A Defined Tuberculosis Vaccine Candidate Boosts BCG and Protects Against Multidrug-Resistant Mycobacterium tuberculosis

A vaccine with a four-protein fusion peptide from Mycobacterium tuberculosis effectively boosts the current childhood TB vaccine and protects against drug-resistant TB. A Superior Shot for Tuberculosis Going to the doctor for routine “shots” is a dreaded childhood right of passage. The freedom from serious diseases—polio, smallpox, and diphtheria—clearly compensates for the pain. But one shot given in many countries (but not the United States)—bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis—has some drawbacks. It wards off TB-induced meningitis in childhood, but within several decades, it is no longer effective and cannot be relied on to prevent TB in adults. Bertholet et al. have now devised a TB vaccine that can boost the residual immunity from the BCG vaccine and, of even greater importance, protect against drug-resistant TB bacteria, a serious and growing problem. To maximize the immunogenicity of the vaccine, the authors chose four proteins known to be vital for the bacteria—virulence and latency factors. They put them together to form a single recombinant fusion protein and used this, along with an oil-in-water adjuvant, as an immunogen. When injected into mice, guinea pigs, and cynomolgus monkeys, this vaccine provokes responses in both CD4 and CD8 T cells. In mice, the vaccine protected against subsequent infection with TB bacteria administered by inhalation, even against a strain of TB that has developed resistance to several common anti-tuberculosis drugs. The protected mice have fewer pathological cellular characteristics in their lungs and infiltration of more granulocytes and T cells that secreted both tumor necrosis factor (TNF) and interferon-γ (IFN-γ). To simulate the weak protection often seen in people, the authors injected guinea pigs with the short-term BCG vaccine. When given after 4 months, their vaccine with the fusion protein protected the guinea pigs against TB infection. This broad study in a range of animal models presents data that suggest that a vaccine based on immunization with an oil-in-water adjuvant and a recombinant four-protein fusion protein may be appropriately tested in a human clinical trial. There is a great need for better protection against TB, in both the developing and the developed world, and the approach presented in this paper is a promising one. Despite the widespread use of the childhood vaccine against tuberculosis (TB), Mycobacterium bovis bacillus Calmette-Guérin (BCG), the disease remains a serious global health problem. A successful vaccine against TB that replaces or boosts BCG would include antigens that induce or recall the appropriate T cell responses. Four Mycobacterium tuberculosis (Mtb) antigens—including members of the virulence factor families PE/PPE and EsX or antigens associated with latency—were produced as a single recombinant fusion protein (ID93). When administered together with the adjuvant GLA-SE, a stable oil-in-water nanoemulsion, the fusion protein was immunogenic in mice, guinea pigs, and cynomolgus monkeys. In mice, this fusion protein–adjuvant combination induced polyfunctional CD4 T helper 1 cell responses characterized by antigen-specific interferon-γ, tumor necrosis factor, and interleukin-2, as well as a reduction in the number of bacteria in the lungs of animals after they were subsequently infected with virulent or multidrug-resistant Mtb strains. Furthermore, boosting BCG-vaccinated guinea pigs with fusion peptide–adjuvant resulted in reduced pathology and fewer bacilli, and prevented the death of animals challenged with virulent Mtb. Finally, the fusion protein elicited polyfunctional effector CD4 and CD8 T cell responses in BCG-vaccinated or Mtb-exposed human peripheral blood mononuclear cells. This study establishes that the protein subunit vaccine consisting of the fusion protein and adjuvant protects against TB and drug-resistant TB in animals and is a candidate for boosting the protective efficacy of the childhood BCG vaccine in humans.