Pulmonary Mycobacterium bovis BCG Vaccination Confers Dose-Dependent Superior Protection Compared to That of Subcutaneous Vaccination

Aguilo, Nacho; Toledo, Ana Maria; López-Román, Eva María; Pérez-Herrán, Esther; Gormley, Eamonn; Rullas-Trincado, Joaquin; Angulo-Barturen, Íñigo; Martín, Carlos

doi:10.1128/cvi.00700-13

Cited by 43 publications

(38 citation statements)

References 19 publications

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“…For example, consistent with short-term studies by Aguilo et al, Chen et al, and Giri et al, who showed that pulmonary administration of BCG was superior to the s.c. route in terms of protection in the lungs at early time points postvaccination, our pulmonary protection results were significantly better for the i.n. route than for the s.c. route at 2 and 4 months postvaccination (14,16,27). However, no differences in lung postchallenge protective responses were seen at 8 and 10 months postvaccination.…”

Section: Discussionmentioning

confidence: 72%

Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice

Derrick

Kolibab

Yang

et al. 2014

Clin Vaccine Immunol

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Despite the widespread use of Mycobacterium bovis BCG, the only licensed vaccine against tuberculosis (TB), TB remains a global epidemic. To assess whether more direct targeting of the lung mucosa by respiratory immunization would enhance the potency and longevity of BCG-induced anti-TB protective immunity, the long-term impact of intranasal (i.n.) BCG vaccination was compared to conventional subcutaneous (s.c.) immunization by using a mouse model of pulmonary tuberculosis. Although significantly improved protection in the lung was seen at early time points (2 and 4 months postvaccination) in i.n. BCG-immunized mice, no differences in pulmonary protection were seen 8 and 10 months postvaccination. In contrast, in all of the study periods, i.n. BCG vaccination induced significantly elevated protective splenic responses relative to s.c. immunization. At five of nine time points, we observed a splenic protective response exceeding 1.9 log 10 protection relative to the s.c. route. Furthermore, higher frequencies of CD4 T cells expressing gamma interferon (IFN-␥) and IFN-␥/tumor necrosis factor alpha, as well as CD8 T cells expressing IFN-␥, were detected in the spleens of i.n. vaccinated mice. Using PCR arrays, significantly elevated levels of IFN-␥, interleukin-9 (IL-9), IL-11, and IL-21 expression were also seen in the spleen at 8 months after respiratory BCG immunization. Overall, while i.n. BCG vaccination provided short-term enhancement of protection in the lung relative to s.c. immunization, potent and extremely persistent splenic protective responses were seen for at least 10 months following respiratory immunization. More than a century after Robert Koch first described how to culture tubercle bacilli, Mycobacterium tuberculosis remains one of the most successful human pathogens and a major global public health threat. According to the recent WHO global tuberculosis (TB) report, 1.3 million people died from TB in 2012 and 8.6 million new cases of the disease were detected (1). Next to HIV, TB is the most important cause of death from an infectious agent in low-income countries. Recommended by the WHO, live, attenuated Mycobacterium bovis BCG is the only TB vaccine approved for human use, being administered intradermally (i.d.) to more than 70% of children worldwide (2). Although i.d. BCG vaccination has been shown to be effective in preventing severe forms of extrapulmonary TB, its ability to protect against pulmonary TB in controlled clinical trials has been highly variable (0 to 80%) (3-5). Importantly, it has been estimated that i.d. BCG immunization prevents only about 5% of vaccine-preventable deaths (6). Clearly, novel, more effective TB immunization strategies are needed.Despite 9 decades of BCG vaccine use, the optimal vaccine dose and route of administration have not been fully defined. Since TB is primarily a pulmonary infection, respiratory BCG immunization has long been considered an attractive alternative to i.d. vaccination. With immune lymphoid mucosal and bronchial tissues being targeted by r...

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Section: Discussionmentioning

confidence: 72%

Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice

Derrick

Kolibab

Yang

et al. 2014

Clin Vaccine Immunol

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“…BCG revaccination regimens using a primary and secondary ID vaccination have been shown to enhance protection against pulmonary M. bovis infection in cattle [13], provide improved early protection against M.tb in mice [14] and moderate improvements in protection against M.tb infection in people [15], [16]; these improvements were dependant on geographical location of the study cohort. Murine studies suggest immunisation delivered directly to the respiratory mucosa may provide a more effective route of vaccination [17], [18] and have indicated that intranasal delivery of a second BCG vaccination improved the outcome of M. tb challenge compared to a single ID BCG vaccination [19]. These studies taken together suggest that the efficacy afforded by multiple applications of BCG are improved by delivery of the second BCG vaccination to the lung.…”

Section: Introductionmentioning

confidence: 95%

Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations

et al. 2016

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Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection.

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“…However, one of the shortcomings of s.c. BCG administration is the overall weak memory lymphocyte generation, which in addition lacks the mucosal-homing chemokine receptors that allow migration to the lung (9). Hence, mucosal vaccination has been suggested as a mimic of natural infection in order to improve local immunity at the site of infection (10–12). Comprehensive analyses of local immunity and correlates of protection in both the lung airways and the parenchyma are essential for the rational design of mucosal TB vaccination strategies using BCG (13, 14).…”

Section: Introductionmentioning

confidence: 99%

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

Perdomo

Zedler

Kühl

et al. 2016

mBio

202

228

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Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.

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Pulmonary Mycobacterium bovis BCG Vaccination Confers Dose-Dependent Superior Protection Compared to That of Subcutaneous Vaccination

Cited by 43 publications

References 19 publications

Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice

Intranasal Administration of Mycobacterium bovis BCG Induces Superior Protection against Aerosol Infection with Mycobacterium tuberculosis in Mice

Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

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