Last updated on February 22nd, 2023 at 12:10 pm
You probably don’t know much about the BCG vaccine, because it isn’t used much these days. And no, it’s not one of the vaccines on the CDC immunization schedule for either adults or children.
The Bacillus Calmette-Guerin vaccine, or BCG vaccine, was initially developed to prevent tuberculosis. The disease is caused by bacteria called Mycobacterium tuberculosis. The bacteria usually attack the lungs, but they can also damage other parts of the body. Tuberculosis is treatable with advanced medicines, but it takes a long time and can be expensive. Without treatment, the patient will die.
So, why does it matter that the BCG vaccine is priced too low or that we have a shortage of it? Well, it has a couple of important uses (one current, and one potential) that has driven demand for the vaccine. And it’s not because there’s a sudden worldwide epidemic of tuberculosis.
So why is the BCG vaccine so important?
The BCG vaccine is one of the oldest vaccines available on the market, first used in 1921 (pdf). With the successful eradication of tuberculosis in many countries, the vaccine isn’t used very much anymore, except in countries with endemic tuberculosis. It is still given to about 100 million children every year.
The BCG vaccine works like most vaccines – it is made from an attenuated, live bovine tuberculosis bacillus, Mycobacterium bovis which induces an adaptive immune response against the tuberculosis bacterium.
However, it’s more than just a vaccine for tuberculosis. The BCG vaccine is one of the most successful immunotherapies for some forms of cancer. In fact, the vaccine is the “standard of care with bladder cancer,” specifically for non-muscle-invasive bladder cancer (NIMBC), since about 1977. The vaccine seems to treat and prevent the recurrence of NIMBC.
For bladder cancer, the vaccine is not injected intra-muscularly like most vaccines, but it is delivered directly into the bladder. I had a conversation with a bladder cancer patient who mentioned that it is a very uncomfortable procedure.
The vaccine has also been evaluated as a therapy for colorectal cancer. It is being evaluated as an adjuvant to autologous colorectal cancer cells for the treatment of stage II colon cancer. Moreover, a number of other cancer vaccines undergoing development use the BCG vaccine as an adjuvant to provide an initial stimulation of the patient’s immune system.
Scientists aren’t sure why the vaccine is effective against some cancers (and please don’t assume that it works as a treatment for the hundreds of other vaccines). It is possible that the BCG vaccine stimulates the immune system in such a way that it causes it to attack the bladder cancer. But more research is necessary to determine the mechanisms, which could help improve it for cancer therapy
Outside of bladder cancer therapy, there is some very preliminary research that the BCG vaccine may help reverse type 1 diabetes. The early research is promising, but we’re far from definitive, robust clinical studies that would mean that type 1 diabetics can rid themselves of the disease.
The mechanism of action of the vaccine in diabetes is a bit better understood, and it may be applicable to how the BCG vaccine works in cancer.
So why the shortage of the BCG vaccine?
In an article in the Washington Post, it appears that there is a nationwide shortage of the vaccine. As a result, many bladder cancer patients are facing the disease without one of the best treatments available.
According to the article,
Because of the BCG shortage, some patients “are being undertreated, and some are going to have to undergo radical surgery and lose their bladders,” said Bernard Bochner, a urologist at Memorial Sloan Kettering Cancer Center. Those patients will have to wear a urine-collection bag or undergo difficult surgery to make a new bladder out of their intestines — life-altering changes, he said.
Fearful of such an outcome, patients are calling hospitals and clinics and scouring chat rooms looking for help. “We are hearing from more and more desperate patients every day,” said Stephanie Chisolm, director of education and research at the Bladder Cancer Advocacy Network, a patient group.
The shortage results from the relatively low price for the vaccine – about $150 per dose, which is probably one of the least expensive cancer treatments on the market (though fairly expensive as a vaccine). The low price disincentivizes the sole manufacturer in the USA, Merck, from producing sufficient doses.
Right now, Merck can produce about 870,000 doses every year, a substantial increase from the 200,000 doses it produced in 2012. However, that’s probably the maximum amount they can make in their current manufacturing facilities. And with an additional 80,000 new bladder cancer cases each year in the USA (of those, about 50,000 can be treated with the vaccine), the shortage becomes more acute.
Here are some of the issues that are constraining the supply:
- With the ongoing outrage about Big Pharma prices, especially for an “ancient” drug, Merck has been very reluctant to do anything beyond modest price increases for the drug. Merck is caught between bad press for raising prices and bad press for not manufacturing sufficient quantities.
- Without a larger income stream from the drug, it is difficult for any company, Merck included, to invest the hundreds of millions of dollars (probably greater than US$1-2 billion) in new, larger manufacturing facilities (see Note 1). I know that there’s a myth that building pharmaceutical manufacturing is “easy,” it’s not. And vaccine manufacturing is even more problematic since it requires much more complex design and engineering than is required for dry drugs like pills.
- All new manufacturing will take years to design, build, and get approval from the FDA (and any other regulatory body across the world where Merck intends to sell the vaccine). From a finance perspective, Merck would have to invest possibly $2 billion without any income for 5-7 years.
- Vaccine manufacturing also has issues with lot failures, especially since it is a live vaccine. There are frequent shortages of many vaccines across the world that result from manufacturing failures.
- These same issues keep any “generic” manufacturer out of the market. Generally, we think that generics are less expensive, but in this case, the investment in manufacturing would be exactly the same as Merck would invest. And they would have to do the R&D and clinical testing to establish that the vaccine they’re manufacturing is equivalent to the Merck version. I’m almost certain that most oncologists would be reluctant to use the new vaccine without a substantial boatload of clinical evidence supporting its efficacy. Some individuals are pushing for the government to manufacture this drug, but the same issues apply. And then some. They would need to hire some of the leading experts in vaccine manufacturing, at salaries that probably far exceed anyone in the Federal Government, invest billions of dollars, and still get regulatory approval. It would be years before that would happen, even if we assume that the Republicans would support it.
- We cannot import the BCG vaccine from other areas of the world because the shortage is actually worldwide. And the World Health Organization isn’t going to release the vaccine to US cancer treatments when it needs to protect children from tuberculosis in poorer countries.
- There are other types of BCG vaccine in the world that could be used for the treatment of bladder cancer but they have not been thoroughly tested for the indication. In other words, no one, patients or oncologists, are going to trust the treatment of the disease to an untested vaccine.
I hate advocating for higher prices for any drug in the USA. And in most cases, it’s hard to support what Big Pharma is doing. But sometimes, the market demands higher prices, especially when there is a hard cap on the amount that can be manufactured.
We all know that if Merck had doubled or tripled the price of the BCG vaccine, the outrage would have filled the internet with inaccurate memes and tropes about the evil of Big Pharma. Some outrage is justified, like the story about the Pharma Bro, Martin Shkreli, who dramatically raised the price of an HIV drug that did not require any new manufacturing facilities. Of course, he’s in prison now.
It’s a matter of simple economics – demand is increasing and supply is constrained by low prices. Something has got to change or a lot of bladder cancer patients (and maybe, in the future, type 1 diabetes patients) may not get the lifesaving vaccine.
- I know many of you want to make the argument that Merck should take the profits from their other vaccines to pay for the BCG vaccine manufacturing, but that’s not good business. If a company invested its profits into unprofitable businesses, then it won’t survive long. And the public shareholders are going to be angry. Of course, it’s more complicated than that. If there was a convincing argument that the long-term return on investment was sufficient, it might be worthwhile.
- I wonder if an anti-vaxxer who has bladder cancer will refuse the BCG vaccine. Oh, they will probably rely upon homeopathy, black salve, and an organic vegan diet to “cure” it.
- Moradi-Marjaneh R, Hassanian SM, Fiuji H, Soleimanpour S, Ferns GA, Avan A, Khazaei M. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol. 2018 Aug;233(8):5613-5622. doi: 10.1002/jcp.26273. Epub 2018 Mar 1. Review. PubMed PMID: 29150944.
- Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, Lagranderie M, Marchal G, Orgeur M, Bouchier C, Bachmann A, Ingersoll MA, Brosch R, Albert ML, Thalmann GN. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol. 2014 Oct;66(4):677-88. doi: 10.1016/j.eururo.2014.02.061. Epub 2014 Mar 12. PubMed PMID: 24674149.