Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Vectors Prime for Strong Cellular Responses to Simian Immunodeficiency Virus Gag in Rhesus Macaques

Sixsmith, Jaimie; Panas, Michael W.; Lee, Sunhee; Gillard, Geoffrey O.; White, Keri Ann; Lifton, Michelle A.; Balachandran, Harikrishnan; Mach, Linh; Miller, John P.; Lavine, Christy L.; Marcó, Clara; Tomaras, Georgia D.; Gee, Connie E.; Porcelli, Steven A.; Larsen, Michelle H.; Frothingham, Richard; Schmitz, Joern E.; Jacobs, William R.; Haynes, Barton F.; Letvin, Norman L.; Korioth-Schmitz, Birgit

doi:10.1128/cvi.00324-14

Cited by 13 publications

(12 citation statements)

References 39 publications

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“…5D). Previously, we described an earlier generation of rBCG vectors that generated strong SIV Gag immune responses in primates (76). Those studies were conducted using bacteria that were freshly grown prior to each immunization and relied on antibiotic selection.…”

Section: Discussionmentioning

confidence: 99%

Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors

Hart

Asrican

Lim

et al. 2015

Clin. Vaccine Immunol.

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The well-established safety profile of the tuberculosis vaccine strain, Mycobacterium bovis bacille Calmette-Guérin (BCG), makes it an attractive vehicle for heterologous expression of antigens from clinically relevant pathogens. However, successful generation of recombinant BCG strains possessing consistent insert expression has encountered challenges in stability. Here, we describe a method for the development of large recombinant BCG accession lots which stably express the lentiviral antigens, human immunodeficiency virus (HIV) gp120 and simian immunodeficiency virus (SIV) Gag, using selectable leucine auxotrophic complementation. Successful establishment of vaccine stability stems from stringent quality control criteria which not only screen for highly stable complemented BCG ⌬leuCD transformants but also thoroughly characterize postproduction quality. These parameters include consistent production of correctly sized antigen, retention of sequence-pure plasmid DNA, freezethaw recovery, enumeration of CFU, and assessment of cellular aggregates. Importantly, these quality assurance procedures were indicative of overall vaccine stability, were predictive for successful antigen expression in subsequent passaging both in vitro and in vivo, and correlated with induction of immune responses in murine models. This study has yielded a quality-controlled BCG ⌬leuCD vaccine expressing HIV gp120 that retained stable full-length expression after 10 24 -fold amplification in vitro and following 60 days of growth in mice. A second vaccine lot expressed full-length SIV Gag for >10 68 -fold amplification in vitro and induced potent antigen-specific T cell populations in vaccinated mice. Production of large, well-defined recombinant BCG ⌬leuCD lots can allow confidence that vaccine materials for immunogenicity and protection studies are not negatively affected by instability or differences between freshly grown production batches. The immense global burden of human immunodeficiency virus (HIV) infection necessitates the development of an efficacious vaccine. There is increasing interest in the use of live recombinant bacterial vectors as HIV vaccines due to the inherent advantages of utilizing a replicating antigen delivery system that is itself an effective adjuvant (1, 2). Previous studies have examined the use of live Gram-positive and Gram-negative bacterial vectors, including recombinant Salmonella, Listeria, Streptococcus, and Escherichia coli, for heterologous expression of HIV antigens, with varying success (3-8).Mycobacterium bovis BCG is the most widely administered vaccine in the world (9). Its extensively documented safety in immunocompetent individuals, relatively low production cost, and well-established infrastructure for vaccine administration make it an ideal candidate for use as an anti-HIV vaccine vehicle (10-12). In addition to the logistical advantages of using BCG, mycobacterial antigen delivery systems possess inherent adjuvant properties which activate innate immunity (13,14). Mycobacteria such as BCG ...

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Section: Discussionmentioning

confidence: 99%

Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors

Hart

Asrican

Lim

et al. 2015

Clin. Vaccine Immunol.

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“…The monkeys were part of an immunogenicity study that aimed to assess the ability of novel rBCG vectors with various SIVmac251 gag -expression cassettes as priming vectors to enhance SIV-specific CD8 + cellular responses upon boost immunization, as we recently described [12]; the previous study did not include an evaluation of vector-specific immunity. Prior to study start, the macaques showed a negative TB skin test against purified protein derivative (PPD).…”

Section: Methodsmentioning

confidence: 99%

“…Each expressed a codon-optimized transgene SIVmac239 gag on a multicopy episomal pMV261 plasmid [12], with a 60-kDa heat shock protein promoter, a human influenza hemagglutinin tag for detection, and a hygromycin resistance marker. Whereas the pSL10-SIVgag expression cassette used an antigen 85 secretion signal, the pSL7-SIVgag employed a 19kDa signal sequence.…”

Section: Methodsmentioning

confidence: 99%

“…Whereas the pSL10-SIVgag expression cassette used an antigen 85 secretion signal, the pSL7-SIVgag employed a 19kDa signal sequence. While BCG-pSL10 was constructed on the unmutated BCG backbone, the AF25 and J13 variants had deletions of operon BCG_2587-2590 (uncharacterized function) or cmaA2 gene (required for mycolic acid cyclopropanation), respectively, as recently described [12]. …”

Section: Methodsmentioning

confidence: 99%

“…We recently described the effectiveness of rBCG vector-based vaccines as priming immunogens for immune responses to SIV Gag in rhesus macaques [12]. Macaques were vaccinated with rBCG vectors expressing SIV Gag, followed by boosting with NYVAC SIVmac142 gag-pol .…”

Section: Introductionmentioning

confidence: 99%

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Rhesus immune responses to SIV Gag expressed by recombinant BCG vectors are independent from pre-existing mycobacterial immunity

Korioth-Schmitz

Perley

Sixsmith

et al. 2015

Vaccine

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Background A recombinant Mycobacterium bovis BCG (rBCG) vector expressing HIV transgenes is an attractive candidate as a dual vaccine against HIV and TB. However, pre-existing immune responses to mycobacteria may influence immune responses to rBCG. We analyzed data from a rhesus rBCG trial to determine the effect of pre-existing mycobacterial immune responses on the vaccine-induced responses to the vector and expressed transgene. Methods Indian-origin rhesus macaques were primed with rBCG expressing simian immunodeficiency virus (SIV) Gag and boosted with attenuated vaccinia NYVAC gag-pol. Mycobacteria responses were measured by M. tuberculosis (Mtb) purified protein derivative (PPD) interferon-γ ELISpot and Mtb whole cell lysate (WCL) ELISA. SIV Gag responses were measured by SIV Gag ELISpot and by p11C tetramer binding. Results Baseline Mtb PPD ELISpot responses and Mtb WCL antibody responses in rhesus macaques overlapped those in human populations. Cellular and antibody responses boosted sharply 4 weeks after rBCG vaccination. Mtb WCL antibody titers at 4 weeks correlated with baseline titers. Primates vaccinated with rBCG developed strong SIV Gag ELISpot and p11C tetramer responses after rBCG prime and NYVAC boost. There were no correlations between the pre-existing mycobacterial immune responses and the SIV Gag T cell responses after vaccination. Conclusions Rhesus immune responses to SIV Gag expressed by rBCG vectors were independent from pre-existing anti-mycobacterial immunity. Rhesus macaques may serve as a surrogate for investigations of pre-existing anti-mycobacterial immunity in humans.

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Vaccine strategies for the Mtb/HIV copandemic

Sharan

Kaushal

2020

npj Vaccines

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One-third of world’s population is predicted to be infected with tuberculosis (TB). The resurgence of this deadly disease has been inflamed by comorbidity with human immunodeficiency virus (HIV). The risk of TB in people living with HIV (PLWH) is 15–22 times higher than people without HIV. Development of a single vaccine to combat both diseases is an ardent but tenable ambition. Studies have focused on the induction of specific humoral and cellular immune responses against HIV-1 following recombinant BCG (rBCG) expressing HIV-1 antigens. Recent advances in the TB vaccines led to the development of promising candidates such as MTBVAC, the BCG revaccination approach, H4:IC31, H56:IC31, M72/AS01 and more recently, intravenous (IV) BCG. Modification of these vaccine candidates against TB/HIV coinfection could reveal key correlates of protection in a representative animal model. This review discusses the (i) potential TB vaccine candidates that can be exploited for use as a dual vaccine against TB/HIV copandemic (ii) progress made in the realm of TB/HIV dual vaccine candidates in small animal model, NHP model, and human clinical trials (iii) the failures and promising targets for a successful vaccine strategy while delineating the correlates of vaccine-induced protection.

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Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Vectors Prime for Strong Cellular Responses to Simian Immunodeficiency Virus Gag in Rhesus Macaques

Cited by 13 publications

References 39 publications

Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors

Stable Expression of Lentiviral Antigens by Quality-Controlled Recombinant Mycobacterium bovis BCG Vectors

Rhesus immune responses to SIV Gag expressed by recombinant BCG vectors are independent from pre-existing mycobacterial immunity

Vaccine strategies for the Mtb/HIV copandemic

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