Monday, February 26, 2024

100-year old TB Vaccine Could Be a New Weapon Against Alzheimer’s

Scientific discoveries can emerge from the strangest places. In early 1900s France, the doctor Albert Calmette and the veterinarian Camille Guérin aimed to discover how bovine tuberculosis was transmitted. To do so, they first had to find a way of cultivating the bacteria. Sliced potatoes – cooked with ox bile and glycerine – proved to be the perfect medium.

As the bacteria grew, however, Calmette and Guérin were surprised to find that each generation lost some of its virulence. Animals infected with the microbe (grown through many generations of their culture) no longer became sick but were protected from wild TB. In 1921, the pair tested this potential vaccine on their first human patient – a baby whose mother had just died of the disease. It worked, and the result was the Bacille Calmette-Guérin (BCG) vaccine that has saved millions of lives.

Calmette and Guérin could have never imagined that their research would inspire scientists investigating an entirely different kind of disease more than a century later. Yet that is exactly what is happening, with a string of intriguing studies suggesting that BCG can protect people from developing Alzheimer’s disease.

If these preliminary results bear out in clinical trials, it could be one of the cheapest and most effective weapons in our fight against dementia. (...)

The idea may sound far-fetched, but decades of research show that BCG can have surprising and wide-ranging benefits that go way beyond its original purpose. Besides protecting people from TB, it seems to reduce the risk of many other infections, for instance. In a recent clinical trial, BCG halved the odds of developing a respiratory infection over the following 12 months, compared with the people receiving a placebo.

BCG is also used as a standard treatment for forms of bladder cancer. Once the attenuated bacteria have been delivered to the organ, they trigger the immune system to remove the tumours, where previously they had passed below the radar. “It can result in remarkable disease-free recoveries,” says Prof Richard Lathe, a molecular biologist at Edinburgh University.

These remarkable effects are thought to emerge from a process called “trained immunity”. After an individual has received BCG, you can see changes in the expression of genes associated with the production of cytokines – small molecules that can kick our other defences, including white blood cells, into action. As a result, the body can respond more efficiently to a threat – be it a virus or bacteria entering the body, or a mutant cell that threatens to grow uncontrollably. “It can be likened to upgrading the security system of a building to be more responsive and efficient, not just against known threats but against any potential intruders,” says Weinberg.

There are good reasons to believe that trained immunity could reduce the risk of Alzheimer’s. By bolstering the body’s defences, it could help keep pathogens at bay before they reach the brain. It could also prompt the brain’s own immune cells to clear away the amyloid beta proteins more effectively, without causing friendly fire to healthy neural tissue. (...)

To find out, Ofer Gofrit of the Hadassah-Hebrew University Medical Centre in Jerusalem and his colleagues collected the data of 1,371 people who had or had not received BCG as part of their treatment for bladder cancer. They found that just 2.4% of the patients treated with BCG developed Alzheimer’s over the following eight years, compared with 8.9% of those not given the vaccine.

Since the results were published in 2019, other researchers have replicated the findings. Weinstein’s team, for instance, examined the records of about 6,500 bladder cancer patients in Massachusetts. Crucially, they ensured that the sample of those who had received BCG and those who hadn’t were carefully matched for age, gender, ethnicity and medical history. The people who had received the injection, it transpired, were considerably less likely to develop dementia.

The precise level of protection varies between studies, with a recent meta-analysis showing an average risk reduction of 45%. If this can be proven with further studies, the implications would be huge. “Simply delaying the development of Alzheimer’s by a couple of years would lead to tremendous savings – both in suffering and our money,” says Prof Charles Greenblatt of the Hebrew University of Jerusalem, who was a co-author of Gofrit’s original paper. (...)

The clinching evidence would come from a randomised controlled trial in which patients are either assigned the active treatment or the placebo. Since dementia is very slow to develop, it will take years to collect enough data to prove that BCG – or any other vaccine – offers the expected protection from full-blown Alzheimer’s compared with a placebo.

In the meantime, scientists have started to examine certain biomarkers that show the early stages of disease. Until recently, this was extraordinarily difficult to do without expensive brain scans, but new experimental methods allow scientists to isolate and measure levels of amyloid beta proteins in blood plasma, which can predict a subsequent diagnosis with reasonable accuracy. (...)

Weinberg has his own grounds for optimism. Working with Dr Steven Arnold and Dr Denise Faustman, he has collected samples of the cerebrospinal fluid that washes around the central nervous system of people who have or have not received the vaccine. Their aim was to see whether the effects of trained immunity could reach the brain – and that is exactly what they found. “The response to pathogens is more robust in specific populations of these immune cells after BCG vaccination,” says Weinberg.

We can only hope that these early results will inspire further trials. For Weinberg, it’s simple. “The BCG vaccine is safe and globally accessible,” he says. It is also incredibly cheap compared with the other options, costing just a few pence a dose. Even if it confers just a tiny bit of protection, he says: “It wins the cost-effectiveness contest hands down.”

by David Robson, The Guardian |  Read more:
Image: French veterinarian Camille Guérin and physician Albert Calmett. Photograph: Musée Pasteur
[ed. This is where the regulatory process loses me. If BCG is already being prescribed as a standard treatment for TB and bladder cancer, has saved millions of lives, and now seems to have some other off-label benefits, why do we need years of further clinical trials (and inevitable price increases) before it becomes generally available? The only other option appears to be an antibody treatment, lecanemab, except:]

"Lecanemab has already sparked debate. Antibody drugs are so costly they are beyond the means of many countries. Lecanemab itself is not easy to administer, unlike pills and capsules: patients are required to attend clinic for an intravenous infusion twice a month. And the side-effects call for extensive monitoring: patients on the trial had regular scans for brain swelling and haemorrhages, a service many hospitals cannot provide at scale.

More importantly, lecanemab might not work very well. From the data released so far, it is unclear what difference it could make to the devastating burden inflicted by Alzheimer’s. Some doctors warn that the benefits of the drug seem so small, patients may not even notice. But others counter that any effect on Alzheimer’s deserves celebration: it proves the disease can be beaten, or at least slowed down. It’s a start, a concrete foundation to build on."