SUMMARY:
Researchers at UCLA’s School of Medicine have developed a potent multi-antigen vaccine for protection against tuberculosis.
BACKGROUND:
Tuberculosis (TB) is an infectious disease that, when active, can affect many organs in the body but can especially cause severe lung disease manifest by chronic cough, fever, and weight loss, and, if left untreated, death. Globally, an estimated 10 million active TB cases are reported each year, resulting in ~1.5 million deaths. The only licensed vaccine against TB (BCG) was developed 100+ years ago; while reasonably effective in protection of infants and young children, BCG vaccine has poor efficacy in adolescents and adults. Thus, of great interest are novel vaccines and booster vaccines that confer potent protection against TB and reduce global mortality. Alternative approaches to the Listeria vectored vaccine described herein, including protein/adjuvant vaccines and viral-vectored vaccines, have delivered poor or only modest results in human studies. In order to end TB as a global health problem, there is an urgent need for an effective and safe vaccine for use in adults and adolescents.
INNOVATION:
UCLA researchers led by Dr. Marcus Horwitz in the School of Medicine have developed novel TB vaccine candidates to operate as stand-alone vaccines for adults or as boosters to BCG-vaccinated persons. The researchers designed their vaccines employing a safe and powerful attenuated Listeria monocytogenes vector to express five or nine highly immunoprotective antigens of Mycobacterium tuberculosis, the bacterium that causes TB. They tested the 5-antigen vaccine as a booster vaccine for BCG in two mouse models and demonstrated that the vaccine enhances the level of protection conferred by BCG against aerosol challenge with the highly virulent Erdman strain of Mycobacterium tuberculosis (Mbt). They subsequently tested the 5-antigen and 9-antigen multi-antigenic vaccines as standalone vaccines in two mouse models and an outbred guinea pig model. The UCLA researchers found that these vaccines, when administered subcutaneously, induce strong antigen-specific CD4+ and CD8+ T-cell responses and protect against aerosol challenge with the Mtb Erdman strain. Both of these vaccine candidates were safe in all these animal models and also in non-human primates. These promising new vaccines hold great promise as a tool for eradicating TB.
POTENTIAL APPLICATIONS:
• Vaccination against TB in people previously vaccinated with BCG
• Vaccination against TB in people not previously vaccinated with BCG
ADVANTAGES:
• Broader and increased protection against TB
• Increases protection in BCG vaccinated and unvaccinated subjects
• Low toxicity. Constructed with a Listeria vector containing two major attenuating deletions and that has been safely administered to humans
• Cleared quickly in vivo and pre-existing immunity does not affect vaccine efficacy, in contrast to viral-vectored vaccines
• Highly immunogenic; induces both CD4+ and CD8 + T cells including polyfunctional T cells, all of which are important to anti-Mtb immunity
• Can be administered by multiple routes (intradermally, subcutaneously, intramuscularly, intranasally, by inhalation, or orally)
• Enhanced capacity to induce CD8+ T cells, especially important in protecting primates from TB
• More robust immunity than single antigen vaccine
• More potent than protein/adjuvant vaccines and virus-vectored vaccines in head-to-head studies
• Can be inexpensively grown in broth culture and is less costly to manufacture than protein(s)/adjuvant vaccines (which require purification of proteins and adjuvant) and virus-vectored vaccines (which require purification from cell cultures).
DEVELOPMENT-TO-DATE:
Various multi-antigen vaccine candidates have been generated and tested in mouse and guinea models of TB both as stand-alone vaccines and booster vaccines in BCG-immunized animals. The lead 9-antigen vaccine has been demonstrated safe in non-human primates.
Related Papers (from the inventors only):
Jia, Q., S. Masleša-Galić, S. Nava and M.A. Horwitz. 2022. Listeria-vectored multi-antigenic tuberculosis vaccine enhances protective immunity against aerosol challenge with virulent Mycobacterium tuberculosis in BCG-immunized C57BL/6 and BALB/c mice. mBio. 13(3): e00687-22, EPub 1 June, 2022. https://doi.org/10.1128/mbio.00687-22
Jia, Q., B.J. Dillon, S. Masleša-Galić, and M.A. Horwitz. 2017. Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis. Infect. Immun. Epub 2017 June 19. PMID: 28630063. PMCID: PMC55633566. doi: 10.1128/IAI.00245-17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563566/?report=classic
Jia, Q., S. Masleša-Galić, S. Nava and M.A. Horwitz. 2022. Listeria-vectored multi-antigenic tuberculosis vaccine induces potent protective immunity against aerosol challenge with virulent Mycobacterium tuberculosis in C57BL/6 and BALB/c mice and in guinea pigs. Communications Biology (2022) 5:138. https://www.nature.com/articles/s42003-022-04345-1.pdf