Comparative leprosy vaccine trial in south India.

This report provides results from a controlled, double blind, randomized, prophylactic leprosy vaccine trial conducted in South India. Four vaccines, viz BCG, BCG+ killed M. leprae, M.w and ICRC were studied in this trial in comparison with normal saline placebo. From about 3,00,000 people, 2,16,000 were found eligible for vaccination and among them, 1,71,400 volunteered to participate in the study. Intake for the study was completed in two and a half years from January 1991. There was no instance of serious toxicity or side effects subsequent to vaccination for which premature decoding was required. All the vaccine candidates were safe for human use. Decoding was done after the completion of the second resurvey in December 1998. Results for vaccine efficacy are based on examination of more than 70% of the original "vaccinated" cohort population, in both the first and the second resurveys. It was possible to assess the overall protective efficacy of the candidate vaccines against leprosy as such. Observed incidence rates were not sufficiently high to ascertain the protective efficacy of the candidate vaccines against progressive and serious forms of leprosy. BCG+ killed M. leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5% protection (CI 48.0-77.0), M.w gave 25.7% protection (CI 1.9-43.8) and BCG gave 34.1% protection (CI 13.5-49.8). Protection observed with the ICRC vaccine and the combination vaccine (BCG+ killed M. leprae) meets the requirement of public health utility and these vaccines deserve further consideration for their ultimate applicability in leprosy prevention.

Studies on rapid assessment methods in leprosy.

A study was undertaken in Pudukottai district, Tamilnadu, India to test rapid assessment methods: viz (i) sample surveys with lower coverages for clinical examination in estimating the disease problem in the community, (ii) utility of registered case prevalence for estimating the actual prevalence in a given area, (iii) leprosy in school-going children and its utility in estimating leprosy prevalence in the community, and (iv) information on disability and smear positivity in estimating leprosy prevalence; and develop correction factors for estimating leprosy situation. A sample of 23 clusters from 582 clusters of contiguous villages and hamlets was further divided into two random sub-samples for two surveys with differing coverages. One team covered nine clusters comprising 34 villages with a population of 17,562 and examined 15,596 with a population of 26,927 and examined 16,622 (62%) persons for leprosy. The results showed that: (i) leprosy sample surveys with lowered coverages would tend to miss valuable information, in terms of quality and quantity; (ii) from 'known case' registers, to estimate the true burden of leprosy disease and to monitor its trend over time is inadequate; (iii) school surveys are of limited value for estimating the disease burden in the community or to monitor its trend over time; (iv) the number of smear-positive cases is to small to serve as an indicator for the total case load in the community; and (v) the prevalence of active disease and that of grade 2 disability in the community are poorly correlated. Reliable methods other than those used here need to be developed for evaluation and monitoring of the disease burden particularly in the post-MDT era.

Sensitization and reactogenicity of two doses of candidate antileprosy vaccine Mycobacterium w.

M.w vaccine is one of the antileprosy vaccines under test in an ongoing comparative vaccine trial in South India. The objective of the present study was to examine the sensitizing ability, as measured by skin test reactions to Rees' MLSA and lepromin, and reactogenicity of M.w vaccine in the local population. Two doses of M.w, 1 x 10(9) bacilli and 5 x 10(9) bacilli, were used, in two separate studies of 395 and 400 "healthy" individuals aged 1-65 years. In each study, the study subjects received either M.w vaccine or normal saline (control), by random allocation. The results showed that healing of vaccination lesions was uneventful although the healing process was somewhat prolonged with the higher dose. The mean size of lesions was 7.0 mm and 9.5 mm with the low and high doses of the vaccine, respectively. The results also showed that M.w vaccine in a dose of 1 x 10(9) bacilli, failed to induce post-vaccination sensitization as measured by reactions to Rees' MLSA and by Fernandez and Mitsuda reactions to lepromin-A. However, when the dose of the vaccine was increased to 5 x 10(9) bacilli the mean sizes of post-vaccination reactions to Rees' MLSA and lepromin-A (both early and late) were significantly larger in the vaccine group compared to that in the control group. The sensitizing effect attributable to the vaccine was of the order of 1.5 mm to 1.8 mm.

Post-vaccination sensitization with ICRC vaccine.

ICRC vaccine is one of the candidate anti-leprosy vaccines under test in a large scale comparative vaccine in trial. The objectives of the present study was to study the sensitization potential, as measured by Rees' MLSA and lepromin, and reactogenicity of this vaccine preparation in the local population. The study included 368 'healthy' individuals aged 1-70 years. Each individual received either ICRC vaccine or normal saline (control) by random allocation. They were also tested with Rees' MLSA and lepromin-A, 12 weeks after vaccination. Reactions to Rees' MLSA were measured after 48 hours and those to lepromin-A after 48 hours and three weeks. Character and size of local response, at the vaccination site, were recorded at 3rd, 8th and 15th week after vaccination. The results of the study showed that healing of vaccination lesion was uneventful, the mean size of the lesion being 10.3 mm. The mean sizes of post-vaccination reactions, to Rees' MLSA and lepromin (both early and late reactions), were significantly higher in the vaccine group compared to that in the normal saline group; the sensitizing effect attributable to the vaccine was of the order of 3.5 mm, 1.7 mm and 2.2 mm respectively. In conclusion, the study has demonstrated that ICRC vaccine was 'safe' and produced significant sensitizing effect as measured by post-vaccination sensitization to Rees' MLSA and lepromin, in the local population.

Diagnostic problems of early leprosy in field studies.

A Series of exercises were undertaken in order to develop methodology for consistency and reliability of clinical diagnosis of leprosy under field conditions in longitudinal studies. It was observed in initial studies that the field investigators could miss about 35% of cases of leprosy, mostly those with early manifestations. After training and experience, the proportion of missed cases came down to about 20%. In about 14% of females with patches suggestive of leprosy the patches were present in the covered areas of the body and so are likely to be missed during examination in field situations. One hundred forty two individuals with suspicious and definite leprosy lesions detected by paramedical workers were examined by a senior medical officer experienced in leprosy on two different occasions at an interval of three months for leprosy diagnosis. The concordance rates for diagnosis and classification of leprosy were about 80% and 70% respectively; and corresponding values for kappa were 0.59 and 0.62 similar to earlier experiences in inter-observer variation studies.

Inter-observer agreement and clinical diagnosis of leprosy for prophylaxis studies.

Clinical diagnosis is still the most useful tool for detecting early cases of leprosy in field research. In prophylaxis studies accuracy of clinical diagnosis of leprosy is important during intake as well as for measuring efficacy of the intervention. This paper reports our observations regarding the extent of inter-observer variations in clinical diagnosis of leprosy and its implications for a prophylaxis study. Information on 225 suspects and cases of leprosy, each examined independently by three senior workers after initial standardization, was used for this purpose. Agreement among the examiners regarding the presence of skin patch, thickened nerve trunk and sensory deficit was fairly high (Kappa = 0.7). Agreement on the presence of infiltration in a skin patch was not satisfactory (Kappa = 0.4-0.5). It was observed that in clinical diagnosis of leprosy, presence of skin patch and sensory deficit, as well as thickened nerve trunk and related anaesthesia were correlated observations. The influence of inter-observer variations on defining leprosy problem in the community can be quite large. The paper suggests some ways of overcoming the problem.