at risk for yellow fever add the vaccine to the routine Expanded Programme on Immunization; studies show that this would be highly cost-effective. To date, financing yellow fever vaccine has been a major problem for these countries, which are among the poorest in the world. For this reason, WHO has launched an appeal to raise $70 million for yellow fever control in Africa.

Earlier epidemiological concepts are discussed briefly. Attention is focussed on several of the puzzling problems in the epidemiology of the disease as seen today. The recurring outbreaks of yellow fever in regions where it has been absent, as well as the absence of yellow fever in regions where the vectors exist are discussed. Features of vaccination are discussed, including the long persistence of humoral antibodies and long duration of effective protection. The possibility of changes in virulence of yellow fever strains is mentioned. In some of the modern outbreaks, virulence for human beings appears to be lower than virulence noted some centuries ago, and a hypothesis is advanced. The possible influence of virus-protecting antibodies acquired by infection by other flaviviruses is mentioned. With respect to the vectors of yellow fever, the possibility of differing susceptibility and of different behaviour of various strains is discussed. Transovarial transmission of the virus in the vector mosquito is mentioned as a possible mechanism for long persistence of the virus in nature. Infection of ticks and transovarial transmission of virus in ticks are also mentioned. The need for a diagnostic test to differentiate immunity produced by a naturally acquired infection from immunity induced by vaccination is stressed.

Yellow fever was responsible for several epidemics among the settlers in tropical areas of the Americas and Africa during the 17th to the 19th centuries. Scientific research into its cause and epidemiology was started at the beginning of the present century and progressed well ahead of other viral disease research. However, epidemics still occur and the worst one ever recorded was in Ethiopia in 1960-62. Epidemiological research has recently provided new findings on the ecology of the virus and the risk of epidemics. Recent breakthroughs in the molecular study of the virus should provide new tools for further progress in treatment and control of the disease. Meanwhile, the risk of urbanization of the disease, deficiencies in treatment, limitations in vector control, and erratic policies in preventive immunization present real problems.

An international seminar on the treatment and laboratory diagnosis of yellow fever, sponsored by the Pan American Health Organization (PAHO) and held in 1984, differed from previous meetings on yellow fever because of its emphasis on the care and management of patients and because the participants included specialists from several branches of medicine, such as hepatology, haematology, cardiology, infectious diseases, pathology and nephrology. The meeting reviewed the current status of yellow fever and problems associated with case-finding and notification; features of yellow fever in individual countries of Latin America; health services and facilities for medical care as they relate to diagnosis and management of cases; prevention strategies for and current status of immunization programmes; clinical and pathological aspects of yellow fever in humans; pathogenesis and pathophysiology of yellow fever in experimental animal models; clinical and specific laboratory diagnosis; treatment of the disease and of complications in the functioning of individual organ systems; prognosis and prognostic indicators; and directions for future clinical and experimental research on pathophysiology and treatment.