Vaccine Platform for Prevention of Tuberculosis and Mother-to-Child Transmission of Human Immunodeficiency Virus Type 1 through Breastfeeding

Abstract

Most children in Africa receive their vaccine against tuberculosis at birth. Those infants born to human immunodeficiency virus type 1 (HIV-1)-positive mothers are at high risk of acquiring HIV-1 infection through breastfeeding in the first weeks of their lives. Thus, the development of a vaccine which would protect newborns against both of these major global killers is a logical yet highly scientifically, ethically, and practically challenging aim. Here, a recombinant lysine auxotroph of Mycobacterium bovis bacillus Calmette-Guérin (BCG), a BCG strain that is safer than those currently used and expresses an African HIV-1 clade-derived immunogen, was generated and shown to be stable and to induce durable, high-quality HIV-1-specific CD4؉ -and CD8؉ -T-cell responses. Furthermore, when the recombinant BCG vaccine was used in a priming-boosting regimen with heterologous components, the HIV-1-specific responses provided protection against surrogate virus challenge, and the recombinant BCG vaccine alone protected against aerosol challenge with M. tuberculosis. Thus, inserting an HIV-1-derived immunogen into the scheduled BCG vaccine delivered at or soon after birth may prime HIV-1-specific responses, which can be boosted by natural exposure to HIV-1 in the breast milk and/or by a heterologous vaccine such as recombinant modified vaccinia virus Ankara delivering the same immunogen, and decrease mother-to-child transmission of HIV-1 during breastfeeding.

Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG

“…Because of the fact that BCG vaccination has been shown to be safe in newborns, infants, and adults, this bacterium arises as an attractive vaccine vector candidate for recombinant antigens. Indeed, several studies have shown that recombinant BCG strains efficiently induce Th1 responses against several pathogens and diseases (24)(25)(26)(27)(28)(29)(30)(31)(32).…”

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

“…Construction and preparation of the BCG.HIVA 222 stock was described previously [11]. Briefly, mycobacterial cultures were grown in Middlebrook 7H9 broth medium or on Middlebrook agar 7H10 medium supplemented with albumin-dextrose complex (ADC, Difco) and containing 0.05% Tween 80 and 25 mg/mL kanamycin.…”

“…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].…”

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

“…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.…”