Phase 1 Trial of a Therapeutic Anti–Yellow Fever Virus Human Antibody

Abstract

BACKGROUNDInsufficient 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. METHODSIn 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. RESULTSA 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. CONCLUSIONSThis 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.

Antibody screening at reduced pH enables preferential selection of potently neutralizing antibodies targeting SARS‐CoV‐2

“… 1 mAbs are used for a variety of indications including autoimmune diseases, cancer, genetic deficiencies, and other applications, and in particular antiviral antibodies can be useful for the prevention and treatment of viral infections. Major clinical indications for antiviral mAbs include human immunodeficiency virus (HIV‐1; ibalizumab), respiratory syncytial virus infection (palivizumab) and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, or its associated coronavirus disease (COVID‐19) (e.g., casirivimab/imdevimab, bamlanivimab); several other anti‐infective antibodies have been used or are currently in clinical trials to prevent or treat numerous other viral infections (e.g., yellow fever virus [YFV], 2 HIV‐1, 3 Ebola virus, 4 and others). While binding to a viral surface antigen is a common feature to all these clinical mAbs, the most promising antiviral antibodies for clinical use show potent viral neutralization, or the ability to prevent viral infection in tissue culture.…”

Isolation of a potently neutralizing and protective human monoclonal antibody targeting yellow fever virus

“…Two mAbs, YFV-121 and YFV-136, showed neutralization activity against YFV-17D, with YFV-136 showing exceptional potency with IC 50 < 10 ng/mL. The potency of YFV-136 represents one of the most potent mAbs against YFV ever isolated [23, 26], prompting us to study this mAb in detail. This mAb also neutralizes several wild-type strains of YFV.…”

“…Other investigators have isolated fully human mAbs with similar ultrapotent (<10 ng/mL IC 50 ) neutralizing activities [28], although animal protection studies are not reported for these mAbs. One human antibody has been tested in a Phase I clinical trial in which the mAb designated TY014 prevented viremia in 5/5 recipients, whereas only 1/5 placebo recipients lacked viremia at 48 or 72 hr following administration of live yellow fever vaccine (strain YF17D-204; Stamaril ) [26]; neutralizing potency and protection in animal studies for this mAb were not reported.…”

New broad-spectrum anti-Flavivirus human antibodies with Zika virus-neutralizing potential

“…These molecules can block the viral infection cycle at different stages and induce an increase in the antigenic presentation and cellular immune responses [14,15]. Safe and efficient Flavivirus neutralizing antibodies are an alternative for vaccination for emerging viruses and immunocompromised people [16]. Human anti-Flavivirus antibodies are reported here.…”