Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa

Loxton, André G.; Knaul, Julia K.; Grode, Leander; Gutschmidt, Andrea; Meller, C; Eisele, B.; Johnstone, Hilary; Spuy, Gian D. van der; Maertzdorf, Jeroen; Kaufmann, Stefan H. E.; Hesseling, Anneke C.; Walzl, Gerhard; Cotton, Mark F.

doi:10.1128/cvi.00439-16

Cited by 116 publications

(103 citation statements)

References 63 publications

(81 reference statements)

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“…We also excluded data for other vaccine candidates assessed in clinical trials at SATVI, such as MTBVAC, VPM1002 and H4:IC31, because data from vaccinated adults or adolescents at the end of study time point were not available. The whole live mycobacterial vaccines, MTBVAC and VPM1002, are known to induce responses by a broader range of immune cells [25,26] than those we observed and might add to the diversity of the immune responses induced by vaccine candidates. Further, we did not include analyses of antigenspecific antibody responses, which may also be important in immunity against M.tb [27,28], largely because antibody responses were not measured in each trial assessed here.…”

Section: Discussionmentioning

confidence: 68%

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

Rodo

Rozot

Nemes

et al. 2018

Preprint

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Eradication of tuberculosis (TB), the world's leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in preclinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFNγ, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of 3 protection the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics. Author summary Tuberculosis (TB) causes more deaths than any other single infectious disease, and a new, improved vaccine is needed to control the epidemic. Many new TB vaccine candidates are in clinical development, but only one or two can be advanced to expensive efficacy trials. In this study, we compared magnitude and functional attributes of memory T cell responses induced in recently conducted clinical trials by six TB vaccine candidates, as well as BCG. The results suggest that these vaccines induced CD4 and CD8 T cell responses with similar functional attributes, but that one vaccine, M72/AS01E, induced the largest responses. This finding may indicate a lack of diversity in T cell responses induced by different TB vaccine candidates. A repertoire of vaccine candidates that induces more diverse immune response characteristics may increase the chances of finding a protective vaccine a...

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Section: Discussionmentioning

confidence: 68%

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

Rodo

Rozot

Nemes

et al. 2018

Preprint

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“…Despite this, a number of TB vaccines in clinical trials are designed to elicit a strong CD8 + T‐cell response (Table ). The VPM1002 vaccine induces a defined subset of CD8 + T cells expressing IL‐17 in humans; however, the potential pathological role of these cells in inflammation indicates that their expansion may need to be tightly regulated . A recombinant human cytomegalovirus vaccine that stimulates CD8 + T cells results in protective immunity against M. tuberculosis infection in nonhuman primates, and it would be of interest to observe if a similar finding is observed in human trials …”

Section: New Tb Vaccine Candidates and T‐cell Memorymentioning

confidence: 99%

The generation of T‐cell memory to protect against tuberculosis

Counoupas

Triccas

2019

Immunol Cell Biol

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Tuberculosis (TB) kills more individuals each year than any other single pathogen and a more effective vaccine is critical for the global control of the disease. Although there has been recent progress in the clinical testing of candidates, no new vaccine has been licensed for use and correlates of protective immunity in humans have not been defined. Prior Mycobacterium tuberculosis infection does not appear to confer long‐term protective immunity in humans; thus mimicking the natural immune response to infection may not be a suitable approach to develop improved TB vaccines. Data from animal testing are used to progress vaccines through the “vaccine pipeline”, but studies in animals have not been able to predict efficacy in humans. Furthermore, although the generation of conventional CD4+ T‐cell responses are considered necessary to control infection with M. tuberculosis, these do not necessarily correlate with protection induced by candidate vaccines and other immune components may play a role, including donor unrestricted T cells, tissue‐resident memory T cells and anti‐M. tuberculosis antibodies. This review will summarize the current understanding of the protective immune responses following M. tuberculosis infection or vaccination, with a particular focus on vaccines that have recently entered clinical trials.

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“…It is estimated that approximately 4 billion people have received BCG since its first human application almost a century ago (http://www.who.int/ immunization/research/development/tuberculosis/en/). Recombinant BCG strains have been developed with a few antigens, demonstrating immunogenicity and protective efficacy against viruses, bacteria, and parasites (24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

Goulart

Rodríguez

Kanno

et al. 2017

Clin Vaccine Immunol

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Pneumococcal diseases remain a substantial cause of mortality in young children in developing countries. The development of potentially serotypetranscending vaccines has been extensively studied; ideally, such a vaccine should include antigens that are able to induce protection against colonization (likely mediated by interleukin-17A [IL-17A]) and invasive disease (likely mediated by antibody). The use of strong adjuvants or alternative delivery systems that are able to improve the immunological response of recombinant proteins has been proposed but poses potential safety and practical concerns in children. We have previously constructed a recombinant Mycobacterium bovis BCG strain expressing a pneumococcal surface protein A (PspA)-PdT fusion protein (rBCG PspA-PdT) that was able to induce an effective immune response and protection against sepsis in a prime-boost strategy. Here, we constructed two new rBCG strains expressing the pneumococcal proteins SP 0148 and SP 2108, which confer IL-17A-dependent protection against pneumococcal colonization in mouse models. Immunization of mice with rBCG 0148 or rBCG 2108 in a prime-boost strategy induced IL-17A and gamma interferon (IFN-␥) production. The combination of these rBCG strains with rBCG PspA-PdT (rBCG Mix), followed by a booster dose of the combined recombinant proteins (rMix) induced an IL-17A response against SP 0148 and SP 2108 and a humoral response characterized by increased levels of IgG2c against PspA and functional antibodies against pneumolysin. Furthermore, immunization with the rBCG Mix prime/rMix booster (rBCG Mix/ rMix) provides protection against pneumococcal colonization and sepsis. These results suggest the use of combined rBCG strains as a potentially serotype-transcending pneumococcal vaccine in a prime-boost strategy, which could provide protection against pneumococcal colonization and sepsis.KEYWORDS protection, Streptococcus pneumoniae, cytokines, recombinant BCG N asopharynx colonization is the first step in the establishment of pneumococcal disease. This colonization process, which affects virtually 100% of young children, can either remain asymptomatic or lead to pathogenic conditions, such as otitis, sinusitis, pneumonia, meningitis, or sepsis (1). Indeed, epidemiologic evidence suggests that in response to pneumococcal carriage, both serotype-specific and -independent immunity to subsequent carriage develop (2, 3).Pneumococcal vaccines available are based on pure polysaccharides or polysaccha-

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Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa

Cited by 116 publications

References 63 publications

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

The generation of T‐cell memory to protect against tuberculosis

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

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