Alphavirus Replicon Particles as Candidate HIV Vaccines

Abstract

SummaryReplicon particles based on Venezuelan equine encephalitis virus (VEE) contain a self-replicating RNA encoding the VEE replicase proteins and expressing a gene of interest in place of the viral structural protein genes. Structural proteins for packaging of replicon RNA into VEE replicon particles (VRPs) are expressed from separate helper RNAs. Aspects of the biology of VEE that are exploited in VRP vaccines include 1) expression of very high levels of immunogen, 2) expression of immunizing proteins in cells in the draining lymph node, and 3) the ability to induce mucosal immunity from a parental inoculation. Results of experiments with VRPs expressing green fluorescent protein or influenza virus hemagglutinin (HA) demonstrated that specific mutations in the VRP envelope glycoproteins affect both targeting in the draining lymph node and efficiency of the immune response in mice. VRPs expressing either the matrix-capsid portion of Gag, the full-length envelope gp160, or the secreted gp140 of cloned SIVsm H-4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIVsm H-4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIVsm E660 was given at 5 months. A vaccine effect was seen in reduced peak virus loads, reduced virus loads both at set point and at 41 weeks postchallenge, and preserved or increased CD4 counts compared to controls. A candidate VRP HIV vaccine expressing Clade C Gag contains a sequence that is very close to the South African Clade C consensus and was selected from a recent seroconverter in the Durban cohort to represent currently circulating genotypes in South Africa. A GMP lot of this vaccine

Priming-Boosting Vaccination with Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and a Nonreplicating Vaccinia Virus Recombinant Leads to Long-Lasting and Effective Immunity

“…Because long-term survival in humans has been observed when HIV-1 replication is controlled by protective immunity (12,29), targeted experimental immunogens have been designed to closely mimic the long-lasting protective immunity induced in long-term human survivors by the natural infection (8,25). Recently, various vaccine modalities, including live viral vectors and DNA, have been used to elicit protective immunity in nonhuman primate models (9). However, before an HIV-1 vaccine regimen can be considered promising, it must be shown to be not only effective at inducing protective immunity, but also safe, affordable, and compatible with other vaccines (2,32).…”

Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles

“…The subgenomic promoter can be engineered to express foreign genes either by duplicating it in the genome or by substituting the foreign gene for the structural proteins (22)(23)(24). In the latter replicon system, these RNAs can be used directly for vaccination (25)(26)(27) or packaged into particles by supplying the viral structural proteins, selected for delivery to specific target cells, in trans (28)(29)(30). The alphaviruses Semliki Forest virus, Venezuelan equine encephalitis virus, and Sindbis virus (SINV) have all been developed as potential vaccine and gene therapy vectors (13,31).…”

Kunjin Virus Replicon Vectors for Human Immunodeficiency Virus Vaccine Development

“…Replicon-based vaccine vectors derived from positive-strand RNA viruses have recently emerged as potentially valuable systems for the development of vaccines (17). Alphavirus-based replicon vaccines have been shown to be capable of inducing potent antibody and CD8 ϩ T-cell responses in mice and monkeys (22,34) and have been applied to the design of HIV type 1 (HIV-1) vaccines (7,39,42).…”