Efficacy of leprosy vaccines across the globe: A systematic review & meta-analysis of randomized controlled trials

Materials & Methods

The study protocol was registered on the PROSPERO International Prospective Register (ID: CRD42024561651).

Results

Altogether 2163 studies were retrieved from three different databases. Initially, 1556 articles were screened after removing 607 duplicate articles. Finally, after full text screening, out of 102 screened articles, 12 articles of RCTs designs were selected^12,26-35 (Figure).

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Figure.

Flowchart of literature search and study selection according to the PRISMA standard.

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Out of these 12 articles, eight studies tested the use of leprosy vaccines for prophylaxis^12,26-31. The earliest and the latest study of leprosy vaccine for prophylaxis were published in the year 1973 and 2008, respectively. Three studies were published from Asia (India, Burma, Vietnam)^27,29,31, while two studies each were published from Africa (Malawi, Uganda)^13,30 and South America (Brazil, Venezuela)^12,28. One study was published from Oceania (Papua New Guinea) continent²⁶. The combined number of participants in these eight studies was 2,41,905, ranging from 565 (Vietnam)³¹ to 92,770 (Brazil) participants¹². Five out of these eight studies were conducted among close contacts of leprosy patients, out of which two studies considered household contacts, including children as well as adult participants^28,29. Three studies included only household contacts who were children, where the age of participants ranged from newborn to 20 yr. These studies were published from Burma, Uganda, and Vietnam^27,30,31. One study each from Malawi¹³ and Papua New Guinea²⁶ included community dwelling individuals from all age groups; while another study conducted in Brazil¹² included school children aged 7-14 yr. Fifty per cent (4/8) of these trials studied intradermal single BCG vaccine in the intervention arm, out of which three studies included unvaccinated participants in the corresponding control arm^12,27,30. Normal saline was used as control against single dose of BCG vaccine in the study conducted in Papua New Guinea, where community-dwelling individuals from all age groups participated in the trial²⁶. The other half (4/8) of the studies included BCG as well as an adjunct therapy in the form of M. leprae bacilli / killed Mycobacterium vaccae/ KML BCG^13,28,29,31. Three of these studies included a placebo arm which consisted of tetanus toxoid injection (in addition to MDT) conducted in India²⁹, 0.2 mg or 0.04 mg BCG vaccine, conducted in Venezuela²⁸ and undefined placebo¹³. The remaining study, conducted in Vietnam among children living in close contact with patients of leprosy, had three study arms where each control arm consisted of unvaccinated children³¹. The total period of follow up in these eight studies ranged from 5-(Venezuela, Malawi)^13,29 to 16 yr (Papua New Guinea)²⁶ (Table I).

We were able to identify four studies where leprosy vaccines were tested for therapeutic benefit^32-35. All these RCTs were from India dating from 1992 to 2004. The combined number of study participants in these studies was 291, with numbers ranging from 40 to 90 participants in the specific studies. The study population comprised multibacillary leprosy patients (all age groups), untreated leprosy patients (> 12 yr), paucibacillary leprosy patients (15-60 yr) and untreated bacteriologically positive multibacillary leprosy patients (>18 yr). In the intervention arm, Mycobacterium w was administered intradermally, eight doses at three-month intervals in one study³¹. In the study conducted by Narang et al³³, in addition to 12 months of MDT-MBR, one intervention arm received WHO-recommended BCG vaccine (live bacilli count 10⁵/dose) intradermally while the other intervention arm received killed Mw/MIP bacilli (first dose: 1×10⁸, and subsequent dose: 0.5×10⁸). Majumder et al³⁴ conducted their study among paucibacillary leprosy patients where the intervention consisted of intradermal injection of low-dose of Convit vaccine (containing 1.6×10⁷ heat-killed M. leprae in 0.1 ml saline) followed by BCG vaccination (1.5×10⁷ BCG in 0.1 ml saline) after three months interval. Both the study arms also received single dose of 600 mg rifampin, 100 mg of minocycline, and 400 mg of ofloxacin. De Sarkar et al³⁵ recruited untreated bacteriologically positive multibacillary leprosy patients where the intervention consisted of WHO/MDT for 12 months plus four doses of intradermal Mw/MIP vaccine, 0.1 ml each, administered at three monthly intervals³⁵. Placebo was used in two studies - micronized starch dissolved in distilled water was used as placebo in one study³² while in the other study, participants in the placebo arm received 0.1 ml of normal saline along with MDT-MBR³³. Single dose of 600 mg rifampin, 100 mg of minocycline, and 400 mg of ofloxacin and MDT were used as comparators in two studies. The total duration of study was one yr in two of these studies while the other two studies lasted for two year (Table II).

Ramu’s score was found to be significantly reduced [-3.06 (95% CI: -3.96 to -2.16)] among the recipients of the therapeutic leprosy vaccine (Supplementary Fig. 1). Bacterial index was found to be insignificant [-0.26 (95% CI: -1.54 to 1.03)] among the recipients of therapeutic leprosy vaccine (Supplementary Fig. 2). Additionally, in the study by Zaheer et al³², 13/31 (41.9%) patients in the leprosy vaccine arm and 5/25 (20%) patients in the comparator arm were bacteriologically negative. In the study by Majumder et al³⁴, 20/60 (33.3%) patients in the leprosy vaccine arm and 4/30 (13.3%) patients in the comparator arm reported resolution of healing.

Overall certainty of generated evidence in outcomes i.e. infection rate, Ramu’s score and bacteriological index were found to be of moderate grade. Mean difference in anticipated absolute effects in four RCTs in Ramu’s score and bacteriological index were 2.93 lower (3.94 lower to 1.93 lower) and 0.48 lower (1.66 lower to 0.71 higher) respectively (Supplementary Table II). About 50 per cent (6/12) of the studies were found to have both medium and high risk of overall bias (Supplementary Table III).

In subgroup analysis, among the eight prophylactic vaccine studies, pooled relative risk was found to be 0.61 (95% CI: 0.41 – 0.91) and was statistically significant (P=0.016). Country-wise, all the studies had significant protective effect among the recipients except the studies from Burma, Brazil and Venezuela^12,27,28. Studies on all age groups had significant protective effect (RR=0.63, 95% CI: 0.51 – 0.77) compared to collective studies on children and young adults (RR=0.59, 95% CI: 0.23 – 1.52). In the control arm, the studies having combined MDT + TT, normal saline, and unnamed placebo had significant protection among the recipients compared to studies having unvaccinated and only BCG in the control arm (Supplementary Fig. 3).

In sensitivity analysis, five studies out of eight studies of prophylactic vaccine were found to be statistically significant (Supplementary Fig. 4)^{12,13,27,28,30}. In therapeutic leprosy vaccine study, all the three studies on Ramu’s score^32,33,35 and one study on bacteriological index³² were statistically significant.

Discussion

Leprosy is one of the oldest diseases of mankind. Despite availability of MDT against leprosy, it continues to occur in more than 120 countries in the globe. India, Brazil and Indonesia contributed more than 10,000 new cases as per WHO estimate on 2019. As a primary level of prevention, administration of single dose of rifampicin among the close household contacts is recommended by WHO³⁶. Moreover, treatment with MDT has also led to several complications like drug resistance, side effects, etc. The effectiveness of MDT in controlling leprosy has hit a plateau, with mathematical models indicating that the disease will continue to be a significant public health issue for several more decades^31,35. Again, mass BCG vaccination against tuberculosis has also significantly contributed to the reduction of leprosy, though this beneficial effect is frequently overlooked in contemporary leprosy control strategies^37,38. A few studies have proved the beneficial role of leprosy vaccine in preventing infection. Leprosy vaccines have been studied both in a prophylactic role (among the non-diseased) and in therapeutic role (among the diseased) separately in some parts of the globe. Of late, greater emphasis has been given on the role of BCG vaccination in both leprosy control and research efforts³⁹. In this background, the present SR/MA was performed to find out the beneficial role of leprosy vaccines among the recipients.

Total number of participants in the selected prophylactic and therapeutic studies were 2,41,905 and 291, respectively. Tawfik et al⁴⁰ studied 3,26,264 participants in their systematic review and network meta-analysis. In all four RCTs of the therapeutic trial, Mw/MIP was administered in three studies either alone or in combination with 12 months WHO MDT. The study by Majumder et al³⁴ administered low-dose Convit vaccine containing 1.6×10⁷ heat-killed M. leprae in 0.1 ml saline and 1.5×10⁷ BCG plus single dose of rifampin (600 mg), ofloxacin (400 mg) and minocycline (100 mg). In contrast, BCG vaccine along with M. leprae (heat killed/human) or single-dose rifampin were used in the intervention arm in the study conducted by Tawfik et al⁴⁰. The present systematic review and meta-analysis included participants from all age group (up to 60 yr) that corroborated the study by Tawfik et al⁴⁰ (0 – 70 yr). About 50 per cent (6/12) of the studies were found to have both medium and high risk of overall bias in the present SR/MA, while all the seven studies except two were found to have low to moderate risk by Tawfik et al⁴⁰.

Our result showed that both prophylactic and therapeutic leprosy vaccine were significantly better compared to the placebo, which is consistent with similar studies^11,37-41. Some studies even reported higher efficacy of the leprosy vaccine ranging from 34-80 per cent³⁸. Among the prophylactic vaccine studies in subgroup analysis, pooled relative risk was found to be 0.61 (95% CI: 0.41 – 0.91) and was statistically significant (P=0.016). In contrast, pooled relative risk ranged from 0.48 – 1.08 in the study by Tawfik et al⁴⁰ but none of them were statistically significant⁴⁰. Present SR/MA showed that when all age groups were considered, leprosy vaccine had significant protective effect (RR=0.63, 95% CI: 0.51–0.77) compared to the collective studies done on children and young adults (RR=0.59, 95% CI: 0.23–1.52), which is contradictory to the finding of Schuring et al¹¹, who found it to be beneficial among children. In contrast, Setia et al⁴¹ showed that the protective effect of BCG did not depend on the age of vaccination⁴¹. Present SR/MA found that the studies having combined MDT + TT, normal saline, and unnamed placebo in the control arm had significant protection among the recipients compared to studies having unvaccinated subjects or only BCG vaccinated subjects in the control arm. In therapeutic vaccine trials, the tested leprosy vaccines were found to be protective with reference to Ramu’s score, in our study, which was similar to the study by Setia et al⁴¹, where overall protective effect was found to be 26 per cent⁴¹. The present SR/MA included studies which exhibited high heterogeneity (i² 91.42%), which was also found in similar studies^38,40.

There are certain limitations of the present SR/MA such as non-availability of some of the full text articles and presence of heterogeneity among the included studies. Literature review yielded several observational studies, which were conducted to evaluate the efficacy of leprosy vaccines including combined chemotherapy and immunotherapy i.e., with Mw/MIP or BCG, some in areas with mandatory BCG vaccination policies, but such studies were not included as our SR/MA focused only on RCTs. Additionally, as the initial focus of the study, was to evaluate the clinical efficacy, immunogenicity, and safety of leprosy vaccines, immunotherapy was not considered as a search term at screening. The strength of the present SR/MA lies in the fact that it represents an up-to date search of the relevant articles with search string in three major databases, conducted as per Cochrane guide and PRISMA flowchart.

A subgroup analysis showcasing the benefit of the combined chemotherapy and immunotherapy (Mw/MIP or BCG) towards achieving quicker therapeutic improvement in comparison to immunotherapy only, would definitely add value. But it has not been performed due to the limited number of available studies on therapeutic vaccines (n=3), which significantly reduces the statistical power necessary for meaningful subgroup evaluations. Given these constraints, the focus of this meta-analysis is on estimating the overall therapeutic effect of combining chemotherapy and immunotherapy. Conducting a subgroup analysis in this context could produce unreliable conclusions. Therefore, the decision of not to include subgroup analysis highlights the need for further research to enable more robust and refined analyses in the future.

Conclusion

Our study found that leprosy vaccines are effective when used both as prophylaxis and for therapeutic benefit. Leprosy vaccine in the form of Mw/MIP along with combination of WHO MDT or BCG vaccine along with second-line treatment with rifampicin was found to be protective among the recipients. When all age groups were considered, leprosy vaccines were found to provide greater protective benefit compared to when only children and younger age groups were considered. Concurrent use of MDT with prophylactic vaccines provided better protective effect than vaccine alone. When used with therapeutic intent, leprosy vaccines significantly improved clinical scores but their effect on bacteriological index remained inconclusive. Of the 12 RCTs included in our study, six were of moderate to high risk of overall bias. Therefore well designed RCTs for leprosy vaccines are needed to generate stronger evidence for such vaccines.