Study points toward progress on TB vaccines

A chance to improve upon a 100-year-old vaccine

Kublin, who is executive director of the HIV Vaccine Trials Network, headquartered at Fred Hutch, is part of an international collaboration that has been applying techniques and lessons learned in the development of potential HIV vaccines to assess how the immune system responds to BCG and other candidate TB vaccines.

“The vaccine hasn’t changed in 100 years, and we now have an opportunity to improve on that,” he said.

The new study was set up in South Africa as a companion to a large-scale test of revaccination evaluating BCG and an experimental TB vaccine known as H4:IC31. That trial, which began in 2014, involved in nearly 1,000 volunteers. In July 2018, in the New England Journal of Medicine, the results of that study found that revaccination with BCG was about 45% effective. That was better than the newer alternative; H4:IC31, which generated some immune activity, was only 31% effective.

Now, nearly two years later, Kublin and colleagues have published the first results of their study looking in depth at how the immune systems of volunteers responded to vaccines they were given in a smaller, parallel trial, known as HVTN 602.

One of the findings of the new study was that protection was linked to an increase in T cells that specifically target the active ingredient of BCG vaccines — a live but relatively harmless relative of M. tuberculosis called Mycobacterium bovis. The study found a notable jump in cells that had developed a “memory” of M. bovis, presumably from the childhood vaccine, that revved up production of those cells after revaccination.

BCG has long been known as an immune system stimulator. “It trains the immune system in such a way that it can provide protection against other infections, even though there may be no similarity of BCG to the infectious organism,” said Kublin.

For example, a recent experiment showed it lowered the level of a weakened strain of yellow fever virus by stirring up protective blood cells of the innate immune system, which are the first responders to the presence of foreign microbes in the bloodstream.

The immune response generated by BCG has also found a use in cancer treatments. At Fred Hutch clinical care partner Seattle Cancer Care Alliance and other cancer centers, the vaccine is used to activate a patient’s immune system against bladder cancer, Kublin said.

Biomarkers that turn up in BCG-vaccinated people who have lower rates of TB are known as “correlates of protection,” and their presence can serve as a kind of biological proxy — a signal that a vaccine might be effective without having to wait to see after a long trial whether that person develops active TB disease.

In fact, the new paper is only the first to be published exploring a variety of possible correlates of protection identified by this study. The researchers are also looking at correlates of protection among those front-line, innate immune responders. For example, did the participants who remained protected show an increase in cells known as monocytes and macrophages after revaccination?

“What’s published in this paper is just the tip of the iceberg,” said Kublin. 

Learning why it works in some people, not in others

The researchers are also looking at biomarkers in stool samples from participants in the trial, because studies have shown that different communities of bacteria in a person’s gut — the microbiome — might determine how well a vaccine works in a given individual.

Fred Hutch researcher Dr. Andrew Fiore-Gartland was lead statistician for HVTN 602. He said the purpose of this smaller, more intense study of the biology of the vaccine is a kind of deep dive into the immune responses of the adolescents, aged 12-17, who received revaccination.

These studies are made possible by advances in molecular biology, such as state-of-the-art flow cytometry, which can search for correlates of protection by seeking out a range of biomarkers at high speed.

“From this, we can learn why it worked in some people, but not in others,” he said. “Once you identify that correlate of protection, you can try to make the vaccine better. If you don’t have those correlates, you are just throwing darts. This is rational vaccine development.”

The lead author for HVTN 602 is Dr. Linda-Gail Bekker of the Desmond Tutu HIV Centre at the University of Cape Town, in South Africa. The project was funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health; the NIH/NIAD Duke Center for AIDS Research; and Aeras, which received funding for the study from the Bill & Melinda Gates Foundation and the United Kingdom Department for International Development. Sanofi Pasteur provided product for the trial.