Antibody-Mediated Protection against Mucosal Simian-Human Immunodeficiency Virus Challenge of Macaques Immunized with Alphavirus Replicon Particles and Boosted with Trimeric Envelope Glycoprotein in MF59 Adjuvant

Abstract

After more than 25 years of human immunodeficiency virus (HIV) research, a prophylactic vaccine able to control or prevent the worldwide spread of HIV/AIDS remains an elusive goal. Recent results in Thailand with the recombinant canary pox (ALVAC-HIV, vCP1521; Sanofi-Pasteur) prime-gp120 (AIDSVAX B/E) protein boost vaccine approach give us hope that such a vaccine is achievable (45). Nevertheless, the results from this trial as well as the disappointing outcome of the Step Study trial (7, 29, 46) vividly highlight the need to better understand the immune correlates of protection and the immune responses engendered by the diverse new vaccine technologies currently under evaluation (13,18,20,49). In the case of viral vectors, this is particularly critical, as the spectrum of immune responses elicited in animal models does not necessarily predict those eventually observed in human clinical trials and will require more thorough evaluations in order to identify the most predictive models. At the moment, nonhuman primate models, such as simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection of macaques appear to be the most informative for guiding vaccine development (3,24,47,55), and more rigorous application of these models has begun to yield new and encouraging insights into protective immunity (5,19,27,56). Moreover, as most HIV transmissions occur through mucosal membranes, understanding the correlates of protection, following successful vaccinations, against mucosal challenge is of strong interest.Alphaviruses are positive-sense single-stranded 11.5-kb RNA viruses in the Togaviridae family. They are relatively simple enveloped viruses of approximately 60-nm diameter that have a cytoplasmic RNA-based life cycle and mature at the plasma membranes of infected cells. Recombinant alphavirus replicon particles used for vaccine applications are composed of a replicon vector that encodes the viral replicases (nonstructural proteins [NSPs]) and the vaccine antigen of interest and two packaging vectors that encode the major viral structural proteins (capsid and glycoproteins E1 and E2) required for particle formation. The chimeric (VEE/SIN) alpha-* Corresponding author. Mailing address: Novartis Vaccines and Diagnostics,

Nonviral delivery of self-amplifying RNA vaccines

“…The potency of this unique LNP/RNA vaccine in mice and cotton rats was comparable to a single-cycle alphavirus vector (VRP, 1 × 10 6 IU) at a reasonable dose of RNA (1 μg) and was generally comparable to pDNA delivered using EP at higher doses. VRPs have been shown to be potent in nonhuman primates and humans at a 100-fold higher dose (1 × 10 8 IU) (22,25), and thus we anticipate that this unique RNA vaccine will be immunogenic at submilligram doses in larger species, but this remains to be directly tested. For pDNA the immune responses in larger species have been generally lower than in small animals, with the amount of pDNA required for effective immunization of larger animals being 1,000-fold higher than for small species (milligrams versus micrograms) (2).…”

“…There are limited published data on the in vivo delivery of self-amplifying RNA using nonviral delivery strategies (3,14,18), and none has taken advantage of the recently developed, clinically suitable delivery systems for siRNA (19,20). There has been extensive work on viral delivery of self-amplifying RNA using viral replicon particles (VRPs) (4,11,(21)(22)(23)(24). VRPs are potent vaccines in mice (10,11), nonhuman primates (11,22), and humans (25).…”

“…There has been extensive work on viral delivery of self-amplifying RNA using viral replicon particles (VRPs) (4,11,(21)(22)(23)(24). VRPs are potent vaccines in mice (10,11), nonhuman primates (11,22), and humans (25). These single-cycle alphavirus vectors were used as the viral delivery benchmark in our studies.…”

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…Passive immunization studies using neutralizing mAbs in nonhuman primates have established unequivocally that antibodies can block infection with simian human immunodeficiency viruses (SHIVs) (100)(101)(102)(103). Surprisingly, aside from homologous challenges where Env vaccines and SHIV Env proteins are matched (104,105), it has been difficult to correlate comparable vaccine-elicited neutralizing antibody titers with protection against SHIV where the Env protein is heterologous to the vaccine (82,106). The principal difference between the two approaches is that passive immunization is carried out against a "clean" background, devoid of ongoing host responses elicited by vaccination.…”

Immunotherapies and Vaccines

“…Other strategies that have been investigated for inducing a cellular response include using various vaccine regimens. One of the vaccine regimens that had proved successful in primates to stimulate a cellular response is a DNA prime followed by protein or viral vector boost (Barnett, Burke et al 2010;Jaoko, Karita et al 2010;Keefer, Frey et al 2011). …”