Childhood Bacillus Calmette–Guérin (BCG) vaccination may be linked to a lower risk of lung cancer in Native American populations, according to the results of a recent study published in JAMA Network Open.
“This finding has potentially important health implications given the high mortality rate associated with lung cancer and the availability of low-cost BCG vaccines,” wrote the authors, led by Nicholas T. Usher, Infectious Diseases Division, Uniformed Services University of the Health Sciences, Bethesda, MD.
The current retrospective review was a 60-year follow-up (1935-1998) of a clinical trial involving 2,963 American Indian and Alaskan Native children who had no history of tuberculosis (TB) and were randomized to receive either the BCG vaccine (n = 1,540) or placebo (n = 1,423). Children were vaccinated at 8 years (median) and followed up when they were a median of 60 years old.
No significant difference with regard to the overall rate of cancer diagnosis—in particular, lymphoma, and leukemia—was observed in BCG vs placebo recipients (HR: 0.82; 95% CI: 0.66-1.02). After controlling for covariates—including sex, region, smoking status, alcohol overuse, and TB status—lung cancer rates in BCG recipients were significantly lower compared with placebo recipients (18.2 vs 45.4 cases per 100,000 person-years; HR: 0.38; 95 % CI: 0.20-0.74; P = 0.005).
In several BCG studies with follow-up periods between 13 and 27 years, BCG vaccination predicted increased incidence and mortality secondary to leukemia and lymphoma—especially non-Hodgkin lymphoma. Other researchers, however, have suggested either decreased or no difference in the incidence and mortality of childhood leukemia.
Importantly, per study findings, only lung cancer incidence was decreased in those receiving the BCG vaccination. Risks of other immunologically active cancer types, such as bladder, neck, and melanoma, were not observed. According to the authors, it could be that the study was too low-powered to detect differences in these other immunologically active cancer types, or the BCG vaccine may be immunospecific to the lung cancer tumor milieu.
Indeed, in mouse models, intradermal BCG vaccination resulted in the recruitment of innate lymphoid cells and NK cells to the lung. In another mouse study, airway-resident memory T cells played a role in BCG-related immunity. Of course, clinical trials are needed to elucidate such effects in humans.
In previous lung cancer trials, BCG vaccination has exerted little or no effect, which could indicate that the immunity of lung cancer prevention and treatment differ. In other words, BCG may prevent but not treat lung cancer.
“While BCG vaccine was associated with preventing TB in this clinical trial with long-term protective effects, the observed decrease in lung cancer was not associated with prior TB infection,” wrote the authors. “The mechanism of this observed protection is unknown, but the association is large and scientifically plausible; we favor trained immunity as a hypothesis.”
On a final note, the trained immunity hypothesis posits that innate immune cells possess analogous durable memory responses to unrelated secondary antigens due to epigenetic remodeling after primary (ie, BCG) exposure. Per the authors, although hypothesized, “it is unknown whether reprogramming of these and other innate immune cells could lead to a heterologous response against early malignant neoplasms of the lung.”