Recently, a paper was published which described a potential lung cancer vaccine. Interestingly, it’s not a novel vaccine, but it’s the BCG vaccine that’s been around for nearly 100 years.
Unless you are really into vaccines or had a typical education as a physician or nurse, you probably don’t know much about the BCG vaccine, because it’s not a typical part of the CDC immunization schedule for either adults or children.
So, let’s talk about this vaccine, and its use as a lung cancer vaccine.
All about the BCG vaccine
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.
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 tuberculosis bacterium.
At this point, you’re wondering why this vaccine is still around or important. Well, it seems it has some other purposes.
- There is some very preliminary, but promising, research that the BCG vaccine may help reverse type 1 diabetes. We’re a long way from knowing if it will work, but it is encouraging for researchers looking for a “cure” for type 1 diabetes.
- 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. Unfortunately, as a result of the low usage of the vaccine, low supplies of the BCG vaccine have caused a shortage of the vaccine for cancer patients.
- 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 cancers). 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.
Lung cancer vaccine paper
The article, by corresponding author Naomi E Aronson, MD of the Uniformed Services University of the Health Sciences, was published in JAMA Network Open, a peer-reviewed, high impact factor medical journal. The researchers showed that American Indian/Alaskan Native adults who received the BCG vaccine against tuberculosis as children had lower rates of lung cancer.
This was a secondary analysis of a BCG vaccination trial, conducted between 1935-1938 (yes, 1935-38), in American Indian/Alaskan Native children age <20 in five states. The participants were assigned to a group that received either the BCG vaccine or saline placebo (see Note 1). Of the original 3,287 participants, data from 2,963 participants were analyzed for this study.
The BCG vaccine group had a significantly lower rate of lung cancer, after adjusting for a variety of confounders including tobacco smoking history, alcohol abuse, and sex of participants. The BCG vaccine group had approximately 18.2 cases per 100,000 person-years compared to 45.4 cases for the placebo group. That is a 2.5X reduction in the risk of lung cancer.
However, there was no statistically significant difference between the two groups in the rates of all cancers. For those of you who are wondering why this bit of data is important, it’s because the health effects of smoking are not limited to lung cancer – it increases the risk of all cancers and all cardiovascular diseases, along with other types of lung diseases.
When researchers find this type of correlation, we need biological plausibility to determine if there might be causation. In an attempt to propose a plausible mechanism of action:
We initially anticipated that BCG vaccination might protect against lung cancer by preventing TB infection, as the granulomatous inflammatory response from TB may be favorable to malignant neoplasms known as scar carcinoma.
BCG vaccination may have more significant effects on immunoregulation in the lung environment.
So is this a lung cancer vaccine? Well…
Lung cancer vaccine research limitations
The first issue I have with this study is that it is a post hoc analysis of a randomized trial that was not constructed with an a priori hypothesis that the BCG vaccine could prevent lung cancer. In other words, the original clinical trial, set up in the mid-1930s, was looking at the safety and effectiveness of the BCG vaccine.
The problem with a post hoc analysis is that you’re looking at the data over and over to find something else. Pharmaceutical companies do this all the time, and it makes researchers’ skin crawl:
First and foremost, it’s important to note that the hypothesis is created by the post-hoc analysis, and that it has not been proven by experiment or generated from a scientific basis. This is extremely important. It’s similar to a sharpshooter “who fires at a barn and then paints a target around the bullet hole. A target shows how accurate the shot was only if it was in place before the shooting. In the same way, statistical tests applied to unusual looking results may give the false impression of a ‘bull’s eye.’
The results of subgroup analysis only become relevant if it can be replicated and shown in a randomized clinical trial. Otherwise, one cannot be certain if the subgroup analysis has any meaning whatsoever.
Second, if a company does enough post-hoc analyses using different subgroups, it is nearly certain to find something statistically significant. This problem is called “multiplicity” in statistics, and results in inflated false positives.
Simply put, the study was created to answer a question wholly unrelated to the hypothesis proposed 85 years later.
Second, because the study is being analyzed well after it was originally run, we cannot have a good handle on known and unknown confounders. There may be environmental differences between then and now that could influence the risk of cancer.
Third, we do clinical trials today with a lot of randomization of ethnic, gender, age, and other groups. The participants in this trial were American Indians and Native Alaskans. Conceivably, there could be some genetic differences between them and the rest of the population that could cause this vaccine to possibly work with that group but not others.
Fourth, we need to repeat this study before anyone would change recommendations for receiving the BCG vaccine. The problem with that is that it could take decades to get results since lung cancer isn’t instantaneous like chickenpox or measles. However, if we can find evidence as to why the BCG vaccine prevents lung cancer (like how we know the HPV vaccine prevents some cancers), we may not need to wait decades.
Fifth, I could not see much data whether it changed the risk of lung cancer in non-smokers (which is admittedly very rare).
Although it has little to do with this potential clinical effect of this lung cancer vaccine, I have concerns from a public health perspective. Tobacco smoking is dangerous:
- 1 in 5 deaths in the USA (which has a relatively low rate of smoking) is related to smoking.
- Smoking causes 30% of all cancer deaths in the USA.
- Smoking shortens male smokers’ lives by about 12 years and female smokers’ lives by about 11 years.
- Smoking cigarettes also presents a greater risk of developing and dying from chronic obstructive pulmonary disorder (COPD). Smoking causes 80 percent of COPD deaths.
I could go on and on. If smokers hear of an inexpensive preventative vaccine, like the BCG vaccine, they might think that they have a shield against it. If this lung cancer vaccine does work, of course, we should give it to smokers. But it has to be accompanied by huge warnings that it does not prevent non-lung cancers (which are still a large risk for smokers), it does not prevent COPD, and it does not prevent cardiovascular disease.
So, do we have a new lung cancer vaccine?
I don’t know. The data is robust, but once you dig below the surface, I am troubled by it. I don’t think this will pressure the CDC to update its recommendations for the BCG vaccine.
On the other hand, the data is compelling enough that we need to begin studies right from the beginning. We need studies that show the mechanism of action. We need better clinical studies in which the hypothesis is clear upfront.
The problem is that the BCG vaccine is essentially a generic product. I’m not convinced any company would be willing to invest hundreds of millions of dollars into these types of studies.
On the other hand, if I were a smoker (and I am decidedly not one), I might get the BCG vaccine. And I have to wonder if anti-vaxxers would get this lung cancer vaccine? Probably not.
- In today’s world, this type of clinical trial would never be authorized by anyone – the FDA, Institutional Review Boards, or research physicians. To not vaccinate children at risk of tuberculosis, which was endemic in the 1930s, would be horrific. This study probably was acceptable back then given how we treated people of color back then. Today, this study would be considered unethical, despite the demands of anti-vaxxers. However, it is not unethical to use the data for analysis today.
- Usher NT, Chang S, Howard RS, Martinez A, Harrison LH, Santosham M, Aronson NE. Association of BCG Vaccination in Childhood With Subsequent Cancer Diagnoses: A 60-Year Follow-up of a Clinical Trial. JAMA Netw Open. 2019 Sep 4;2(9):e1912014. doi: 10.1001/jamanetworkopen.2019.12014. PubMed PMID: 31553471.