The recent groundbreaking experiment using a single neutralizing monoclonal antibody (nmAb) to reduce the death rate in Ebola virus (EBOV)-infected individuals highlights the importance of this class of drug in the treatment of infectious disease. In August 2019, Dr. Anthony Fauci announced that administration of mAb114 had reduced the death rate from 70% to approximately 35% in EBOV-infected patients. EBOV infection is no longer considered a uniformly fatal disease. Similar to EBOV infection, wild-type yellow fever virus (wtYFV) infection results in high viral loads and a death rate of up to 50% in hospitalized patients. Once infected, there is no current treatment available. While the YFV17D vaccine is generally efficacious, it has some potentially severe side effects which diminish its coverage. Unfortunately, the World Health Organization (WHO) reported approximately 100 cases of severe adverse effects due to mass vaccination campaigns in Brazil, dissuading many people from receiving the vaccine. Even though vaccination campaigns were launched, immunization coverage remains low, leaving a significant number of people at risk. Most of the world, including the U.S., is vulnerable to mosquito-transmitted diseases, as shown by the emergence of two related flaviviruses dengue (DENV) and Zika (ZIKV). At Mabloc LLC, through our collaborations with the Watkins, Kallas and Burton laboratories, and Adimab LLC, we have assembled a large collection of flavivirus-specific neutralizing monoclonal antibodies (nmAbs). Indeed, the Watkins laboratory has already shown that these mAbs can be used for the prevention and treatment of flavivirus infections. The Watkins and Burton laboratories, and more recently others, have demonstrated that ZIKV infection can be prevented in Indian rhesus macaques by using either a nmAb cocktail or a single nmAb. Additionally, the Watkins and Burton laboratories have also shown that this cocktail can reduce viral load to undetectable levels in ZIKV-infected pregnant macaques. These data demonstrated, for the first time, that post-exposure treatment with nmAbs can reduce flavivirus replication in a relevant non- human primate (NHP) model. In Phase I of this application, we plan to identify at least five nmAbs from our existing pool of mAbs for wtYFV treatment using in vitro assays and in vivo screening in Syrian golden hamsters. In Phase II, we will perform tissue cross reactivity studies using our best YFV-specific nmAbs. We will then test the efficacy of the best three nmAbs in treating wtYFV-infected monkeys. After the completion of this Fast-Track Phase I/II application, we plan to have at least a commercially viable cocktail or a single nmAb that can efficaciously suppress viral replication in wtYFV-challenged NHPs, and thereby save them from the sequelae of wtYFV infection, namely death.
Public Health Relevance Statement: PROJECT NARRATIVE The recent outbreaks of fatal yellow fever virus infections are causing alarm and vaccine shortages worldwide. Nearly one billion people are at risk of yellow fever infection and, once infected, there is no current treatment available for this disease. We plan to use neutralizing monoclonal antibodies to prevent this normally fatal infection.
Project Terms: Monoclonal Antibodies; Clinical Treatment Moab; mAbs; Biotechnology; Biotech; Brazil; Cessation of life; Death; Dengue; Dengue Virus; Breakbone Fever Virus; Dengue fever virus; Diagnosis; Disease; Disorder; Disease Outbreaks; Outbreaks; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Ebola virus; EBOV; ebolavirus; Flavivirus; Group B Arbovirus; Mesocricetus auratus; Golden Hamsters; Golden Syrian Hamsters; Syrian Hamsters; Immunization; Immunologic Sensitization; Immunologic Stimulation; Immunological Sensitization; Immunological Stimulation; Immunostimulation; In Vitro; Incidence; Infection; Laboratories; Learning; Macaca; Macaque; Macaca mulatta; M mulatta; M. mulatta; Rhesus Macaque; Rhesus Monkey; Monkeys; mortality; Culicidae; Mosquitoes; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Patients; Play; Research Institute; Research Personnel; Investigators; Researchers; Risk; Role; social role; Testing; Time; Tissues; Body Tissues; Universities; Vaccination; Vaccines; Virion; Virus Particle; Virus Diseases; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus Replication; viral multiplication; viral replication; virus multiplication; Virus; World Health Organization; Yellow Fever; Yellow fever virus; Diagnostic tests; base; virus envelope; Phase; Death Rate; Flavivirus Infections; Individual; non-human primate; nonhuman primate; Collaborations; Viral Burden; Viral Load; Viral Load result; human tissue; Mosquito-borne disease; Mosquito-borne infectious disease; success; PBMC; Peripheral Blood Mononuclear Cell; novel; Prevention; Reporting; Yellow Fever Virus Infection; Modeling; cross reactivity; Adverse effects; Mass Vaccinations; preventing; prevent; Data; in vitro Assay; in vivo; Collection; infectious disease treatment; Vaccinated; Characteristics; developmental; Development; neutralizing mAb; neutralizing monoclonal antibodies; pregnant; efficacy testing; public health emergency; screening; ZIKV; zikav; Zika Virus; experiment; experimental research; experimental study; new drug class; novel drug class; ZIKV positive; Zika virus infection; zika infection; zika viral infection; ZIKV infection; side effect; ZIKA; Ebola
