Boosting TB Vaccine Effectiveness: Immune Responses & New Research

Global Collaboration Advances Tuberculosis Vaccine Research

Scientists are working to refine tuberculosis (TB) vaccine candidates, leveraging insights into immune responses and employing innovative trial designs, including controlled human infection models. A team led by Erica Andersen-Nissen, PhD, at Fred Hutchinson Cancer Center’s Cape Town Lab, is analyzing immune responses from TB vaccine trials to improve vaccine design and identify indicators of potential protection.

Andersen-Nissen’s team focuses on T cells, critical components of the immune system that target and eliminate infected cells. They measure various T-cell populations and immune molecules, known as cytokines, to understand how the body responds to vaccination. Recent research, published in Nature, revealed changes in “helper” T cells after BCG revaccination in teenagers, suggesting a potential link between these cells and vaccine efficacy.

“There are a lot of great South African powerhouse research labs that do amazing work here,” Andersen-Nissen said. “We bring the analysis of clinical trial samples piece.”

A key challenge in TB vaccine research is distinguishing immune responses to the disease-causing M. Tb bacterium from those triggered by other mycobacteria commonly found in the environment. Andersen-Nissen’s work highlights the importance of polyfunctional CD4 T cells and donor-unrestricted T cells in protective immunity against TB.

Statistical analysis, conducted by a team led by Fiore-Gartland, complements the immunological data. They analyze trial results to identify “correlates of protection” – specific immune responses associated with vaccine efficacy, particularly in vaccines with partial effectiveness. Currently, they are evaluating data from a trial testing BCG revaccination in teenagers, which demonstrated 45% efficacy in preventing sustained conversion from a negative to positive IGRA test, a marker of TB infection.

The methodological framework developed for HIV vaccine trials and refined during COVID-19 vaccine trials is being adapted for TB research. Although, TB presents unique challenges, requiring new approaches to assess vaccine-induced immune responses in individuals who may have prior exposure to M. Tb or BCG vaccination. Andersen-Nissen’s team is currently analyzing immune data from the Phase 2b trial of the M72 vaccine.

“If we can identify protective immune responses made by M72, that could help us figure out which other vaccines to prioritize for further clinical development,” Fiore-Gartland said.

Researchers are also employing single-cell analysis, a highly detailed method for examining individual immune cells, to gain deeper insights into vaccine responses. Lamar Fleming, a staff scientist, is preparing for what Andersen-Nissen describes as “one of the biggest single-cell studies ever done,” utilizing case-control samples to potentially reveal mechanistic insights into vaccine effectiveness.

While a TB vaccine is still at least five years away from deployment, the World Health Organization is urging countries to begin developing implementation plans. Vaccine acceptability research, led by Shapiro, indicates strong enthusiasm for a potential TB vaccine in communities most affected by the disease.

Researchers are also exploring challenge studies, where human volunteers are intentionally infected with TB and then treated, as a means to accelerate vaccine development. Kublin has previously used BCG in a skin challenge model and is currently analyzing data from a challenge model combining BCG, and rifampin. He is also collaborating with Harvard University to develop a more advanced challenge model using an engineered strain of M. Tb incorporating “kill switches” to enhance safety.

“This avenue of research could really help advance both vaccine and drug studies against TB,” Kublin said.

Through IMPAc-TB, Edlefsen contributes to the effort to identify essential protective immune responses against M. Tb and trains the next generation of TB biostatisticians at Stellenbosch University in South Africa.