SBIR-STTR Award

Direct to Phase II

Yellow fever virus (YFV) is a mosquito-borne emerging/re-emerging hemorrhagic fever virus that causes 20- 60% mortality and is endemic in >40 countries. The current live attenuated YFV vaccine was developed in 1936 and has proven to be effective at saving millions of lives from this devastating disease. Nevertheless, this is a live-attenuated vaccine that is contraindicated in healthy people who have egg allergies as well as vulnerable populations including young infants, pregnant or breastfeeding women, and the elderly. During recent outbreaks, these at-risk groups have had no alternatives to live yellow fever vaccination and our goal is to produce a vaccine that is safe for both healthy and vulnerable populations. According to the CDC, live YFV vaccines cause 47 serious adverse events (SAE) per million vaccinations (SAE defined as resulting in hospitalization, long-term disability, or death). Vaccine-associated neurological disease occurs at a rate of up to 1 case per 10,000 vaccinations. YFV vaccination of infants <9 months of age has been contraindicated since the 1960's due to excessively high rates of vaccine-associated encephalitis in this age group. More recently, live YFV vaccination has been contraindicated in breastfeeding mothers due to documented cases of virus transmission via breastmilk to infants who later developed YFV-associated neurological disease including seizures. In patients >60 years of age, YFV vaccination causes severe viscerotropic disease at an incidence rate of approximately 1:50,000 with a mortality rate of >50%. The overall mortality rate following YFV vaccination (all ages) is estimated at 1 to 2 deaths per million doses. Despite these clear gaps in vaccination coverage, there is currently no commercial vaccine available for these vulnerable populations. To address this critical unmet need, we have discovered a safe and immunogenic peroxide-inactivated yellow fever vaccine, HydroVax-YFV. Importantly, this advanced vaccine is safe and provides complete protection against lethal viscerotropic yellow fever in a robust non-human primate model. Here, we propose a double-blind, randomized, placebo-controlled Phase I dose escalation trial to evaluate the preliminary safety and immunogenicity of HydroVax-YFV. Our goal is to eventually expand vaccine coverage to a broader range of patients and the successful completion of this study will represent a key milestone in the advancement of a clinically relevant vaccine against yellow fever and provide a much-needed approach to protect the most susceptible members of society including infants, elderly, and those with potentially compromised immune functions.

Public Health Relevance Statement:
In this proposal, we provide preclinical data demonstrating the safety, immunogenicity, and protective efficacy of an advanced HydroVax vaccine platform and propose to evaluate the safety and immunogenicity of a novel peroxide-inactivated whole-virus yellow fever vaccine in a double-blind placebo-controlled Phase I clinical trial.

Project Terms:
Adult; adulthood; Adult Human; 21+ years old; Age; ages; Elderly; senior citizen; older person; older adult; later life; late life; geriatric; elders; advanced age; Award; Breast Feeding; Breastfeeding; Breastfed; Breast fed; United States Centers for Disease Control and Prevention; United States Centers for Disease Control; Centers for Disease Control and Prevention; Centers for Disease Control; CDC; Centers for Disease Control and Prevention (U.S.); Clinical Protocols; Clinical Study; Clinical Research; Clinical Trials; data interpretation; Data Analysis; Data Analyses; Death; Cessation of life; Disorder; Disease; Outbreaks; Disease Outbreaks; Double-Masked Study; Double-Masked Method; Double-Blinded; Double-Blind Study; Double-Blind Method; Investigational New Drugs; Investigational Drugs; ebolavirus; Ebola; EBOV; Ebola virus; Brain Inflammation; Encephalitis; Female; febris; febrile; Pyrexia; Fever; Group B Arbovirus; Flavivirus; Goals; Grant; blood loss; Bleeding; Hemorrhage; Hepatitis; Hospital Admission; Hospitalization; Hydroperoxide; H2O2; Hydrogen Peroxide; Immunostimulation; Immunological Stimulation; Immunological Sensitization; Immunologic Stimulation; Immunologic Sensitization; Immunization; Incidence; Infant; Institutes; Laboratories; male; maternal milk; Mother's Milk; Mammary Gland Milk; Human Mother's Milk; Breastmilk; Breast Milk; Human Milk; mortality; Mothers; National Institutes of Health; NIH; United States National Institutes of Health; Nausea and Vomiting; neurological disease; Neurological Disorders; Neurologic Disorders; Nervous System Diseases; nervous system disorder; Package Insert; Patients; Peroxides; sham therapy; Sham Treatment; Placebos; pregnant mothers; expecting mother; expectant mother; Pregnant Women; Production; Renal Insufficiency; Renal Failure; Kidney Insufficiency; Kidney Failure; Researchers; Investigators; Research Personnel; Risk; Safety; Savings; Seizures; Diagnostic Findings; Signs and Symptoms; Societies; Technology; Testing; Time; Toxicology; Vaccination; Vaccines; live vaccine; Attenuated Vaccines; Veterans; General Viruses; Virus; West Nile; WNV; Egypt 101 virus; West Nile virus; Woman; Wood; Wood material; Yellow Fever; Yellow fever virus; Outcome Measure; Investigational New Drug Application; base; Acute; Clinical; Phase; Medical; disability; Individual; nonhuman primate; non-human primate; Case Fatality Rates; Yellow Fever Vaccine; Attenuated; Protocols documentation; Protocol; Country; Test Result; Allergy to eggs; egg allergy; allergic to eggs; Egg Hypersensitivity; age group; vaccine development; vaccine formulation; development of a vaccine; develop a vaccine; Toxic effect; Toxicities; novel; member; Prevention; hemorrhagic fever virus; Reporting; Modeling; immunogenic; Adverse event; Adverse Experience; Phase I Clinical Trials; phase I protocol; phase 1 trial; Phase 1 Clinical Trials; Early-Stage Clinical Trials; Vulnerable Populations; vulnerable group; Cellular Immune Function; immune function; Address; Dose; Age-Months; Age-Years; Data; National Institute of Allergy and Infectious Disease; NIAID; Randomized; randomly assigned; randomization; randomisation; Attenuated Live Virus Vaccine; Live-attenuated Vaccine; Enrollment; enroll; Phase I and II Vaccine Trials; Serious Adverse Event; serious adverse reaction; serious adverse experience; Severe Adverse Event; Development; developmental; pre-clinical; preclinical; burden of illness; years of life lost to disease; years of life lost to disability; disease burden; burden of disease; immunogenicity; man; man's; clinically relevant; clinical relevance; pregnant; FDA approved; cGMP production; vaccine candidate; protective efficacy; stability testing; phase I trial; seroconversion; vaccine trial; vaccine study; vaccination trial; vaccination study; viral transmission; virus transmission; nursing mothers; secondary endpoint; secondary end point; primary endpoint; primary end point; Infrastructure; safety assessment; mosquito-borne pathogen; mosquitoborne pathogen; mosquito-borne; mosquitoborne