Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis

Larson, Erica C.; Ellis-Connell, Amy L.; Rodgers, Mark A.; Gubernat, Abigail K; Gleim, Janelle L; Moriarty, Ryan V.; Balgeman, Alexis J.; Ameel, Cassaundra L; Jauro, Solomon; Tomko, Jaime; Kracinovsky, Kara; Maiello, Pauline; Borish, H. Jacob; White, Alexander G.; Klein, Edwin; Bucşan, Allison N.; Darrah, Patricia A.; Seder, Robert A.; Mason, Rosemarie D.; Lin, Philana Ling; Flynn, JoAnne L.; O’Connor, Shelby L.; Scanga, Charles A.

doi:10.21203/rs.3.rs-2802306/v1

Cited by 4 publications

(2 citation statements)

References 55 publications

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“…The data do not rule out the possibility that through repeated boosting (25) or the use of a specially engineered bacterial strain (36) protection against COVID-19 could be generated through conventional ID or SC vaccination although it is likely that such resistance would involve a different mechanism. There is currently considerable interest in the possible use of IV administered BCG for vaccination against M. tuberculosis because of its ability to confer sterile immunity against this important pathogen in rhesus monkeys (11,13). This has stimulated efforts to develop attenuated BCG mutants (e.g.…”

Section: Discussion and Translational Implicationsmentioning

confidence: 99%

“…In the second report, Darrah and colleagues showed that IV in contrast to SC administered BCG induces sterile immunity against M. tuberculosis (Mtb) challenge in a rhesus monkey model (11), a dramatic finding that the authors attributed to the direct targeting of the lung and the induction of a strong local memory T cell response when the vaccine is given by this route (12). Recent studies indicate that in macaques such resistance can persist after the clearance of culturable BCG bacilli (13). Nevertheless, the contribution of BCG stimulated innate immune mechanisms to this striking protection is at present unclear.…”

Section: Introductionmentioning

confidence: 99%

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BCG mediated protection of the lung against experimental SARS-CoV-2 infection

Hilligan,

Namasivayam,

Sher

2023

Front. Immunol.

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The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent epidemiologic studies and clinical trials have largely failed to support this hypothesis. Furthermore, in small animal model studies all investigators have failed to observe resistance to viral challenge in response to BCG immunization by the conventional and clinically acceptable intradermal or subcutaneous routes. Nevertheless, BCG administered by the intravenous (IV) route has been shown to strongly protect both hamsters and mice against SCV2 infection and disease. In this Perspective, we review the current data on the effects of BCG vaccination on resistance to COVID-19 as well as summarize recent work in rodent models on the mechanisms by which IV administered BCG promotes resistance to the virus and discuss the translational implications of these findings.

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Section: Discussion and Translational Implicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

Hilligan,

Namasivayam,

Sher

2023

Front. Immunol.

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Intravenous Immunization with Triple Auxotrophs ofMycobacterium tuberculosis: A novel vaccine strategy against tuberculosis

Vilchèze,

Rajagopalan,

Jacobs

2024

Preprint

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Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against Mtb pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of Mtb lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a Mtb triple auxotrophic strain, mc27902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent Mtb infection. The route of immunization was a crucial factor for protection with mc27902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from Mtb challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc27902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent Mtb, mc27902 Δesx1 provided similar protection to mc27902. This robust protection against Mtb infection conferred by mc27902 and mc27902 Δesx1 in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic Mtb strains.

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Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques¹

Jauro,

Larson,

Gleim

et al. 2024

Preprint

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death due to an infectious agent. Coinfection with HIV exacerbates Mtb infection outcomes in people living with HIV (PLWH). Bacillus Calmette-Guerin (BCG), the only approved TB vaccine, is effective in infants, but its efficacy in adolescents and adults is limited. Here, we investigated the immune responses elicited by BCG administered via intravenous (IV) or intradermal (ID) routes in Simian Immunodeficiency Virus (SIV)-infected Mauritian cynomolgus macaques (MCM) without the confounding effects of Mtb challenge. We assessed the impact of vaccination on T cell responses in the airway, blood, and tissues (lung, thoracic lymph nodes, and spleen), as well as the expression of cytokines, cytotoxic molecules, and key transcription factors. Our results showed that IV BCG induces a robust and sustained immune response, including tissue-resident memory T (TRM) cells in lungs, polyfunctional CD4+ and CD8+ T cells expressing multiple cytokines, and CD8+ T cells and NK cells expressing cytotoxic effectors in airways. We also detected higher levels of mycobacteria-specific IgG and IgM in the airways of IV BCG-vaccinated MCM. Although IV BCG vaccination resulted in an influx of TRM cells in lungs of MCM with controlled SIV replication, MCM with high plasma SIV RNA (>105 copies/mL) typically displayed reduced T cell responses, suggesting that uncontrolled SIV or HIV replication would have a detrimental effect on IV BCG-induced protection against Mtb.

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Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis

Cited by 4 publications

References 55 publications

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

Intravenous Immunization with Triple Auxotrophs ofMycobacterium tuberculosis: A novel vaccine strategy against tuberculosis

Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques¹

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Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis

Cited by 4 publications

References 55 publications

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

BCG mediated protection of the lung against experimental SARS-CoV-2 infection

Intravenous Immunization with Triple Auxotrophs ofMycobacterium tuberculosis: A novel vaccine strategy against tuberculosis

Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques1

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Intravenous BCG induces a more potent airway and lung immune response than intradermal BCG in SIV-infected macaques¹