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Updated: May 10, 2026
Protective Efficacy and Pulmonary Immune Response Following Subcutaneous and Intranasal BCG Administration in Mice
Published on: September 19, 2016
Vaccination with recombinant Mycobacterium tuberculosis PknD attenuates bacterial dissemination to the brain in
Ciaran Skerry1, Supriya Pokkali, Michael Pinn
1Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Background:
We have previously identified Mycobacterium tuberculosis PknD to be an important virulence factor required for the pathogenesis of central nervous system (CNS) tuberculosis (TB). Specifically, PknD mediates bacillary invasion of the blood-brain barrier, which can be neutralized by specific antisera, suggesting its potential role as a therapeutic target against TB meningitis.
Methodology/Principal Findings:
We utilized an aerosol challenge guinea pig model of CNS TB and compared the protective efficacy of recombinant M. tuberculosis PknD subunit protein with that of M. bovis BCG against bacillary dissemination to the brain. BCG vaccination limited the pulmonary bacillary burden after aerosol challenge with virulent M. tuberculosis in guinea pigs and also reduced bacillary dissemination to the brain (P = 0.01). PknD vaccination also offered significant protection against bacterial dissemination to the brain, which was no different from BCG (P>0.24), even though PknD vaccinated animals had almost 100-fold higher pulmonary bacterial burdens. Higher levels of PknD-specific IgG were noted in animals immunized with PknD, but not in BCG-vaccinated or control animals. Furthermore, pre-incubation of M. tuberculosis with sera from PknD-vaccinated animals, but not with sera from BCG-vaccinated or control animals, significantly reduced bacterial invasion in a human blood-brain barrier model (P<0.01).
Conclusion:
Current recommendations for administering BCG at birth are based on protection gained against severe disease, such as TB meningitis, during infancy. We demonstrate that vaccination with recombinant M. tuberculosis PknD subunit offers a novel strategy to protect against TB meningitis, which is equivalent to BCG in a guinea pig model. Moreover, since BCG lacks the PknD sensor, BCG could also be boosted to develop a more effective vaccine against TB meningitis, a devastating disease that disproportionately affects young children.
Insights
Vaccinating with Mycobacterium tuberculosis PknD protects against TB meningitis, similar to BCG. This offers a new strategy for TB meningitis vaccines, especially for children.
Area of Science:
- Immunology
- Infectious Diseases
- Vaccinology
Background:
- Mycobacterium tuberculosis PknD is a key virulence factor in central nervous system (CNS) tuberculosis (TB).
- PknD facilitates bacterial entry across the blood-brain barrier, indicating its potential as a therapeutic target for TB meningitis.
Purpose of the Study:
- To evaluate the efficacy of recombinant M. tuberculosis PknD subunit protein as a vaccine against CNS TB.
- To compare PknD vaccination with M. bovis BCG in a guinea pig model of TB meningitis.
Main Methods:
- Aerosol challenge guinea pig model of CNS TB.
- Comparison of recombinant M. tuberculosis PknD subunit protein and M. bovis BCG efficacy.
- Assessment of bacillary dissemination to the brain and pulmonary bacterial burden.
- Measurement of PknD-specific IgG levels.
- In vitro human blood-brain barrier invasion assay.
Main Results:
- BCG vaccination reduced pulmonary bacterial burden and bacillary dissemination to the brain.
- PknD vaccination provided significant protection against brain dissemination, comparable to BCG.
- PknD vaccination induced PknD-specific IgG, which reduced M. tuberculosis invasion in a human blood-brain barrier model.
Conclusions:
- Recombinant M. tuberculosis PknD subunit vaccination is a promising strategy against TB meningitis, demonstrating efficacy equivalent to BCG in a preclinical model.
- BCG vaccination could potentially be enhanced by incorporating PknD to improve protection against TB meningitis.
- This novel approach holds potential for developing more effective vaccines against TB meningitis, a severe disease disproportionately affecting young children.
