https://www.slu.edu | To Build Better Tuberculosis Vaccines, Saint Louis University Researchers Develop a New Model by Leveraging an Old Vaccine

11/29/2023

Scientists Believe They Can Use One Vaccine to Study Others 

Each year, tuberculosis (TB) kills more people than any other infectious disease,
falling out of the top spot only temporarily during the COVID-19 pandemic. 

Despite TB’s wide reach and some lost progress during the COVID-19 pandemic, researchers
believe it is possible to eradicate TB through advances in vaccine development and
public health. To cross the finish line, scientists must find ways to test new vaccines
rapidly to prevent TB infections more effectively.  

In a paper published in The Journal of Infectious Diseases, Daniel Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine
Development, and colleagues from Saint Louis University, Emory University School of
Medicine, The Emmes Company, LLC, the National Institute of Allergy and Infectious
Diseases, part of the National Institutes of Health, and New York University Grossman
School of Medicine, report a promising new approach to speed vaccine testing for TB.
 

Hoft, who also serves as professor and chair of infectious diseases, allergy, and
immunology at the Saint Louis University School of Medicine, sought data that could
only be gathered by challenging the human immune system directly. This approach, Hoft
hypothesized, could provide answers to some TB unknowns. For example, TB animal models
do not fully mimic how the bacteria behaves in people, and vaccine developers do not
have well-defined data about what TB immune responses offer optimal protection against
the bacteria.  

To test new vaccines, infectious diseases researchers sometimes conduct human challenge
studies to quickly learn about how well a vaccine candidate works against an infectious
disease, such as influenza. In these studies, researchers first deliver an investigational
vaccine or placebo to separate groups of healthy volunteers, and then intentionally
infect study participants with a flu virus, all in carefully controlled settings and
under close medical supervision, to determine whether the investigational experimental
vaccine provides protection compared with the control group. This approach can be
instrumental in generating data supporting the approval of novel vaccines.  

Mycobacterium tuberculosis, the bacteria that cause TB, however, is too dangerous
for human challenge with the fully pathogenic bacteria. The team needed to find another,
safer way to challenge the human immune system to find answers to their questions.
 

Hoft found a workaround in the Bacillus Calmette-Guérin (BCG) vaccine. 

The most widely used vaccine in history, with more than 4 billion doses given to patients
since 1921, the BCG vaccine contains a live but weakened version of the TB bacteria.
The BCG vaccine is given to newborns to reduce their TB risk, but it is less effective
against pulmonary TB and often wanes in effectiveness, providing little to no protection
in adults.   

With the BCG vaccine, Hoft saw a chance to gather data about TB in a human study without
the risk of exposing participants to full strength M. tuberculosis bacteria. To test
this idea, the researchers gave 92 healthy adults the BCG vaccine, with participants
receiving one of four different doses. 

With participants’ immune response to the BCG vaccine serving as a proxy for their
exposure to a true infection, the researchers gathered much-needed data about how
the immune system responds when it encounters TB.  

The team applied a battery of analysis methods to samples collected from the BCG challenge
sites and blood, looking for associations between BCG at the injection site, and immune
responses as well as gene expression changes in blood.  

The findings open up new doors for TB vaccine development. 

“Our findings are important for two reasons,” Hoft said. “First, this approach could
enable us to screen new TB vaccines early in the pipeline and prioritize the most
promising concepts, saving time and  money.”  

“Second, we have a model to better determine what a new vaccine needs to do to protect
against TB. We will be able to identify biomarkers indicating whether new vaccines
could better protect someone against TB.”  

Among the findings that will help vaccine developers as they create new vaccines,
 

• The researchers determined that BCG challenge doses of up to 8 x 106 CFU were safe.
   
• They found that BCG at the challenge sites increases as the BCG dose increases.  
• The researchers identified the most consistent and precise measure of BCG at challenge
  sites.  
• Gene expression analysis found potential biomarkers of immunity that correlated with
  inhibition of BCG in people that may provide a TB protective signature.  
• And they uncovered immunological and gene expression differences that could underlie
  the different risks of men and women developing active TB.  

This last point is an intriguing finding. Doctors have long observed that men appear
to be more at risk of developing an active form of TB infection, but they do not know
why. In this study, researchers found differences in the immune responses of men and
women to the BCG challenge, a finding that parallels doctors’ observations with patients
who develop the illness.  

Researchers hope this new model will help advance our understanding of why men and
women have different levels of general immunity.  

Hoft is enthused by the study’s findings, which he says could provide a road map for
future TB vaccine testing.  

“The BCG human challenge model is a promising approach for studying TB immunity,”
Hoft said. “The new data will facilitate the vaccine development process, allowing
us to make progress toward our ultimate goal of eradicating TB.” 

Research reported in this study was supported by the National Institute of Allergy
and Infectious Diseases, part of the National Institutes of Health under award numbers
HHSN272200800003C (SLU), HHSN272201300021I (SLU), HHSN272200800005C (Emory), and HHSN272201300018I
(Emory).  

The content in this press release is solely the responsibility of the authors and
does not necessarily represent the official views of the National Institutes of Health.
 

About the Saint Louis University Center for Vaccine Development

Saint Louis University has been on the front lines in the fight against pandemics
and global health crises for more than three decades and first received federal funding
for vaccine research in 1989. Led by Daniel Hoft, M.D., Ph.D., SLU’s Center for Vaccine
Development is one of only 10 institutions selected by the National Institutes of
Health as a Vaccine and Treatment Evaluation Unit (VTEU). As a VTEU, the Center helps
develop and evaluate vaccines that will protect people from infectious diseases and
emerging threats. It conducts Phase 1 through 4 vaccine and treatment trials, including
clinical studies in collaboration with industry partners.