BCG vax: A shot against lung cancer in native populations?

60-year follow-up data from a vaccine trial found surprising results

American Indian/Alaskan Native adults who received the bacillus Calmette-Guerin (BCG) vaccine against tuberculosis (TB) as children had lower rates of lung cancer, a secondary analysis of a randomized trial found.

Compared with those who received placebo, the group who received the BCG vaccine had a significantly lower rate of lung cancer, even after adjusting for a variety of confounders including smoking status, alcohol overuse, and sex of participant (18.2 cases per 100,000 person years vs 45.4 cases per 100,000, hazard ratio 0.38, 95% CI 0.20-0.74, P=0.005), reported Naomi Aronson, MD, of Uniformed Services University of the Health Sciences in Bethesda, Maryland, and colleagues.

However, there was no significant difference between the two groups in rates of overall cancer diagnoses (HR 0.82, 95% CI 0.66-1.02), the authors wrote in JAMA Network Open.

The BCG vaccine found itself in the spotlight at the 2018 American Diabetes Association annual meeting, showing promise for glycemic control in patients with type 1 diabetes. But research about its effect on cancer has been mixed at best, with some studies showing increased incidence of mortality due to leukemia and lymphoma, while some found no effect, and others a non-significant effect on childhood leukemia.

Why then did this vaccine have an effect on lung cancer? Researchers noted that BCG vaccination was linked with "diverse immunological effects independently of" TB.

"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 carcinomas," they wrote.

They added that preclinical studies suggested "BCG vaccination may have more significant effects on immunoregulation in the lung environment."

This was a secondary analysis of a BCG vaccination trial in American Indian/Alaskan Native children age <20 in five states. The original trial was conducted from 1935 to 1938, with participants assigned to receive either the BCG vaccine or saline placebo. A retrospective records review was performed from 1992 to 1998. Of the original 3,287 participants, data from 2,963 participants was analyzed for this study, though the authors noted that 97 participants in the placebo group and 106 in the BCG group could not be located.

Interestingly, the authors said that "the association of BCG vaccination specifically with subsequent lung cancer diagnosis was not an a priori hypothesis," meaning this was not something the researchers assumed at the beginning of the study.

About half the participants in both study groups were women, and vaccination occurred at a median age of 8, with follow-up at a median age of 60. Overall, 633 participants died in the placebo group and 632 died in the vaccination group.

A total of 325 malignant neoplasms were reported across groups, including 42 cases of lung cancer, the authors said. While there was no significant difference in cancer incidence between groups (222 per 100,000 person years in the vaccine group vs 262 per 100,000 in the placebo group, respectively), they noted an approximately 2.5-fold lower rate of lung cancer in the vaccine group. There was no significant difference in the rates of other types of cancers, with the authors specifically saying rates of leukemia and lymphoma were similar between groups (HR 0.80, 95% CI 0.35-1.82).

There was a sex difference in the incidence of lung cancer, with a significantly reduced incidence among men who received the vaccination (HR 0.35, 95% CI 0.15-0.83), but not among vaccinated women (HR 0.49, 95% CI 0.18-1.36), they noted.

The researchers cited the three incidences of lung cancer in the placebo group, which were all found in participants with prior TB infection.

"This suggests that the association is mediated directly by the immune response to BCG," they wrote.

However, they added that treatment with BCG in lung cancer trials has been met with "limited to no success," suggesting that its effectiveness lies in prevention, not treatment.

Limitations to the data include the potential for unmeasured confounders, and that it is a post hoc analysis of a randomized trial.

"The mechanism of this observed protection is unknown, but the association is large and scientifically plausible; we favor trained immunity as a hypothesis," they concluded.