Anti-Yellow Fever Virus Antibody Passes Phase 1 Trial

A therapeutic anti-yellow fever virus antibody treatment showed potential clinical benefits in a Phase 1 trial in Singapore, justifying further study of the therapy as a prophylaxis or post-exposure treatment.

The study, published in the New England Journal of Medicine, assessed the safety, side-effect profile, and pharmacokinetics of the human IgG1 monoclonal antibody TY014. It works by targeting the envelop protein on the surface of the yellow fever virus to prevent viral replication by limiting viral fusion to host cells.

The trial was led by Jenny Low, MBBS, MRCP, MPH, senior consultant, department of infectious diseases, Singapore General Hospital and co-director, Viral Research and Experimental Medicine Center (ViREMiCS) a joint research institute set up between SingHealth and Duke-NUS. TY014 is the first potential yellow fever treatment to advance to clinical trials.

Instances of yellow fever are on the rise. The disease causes about 200,000 infections and 30,000 deaths a year in South America and Africa. Manufacturing of vaccines against the yellow fever virus hasn’t kept up with needs during outbreaks, and the vaccine is contraindicated in infants, pregnant women, the elderly and immunocompromised people.

“The availability of a therapeutic agent to treat yellow fever would alleviate the stress on global health care system in managing outbreaks,” the study authors noted.

The placebo-controlled study included 27 healthy participants in Phase 1a and 10 in Phase 1b, using the YF17D-204 strain vaccine to test the safety and efficacy of the TY014 antibody treatment. It took place from December 2018 to July 2019. Sponsored by Tysana, the study included investigators with Duke-National University of Singapore Medical School, Singapore General Hospital and Singapore-MIT Alliance for Research and Technology.

The Phase 1a dose-escalation phase included a maximum dose of 20 mg per kilogram of body weight, during which the safety, side effects and pharmacokinetics of TY014 were assessed. In that phase 22 participants received the TY014 and 5 received a placebo. One serious adverse event was reported in a participant who was found to have an existing benign cardiac abnormality.

During the Phase 1b efficacy phase, participants received a full dose of YF17D vaccine before 5 received the antibody treatment and the other 5 a placebo. No serious adverse events were reported. Viremia was detected in none of the participants who received TY014 and 2 of those who received the placebo. Virus isolation remained negative 72 hours after infusion among those who received the antibody treatment and only 1 of those who received the placebo.

TY014 reduced the incidence of symptoms. Gene expression also differed, with 24 immune genes reduced among those in the TY014 group.

“The finding that TY014 treatment not only lowered the percentage of patients with detectable viremia but also prevented the induction of such innate immune and proinflammatory response genes, in contrast to the participants who received placebo, further supports the potential of TY014 to alter infection outcome,” the study authors wrote. “Likewise, the lack of detectable neutralizing antibody at 1 month after infection suggests that TY014 treatment not only prevented viremia but also abrogated infection in the draining lymph nodes. Collectively, these findings suggest the potential of TY014 as a therapeutic monoclonal antibody to interrupt yellow fever pathogenesis.”

A Phase 2 trial will be conducted in areas where yellow fever is endemic.