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1.
PLoS One ; 17(2): e0262149, 2022.
Article in English | MEDLINE | ID: covidwho-1910485

ABSTRACT

There is an urgent need for better diagnostic and analytical methods for vaccine research and infection control in virology. This has been highlighted by recently emerging viral epidemics and pandemics (Zika, SARS-CoV-2), and recurring viral outbreaks like the yellow fever outbreaks in Angola and the Democratic Republic of Congo (2016) and in Brazil (2016-2018). Current assays to determine neutralising activity against viral infections in sera are costly in time and equipment and suffer from high variability. Therefore, both basic infection research and diagnostic population screenings would benefit from improved methods to determine virus-neutralising activity in patient samples. Here we describe a robust, objective, and scalable Fluorescence Reduction Neutralisation Test (FluoRNT) for yellow fever virus, relying on flow cytometric detection of cells infected with a fluorescent Venus reporter containing variant of the yellow fever vaccine strain 17D (YF-17D-Venus). It accurately measures neutralising antibody titres in human serum samples within as little as 24 h. Samples from 32 vaccinees immunised with YF-17D were tested for neutralising activity by both a conventional focus reduction neutralisation test (FRNT) and FluoRNT. Both types of tests proved to be equally reliable for the detection of neutralising activity, however, FluoRNT is significantly more precise and reproducible with a greater dynamic range than conventional FRNT. The FluoRNT assay protocol is substantially faster, easier to control, and cheaper in per-assay costs. FluoRNT additionally reduces handling time minimising exposure of personnel to patient samples. FluoRNT thus brings a range of desirable features that can accelerate and standardise the measurement of neutralising anti-yellow fever virus antibodies. It could be used in applications ranging from vaccine testing to large cohort studies in systems virology and vaccinology. We also anticipate the potential to translate the methodology and analysis of FluoRNT to other flaviviruses such as West Nile, Dengue and Zika or to RNA viruses more generally.


Subject(s)
Antibodies, Neutralizing/immunology , Yellow Fever/immunology , Yellow fever virus/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , Chlorocebus aethiops , Fluorescence , Humans , Neutralization Tests/economics , Neutralization Tests/methods , Vero Cells , Yellow Fever/blood , Yellow Fever/virology
2.
Rev Saude Publica ; 56: 45, 2022.
Article in English | MEDLINE | ID: covidwho-1893354

ABSTRACT

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


Subject(s)
COVID-19 , Yellow Fever Vaccine , Yellow Fever , Brazil/epidemiology , COVID-19/epidemiology , COVID-19/prevention & control , Humans , Pandemics/prevention & control , Vaccination , Yellow Fever/epidemiology , Yellow Fever/prevention & control , Yellow fever virus
3.
Rev Med Virol ; 32(4): e2333, 2022 07.
Article in English | MEDLINE | ID: covidwho-1669637

ABSTRACT

This last decade has seen a resurgence of yellow fever (YF) in historical endemic regions and repeated attempts of YF introduction in YF-free countries such as the Asia-Pacific region and the Caribbean. Infected travellers are the main entry routes in these regions where competent mosquito vectors proliferate in appropriate environmental conditions. With the discovery of the 17D vaccine, it was thought that YF would be eradicated. Unfortunately, it was not the case and, contrary to dengue, chikungunya and Zika, factors that cotribute to YF transmission remain under investigation. Today, all the signals are red and it is very likely that YF will be the next pandemic in the YF-free regions where millions of people are immunologically naïve. Unlike COVID-19, YF is associated with a high case-fatality rate and a high number of deaths are expected. This review gives an overview of global YF situation, including the non-endemic Asia-Pacific region and the Caribbean where Aedes aegypti is abundantly distributed, and also proposes different hypotheses on why YF outbreaks have not yet occurred despite high records of travellers importing YF into these regions and what role Aedes mosquitoes play in the emergence of urban YF.


Subject(s)
Aedes , COVID-19 , Chikungunya Fever , Yellow Fever , Zika Virus Infection , Zika Virus , Animals , Humans , Mosquito Vectors , Yellow Fever/epidemiology , Yellow fever virus
4.
Vaccine ; 39(48): 6990-7000, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1499072

ABSTRACT

The genus flavivirus of the Flaviridae family includes several human pathogens, like dengue, Zika, Japanese encephalitis, and yellow fever virus. These viruses continue to be a significant threat to human health. Vaccination remains the most useful approach to reduce the impact of flavivirus fever. However, currently available vaccines can induce severe side effects or have low effectiveness. An alternative is the use of recombinant vaccines, of which virus-like particles (VLP) and single-round infectious particles (SRIP) are of especial interest. VLP consist of the virus structural proteins produced in a heterologous system that self-assemble in a structure almost identical to the native virus. They are highly immunogenic and have been effective vaccines for other viruses for over 30 years. SRIP are promising vaccine candidates, as they induce both cellular and humoral responses, as viral proteins are expressed. Here, the state of the art to produce both types of particles and their use as vaccines against flaviviruses are discussed. We summarize the different approaches used for the design and production of flavivirus VLP and SRIP, the evidence for their safety and efficacy, and the main challenges for their use as commercial vaccines.


Subject(s)
Flavivirus , Viral Vaccines , Zika Virus Infection , Zika Virus , Humans , Vaccines, Synthetic , Yellow fever virus , Zika Virus Infection/prevention & control
6.
Front Immunol ; 11: 1836, 2020.
Article in English | MEDLINE | ID: covidwho-1389162

ABSTRACT

Examining CD8+ and CD4+ T cell responses after primary Yellow Fever vaccination in a cohort of 210 volunteers, we have identified and tetramer-validated 92 CD8+ and 50 CD4+ T cell epitopes, many inducing strong and prevalent (i.e., immunodominant) T cell responses. Restricted by 40 and 14 HLA-class I and II allotypes, respectively, these responses have wide population coverage and might be of considerable academic, diagnostic and therapeutic interest. The broad coverage of epitopes and HLA overcame the otherwise confounding effects of HLA diversity and non-HLA background providing the first evidence of T cell immunodomination in humans. Also, double-staining of CD4+ T cells with tetramers representing the same HLA-binding core, albeit with different flanking regions, demonstrated an extensive diversification of the specificities of many CD4+ T cell responses. We suggest that this could reduce the risk of pathogen escape, and that multi-tetramer staining is required to reveal the true magnitude and diversity of CD4+ T cell responses. Our T cell epitope discovery approach uses a combination of (1) overlapping peptides representing the entire Yellow Fever virus proteome to search for peptides containing CD4+ and/or CD8+ T cell epitopes, (2) predictors of peptide-HLA binding to suggest epitopes and their restricting HLA allotypes, (3) generation of peptide-HLA tetramers to identify T cell epitopes, and (4) analysis of ex vivo T cell responses to validate the same. This approach is systematic, exhaustive, and can be done in any individual of any HLA haplotype. It is all-inclusive in the sense that it includes all protein antigens and peptide epitopes, and encompasses both CD4+ and CD8+ T cell epitopes. It is efficient and, importantly, reduces the false discovery rate. The unbiased nature of the T cell epitope discovery approach presented here should support the refinement of future peptide-HLA class I and II predictors and tetramer technologies, which eventually should cover all HLA class I and II isotypes. We believe that future investigations of emerging pathogens (e.g., SARS-CoV-2) should include population-wide T cell epitope discovery using blood samples from patients, convalescents and/or long-term survivors, who might all hold important information on T cell epitopes and responses.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Vaccination , Yellow Fever Vaccine/immunology , Yellow Fever/prevention & control , Yellow fever virus/immunology , Betacoronavirus/immunology , COVID-19 , Cohort Studies , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Healthy Volunteers , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Humans , Immunogenicity, Vaccine , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , SARS-CoV-2 , Yellow Fever/virology
7.
Front Immunol ; 11: 575074, 2020.
Article in English | MEDLINE | ID: covidwho-1256374

ABSTRACT

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.


Subject(s)
Dengue Virus/immunology , Immunity, Cellular , Orthomyxoviridae/immunology , Respiratory Syncytial Virus, Human/immunology , Rotavirus/immunology , Viral Vaccines/therapeutic use , Virus Diseases/immunology , Yellow fever virus/immunology , Biomarkers/blood , Dengue/blood , Dengue/immunology , Dengue/prevention & control , Dengue/virology , Dengue Vaccines/therapeutic use , Dengue Virus/pathogenicity , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Immunogenicity, Vaccine , Influenza Vaccines/therapeutic use , Influenza, Human/blood , Influenza, Human/immunology , Influenza, Human/prevention & control , Influenza, Human/virology , Oligonucleotide Array Sequence Analysis , Orthomyxoviridae/pathogenicity , Predictive Value of Tests , RNA, Messenger/blood , RNA, Messenger/genetics , Respiratory Syncytial Virus Infections/blood , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/pathogenicity , Rotavirus/pathogenicity , Rotavirus Infections/blood , Rotavirus Infections/immunology , Rotavirus Infections/prevention & control , Rotavirus Infections/virology , Rotavirus Vaccines , Signal Transduction/genetics , Virus Diseases/blood , Virus Diseases/prevention & control , Virus Diseases/virology , Yellow Fever/blood , Yellow Fever/immunology , Yellow Fever/prevention & control , Yellow Fever/virology , Yellow Fever Vaccine/therapeutic use , Yellow fever virus/pathogenicity
8.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1066211

ABSTRACT

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Subject(s)
Antibodies, Neutralizing/immunology , Autoantibodies/immunology , Autoimmune Diseases , COVID-19 , Genetic Diseases, Inborn , Interferon-alpha , Receptor, Interferon alpha-beta , SARS-CoV-2 , Yellow Fever Vaccine , Yellow fever virus , Adolescent , Adult , Aged , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , COVID-19/genetics , COVID-19/immunology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , HEK293 Cells , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Male , Middle Aged , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/genetics , Yellow Fever Vaccine/immunology , Yellow fever virus/genetics , Yellow fever virus/immunology
9.
Cell ; 184(1): 133-148.e20, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-987228

ABSTRACT

Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.


Subject(s)
Flavivirus Infections/genetics , Flavivirus/physiology , Membrane Proteins/metabolism , Animals , Autophagy , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , CRISPR-Cas Systems , Cell Line , Flavivirus Infections/immunology , Flavivirus Infections/metabolism , Flavivirus Infections/virology , Gene Knockout Techniques , Genome-Wide Association Study , Host-Pathogen Interactions , Humans , Immunity, Innate , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , SARS-CoV-2/physiology , Virus Replication , Yellow fever virus/physiology , Zika Virus/physiology
10.
Viruses ; 12(12)2020 11 25.
Article in English | MEDLINE | ID: covidwho-945954

ABSTRACT

Since the recent epidemics of yellow fever in Angola and Brazil as well as the importation of cases to China in 2016, there has been an increased interest in the century-old enigma, absence of yellow fever in Asia. Although this topic has been repeatedly reviewed before, the history of human intervention has never been considered a critical factor. A two-stage literature search online for this review, however, yielded a rich history indispensable for the debate over this medical enigma. As we combat the pandemic of COVID-19 coronavirus worldwide today, we can learn invaluable lessons from the historical events in Asia. In this review, I explore the history first and then critically examine in depth major hypotheses proposed in light of accumulated data, global dispersal of the principal vector, patterns of YF transmission, persistence of urban transmission, and the possibility of YF in Asia. Through this process of re-examination of the current knowledge, the subjects for research that should be conducted are identified. This review also reveals the importance of holistic approach incorporating ecological and human factors for many unresolved subjects, such as the enigma of YF absence in Asia, vector competence, vector dispersal, spillback, viral persistence and transmission mechanisms.


Subject(s)
Aedes/physiology , Mosquito Vectors/physiology , Yellow Fever/prevention & control , Yellow Fever/transmission , Aedes/virology , Animal Distribution , Animals , Asia , Humans , Mosquito Vectors/virology , Yellow fever virus
11.
Antiviral Res ; 182: 104874, 2020 10.
Article in English | MEDLINE | ID: covidwho-891945

ABSTRACT

Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-ß (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target.


Subject(s)
Betacoronavirus/physiology , DNA Topoisomerases, Type I/metabolism , RNA Viruses/metabolism , Virus Replication/physiology , Cell Line , Dengue Virus/physiology , Ebolavirus/physiology , Gene Knockout Techniques , Humans , Influenza A virus/physiology , SARS-CoV-2 , Yellow fever virus/physiology , Zika Virus/physiology
12.
N Engl J Med ; 383(5): 452-459, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-692294

ABSTRACT

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Yellow Fever Vaccine , Yellow Fever/drug therapy , Yellow fever virus/immunology , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Kaplan-Meier Estimate , Viremia/drug therapy , Yellow Fever/virology , Yellow fever virus/drug effects
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