Long-Term Efficacy of BCG Vaccine in American Indians and Alaska Natives: A 60-Year Follow-Up Study.

Long-Term Efficacy of BCG Vaccine in American Indians and Alaska Natives: A 60-Year Follow-Up Study.
2004
Commentary
By Lewellys Barker, Senior Medical Advisor,
Aeras Global TB Vaccine Foundation
Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH, Rhoades ER, and Harrison LH.
From the Department of Medicine, Infectious Disease Division, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Abstract:
This retrospective study examined the long-term duration of protection of a bacille Calmette-Gu?rin (BCG) vaccine that had previously proven efficacious. Indian Health Service records, tuberculosis registries, death certificates, and supplemental interviews with trial participants were reviewed. Between 1948 and 1998, American Indians and Alaska Natives who participated in a placebo-controlledBCG vaccine trial during 1935-1938, and who were still at risk of developing TB, were followed. Data from 1,483 participants in the BCG vaccine group and 1,309 in the placebo group were analyzed. The overall incidence of TB was 66 and 138 cases per 100,000 person-years in the BCG vaccine and placebo groups, respectively, for an estimated vaccine efficacy of 52 percent (95% CI, 27%-69%). Of 102 total cases, 90 (n=27 in the BCG group and n=63 in the placebo group) were culture confirmed. BCG vaccine also had an efficacy of 44% (95% CI -22% to 75%) for preventing death due to TB. Adjustments for age at vaccination, tribe, subsequent BCG vaccination, chronic medical illness, isoniazid use, and bacille Calmette-Gu?rin strain did not substantially affect vaccine efficacy. There was slight but not statistically significant waning of the efficacy of BCG vaccination over time; this was greater among men than women. In this trial, the BCG vaccine efficacy persisted for 50 to 60 years, suggesting that a single dose of an effective BCG vaccine can have a long duration of protection.
(From CDC TB-Related News and Journal Items Weekly Update, May 9-15, 2004)
Commentary:
The original reports of the Aronson BCG trial in American Indians and Alaska Natives and also of an MRC prospective, placebo-controlled BCG trial in the UK in the 1950s (latter conducted in adolescents and young adults) showed 70-80% efficacy of BCG for 15-20 years, mainly against pulmonary TB. However, the most recent large, placebo-controlled BCG trial in South India over a range of ages showed no efficacy, and BCG is not thought to have much current effectiveness against adult pulmonary TB.
As stated in an accompanying editorial (Dye C., A Booster for tuberculosis vaccines. JAMA 2004; 291:2127-8), ?The remarkable results of the 60-year follow-up study by Aronson et al still leave plenty of questions about vaccination unanswered.? The original study was lead by JD Aronson, the grandfather of the author of this report. The surprising durability of protection for a disease where the risk is life-long surely gives encouragement to current efforts to improve on BCG vaccination.
What then are some of the features of the Aronson study that might help explain the results? Among the possibilities are:
Freshly prepared liquid BCG vs. lyophilized/reconstituted BCG
Vaccination of young children up to young adults vs. neonates
High rate of infection providing natural boosting of protection
Clearly the study population was at extremely high risk of TB infection. At the time of enrollment into the study, the range of positive tuberculin reaction prevalence (age range in parentheses) in the tribes was 6-25% (age 0-5), 23-46% (5-9), 49-72% (10-14), 72-91% (15-19), 72-100% (20-24) (Aronson JD. Protective vaccination against tuberculosis with special reference to BCG vaccination. Amer Rev of Tuberculosis 1948; 58:255-81). All trial participants were non-reactors to both one and 250 tuberculin unit skin tests. As both Aronson et al and Dye indicate, the high density of infection in the population (and active TB disease as well) suggests that boosting by constant TB exposure may have contributed to the strength and durability of BCG protection. The non-reactivity in vaccines at entry to a high tuberculin dose is taken to indicate they were relatively free of infection with non-tuberculous mycobacteria at the time of vaccination, but this does not tell us what role these environmental mycobacteria may also have played in boosting protection post-vaccination.
There are differences in the Aronson trial from modern BCG practice which may be important. First, the vaccine was freshly made at the field sites and used within a few days without lyophilization. Since the 1960s BCG vaccine used routinely is a lyophilized product, and we know of no direct comparison telling how this variable relates to protection in humans. Nor, for that matter, do we know how much the many mutations since the 1930s that have occurred in the panoply of BCGs in current use may have changed the protective power of these products. Also modern BCG practice calls for immunization of newborn infants or as soon as possible after birth, and there is evidence in published studies cited by Aronson et al of waning protection following vaccination of neonates. In the Aronson trial less than 5% of vaccinees were under age one and over 70% were over age 5. It is noteworthy that the MRC trial in the 1950s which showed high BCG efficacy also used liquid vaccines, and the age of the study population was 13-14, albeit the risk of TB exposure was probably lower than in the Aronson trial. Whether the response to BCG vaccination lowered the likelihood of progression of latent TB infections acquired post-immunization to later reactivation is an intriguing question raised by Dye. There is also an unexplained reduction in late efficacy in men compared with women, although the low total number of cases in the last two decades of long-term follow-up makes it difficult to draw conclusions there.
In summary, we agree with Dye that these findings provide a booster to hope that better immunization against TB may be achieved with improved products and regimens. We also agree that the full benefit of improvements may require a relatively long time to measure unless some modern techniques for predicting the long-term disease outcome of TB infections come from the laboratory at the same time as better vaccines are being developed.