Victoria Chinnell, Gail Broder, Theresa E. Latham, Nadine Rouphael, Mark J. Mulligan, Spyros A. Kalams, Jonathan D. Fuchs, Rebecca L. Sheets, Ian Frank, Shelly Ramirez, Scharla Estep, Sue Li, Theresa Wagner, Reese Isbell, Gina Escamilla, Srilatha Edupuganti, David K. Clarke, Michael A. Egan, Terry J. Higgins, Nidhi Kochar, Ramey Fair, Deb Dunbar, John H. Eldridge, Nicole Frahm, Georgia D. Tomaras, Jenny Tseng, Kyle Rybczyk, Adi Ferrara, Mary Allen, Marc Tremblay, Susan Buchbinder, Michael Pensiero, Jin Bae, Liz Briesemeister, and Marnie Elizaga
Attenuated, replication-competent viral vector vaccines are highly immunogenic in that they mimic natural infection. They offer the promise of eliciting a more integrated immune response and more abundant and sustained expression of the encoded viral antigens. Although a vaccine to prevent human immunodeficiency virus (HIV) infection remains an urgent global health priority, concerns about the safety of using live-attenuated HIV itself as a vaccine [1] has led the field to focus heavily on the exploration of replication-defective viral vectors to deliver HIV-1 antigens. There are limited data to suggest these vectors are able to induce an optimal, integrated immune response, which may include CD4+ T-cell help for B-cell/antibody and polyfunctional cytotoxic T-cell responses together with long-term immunologic memory [2]. To date, only 1 replication-defective viral vector, based on canarypox, administered sequentially with a gp120 subunit boost vaccine, has demonstrated partial protection from HIV acquisition in an efficacy trial [3]. Currently, only a few replicating viruses, including vaccinia (clinical trial ID NCT01705223), Sendai virus (NCT01705990), measles (NCT01320176), and adenovirus subtype 4 (NCT01989533), have advanced to clinical trials as HIV-1 vaccine vectors. Vesicular stomatitis virus (VSV) is a member of the genus Vesiculovirus in the family Rhabdoviridae. The 2 major serotypes are New Jersey and Indiana. Vesicular stomatitis virus has a single-strand, negative-sense, nonsegmented RNA genome. Similar to Sendai and measles viruses, the virus genomic organization of VSV (Figure (Figure1A)1A) and life cycle make it particularly attractive as a candidate vaccine vector because the genome can accommodate multiple gene inserts, is stable over many generations, and does not undergo recombination. In addition, the VSV genome replicates in the cytoplasm and is incapable of integrating within the genomes of infected host cells. Finally, VSV is a zoonosis, cycling between biting insects and livestock (cattle, horses, and swine). Human infection with VSV is rare in most regions of the world except in certain regions of Central and South America where VSV is endemic. Where VSV infection does occur, it is typically asymptomatic or is associated with an acute influenza-like illness with symptoms such as fever, muscle aches, and malaise [4, 5]. Thus, the general population is largely free of pre-existing, virus-neutralizing immunity—a factor that has limited the clinical utility of HIV-1 vaccines based on adenovirus subtype 5 [6, 7]. Figure 1. (A) Wild-type vesicular stomatitis virus (VSV) genome organization and virion structure. Viral transcription is polar, initiating at the single 3′ promoter and proceeding to the 5′ end of the genome, producing a steep 3′ to 5′ ... Recombinant VSV (rVSV) has been extensively studied as a potential HIV vaccine vector in preclinical, nonhuman primate (NHP) models [8–11]. After 2 sequential immunizations, rhesus macaques that received rVSV expressing HIV-1 env and simian immunodeficiency virus (SIV) gag were all infected but were protected from disease progression for 4 years or more after infection with SHIV 89.6P, maintaining low or undetectable viral load set points and preserved CD4+ T-cell counts [11]. This encouraging level of postchallenge protection from disease suggested that rVSV vectors expressing HIV genes might be an effective HIV vaccine in humans. To maximize safety for first-in-human clinical evaluation, a highly attenuated form of rVSV Indiana was developed. This involved downregulating VSV N protein expression by translocating the N gene further away from the 3′ transcription promoter and truncating the VSV G protein cytoplasmic tail from 29 amino acids found in wild-type virus to a single amino acid [12]. In addition, HIV-1 gag expression was achieved by insertion of the gag gene adjacent to the 3′ transcription promoter (Figure (Figure1B).1B). The resulting vector (rVSVN4CT1gag1) was shown to be safe, well tolerated, and immunogenic in several murine and NHP studies [13, 14]. In the work described here, the HIV Vaccine Trials Network (HVTN) evaluated the safety and immunogenicity of this novel vaccine vector in a phase 1a dose-escalation, first-in-human trial, HVTN 090.