Abstract
Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV-1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA222–mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti-HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after birth is highly desirable and may provide a basis for lifetime protection maintained by boosts later in life.
Highlights
Despite great efforts in distributing anti-retroviral therapy (ART) to infected mothers in resource-poor countries, universal accessibility to ART remains challenging [1]
Because protection against both of these major killers is required from birth and the first four months of life are already very busy with the scheduled Expanded Programme for Immunization (EPI) vaccinations, we thought it was advantageous to combine the antiTB and anti-human immunodeficiency virus type 1 (HIV-1) vaccine strategies into a single dual vaccine regimen consisting of priming with recombinant BCG (rBCG) expressing an HIV1-derived immunogen and a single-vaccine-construct TB/HIV-1 boost
Green fluorescent protein (GFP) expression served as a selection marker for recombinant identification and for the mMVA.HIVA.85A vaccine, the marker gene was flanked by two direct 200-nucleotide repeat sequences derived from the A26L gene to facilitate excision of the marker via in cis homologous recombination resulting in a markerless recombinant modified vaccinia virus Ankara (rMVA)
Summary
Despite great efforts in distributing anti-retroviral therapy (ART) to infected mothers in resource-poor countries, universal accessibility to ART remains challenging [1]. The best solution to preventing mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding, which does not require a daily compliance, is development of an effective infant vaccine [2]. Induced HIV-1 responses can be boosted later by a heterologous vector such as modified vaccinia virus Ankara (MVA) delivering the same HIV-1-derived transgene. The main goal in preventing HIV-1 infection is development of a vaccine eliciting broadly neutralizing antibodies (bNAb). Even if such a vaccine can be made [9], it will be hard to stop some virus infection occurring e.g. through cellcell transmission and control of infection will require T cell-mediated immune responses. A vaccine inducing strong longlasting T cell memory alone without bNAbs is likely to have an impact on the HIV-1 transmission
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