Novel RecombinantMycobacterium bovisBCG, Ovine Atadenovirus, and Modified Vaccinia Virus Ankara Vaccines Combine To Induce Robust Human Immunodeficiency Virus-Specific CD4 and CD8 T-Cell Responses in Rhesus Macaques

Abstract

Mycobacterium bovis bacillus Calmette-Guérin (BCG), which elicits a degree of protective immunity against tuberculosis, is the most widely used vaccine in the world. Due to its persistence and immunogenicity, BCG has been proposed as a vector for vaccines against other infections, including HIV-1. BCG has a very good safety record, although it can cause disseminated disease in immunocompromised individuals. Here, we constructed a recombinant BCG vector expressing HIV-1 clade A-derived immunogen HIVA using the recently described safer and more immunogenic BCG strain AERAS-401 as the parental mycobacterium. Using routine ex vivo T-cell assays, BCG.HIVA 401 as a stand-alone vaccine induced undetectable and weak CD8 T-cell responses in BALB/c mice and rhesus macaques, respectively. However, when BCG.HIVA 401 was used as a priming component in heterologous vaccination regimens together with recombinant modified vaccinia virus Ankaravectored MVA.HIVA and ovine atadenovirus-vectored OAdV.HIVA vaccines, robust HIV-1-specific T-cell responses were elicited. These high-frequency T-cell responses were broadly directed and capable of proliferation in response to recall antigen. Furthermore, multiple antigen-specific T-cell clonotypes were efficiently recruited into the memory pool. These desirable features are thought to be associated with good control of HIV-1 infection. In addition, strong and persistent T-cell responses specific for the BCG-derived purified protein derivative (PPD) antigen were induced. This work is the first demonstration of immunogenicity for two novel vaccine vectors and the corresponding candidate HIV-1 vaccines BCG.HIVA 401 and OAdV.HIVA in nonhuman primates. These results strongly support their further exploration.

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

“…rBCG vaccines have been shown to efficiently prime the immune response to the heterologous antigen in recombinant adenovirus, recombinant poxvirus, and protein prime-boost combinations (24,26,27,30,57,58). We (27,44,52) and others (59) have previously shown that a Gag VLP boost, used in heterologous prime-boost modality, is a (62).…”

“…Mycobacterium bovis BCG has been investigated as a live vaccine vector for a variety of human infections (20)(21)(22)(23)(24)(25), including HIV-1 infections (26)(27)(28)(29)(30). An important and attractive feature of using BCG is its long safety record as a tuberculosis (TB) vaccine, having being injected into over 3 billion people worldwide.…”

Optimizing HIV‐1‐specific CD8+ T‐cell induction by recombinant BCG in prime‐boost regimens with heterologous viral vectors

“…It has been postulated that the resultant phenotypic differences contribute to variable anti-tuberculosis vaccine efficacy [37], although in humans real evidence for this is lacking [38,39]. Previously, we reported the construction of two candidate HIV-1 vaccines BCG.HIVA 401 [13] and BCG.HIVA 222 [11], which employed two distinct BCG strains that were rationally engineered to increase safety and T-cell immunogenicity. and a significant decrease was seen for CCL2 (MCP1) (Fig.…”

“…To facilitate both comparison and combination of different vaccination modalities, HIVA has been expressed and presented to the immune system from plasmid DNA [8], several non-replicating mammalian viruses [8,10] attenuated strains of mycobacteria [11][12][13] and as a protein on the surface of baculovirus/insect cell-expressed bluetongue virus microtubules [14,15]. In some vaccination regimens, HIVA afforded protection against model surrogate virus challenges including chimeric EcoHIV/NDK [16].…”

Safety and Immunogenicity of Novel Recombinant BCG and Modified Vaccinia Virus Ankara Vaccines in Neonate Rhesus Macaques

“…It has been reported by several studies to promote an adultlike Th1 response in newborns (16,24,34,43), although it was also suggested that delaying the BCG delivery to 10 weeks of age benefits the quantity and quality of BCG-induced CD4 T-cell responses (20). BCG and related mycobacterial vectors have been explored as vaccines against other infectious agents, including human and simian immunodeficiency viruses (19), and in adult animals showed immunogenicity and protection (3,36,39,47,48). The only clinical study of recombinant BCG (rBCG) in adults failed to provide consistent efficacy (7).…”