BCG vaccine: WHO position paper, February 2018 - Recommendations.

This article presented the World Health Organization's (WHO) recommendations on the use of on Bacille Calmette-Guérin (BCG) vaccine excerpted from the BCG vaccines: WHO position paper - February 2018 published in the Weekly Epidemiological Record [1]. This position paper replaces the 2004 WHO position paper on Bacille Calmette-Guérin (BCG) vaccine [2] and the 2007 WHO revised BCG vaccination guidelines for infants at risk for human immunodeficiency virus (HIV) infection [3]. It incorporates recent developments in the tuberculosis (TB) field, provides revised guidance on the immunization of children infected with HIV, and re-emphasizes the importance of the birth dose. This position paper also includes recommendations for the prevention of leprosy. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_background_docs/en/.

ILEP organisations should strive for high BCG coverage in communities at risk of leprosy.

The central thesis of this paper is that the EPI policy of a BCG vaccination at birth or in the first year of life provides proven partial protection against leprosy and that ILEP organisations should actively encourage government health services to maintain a high coverage. A literature review identified 12 case-control studies showing a median vaccine efficacy of 63% (range 20-90%). Two prospective studies and two randomised community trials showed a median efficacy of 70% (range 42-80%). The duration of this partial protection is at least 10-15 years. Studies of the long-term protective effect of BCG vaccination against leprosy have not been conducted. One trial has demonstrated a reduction of tuberculosis incidence up to 40 years after vaccination with BCG. There is a growing consensus that BCG works by 'upgrading' the immune response to M. leprae, moving leprosy cases from the lepromatous end of the Ridley-Jopling classification to the tuberculoid end or even makes it possible for infection to remain subclinical. An analysis of national BCG coverage figures as reported to WHO showed that the global mean coverage increased from 58% in 1980 to 88% in 2003. The absolute number of countries reporting less than 80% coverage has decreased from 78 out of 105 in 1981 to 32 of 157 in 2003. Only four countries reported coverages below 60% in 2003. Twenty of the 53 African countries reported coverages below 80% in 2003 against five of 38 countries in Asia, five of 13 countries in Oceania and two of 27 in Central and South America. Comparison of officially reported national coverage to estimates of coverage from special surveys clearly shows that the national figure may not adequately reflect the local situation. Rural communities often have lower coverage than urban populations. Slum households have lower coverage than non-slum households. Remote areas may not be touched by modem health services. Pockets of low BCG coverage exist in countries where leprosy is endemic and ILEP organisations are active. ILEP organisations can make an impact, not by getting involved in vaccination work directly, but by monitoring the BCG coverage and advocating for adequate provision of MCH services in the communities in which they work. This will reduce the risk of leprosy in children up to 15 years of age, provide a number of other benefits to the mothers and children involved and potentially contribute to a reduction of leprosy incidence on the longer term. If the partial protection imparted by BCG is life-long, adding a consistently high BCG coverage to the usual strategy of early case detection and treatment could result in a halving of the leprosy incidence in 2020.

[Where do we stand with BCG vaccination programme in Japan?].

The current BCG vaccination program of Japan is critically discussed based on recent knowledge, especially with regard to its epidemiological aspects, in order to put the problem into perspective for Japan's future tuberculosis control program. 1. EFFICACY AND OVERALL EFFECTIVENESS: Various indicators of BCG efficacy have been proposed, and the meticulous analysis on the variability and the quality of these indicators seems to have formed a consensus on the efficacy, as seen in the recent meta-analysis studies. However, much has been left unanswered concerning the conditions under which the efficacy is guaranteed. The impact of the vaccination program on the population should also be considered in order to make decisions on the program. Comparing the age-specific tuberculosis notification rate between Japan and the USA, where there has been no BCG vaccination program, shows that the rate for 0 to 4 year olds is clearly lower in Japan than in the USA, while it is more than five times higher for all ages in Japan than in the USA. The statistics for Japanese children are superior to those of US children with respect to the speed of decline in notification rate as well. These observations support the overall effectiveness of BCG vaccination in Japan. 2. MECHANISMS OF BCG VACCINATION EFFICACY AND ITS DURATION: Two possible mechanisms of how BCG works to prevent tuberculosis were proposed. Epidemiological models based on each mechanism were subsequently tested by simulating 20 years' development of cases in the BCG vaccination trial by BMRC. In mechanism 1, the BCG-induced immunity is assumed to boost TB immunity in inhibiting the clinical breakdown of tuberculosis during the 10 to 15 years after the vaccination. In mechanism 2, the immunity makes the infection process abort (presumably, at 90%, during the seven years after infection, for example), leading to a smaller risk of future clinical development. So far, most epidemiological models implicitly assume mechanism 1 above. In animal experimental models, however, it has been difficult to simulate the mechanisms differentially, which has been one of the drawbacks to this argument. 3. EFFECTIVENESS OF REVACCINATION: Revaccination with BCG vaccine aims to restore or to endow immunological resistance through repeating vaccination to those who have partially or totally lost the immunity acquired from the primary vaccination. Although some animal experiments support the efficacy of revaccination with BCG, studies in humans have been rare and the results are variable. The observation of Polish infants and schoolchildren is suggestive of the efficacy, but it is not randomized and of questionable value. The recent study of Malawi is a randomized trial. It demonstrated that BCG revaccination protects against leprosy, but does not protect significantly against tuberculosis. It is possible, however, that it does protect against tuberculous lymphadenitis. The two above-mentioned possible mechanisms of BCG immunity were applied to a model analysis of BCG revaccination. It was known that revaccination effectiveness is very limited under any assumption, given the current Japanese epidemiological situation of tuberculosis, so that the demerits due to revaccination, such as strong local reactions, must not be neglected but should be carefully considered. At the same time, we should remember that this model analysis assumes that the primary vaccination is given to new borns with advanced and uniform techniques, which is not always true, and revaccination may supplement the technical failure of the primary vaccination. 4. DECIDING ON THE TOTAL DISCONTINUATION OF BCG VACCINATION PROGRAMME, JAPAN: The recommendations of WHO or IUATLD on the discontinuation of the BCG vaccination program are just conventional ones and the theoretical reasonings is difficult to accept. After all, the decision making should depend on the lay decision makers' subjective judgment balancing benefit and loss in terms of costs and health incurred by the policy, as shown by Waaler and Rouillon. The current Japanese BCG vaccination program is very expensive, but brings about some, though very small, benefit. This balance was compared with that of Sweden around 1975, when the program was discontinued. The comparison clearly showed that the cost-effectiveness of the program in Japan today in superior to that of Sweden in 1975.

Vaccination against leprosy at Ben San Leprosy Centre, Ho Chi Minh City, Vietnam.

Three vaccines, BCG alone, BCG + 10(7) killed Mycobacterium vaccae and 10(8) killed M. vaccae alone, were studied in children living in close contact with leprosy. In the year before vaccination, 14/446 (3.1%) children had developed leprosy. Among those who were not vaccinated, 9/74 (12.2%) developed the disease in the first 4 years of the study and 5/65 (7.7%) developed the disease in the second 4 years. In comparison with this, among those vaccinated, 20/343 (5.8%) developed leprosy in the first 4 years and 5/323 (1.5%) developed leprosy in the second 4 years. This represents 52.5% protection in the first 4 years and 80.5% in the second 4 years. There were no significant differences in protection afforded by each of the three vaccines but the success of the killed preparation of M. vaccae is an important finding.

Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention Trial Group.

BACKGROUND: Repeat BCG vaccination is standard practice in many countries for prevention of tuberculosis and leprosy, but its effectiveness has not been evaluated. The addition of Mycobacterium leprae antigens to BCG might improve its effectiveness against leprosy. A double-blind, randomised, controlled trial to evaluate both these procedures was carried out in Karonga District, northern Malawi, where a single BCG vaccine administered by routine health services had previously been found to afford greater than 50% protection against leprosy, but no protection against tuberculosis. METHODS: Between 1986 and 1989, individuals lacking a BCG scar were randomly assigned BCG alone (27,904) or BCG plus killed M leprae (38,251). Individuals with a BCG scar were randomly allocated placebo (23,307), a second BCG (23,456), or BCG plus killed M leprae (8102). Incident cases of leprosy and tuberculosis were ascertained over the subsequent 5-9 years. FINDINGS: 139 cases of leprosy were identified by May, 1995; 93 of these were diagnostically certain, definitely postvaccination cases. Among scar-positive individuals, a second BCG vaccination gave further protection against leprosy (about 50%) over a first BCG vaccination. The rate ratio for all diagnostically certain, definitely postvaccination cases, all ages, was 0.51 (95% CI 0.25-1.03, p = 0.05) for BCG versus placebo. This benefit was apparent in all subgroups, although the greatest effect was among individuals vaccinated below 15 years of age (RR = 0.40 [95% CI 0.15-1.01], p = 0.05). The addition of killed M leprae did not improve the protection afforded by a primary BCG vaccination. The rate ratio for BCG plus killed M leprae versus BCG alone among scar-negative individuals was 1.06 (0.62-1.82, p = 0.82) for all ages, though 0.37 (0.11-1.24, p = 0.09) for individuals vaccinated below 15 years of age. 376 cases of postvaccination pulmonary tuberculosis and 31 of glandular tuberculosis were ascertained by May, 1995. The rate of diagnostically certain tuberculosis was higher among scar-positive individuals who had received a second BCG (1.43 [0.88-2.35], p = 0.15) than among those who had received placebo and there was no evidence that any of the trial vaccines contributed to protection against pulmonary tuberculosis. INTERPRETATION: In a population in which a single BCG vaccination affords 50% or more protection against leprosy, but none against tuberculosis, a second vaccination can add appreciably to the protection against leprosy, without providing any protection against tuberculosis.