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Dual neonate vaccine platform against HIV-1 and M. tuberculosis.

Hopkins R, Bridgeman A, Joseph J, Gilbert SC, McShane H, Hanke T - PLoS ONE (2011)

Bottom Line: The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB.While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

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.HIVA(222). 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.HIVA(222)-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.

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Induction of HIV-1- and M. tuberculosis-specific T                            cell responses.(A) Groups of 4 BALB/c mice were immunized with                                107 PFU i.m. of either 7.5MVA.HIVA, 7.5MVA.85A or                            sMVA.HIVA.85A, sacrificed 2 weeks later and splenocytes from individual                            mice were analyzed for IFN-γ production following peptide                            stimulation. Data are represented as means ± SD.                                (B–C) Groups of 4 BALB/c mice were immunized i.m.                            with 105 PFU of either 7.5MVA.HIVA (triangles), mMVA.HIVA.85A                            (circles) or sMVA.HIVA.85A (squares) vaccines. Two weeks later, mice                            were sacrificed and the ability of splenocytes from individual animals                            to respond to increasing amounts of peptide H was assessed in an                            IFN-γ ELISPOT (B), ICS (C) and in                                vivo killing (D) assays. Mean ± SD are                            shown. Only stimulation with 1 µM H peptide in an IFN-γ                            ELISPOT assay provided a statistically significant difference                                (p = 0.04) between frequencies                            induced using the mH5 and ssp promoters.
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pone-0020067-g003: Induction of HIV-1- and M. tuberculosis-specific T cell responses.(A) Groups of 4 BALB/c mice were immunized with 107 PFU i.m. of either 7.5MVA.HIVA, 7.5MVA.85A or sMVA.HIVA.85A, sacrificed 2 weeks later and splenocytes from individual mice were analyzed for IFN-γ production following peptide stimulation. Data are represented as means ± SD. (B–C) Groups of 4 BALB/c mice were immunized i.m. with 105 PFU of either 7.5MVA.HIVA (triangles), mMVA.HIVA.85A (circles) or sMVA.HIVA.85A (squares) vaccines. Two weeks later, mice were sacrificed and the ability of splenocytes from individual animals to respond to increasing amounts of peptide H was assessed in an IFN-γ ELISPOT (B), ICS (C) and in vivo killing (D) assays. Mean ± SD are shown. Only stimulation with 1 µM H peptide in an IFN-γ ELISPOT assay provided a statistically significant difference (p = 0.04) between frequencies induced using the mH5 and ssp promoters.

Mentions: To assess the dual vaccine immunogenicity, induction of MHC class I- and II-restricted T cell responses to the HIVA and Ag85A immunogens was compared between the dual sMVA.HIVA.85A and single 7.5MVA.HIVA and 7.5MVA.85A vaccines at the 107 PFU dose delivered i.m., and found similar. For the sMVA.HIVA,85A vaccine, specific CD8+ T cell frequencies were dominated by responses against the H epitope, and responses to the other tested known MHC class I and II epitopes were clearly detectable (Fig. 3 A). Thus, the dual vaccine can substitute for the two single-immunogen constructs inducing both CD4+ and CD8+ T cell responses against both pathogens.


Dual neonate vaccine platform against HIV-1 and M. tuberculosis.

Hopkins R, Bridgeman A, Joseph J, Gilbert SC, McShane H, Hanke T - PLoS ONE (2011)

Induction of HIV-1- and M. tuberculosis-specific T                            cell responses.(A) Groups of 4 BALB/c mice were immunized with                                107 PFU i.m. of either 7.5MVA.HIVA, 7.5MVA.85A or                            sMVA.HIVA.85A, sacrificed 2 weeks later and splenocytes from individual                            mice were analyzed for IFN-γ production following peptide                            stimulation. Data are represented as means ± SD.                                (B–C) Groups of 4 BALB/c mice were immunized i.m.                            with 105 PFU of either 7.5MVA.HIVA (triangles), mMVA.HIVA.85A                            (circles) or sMVA.HIVA.85A (squares) vaccines. Two weeks later, mice                            were sacrificed and the ability of splenocytes from individual animals                            to respond to increasing amounts of peptide H was assessed in an                            IFN-γ ELISPOT (B), ICS (C) and in                                vivo killing (D) assays. Mean ± SD are                            shown. Only stimulation with 1 µM H peptide in an IFN-γ                            ELISPOT assay provided a statistically significant difference                                (p = 0.04) between frequencies                            induced using the mH5 and ssp promoters.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094449&req=5

pone-0020067-g003: Induction of HIV-1- and M. tuberculosis-specific T cell responses.(A) Groups of 4 BALB/c mice were immunized with 107 PFU i.m. of either 7.5MVA.HIVA, 7.5MVA.85A or sMVA.HIVA.85A, sacrificed 2 weeks later and splenocytes from individual mice were analyzed for IFN-γ production following peptide stimulation. Data are represented as means ± SD. (B–C) Groups of 4 BALB/c mice were immunized i.m. with 105 PFU of either 7.5MVA.HIVA (triangles), mMVA.HIVA.85A (circles) or sMVA.HIVA.85A (squares) vaccines. Two weeks later, mice were sacrificed and the ability of splenocytes from individual animals to respond to increasing amounts of peptide H was assessed in an IFN-γ ELISPOT (B), ICS (C) and in vivo killing (D) assays. Mean ± SD are shown. Only stimulation with 1 µM H peptide in an IFN-γ ELISPOT assay provided a statistically significant difference (p = 0.04) between frequencies induced using the mH5 and ssp promoters.
Mentions: To assess the dual vaccine immunogenicity, induction of MHC class I- and II-restricted T cell responses to the HIVA and Ag85A immunogens was compared between the dual sMVA.HIVA.85A and single 7.5MVA.HIVA and 7.5MVA.85A vaccines at the 107 PFU dose delivered i.m., and found similar. For the sMVA.HIVA,85A vaccine, specific CD8+ T cell frequencies were dominated by responses against the H epitope, and responses to the other tested known MHC class I and II epitopes were clearly detectable (Fig. 3 A). Thus, the dual vaccine can substitute for the two single-immunogen constructs inducing both CD4+ and CD8+ T cell responses against both pathogens.

Bottom Line: The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB.While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

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.HIVA(222). 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.HIVA(222)-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.

Show MeSH
Related in: MedlinePlus