Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection

AbstractGiven the encouraging clinical results of both candidate subunit vaccines and revaccination with Bacillus Calmette-Guérin (BCG) against tuberculosis (TB), there is support for combining BCG and subunit vaccination for increased efficacy. BCG and Mycobacterium tuberculosis (Mtb) share ~98% of their genome and current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study is to design a TB subunit vaccine composed of antigens not shared with BCG and explore the advantages of this design in a BCG + subunit co-administration vaccine strategy. Eight protective antigens are selected to create an Mtb-specific subunit vaccine, named H107. Whereas traditional vaccines containing BCG-shared antigens exhibit in vivo cross-reactivity to BCG, H107 shows no cross-reactivity and does not inhibit BCG colonization. Instead, co-administering H107 with BCG leads to increased adaptive responses against both H107 and BCG. Importantly, rather than expanding BCG-primed T cells, H107 broadens the overall vaccine repertoire with new T cell clones and introduces ‘adjuvant-imprinted’ qualities including Th17 responses and less-differentiated Th1 cells. Collectively, these features of H107 are associated with a substantial increase in long-term protection.

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Fusion Cytokines IL-7-Linker-IL-15 Promote Mycobacterium Tuberculosis Subunit Vaccine to Induce Central Memory like T Cell-Mediated Immunity

Vaccines ◽

10.3390/vaccines8040715 ◽

2020 ◽

Vol 8 (4) ◽

pp. 715

Author(s):

Chunxiang Bai ◽

Lijun Zhou ◽

Junxia Tang ◽

Juanjuan He ◽

Jiangyuan Han ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Protective Efficacy ◽

Central Memory ◽

Control Group ◽

Cell Mediated Immunity ◽

Protein Subunit ◽

Subunit Vaccines ◽

Ifn Γ

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is among the most serious infectious diseases worldwide. Adjuvanted protein subunit vaccines have been demonstrated as a kind of promising novel vaccine. This study proposed to investigate whether cytokines interliukine-7 (IL-7) and interliukine-15 (IL-15) help TB subunit vaccines induce long-term cell-mediated immune responses, which are required for vaccination against TB. In this study, mice were immunized with the M. tuberculosis protein subunit vaccines combined with adnovirus-mediated cytokines IL-7, IL-15, IL-7-IL-15, and IL-7-Linker-IL-15 at 0, 2, and 4 weeks, respectively. Twenty weeks after the last immunization, the long-term immune responses, especially the central memory-like T cells (TCM like cell)-mediated immune responses, were determined with the methods of cultured IFN-γ-ELISPOT, expanded secondary immune responses, cell proliferation, and protective efficacy against Mycobacterium bovis Bacilli Calmette-Guerin (BCG) challenge, etc. The results showed that the group of vaccine + rAd-IL-7-Linker-IL-15 induced a stronger long-term antigen-specific TCM like cells-mediated immune responses and had higher protective efficacy against BCG challenge than the vaccine + rAd-vector control group, the vaccine + rAd-IL-7 and the vaccine + rAd-IL-15 groups. This study indicated that rAd-IL-7-Linker-IL-15 improved the TB subunit vaccine’s efficacy by augmenting TCM like cells and provided long-term protective efficacy against Mycobacteria.

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Epitope promiscuity and population coverage of Mycobacterium tuberculosis protein antigens in current subunit vaccines under development

Infection Genetics and Evolution ◽

10.1016/j.meegid.2020.104186 ◽

2020 ◽

Vol 80 ◽

pp. 104186 ◽

Cited By ~ 3

Author(s):

Edison Ong ◽

Yongqun He ◽

Zhenhua Yang

Keyword(s):

Mycobacterium Tuberculosis ◽

Population Coverage ◽

Protein Antigens ◽

Subunit Vaccines

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Oral Vaccination with Subunit Vaccines Protects Animals against Aerosol Infection with Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.70.6.3111-3121.2002 ◽

2002 ◽

Vol 70 (6) ◽

pp. 3111-3121 ◽

Cited By ~ 74

Author(s):

T. Mark Doherty ◽

Anja Weinrich Olsen ◽

Laurens van Pinxteren ◽

Peter Andersen

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Lipid A ◽

Vaccination Strategy ◽

Oral Immunization ◽

Subunit Vaccines ◽

Monophosphoryl Lipid A ◽

Subcutaneous Immunization ◽

Aerosol Infection

ABSTRACT Immunity against Mycobacterium tuberculosis depends largely on activation of cell-mediated responses, and gamma interferon has been shown to play a crucial role in this process in both humans and animal models. Since the lung is normally the organ in which infection is initiated and is the major site of pathology, immune responses in the lung play a significant role in restricting initial infection with M. tuberculosis. The aim of the present study was to stimulate efficient immunity in the lung by targeting the gut mucosa. Detoxified monophosphoryl lipid A (MPL) has been shown to be a relatively nontoxic adjuvant which efficiently promotes the induction of type 1 responses when it is given by the traditional subcutaneous route. We have therefore compared subcutaneous immunization of mice to oral immunization by using a model subunit vaccine carrying two immunodominant proteins from M. tuberculosis, in combination with MPL-based adjuvants. While less effective when used to prime a response, a heterologous priming and boosting vaccination strategy employing oral boosting induced significant systemic type 1 responses which equaled and surpassed those attained by subcutaneous immunization protocols. Moreover, the increased immune responses observed correlated with the induction of substantial protection against subsequent aerosol infection with virulent M. tuberculosis at levels comparable to, or better than, those obtained by multiple subcutaneous vaccinations. These results demonstrate that booster vaccinations via mucosal surfaces, by combining efficient subunit vaccines with the potent adjuvant MPL, may be an effective method of addressing some of the shortcomings of current vaccination strategies.

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A novel Mycobacterium tuberculosis-specific subunit vaccine provides synergistic immunity upon co-administration with Bacillus Calmette-Guérin

10.1101/2021.03.18.435784 ◽

2021 ◽

Author(s):

Joshua S Woodworth ◽

Helena Strand Clemmensen ◽

Hannah Battey ◽

Karin Dijkman ◽

Thomas Lindenstrøm ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

Cd4 T Cells ◽

Subunit Vaccine ◽

Cross Reactivity ◽

Bacillus Calmette Guerin ◽

Cell Repertoire ◽

Subunit Vaccines ◽

Health Crisis ◽

A Subunit

Tuberculosis (TB) remains a global health crisis. Following encouraging clinical results of subunit vaccination and revaccination with Bacillus Calmette-Guérin (BCG), it has been suggested to combine BCG and subunit vaccines for increased efficacy. Current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study was to design a subunit vaccine that does not share antigens with BCG and explore the advantages of a BCG+subunit vaccine co-administration strategy, where the two vaccines do not cross-react. Eight protective antigens were selected to create a Mycobacterium tuberculosis (Mtb)-specific subunit vaccine, named H107. Whereas subunit vaccines with BCG-shared antigens displayed cross-reactivity to BCG in vivo in both mice and humans, H107 showed no cross-reactivity and did not inhibit BCG colonization in mice. Encouragingly, co-administering H107 with BCG (BCG+H107) led to increased adaptive immune responses against both H107 and BCG leading to improved BCG-mediated immunity. In contrast to subunit vaccines with BCG-shared antigens, 'boosting' BCG with H107 led to substantial expansion of clonal diversity in the T cell repertoire, and BCG+H107 co-administration conferred significantly increased Th17 responses and less differentiated CD4 T cells. CD4 T cells induced by BCG+H107 maintained functional superiority after Mtb infection, and BCG+H107 provided significantly increased long-term protection compared to both BCG and H107 alone, as well as, BCG co-administered with a subunit vaccine composed of antigens shared with BCG. Overall, we identify several advantages of combining an Mtb-specific subunit vaccine with BCG and introduce H107 as a BCG-complementing vaccine with distinctive value for co-administration with BCG.

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Immunogenicity of Mycobacterium tuberculosis Antigens in Mycobacterium bovis BCG-Vaccinated and M. bovis-Infected Cattle

Infection and Immunity ◽

10.1128/iai.01660-05 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4566-4572 ◽

Cited By ~ 28

Author(s):

A. S. Mustafa ◽

Y. A. Skeiky ◽

R. Al-Attiyah ◽

M. R. Alderson ◽

R. G. Hewinson ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mycobacterium Bovis ◽

Infected Cattle ◽

Subunit Vaccines ◽

Vaccine Candidates ◽

Future Evaluation ◽

Research Challenge ◽

Interferon Responses ◽

Recombinant Bcg

ABSTRACT The development of novel vaccine strategies supplementing Mycobacterium bovis BCG (BCG) constitutes an urgent research challenge. To identify potential subunit vaccine candidates, we have tested a series of eight recently identified Mycobacterium tuberculosis antigens in M. bovis-infected and BCG-vaccinated cattle. These antigens were characterized on the basis of their ability to induce in vitro gamma interferon responses in infected or BCG-vaccinated calves. We were able to establish a hierarchy of these antigens based on how frequently they were recognized in both groups of animals. In particular, we were able to prioritize frequently recognized proteins like Rv0287, Rv1174, and Rv1196 for future evaluation as subunit vaccines to be used in BCG-protein heterologous prime-boost vaccination scenarios. In addition, the antigen most dominantly recognized in M. bovis-infected cattle in this study, Rv3616c, was significantly less frequently recognized by BCG vaccinees and could be a target to improve BCG, for example, by increasing its secretion, in a recombinant BCG vaccine.

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Microstructured liposome subunit vaccines reduce lung inflammation and bacterial load after Mycobacterium tuberculosis infection

Vaccine ◽

10.1016/j.vaccine.2014.06.037 ◽

2014 ◽

Vol 32 (34) ◽

pp. 4324-4332 ◽

Cited By ~ 5

Author(s):

Monalisa Martins Trentini ◽

Fábio Muniz de Oliveira ◽

Marilisa Pedroso Nogueira Gaeti ◽

Aline Carvalho Batista ◽

Eliana Martins Lima ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Lung Inflammation ◽

Bacterial Load ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection ◽

Subunit Vaccines

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Enhanced Immunogenicity and Protective Efficacy with the Use of Interleukin-12-Encapsulated Microspheres plus AS01B in Tuberculosis Subunit Vaccination

Infection and Immunity ◽

10.1128/iai.01781-05 ◽

2006 ◽

Vol 74 (8) ◽

pp. 4954-4959 ◽

Cited By ~ 22

Author(s):

Sang-Jun Ha ◽

Su-Hyung Park ◽

Hye-Ju Kim ◽

Seung-Chul Kim ◽

Hyang-Ju Kang ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Sustained Release ◽

Protective Efficacy ◽

Interleukin 12 ◽

Subunit Vaccines ◽

Th1 Immune Responses

ABSTRACT Tuberculosis subunit vaccines codelivered with interleukin-12 (IL-12)-encapsulated microspheres (IL-12EM) are designed for a sustained release of IL-12 and could induce strong Th1 immune responses specific to Ag85A and ESAT-6. The adjuvant combination of IL-12EM plus AS01B was a more efficient way to induce a sustained Th1 immunity and protection against Mycobacterium tuberculosis.

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Adjuvants and Antigen-Delivery Systems for Subunit Vaccines against Tuberculosis

Vaccines ◽

10.3390/vaccines9090972 ◽

2021 ◽

Vol 9 (9) ◽

pp. 972

Author(s):

Abu Salim Mustafa

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Pulmonary Disease ◽

Delivery Systems ◽

Antigen Delivery ◽

Special Issue ◽

Subunit Vaccines ◽

Recombinant Bcg ◽

New Vaccines ◽

Antigen Delivery Systems

The only licensed vaccine against tuberculosis is BCG. However, BCG has failed to provide consistent protection against tuberculosis, especially pulmonary disease in adults. Furthermore, the use of BCG is contraindicated in immunocompromised subjects. The research towards the development of new vaccines against TB includes the use of Mycobacterium tuberculosis antigens as subunit vaccines. Such vaccines may be used either alone or in the prime-boost model in BCG-vaccinated people. However, the antigens for subunit vaccines require adjuvants and/or delivery systems to induce appropriate and protective immune responses against tuberculosis and other diseases. Articles published in this Special Issue have studied the pathogenesis of BCG in children and the use of BCG and recombinant BCG as potential vaccines against asthma. Furthermore, the use of different adjuvants and delivery systems in inducing the protective immune responses after immunization with subunit vaccines has been described.

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