Opportunistic etiological agents causing lung infections: emerging need to transform lung-targeted delivery

Could The BCG Vaccine Provide A Cheap Way Of Reversing Type 1 Diabetes?

Academic researchers in Massachusetts believe the standard BCG (bacillus Calmette-Guérin) vaccine could have a remarkable second use: a treatment to reverse advanced type 1 diabetes.

The cause of type 1 diabetes is well understood – it is the autoimmune destruction of insulin-producing beta cells. But despite many different methods being tried to reverse this effect, no-one has succeeded in producing a treatment.A number of companies, including type 1 diabetes giant Novo Nordisk, have been investing in stem cell research and beta cell regeneration methods, but none are yet close to gaining approval.

Researchers have known for some time that restoring levels of Treg cells, which prevent autoimmune attackes - might halt the abnormal self-reactivity in type 1 diabetes and other autoimmune diseases.But therapies to restore this immune balance haven't achieved long-lasting result.

[caption id="attachment_28827" align="alignnone" width="250"] Denise Faustman[/caption]

Now interim results presented by Denise Faustman, MD, PhD, director of the Massachusetts General Hospital Immunobiology Laboratory and a long-term researcher in the field, show greater promise.Her research suggests that BCG may induce a permanent increase in expression of genes that restore the beneficial regulatory T cells (Tregs), and thereby prevent the immune system from attacking the body's own tissue.Faustman's Massachusetts General Hospital team has discovered that BCG restores Tregs through epigenetics - a process that modulates whether or not genes are expressed.

Faustman says this is an exciting development. "This now provides a better idea of how BCG vaccination appears to work by powerfully modulating Treg induction and resetting the immune system to halt the underlying cause of the disease."

Tregs are the immune system's "brakes" that normally prevent misdirected attacks against tissues without dampening the entire system. Several research groups have suggested methods for harnessing Tregs to treat type 1 diabetes patients, but to date no therapies have been approved.

Best known for its role in tuberculosis prevention, the BCG vaccine is based on a harmless strain of bacteria related the one that causes tuberculosis. A generic drug with over 100 years of clinical use and safety data, BCG is currently approved by the FDA for vaccination against tuberculosis and for the treatment of bladder cancer.Faustman has spent 20 years searching for a cure for type 1 diabetes, and has met with considerable opposition and scepticism about her work, including the JDRF, the powerful US research charity.

The research is funded entirely by private philanthropy from individuals and family foundations, most notably the famous American ex-automotive industry leader Lee Iacocca. He has been funding Faustman's work since the 1990s via his Iacocca Family Foundation in memory of his wife, who died from complications of the disease.

"BCG is interesting because it brings into play so many areas of immunology that we as a community have been looking at for decades, including Tregs and the hygiene hypothesis," says Faustman. "Repeat BCG vaccination appears to permanently turn on signature Treg genes, and the vaccine's beneficial effect on host immune response recapitulates decades of human co-evolution with myocbacteria, a relationship that has been lost with modern eating and living habits. It is incredible that a safe and inexpensive vaccine may be the key to stopping these terrible diseases."

Despite resistance to her approaches, Faustman's work now appears to be gaining greater mainstream support. Faustman's research team was the first group to document reversal of advanced type 1 diabetes in mice and subsequently completed a successful phase I human clinical trial of BCG vaccination. The five-year, 150-person, phase 2 trial is investigating whether repeat BCG vaccination can clinically improve type 1 diabetes in adults with existing disease and is almost fully enrolled.

Long-term follow-up data from the phase I trial will be published later this year.

Tuberculosis: The Forgotten Pandemic

On July 18, 1921, the first infant was inoculated with a live bovine strain of bacteria (Mycobacterium bovis). His mother had died from an infection with the closely related human pathogen M. Tuberculosis following his birth at a Paris hospital a few hours earlier. The child's grandmother, who would care for him, also had tuberculosis (TB). In an attempt to protect the newborn from the disease, doctors gave him an oral dose of what was later named Bacille Calmette-Guérin (BCG) vaccine, for its developers Albert Calmette and Camille Guérin. The duo had cultured M. Bovis for more than a decade until it no longer caused disease in animals.

Nowadays, BCG is given to more than 100 million babies each year, primarily in the developing world, and saves tens of thousands of lives. But it provides incomplete protection, and TB remains the number one infectious ...

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Self-destructing Vaccine Offers Safer TB Protection In Monkeys

A self-destructing vaccine administered intravenously provides additional safety and protection against tuberculosis (TB) in macaque monkeys, suggests new University of Pittsburgh research published today in Nature Microbiology.

The in-built safety mechanisms circumvent the possibility of an accidental self-infection with weakened mycobacteria, offering a safe and effective way to combat the disease that was named as the deadliest of 2024 by the World Health Organization.

Although the idea of intravenous vaccination with a live vaccine may sound scary, it was very effective in our previous studies in non-human primates. Here, we focused on the safety aspect of IV vaccination and used a strain of mycobacteria that kills itself once administered to the animals. To our surprise, it was equal or slightly better than the regular TB vaccine in protecting monkeys against infection, providing sterilizing immunity in almost all animals. The live-attenuated form of the mycobacteria does not need to be alive for very long to provide outstanding protection and with this strain there is essentially no chance for a vaccine-derived infection, even in an immunocompromised host."

JoAnne Flynn, Ph.D., distinguished professor and chair of microbiology and molecular genetics at Pitt

Despite the ongoing global public health burden of TB, safe and effective protection strategies against the infection are lacking. Bacillus Calmette-Guérin (BCG) vaccine – named for its developers – contains inactivated mycobacteria that infect cattle and remains the only vaccination strategy against the infection in humans. Injected into the skin, it provides only partial protection against TB in young children and no protection in adults.

To develop a more universally effective vaccination approach, Flynn partnered with colleagues at Cornell University. In Flynn's earlier work in macaque monkeys with collaborators at the National Institutes of Health, researchers saw a 100,000-fold reduction in bacterial burden in the lungs of animals who were given the BCG vaccine intravenously compared with the standard intradermal route. Nine out of 10 animals showed no inflammation in their lungs.

To improve the safety of IV BCG delivery in the new study, researchers engineered two built-in mechanisms that instruct the BCG particles to dissolve either upon exposure to the antibiotic doxycycline or when chronic doxycycline treatment is stopped. Mouse experiments showed that the BCG vaccine containing this dual safety switch protects the animals against TB comparable to a standard BCG vaccination but has the added benefit of faster elimination and safety, even for mice that were immunocompromised.

In macaque monkeys, the updated self-destructing BCG vaccine caused an even stronger immune response and better protection against TB than a standard IV BCG injection. None of the monkeys that received the updated BCG vaccine had any detectable level of lung inflammation eight weeks after being infected with live Mycobacterium tuberculosis. In addition, six out of eight monkeys had no traces of recoverable live M. Tuberculosis compared to two out of eight monkeys that received the standard BCG intravenously.

Despite the additional challenges of clinical testing required for expanding the use of the updated BCG vaccine in humans, researchers are optimistic.

"We hope that this 'kill switch' BCG strain could limit safety concerns over intravenous vaccine administration and provide an option for a safer and more effective vaccination route for individuals who are immunocompromised," Flynn said.

The other senior authors of this research are Dirk Schnappinger, Ph.D., and Sabine Ehrt, Ph.D. Of Weill Cornell Medicine. Other authors of this research are Alexander Smith, Ph.D., Pauline Maiello, M.S., H. Jacob Borish, Ph.D., Caylin Winchell, Ph.D., Andrew Simonson, Ph.D., Philana Ling Lin, M.D., Mark Rodgers, M.S., Daniel Fillmore and Jennifer Sakal, all of Pitt; and Hongwei Su, Ph.D., Joshua Wallach, Yao Liu, Ph.D., Kan Lin, Ph.D., Valerie Vinette, Ph.D., all of Weill Cornell Medicine.

Source:

Journal reference:

Smith, A. A., et al. (2025). A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity. Nature Microbiology. Doi.Org/10.1038/s41564-024-01895-4.

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