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Introduction: Yellow fever is caused by an RNA flavivirus. Immunisation in conjunction with vector control is at the forefront of yellow fever control and elimination. Objective: This narrative review describes the impact and importance of yellow fever vaccinations for northern Australian health practitioners. Design: Selected key policies, studies and medical guidelines are reviewed and presented. Finding: Large yellow fever outbreaks, associated with vector spread, have occurred in the last decade in Africa and South America, increasing the risk of international spread of the virus. Mobile populations, like travellers or migrant workers, continue to be at risk of yellow fever. Quality assurance, including yellow fever centre accreditation and initiatives to decrease fraudulent yellow fever vaccination documentation, has evolved in the past few years. Fractional dosing of yellow fever vaccines has been shown to provide protection for 1 year in outbreak scenarios, but further studies are needed. Discussion: Although Australia is yellow fever‐free, the disease could be introduced by viraemic persons as a competent Aedes mosquito vector is present in northern Australia. In addition to surveillance and vector control, health education and yellow fever vaccination remain the best lines of defence. In the event of an outbreak, a response via fractional dosing could prove to be effective in controlling the virus. Conclusion: Health care providers in northern Australia should be aware of the risks of yellow fever and its introduction to northern Australia and be able to discuss vaccination status with their clients when needed. [ABSTRACT FROM AUTHOR]

In 2009, Bio-Manguinhos conducted a dose-response study with the yellow fever vaccine, administering the vaccine in the usual mean dose of 27,476 IU (full dose, reference) and in tapered doses (10,447 IU, 3013 IU, 587 IU, 158 IU, and 31 IU) by the usual subcutaneous route and usual volume (0.5 mL). Tapered doses were obtained by dilution in the manufacturer’s laboratory, and the test batches presented industrial quality. Doses down to 587 IU showed similar immunogenicity to the full dose (27,476, reference), while the 158 IU and 31 IU doses displayed lower immunogenicity. Seropositivity was maintained at 10 months, except in the group that received the 31 IU dose. The current study aims to determine whether yellow fever seropositivity was maintained eight years after YF vaccination in non-revaccinated individuals. According to the current study’s results, seropositivity was maintained in 85% of 318 participants and was similar across groups. The findings support the use of the yellow fever vaccine in fractional doses during outbreaks, but each fractional dose should have at least 587 IU. This study also supports the minimum dose required by WHO, 1000 IU. Clinical trials registration: Clinicaltrials.gov NCT 03338231 . [ABSTRACT FROM AUTHOR]

In this investigation, machine-enhanced techniques were applied to bring about scientific insights to identify a minimum set of phenotypic/functional memory-related biomarkers for post-vaccination follow-up upon yellow fever (YF) vaccination. For this purpose, memory status of circulating T-cells (Naïve/early-effector/Central-Memory/Effector-Memory) and B-cells (Naïve/non-Classical-Memory/Classical-Memory) along with the cytokine profile (IFN/TNF/IL-5/IL-10) were monitored before-NV(day0) and at distinct time-points after 17DD-YF primary vaccination—PV(day30-45); PV(year1-9) and PV(year10-11). A set of biomarkers (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) were observed in PV(day30-45), but not in NV(day0), with most of them still observed in PV(year1-9). Deficiencies of phenotypic/functional biomarkers were observed in NV(day0), while total lack of memory-related attributes was observed in PV(year10-11), regardless of the age at primary vaccination. Venn-diagram analysis pre-selected 10 attributes (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 and IL-5CD4), of which the overall mean presented moderate accuracy to discriminate PV(day30-45)&PV(year1-9) from NV(day0)&PV(year10-11). Multi-parameter approaches and decision-tree algorithms defined the EMCD8 and IL-5CD4 attributes as the top-two predictors with moderated performance. Together with the PRNT titers, the top-two biomarkers led to a resultant memory status observed in 80% and 51% of volunteers in PV(day30-45) and PV(year1-9), contrasting with 0% and 29% found in NV(day0) and PV(year10-11), respectively. The deficiency of memory-related attributes observed at PV(year10-11) underscores the conspicuous time-dependent decrease of resultant memory following17DD-YF primary vaccination that could be useful to monitor potential correlates of protection in areas under risk of YF transmission. [ABSTRACT FROM AUTHOR]

Arboviruses, ar thropod- bo rne viruses , are frequency associated to human outbreak and represent a serious health problem. The genus Flavivirus, such as Yellow Fever Virus (YFV) and Saint Louis Encephalitis Virus (SLEV), are important pathogens with high morbidity and mortality worldwide. In Brazil, YFV is maintained in sylvatic cycle, but many cases are notified annually, despite the efficiency of vaccine. SLEV causes an acute encephalitis and is widely distributed in the Americas. There is no specific antiviral drugs for these viruses, only supporting treatment that can alleviate symptoms and prevent complications. Here, we evaluated the potential anti-YFV and SLEV activity of a series of thiosemicarbazones and phthalyl-thiazoles. Plaque reduction assay, flow cytometry, immunofluorescence and cellular viability were used to test the compounds in vitro . Treated cells showed efficient inhibition of the viral replication at concentrations that presented minimal toxicity to cells. The assays showed that phthalyl-thiazole and phenoxymethyl-thiosemicarbazone reduced 60% of YFV replication and 75% of SLEV replication. [ABSTRACT FROM AUTHOR]

If statesmanship can be characterized as a bed rock of principles, a strong moral compass, a vision, and an ability to articulate and effect that vision, then the fortitude, tenacity, imperturbability, and resilience of William Crawford Gorgas cannot be overestimated. As Chief Sanitary Officer in Cuba and as Chief Medical Officer in Panama, he actualized strategies to eradicate the vectors of yellow fever and malaria. His superiors initially pigeonholed his requisitions, refused to provide him with any authority, and clamored for his dismissal. Nevertheless, with dogged persistence he created a coalition of the willing, who eventually implemented those reforms. As Surgeon General in the United States Army, he organized and expanded the Active Duty and Medical Reserve Corps in anticipation of World War I. Skilled university affiliated surgeons and personnel from throughout North America, manned base hospitals in Europe. Those lessons impacted upon subsequent military and civilian surgical care-organizationally, logistically, and clinically. He was universally recognized for his bonhomie, savoir-faire, modesty, discretion, decorum, courtesy, and graciousness. To those attributes must be added his devotion to duty, discipline, integrity, and authenticity, which characterized his leadership and statesmanship. Those attributes are most worthy of emulation and perpetuation by clinicians, academicians, educators, and investigators. [ABSTRACT FROM AUTHOR]

Background: The ongoing yellow fever epidemic in Angola strains the global vaccine supply, prompting WHO to adopt dose sparing for its vaccination campaign in Kinshasa, Democratic Republic of the Congo, in July-August, 2016. Although a 5-fold fractional-dose vaccine is similar to standard-dose vaccine in safety and immunogenicity, efficacy is untested. There is an urgent need to ensure the robustness of fractional-dose vaccination by elucidation of the conditions under which dose fractionation would reduce transmission.Methods: We estimate the effective reproductive number for yellow fever in Angola using disease natural history and case report data. With simple mathematical models of yellow fever transmission, we calculate the infection attack rate (the proportion of population infected over the course of an epidemic) with various levels of transmissibility and 5-fold fractional-dose vaccine efficacy for two vaccination scenarios, ie, random vaccination in a hypothetical population that is completely susceptible, and the Kinshasa vaccination campaign in July-August, 2016, with different age cutoff for fractional-dose vaccines.Findings: We estimate the effective reproductive number early in the Angola outbreak was between 5·2 and 7·1. If vaccine action is all-or-nothing (ie, a proportion of vaccine recipients receive complete protection [VE] and the remainder receive no protection), n-fold fractionation can greatly reduce infection attack rate as long as VE exceeds 1/n. This benefit threshold becomes more stringent if vaccine action is leaky (ie, the susceptibility of each vaccine recipient is reduced by a factor that is equal to the vaccine efficacy). The age cutoff for fractional-dose vaccines chosen by WHO for the Kinshasa vaccination campaign (2 years) provides the largest reduction in infection attack rate if the efficacy of 5-fold fractional-dose vaccines exceeds 20%.Interpretation: Dose fractionation is an effective strategy for reduction of the infection attack rate that would be robust with a large margin for error in case fractional-dose VE is lower than expected.Funding: NIH-MIDAS, HMRF-Hong Kong. [ABSTRACT FROM AUTHOR]

A set of aryl- and phenoxymethyl-(thio)semicarbazones were synthetized, characterized and biologically evaluated against the larvae of Aedes aegypti ( A. aegypti ), the vector responsible for diseases like Dengue and Yellow Fever. (Q)SAR studies were useful for predicting the activities of the compounds not included to create the QSAR model as well as to predict the features of a new compound with improved activity. Docking studies corroborated experimental evidence of AeSCP- 2 as a potential target able to explain the larvicidal properties of its compounds. The trend observed between the in silico Docking scores and the in vitro pLC50 (equals −log LC50, at molar concentration) data indicated that the highest larvicidal compounds, or the compounds with the highest values for pLC50, are usually those with the higher docking scores (i.e., greater in silico affinity for the AeSCP-2 target). Determination of cytotoxicity for these compounds in mammal cells demonstrated that the top larvicide compounds are non-toxic. [ABSTRACT FROM AUTHOR]

Yellow fever virus (YFV) is the prototypical hemorrhagic fever virus, yet our understanding of its phenotypic diversity and any molecular basis for observed differences in disease severity and epidemiology is lacking, when compared to other arthropod-borne and haemorrhagic fever viruses. This is, in part, due to the availability of safe and effective vaccines resulting in basic YFV research taking a back seat to those viruses for which no effective vaccine occurs. However, regular outbreaks occur in endemic areas, and the spread of the virus to new, previously unaffected, areas is possible. Analysis of isolates from endemic areas reveals a strong geographic association for major genotypes, and recent epidemics have demonstrated the emergence of novel sequence variants. This review aims to outline the current understanding of YFV genetic and phenotypic diversity and its sources, as well as the available animal models for characterizing these differences in vivo . The consequences of genetic diversity for detection and diagnosis of yellow fever and development of new vaccines and therapeutics are discussed. [ABSTRACT FROM AUTHOR]

The results of a high-throughput screening assay using the dengue virus-2 replicon showed that the imidazole 4,5-dicarboxamide (I45DC) derivative ( 15a ) has a high dengue virus inhibitory activity. Based on 15a as a lead compound, a novel class of both disubstituted I45DCs and the resembling pyrazine 2,3-dicarboxamides (P23DCs) were synthesized. Here, we report on their in vitro inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Some of these first generation compounds have shown activity against both viruses in the micromolar range. Within this series, compound 15b was observed to display the highest antiviral potency against YFV with an EC 50 = 1.85 μM. In addition, compounds 20a and 20b both potently inhibited replication of DENV (EC 50 = 0.93 μM) in Vero cells. [ABSTRACT FROM AUTHOR]

Exploiting the inhibition of host signaling pathways aiming for discovery of potential antiflaviviral compounds is clearly a beneficial strategy for the control of life-threatening diseases caused by flaviviruses. Here we describe the antiviral activity of the MEK1/2 inhibitor U0126 against Yellow fever virus 17D vaccine strain (YFV-17D). Infection of VERO cells with YFV-17D stimulates ERK1/2 phosphorylation early during infection. Pharmacological inhibition of MEK1/2 through U0126 treatment of VERO cells blockades not only the YFV-stimulated ERK1/2 phosphorylation, but also inhibits YFV replication by ∼99%. U0126 was also effective against dengue virus (DENV-2 and -3) and Saint-Louis encephalitis virus (SLEV). Levels of NS4AB, as detected by immunofluorescence, are diminished upon treatment with the inhibitor, as well as the characteristic endoplasmic reticulum membrane invagination stimulated during the infection. Though not protective, treatment of YFV-infected, adult BALB/c mice with U0126 resulted in significant reduction of virus titers in brains. Collectively, our data suggest the potential targeting of the MEK1/2 kinase as a therapeutic tool against diseases caused by flaviviruses such as yellow fever, adverse events associated with yellow fever vaccination and dengue. [ABSTRACT FROM AUTHOR]

Highlights: [•] Humanized MAb is effective for yellow fever (YF) immunotherapy in a hamster model. [•] Treatment with 380 or 38μg MAb 24h prior to YFV challenge improves survival. [•] MAb given up to 3days post-challenge results in significant survival rates. [•] MAb therapeutic efficacy is improved in an immunocompetent animal model. [ABSTRACT FROM AUTHOR]

This section offers travel health news briefs. Chapter 17 of the "Green Book on Hepatitis A" was updated on December 4, 2013. The website www.fitfortravel.nhs.uk, developed by Health Protection Scotland, provides resource for travellers. There was a rise in the number cases of Avian flu virus reported in China in the run-up to the Chinese New Year on January 31, 2014.

West Nile (WNV) and Dengue (DENV) viruses are major arboviral human pathogens belonging to the genus Flavivirus. At the current time, there are no approved prophylactics (e.g., vaccines) or specific therapeutics available to prevent or treat human infections by these pathogens. Due to their minimal genome, these viruses require many host molecules for their replication and this offers a therapeutic avenue wherein host factors can be exploited as treatment targets. Since several host factors appear to be shared by many flaviviruses the strategy may result in pan-flaviviral inhibitors and may also attenuate the rapid emergence of drug resistant mutant viruses. The scope of this strategy is greatly enhanced by the recent en masse identification of host factors impacting on WNV and DENV infection. Excellent proof-of-principle experimental demonstrations for host-targeted control of infection and infection-induced pathogenesis have been reported for both WNV and DENV. These include exploiting not only those host factors supporting infection, but also targeting host processes contributing to pathogenesis and innate immune responses. While these early studies validated the host-targeting approach, extensive future investigations spanning a range of aspects are needed for a successful deployment in humans. [ABSTRACT FROM AUTHOR]

Yellow fever terrorized communities in tropical and urban settings during its height in the nineteenth-century American south. Carried by Aedes aegypti mosquitoes, which breed in stagnant water, the virus infects humans fervently and is most known for its symptoms of jaundice and vomito negro, a dark vomit of coagulated blood. During the near-annual outbreaks of yellow fever, caregivers struggled to cope with the emotional consequences of failing medicine, sometimes leaving behind clues to their confusion in treating the disease and offering salient reflections on their inadequacies. The disease ravaged the Gulf region for decades. Records of the health workers' feelings of futility reflect their questions of what to do for others and what to do for themselves, offering a new perspective on yellow-fever scholarship and insight into contemporary clinical practice and research. [ABSTRACT FROM AUTHOR]

Abstract: A number of viruses in the family Flaviviridae are the focus of efforts to develop effective antiviral therapies. Success has been achieved with inhibitors for the treatment of hepatitis C, and there is interest in clinical trials of drugs against dengue fever. Antiviral therapies have also been evaluated in patients with Japanese encephalitis and West Nile encephalitis. However, no treatment has been developed against the prototype flavivirus, yellow fever virus (YFV). Despite the availability of the live, attenuated 17D vaccine, thousands of cases of YF continue to occur each year in Africa and South America, with a significant mortality rate. In addition, a small number of vaccinees develop severe systemic infections with the 17D virus. This paper reviews current efforts to develop antiviral therapies, either directly targeting the virus or blocking detrimental host responses to infection. [Copyright &y& Elsevier]

Abstract: Yellow fever virus (YFV) continues to cause outbreaks of disease in endemic areas where vaccine is underutilized. Due to the effectiveness of the vaccine, antiviral development solely for the treatment of YFV is not feasible, but antivirals that are effective in the treatment of related viral diseases may be characterized for potential use against YFV as a secondary indication disease. 2′-C-methylcytidine (2′-C-MeC), a compound active against hepatitis C virus, was found to have activity against the 17D vaccine strain of YFV in cell culture (EC90 =0.32μg/ml, SI=141). This compound was effective when added as late as 16h after virus challenge of Vero cells. When administered to YFV-infected hamsters 4h prior to virus challenge at a dose as low as 80mg/kg/d, 2′-C-MeC was effective in significantly improving survival and other disease parameters (weight change, serum ALT, and liver virus titers). Disease was improved when compound was administered beginning as late as 3 d post-virus infection. Broadly active antiviral compounds, such as 2′-C-MeC, represent potential for the development of compounds active against related viruses for the treatment of YFV. [Copyright &y& Elsevier]

In this case report, we describe a 63-year-old female with Crohn's disease since age 16 years, and on adalimumab therapy, who inadvertently received a yellow fever vaccine ( YFV) 4 days before her next dose of adalimumab. She had never received YFV. Her next dose of tumor necrosis factor ( TNF) antagonist was held. She did not report any adverse effects referable to the vaccine. Reverse transcriptase-polymerase chain reaction ( RT-PCR) for yellow fever ( YF) viral RNA on days 12 and 18 postvaccination was negative. Neutralizing antibody to YF virus vaccine was immunoprotective on day 18 following vaccination, which further increased by day 26. A neutralizing antibody obtained 2 years following vaccination also remained immunoprotective. [ABSTRACT FROM AUTHOR]

In April 2016, a yellow fever outbreak was detected in Uganda. Removal of contaminating ribosomal RNA in a clinical sample improved the sensitivity of next-generation sequencing. Molecular analyses determined the Uganda yellow fever outbreak was distinct from the concurrent yellow fever outbreak in Angola, improving our understanding of yellow fever epidemiology. [ABSTRACT FROM AUTHOR]

Summary: High-throughput screening of the host transcriptional response to various viral infections provides a wealth of data, but utilization of microarray and next generation sequencing (NGS) data for analysis can be difficult. The Host Transcriptional Response DataBase (HoTResDB), allows visitors to access already processed microarray and NGS data from non-human primate models of viral hemorrhagic fever to better understand the host transcriptional response. [ABSTRACT FROM AUTHOR]

The article offers information on yellow fever, which refers to a hemorrhagic and lethal RNA virus that caused an outbreak in Angola, Democratic Republic of Congo and Uganda. Topics covered include the transmission and infection of yellow fever, the clinical manifestations of the disease and the care for patients with yellow fever. Also mentioned are the tools used for diagnosis such as serology and immunocytochemistry.

The article focuses on a vaccine developed by Pasteur Institute in Paris, France that offers lifelong protection against yellow fever. Topics discussed include combined output of the vaccine of the institute which has caused resurgence of the virus in Luanda, Angola; low-tech and hard to scale up vaccine, transmission of the fever through the bite of yellow fever mosquito Aedes aegypti, and introducing vaccination campaigns to aware the citizens.