March 22, 2019

IAVI-Led Study Explores Gene Transfer for HIV Antibody Expression

First-in-human clinical trial results of IAVI A003 study published in The Lancet HIV.

The last decade of preventive HIV vaccine research and development has focused significantly on broadly neutralizing antibodies (bnAbs): rare, naturally occurring antibodies that can neutralize HIV in lab tests. Scientists, including those with IAVI and partners, are studying bnAbs as targets for vaccine design, as therapeutics, and as long-acting preventive agents as an alternative to daily pills.

On March 15, the The Lancet HIV published the results of IAVI A003 (NCT01937455), a first-in-human clinical trial led by IAVI and partners. The study tested the use of a recombinant adeno-associated virus (rAAV) vector to deliver genes for a broadly neutralizing HIV antibody to healthy adults for prevention of HIV-1 infection. If successful, this technology uses an inactivated and harmless virus to deliver the HIV antibody into muscle cells, where the cells’ own machinery produces the antibody on a continuous basis.

In this study, the antibody gene used was for the broadly neutralizing PG9 antibody, identified through IAVI’s Protocol G study which identified dozens of new HIV bNAbs. The regimen was shown to be safe, and the serum of four study participants demonstrated neutralizing responses to HIV-1 for up to a year. However, circulating levels of the target antibody were too low to be detected, and study volunteers developed antibodies against both the AAV vector and the HIV antibody, suggesting that improvements to the approach are needed before moving to advanced testing.

Gene transfer with rAAV has shown promise in the treatment of genetic diseases in clinical studies; however, IAVI A003 marks what the authors believe is the first attempt to use the technology for infectious disease prevention.

“Overall, the study provides supportive data for the further development of viral vectors for antibody gene delivery, but it also highlights the challenges,” reads an accompanying commentary by Marina Caskey, MD, associate professor of clinical investigation with The Rockefeller University (DOI: 10.1016/S2352-3018(19)30041-4).

This study was made possible by the generous support of the American people through USAID, the Bill & Melinda Gates Foundation, and the U.S. National Institutes of Health (R01 AI106509–01 and 272201400042C-0–0-1). The contents of this Article are the responsibility of IAVI and do not necessarily reflect the views of USAID or the U.S. Government.

Priddy, F.H., D.J.M. Lewis, H.C. Gelderblom, H. Hassanin, C. Streatfield, C. LaBranche, J. Hare, J.H. Cox, L. Dally, D. Bendel, D. Montefiori, E. Sayeed, J. Ackland, J. Gilmour, B.C. Schnepp, J.F. Wright, and P. Johnson (2019).”Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial.” The Lancet HIV. DOI: 10.1016/S2352-3018(19)30003-7