Robust Immunity to an Auxotrophic Mycobacterium bovis BCG-VLP Prime-Boost HIV Vaccine Candidate in a Nonhuman Primate Model

Abstract

We previously reported that a recombinant pantothenate auxotroph of Mycobacterium bovis BCG expressing human immunodeficiency virus type 1 (HIV-1) subtype C Gag (rBCGpan-Gag) efficiently primes the mouse immune system for a boost with a recombinant modified vaccinia virus Ankara (rMVA) vaccine. In this study, we further evaluated the immunogenicity of rBCGpan-Gag in a nonhuman primate model. Two groups of chacma baboons were primed or mock primed twice with either rBCGpan-Gag or a control BCG. Both groups were boosted with HIV-1 Pr55 gag virus-like particles (Gag VLPs). The magnitude and breadth of HIV-specific cellular responses were measured using a gamma interferon (IFN-␥) enzyme-linked immunosorbent spot (ELISPOT) assay, and the cytokine profiles and memory phenotypes of T cells were evaluated by polychromatic flow cytometry. Gag-specific responses were detected in all animals after the second inoculation with rBCGpan-Gag. Boosting with Gag VLPs significantly increased the magnitude and breadth of the responses in the baboons that were primed with rBCGpan-Gag. These responses targeted an average of 12 Gag peptides per animal, compared to an average of 3 peptides per animal for the mockprimed controls. Robust responses of Gag-specific polyfunctional T cells capable of simultaneously producing IFN-␥, tumor necrosis alpha (TNF-␣), and interleukin-2 (IL-2) were detected in the rBCGpan-Gag-primed animals. Gag-specific memory T cells were skewed toward a central memory phenotype in both CD4؉ and CD8 ؉ T cell populations. These data show that the rBCGpan-Gag prime and Gag VLP boost vaccine regimen is highly immunogenic, inducing a broad and polyfunctional central memory T cell response. This report further indicates the feasibility of developing a BCG-based HIV vaccine that is safe for childhood HIV immunization.

Priming with Recombinant Auxotrophic BCG Expressing HIV-1 Gag, RT and Gp120 and Boosting with Recombinant MVA Induces a Robust T Cell Response in Mice

“…Slow BCG replication rates within phagosomes and limited levels of antigen expression that peaks in the second weak after infection are factors that participate in this process [5], [30]. A previous study of ours showed that a rBCGpan-Gag prime and Gag VLPs boost vaccine regimen is highly immunogenic and induces a broad and polyfunctional central memory T cell response in baboons [10]. Other studies by Hanke et al .…”

“…When used in a prime-boost combination with a recombinant MVA expressing a matching Gag antigen, the rBCGΔ panCD expressing Gag (rBCGpan-Gag) primed higher Gag-specific CD8 + T cell responses than the wild type strain and protected against a surrogate vaccinia virus challenge [5]. In a further study we found that high levels of Gag-specific, polyfunctional CD8 + and CD4 + T cells and anti-Gag antibodies were induced in baboons primed with rBCGpan-Gag and boosted with Pr55 Gag virus-like particles [10].…”

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

“…In fact, among the new TB vaccine candidates under development, several are based on additional attenuations of M. bovis within the existing BCG vaccine or on attenuated M. tuberculosis strains similar to the auxotroph AMtb vaccines used here (17)(18)(19)(20)(21). Recombinant BCG strains expressing HIV antigens are also in development as potential HIV vaccines and have been tested in mice (22)(23)(24) and in adult (25)(26)(27)(28)(29) and neonatal (30) macaques. Considering the high risk of HIV and TB infection in infants, especially in sub-Saharan Africa, we deemed it important to understand how novel TB vaccines or combination HIV-TB vaccines might impact HIV acquisition.…”

Plant-based vaccines against viruses

“…The most successful expression of full-length Pr 55 Gag precursor polyprotein to date was done with subtype B HIV-1 Gag in transplastomic tobacco, with yields of enveloped~100 nm diameter VLPs of up to 400 mg/kg biomass [117]. This was close to 10 000-fold more than a previous best by our group, with VLPs produced in transgenic tobacco [81], and represents a viable yield for a product with serious vaccine potential: recent evidence that lack of progression to AIDS is linked to strong CTL responses to Gag [118][119][120] reinforces the need for vaccines that can target such responses, and Pr 55 Gag VLPs are potent elicitors of CTL, especially when used as a protein boost to a heterologous prime in primate models [121,122]. A recent paper details how HIV-1 p24 antigen expressed transgenically in either Arabidopsis thaliana or Daucus carota showed a priming effect in mice fed whole plant material, eliciting humoral immune responses detected as serum anti-p24-specific IgG after an intramuscular purified p24 protein boost [123].…”