Document text
Principal Investigator: William Messer
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2021
Award: $191,724
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Yellow fever virus (YFV) is the prototype flavivirus and is historically the most important arthropod-borne viral
pathogen of humans worldwide with ~200,000 infections annually and a mortality of ~50% in those who develop
severe symptoms. YFV is endemic throughout Africa and South America and had been largely controlled through
mass vaccination. The YFV vaccine 17D is considered one of the most effective live-attenuated virus (LAV)
vaccines ever developed. Even so, every 10-year boosts have been recommended to maintain immunity.
However, falling vaccination rates have led to a dramatic resurgence of disease in both Africa and South
America, and subsequent vaccination campaigns have depleted the global supply of 17D. In response to these
vaccine shortages, the WHO and CDC revised the 10-year boost to a once-in-a-lifetime vaccination
recommendation, despite limited supporting data: although serosurveys find that ~90% of vaccinees have
detectable neutralizing antibodies to YFV, careful review of these surveys finds that among individuals living in
YFV non-endemic settings, at least 20% of YFV vaccinees lack detectable neutralizing antibodies at >10 years
post-vaccination. While this finding must be critically evaluated in the context of ongoing outbreaks and vaccine
shortages, it also represents a unique opportunity to study how 17D induces and maintains neutralizing
antibodies in some vaccinees but not in others. Our central premise is that long-term YFV immunity is established
by host immune activation in response to vaccine viremia at the time of vaccination: downstream effects of
detectable differences in duration and magnitude of vaccine viremia at vaccination determine whether or not a
vaccinee develops life-long immunity. We propose to evaluate this premise and its broader implications in three
separate Aims: Aim 1 tests the hypothesis that vaccine viremia correlates with the long-term durability of of YFV
neutralizing antibodies. We will enroll YFV pre-vaccinees and prospectively characterize acute vaccine viremia,
acute innate immune and adaptive immune responses, and neutralizing antibody titers up to 5 years thereafter.
Aim 2 tests the hypothesis that at least 20% of 17D vaccinated subjects will lose YFV immunity between 3- and
7-years post vaccination. We will recruit and prospectively follow a cohort of 17D vaccinees vaccinated 2-3 years
prior to enrollment, comparing changes in YFV neutralizing antibodies and other immune markers over time and
characterizing individual and cohort antibody decay kinetics. In Aim 3 we use 17D revaccination as a live-virus
challenge to test the hypothesis that neutralizing antibody titers correlate with YFV protection. We will
prospectively characterize pre-boost antibodies titers, vaccine viremia, acute immune responses and post-boost
titers in vaccinees receiving boost 17D vaccinations. We expect to identify neutralizing antibody titers above
which sterilizing immunity is conferred and titers below which it is not. These Aims will set a foundation for future
studies to further dissect determinants of 17D and other LAV induced immunity and establish metrics that could
allow efficient prioritization of 17D vaccination and optimize 17D use in the face of current and future outbreaks.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Aching muscles><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Age><Allergy><Antiviral Agents><Antiviral Drugs><Antivirals><Blood Sample><Blood specimen><CAT scan><COPD><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 virus><COVID19><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Caring><China><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Airway Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Circulatory Collapse><Clinical><CoV emergence><CoV-2><CoV2><Cohort Studies><Collection><Computed Tomography><Concurrent Studies><Controlled Clinical Trials><Conventional X-Ray><Coughing><Da Nang Lung><Data><Development><Diabetes Mellitus><Diagnostic Radiology><Diagnostic X-Ray><Diagnostic X-Ray Radiology><Diagnostic radiologic examination><Disease><Disease Progression><Disorder><Extracorporeal Membrane Oxygenation><Fostering><Genomics><Glass><History><Host Factor><Host Factor Protein><Human><Hypersensitivity><Hypoxemia><Immune response><Immunity><Immunologic Factors><Immunologic Subtyping><Immunological Factors><Immunological response><Immunology><Immunophenotyping><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Integration Host Factors><Intervention><Intervention Strategies><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Kinetics><Knowledge><Label><Laboratories><Life><Lobar><Mainland China><Malaise><Measures><Microbial Superinvasion><Mission><Modern Man><Morbidity><Morbidity - disease rate><Muscle discomfort><Muscle pain><Muscle pain/fibrositis><Muscle sorenesss><Myalgia><Myalgic><Myocardial Ischemia><Myodynia><Myoneuralgia><Myosalgia><NIAID><NIH><National Institute of Allergy and Infectious Disease><National Institutes of Health><Organ failure><Patients><Phenotype><Pneumonia><Prospective cohort study><Radiography><Randomized Controlled Trials><Recording of previous events><Recovery><Research><Resolution><Risk><Roentgenography><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Shock><Shock Lung><Site><Stiff lung><Symptoms><Therapeutic><Therapeutic Intervention><Tomodensitometry><Transplantation><United States National Institutes of Health><Viral><Virus Replication><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><X-Ray Imaging><X-Ray Medical Imaging><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Xray imaging><Xray medical imaging><ages><anti-viral agents><anti-viral drugs><anti-virals><burden of disease><burden of illness><cardiac ischemia><catscan><chest CT><chest computed tomography><circulatory shock><co-morbid><co-morbidity><comorbidity><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><conventional Xray><corona virus disease 2019><corona virus emergence><coronary ischemia><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus emergence><coronavirus patient><developmental><diabetes><diagnostic Xray><diagnostic Xray radiology><disease burden><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><hCoV19><heart ischemia><host response><hypoxemic><immune suppression><immune system response><immunologic substance><immunological substance><immunophenotype><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><intervention therapy><interventional strategy><mortality><myocardial ischemia/hypoxia><myocardium ischemia><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><pathogen><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><prospective><public health relevance><respiratory><sample collection><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><specimen collection><super infection><superinfection><transplant><viral multiplication><viral replication><virus multiplication><wet lung><years of life lost to disability><years of life lost to disease>