Journal Pre-proof

Efficacy of chemoprophylaxis and immunoprophylaxis in leprosy prevention: a

systematic review and network meta-analysis of randomized controlled trials

Gehad Mohamed Tawfik, Marwa Biala, Yomna Mahmoud Yousef, Ranjit Tiwari,
Monica Dobs, Caroline Ibrahim Lotfy, Doha Ahmed Farrag, Anh Tran Hue, Rie
Roselyne Yotsu, Nguyen Tien Huy
PII: S1198-743X(21)00424-9
DOI: https://doi.org/10.1016/j.cmi.2021.07.032
Reference: CMI 2639

To appear in: Clinical Microbiology and Infection

Received Date: 22 June 2020

Revised Date: 29 June 2021
Accepted Date: 19 July 2021

Please cite this article as: Tawfik GM, Biala M, Yousef YM, Tiwari R, Dobs M, Lotfy CI, Farrag DA, Hue
AT, Yotsu RR, Huy NT, Efficacy of chemoprophylaxis and immunoprophylaxis in leprosy prevention: a
systematic review and network meta-analysis of randomized controlled trials, Clinical Microbiology and
Infection, https://doi.org/10.1016/j.cmi.2021.07.032.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.

© 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.
 1 Efficacy of chemoprophylaxis and immunoprophylaxis in leprosy prevention: a systematic review
2 and network meta-analysis of randomized controlled trials

4 Gehad Mohamed Tawfik1,2, Marwa Biala3, Yomna Mahmoud Yousef2,4, Ranjit Tiwari2,5, Monica
5 Dobs2,6, Caroline Ibrahim Lotfy2,7, Doha Ahmed Farrag2,8, Anh Tran Hue2,9, Rie Roselyne Yotsu10,11,*,
6 Nguyen Tien Huy12,13,*

8 Affiliations

of
1
9 Faculty of Medicine, Ain Shams University, Cairo, Egypt.

ro
2
10 Online Research Club (http://onlineresearchclub.org), Nagasaki, 852-8523, Japan.

-p
3
11 Faculty of Medicine, Tripoli University, Tripoli, Libya.
re
4
12 Faculty of Medicine, Misr University for Science and Technology, Giza, Egypt.
5
lP

13 Faculty of Medicine, Institute of Medicine, Tribhuvan University, Kathmandu, 44600, Nepal.

6
14 Faculty of Medicine, Assuit University, Assuit, Egypt.
na

7
15 Faculty of Pharmacy, Assuit University, Assuit, Egypt.
ur

8
16 Faculty of Medicine, Aswan University, Aswan, Egypt.
Jo

9
17 School of Medicine, International University of Health and Welfare, Tochigi, Japan

10
18 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan

11
19 Department of Dermatology, National Center for Global Health and Medicine, Tokyo, Japan.

12
20 Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam.
13
21 Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki
22 University, Nagasaki 852-8523, Japan.

23 *Correspondence to: Nguyen Tien Huy, Institute of Tropical Medicine (NEKKEN), School of Tropical
24 Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan.

25 Or Rie Roselyne Yotsu

26 Emails and ORCIDs

27 GMT: dr.gehadmohamed@hotmail.com (ORCID: 0000-0003-3459-193X)

1
28 MB: marwabiala07@gmail.com (ORCID: 0000-0002-2707-3133)

29 YMY: yomna.mahmoud163@gmail.com (ORCID: 000-0002-4304-2425)

30 RT: docranjittiwari@gmail.com (ORCID: 0000-0002-2148-4839)

31 MIL: monicaibrahim9111@gmail.com (ORCID: 0000-0002-7684-1493)

32 CIL: caro. Ibrahim111@gmail.com (ORCID: 0000-0002-9528-8363)

33 DAF: dohaahmedfarrag@gmail.com (ORCID: 0000-0002-9699-6759)

34 ATH: atranhue98@gmail.com (ORCID: 0000-0002-4110-520X)

of
35 RRY: rieyotsu@hosp.ncgm.go.jp (ORCID: 0000-0001-9102-1912)

ro
36 NTH: tienhuy@nagasaki-u.ac.jp (ORCID: 0000-0002-9543-9440)

-p
re
lP
na
ur
Jo

2
37 Abstract:

38 Background: Vaccination and single-dose rifampin are the main proven effective intervention types for
39 preventing leprosy among contacts of Mycobacterium leprae endemic areas. Currently, no high-quality
40 evidence is available regarding the best prophylactic intervention.

41 Objectives: Our primary study aim is to detect the most effective prophylactic intervention for the
42 prevention of leprosy.

43 Data sources: In May 2019, 12 databases were searched systematically. Updated search terms were
44 developed in March 2020 to complete an updated search.

45

of
Study eligibility criteria: All randomized controlled trials (RCTs) comparing the different types of
46 chemoprophylactic and immunoprophylactic interventions in leprosy prevention were included.

ro
47 Participants: Our participants were contacts of patients with leprosy or people residing in leprosy
48 endemic communities.
-p
re
49 Interventions: We searched for different types of chemoprophylactic and immunoprophylactic
lP

50 interventions used in leprosy prevention.

51 Methods: We used network meta-analysis and meta-analysis. Quality assessment was performed using
na

52 Cochrane Risk of Bias for included RCTs, in which all included RCTs were rated to be either low to
53 moderate risk. We registered our protocol in Prospero with ID CRD42019143207.
ur

54 Results: Among 11 included studies (326,264 patients) from original and updated search term, eight were
Jo

55 eligible for NMA while four were eligible for MA. Findings suggest that BCG vaccination was the most
56 effective intervention compared to placebo (risk ratios (RRs) 0.49 [0.30, 0.80] {P score=0.77}), followed
57 by combined BCG vaccination and single-dose rifampicin (SDR) with similarly low values (RR 48%, P
58 score=0.77). BCG revaccination was the least effective intervention compared to placebo (RR 1.08 [0.36,
59 3.22] {P score=0.26}).

60 Conclusion: Compared to placebo, the BCG vaccine was the most effective prophylactic intervention.
61 The combination of BCG vaccination + SDR had nearly the same efficacy as BCG vaccination alone,
62 while BCG revaccination was the least effective. Thus, vaccination proved to be a more effective
63 treatment than SDR alone. A well-designed multicenter RCT is warranted to evaluate the safety of these
64 vaccines.

65 Keywords: chemoprevention; humans; immunization; leprosy, chemoprophylaxis.

3
66 Introduction

67 According to World Health Organization (WHO), 13 countries of the world, namely Brazil, Bangladesh,
68 Democratic Republic of Congo, India, Ethiopia, Indonesia, Myanmar, Madagascar, Nepal, Philippines,
69 Nigeria, Sri Lanka, and the United Republic of Tanzania account for 94% for leprosy patients worldwide.
70 Among those, three countries with huge populations – Brazil, Indonesia, and India report more than
71 10,000 new cases a year. In the last five years, there has been only a modest decline in the detection of
72 new cases.(1)

73 Leprosy is caused by Mycobacterium leprae bacteria as well as Mycobacterium lepromatosis.(2) There

74 are three cardinal signs of leprosy, which include altered sensation, thickening of peripheral nerves, and

of
75 demonstration of bacilli on microscopy. Contact with a lepromatous patient typically occurs in those who
76 share the same household, neighborhood, or work in the same office or community. The main mode of

ro
77 transmission of leprae bacilli is through nasal droplets.(3) Therefore, persons who are in contact with

-p
78 infected patients have a high chance of transmission.(4) A study done by Bakker et al. (5) showed that
79 there was a 4-fold higher risk of leprosy in contacts of patients. Similarly, Ximenes et al. (6) showed that
re
80 patients having contact had a higher risk of reinfection after treatment. These studies emphasize the
lP

81 importance of prophylaxis for contact patients.

82 The risk of transmission in contact depends upon several factors: physical distance from patient index,
na

83 genetic relationship to the patient, patient type of leprosy, and age of contact, i.e., multibacillary leprosy
ur

84 has a higher chance of transmission compared to paucibacillary. (7) The type of leprosy after getting
85 infected is settled by degree of cell-mediated immunity that is mounted against the bacteria. Early
Jo

86 diagnosis and treatment are imperative for the prevention of complications and also for prevention of
87 transmission to healthy subjects.

88 WHO has been focusing more on treatment of leprosy but to date; guidelines regarding chemoprophylaxis
89 or immune prophylaxis for contacts of lepromatous patient has not been implemented worldwide. In a
90 cluster randomized controlled trial (RCT), Moet et.al found that chemoprophylaxis with single-dose
91 rifampin (SDR) was effective.(8) Dapsone or acedapsone has also been used for chemoprophylaxis in
92 previous trials (9, 10) but is not preferred due to drug resistance and poor compliance. The reason for
93 preferring rifampin is its single dosing and bactericidal property.(11, 12) The expert meeting held in
94 November 2016 in Amsterdam, the Netherlands concluded that combination of three doses of both
95 rifampin and moxifloxacin must be used for post-exposure prophylaxis since SDR has limited
96 efficacy.(13) Immunoprophylaxis with Bacillus Calmette Guerin (BCG) & heat-killed M. leprae + BCG
97 vaccine has also been tested in some studies.(14, 15) Due to shared antigenicity of M. leprae with

4
 98 Mycobacterium tuberculosis, BCG vaccine has been shown to protect against leprosy.(15, 16) Schuring R
99 P et al(17) did a secondary analysis of data from COLEP trial(17) investigating efficacy of combined
100 BCG vaccine at infancy and single-dose rifampicin (SDR). They showed that a combination of vaccine
101 and single-dose rifampin reduced the chance of contracting leprosy by about 80%. In a cluster-
102 randomized community trial, Cunha et al found that second dose BCG vaccination was not effective for
103 leprosy prevention which is in contrast to RCT by the Karonga prevention trial group, which have shown
104 that a second dose BCG vaccination confers protection against leprosy. (18, 19)

105 Although many studies emphasizing the importance of chemoprophylaxis and immunoprophylaxis for the
106 prevention of leprosy are available to date, to our knowledge, this is the first network meta-analysis of
107 randomized controlled trials on this topic. So, our study aimed to evaluate the efficacy and safety of drugs

of
108 and vaccines used in chemoprophylaxis and immunoprophylaxis against leprosy. Since the two RCTs on

ro
109 BCG revaccination for prevention of leprosy(18, 19) shown contrasting results, we also intended to
110 investigate it. Besides, we also planned to integrate the best available evidence regarding the most
111 effective regimen for leprosy prevention.
-p
re
112
lP

113 Methods
na

114 Our SR/NMA was reported following the widely accepted Preferred Reporting Items for Systematic
115 Review and Meta-analysis Statement 2009 (PRISMA), which is available in Supplementary Table 1 and
ur

116 other summarized articles.(20, 21) We made a protocol before commencing the study and registered it on
Jo

117 the PROSPERO-International prospective register (CRD42019143207).

118 Eligibility criteria
119 We included only RCTs assessing different types of chemoprophylactic and immunoprophylactic
120 interventions for the prevention of leprosy among contacts of patients infected with this disease and
121 people residing in communities endemic to leprosy. No restrictions were made regarding language, age,
122 gender, race, ethnicity, geographical distribution, or the date of publication. We excluded studies
123 incorporating participants with a previous history of leprosy. We also excluded abstract-only articles,
124 letters, editorials, notes, thesis papers, books, reviews, author responses, or any study design other than
125 RCT. We also did not take into account studies having insufficient or overlapped data.
126 Literature search
127 On 4th May 2019, we searched for relevant articles throughout 12 databases (PubMed, Web of Science
128 (ISI), EMBASE, Virtual Health Library (VHL), WHO Global Health Library (GHL), Cochrane, Clinical
129 trials.gov, Controlled Trials (RCT), Science Direct, World Health Organization (WHO), and System for

5
130 Information on Grey Literature in Europe (SIGLE)). After data extraction, we performed a manual search
131 looking for any possible missed relevant articles by looking into the references from already included
132 papers, reviews to the topic, citing papers, related papers within Google Scholar and PubMed's first
133 results pages, and papers suggested through contacting subject matter authors or experts. We used a
134 standard search strategy which was later adjusted according to each database. The main search terms
135 were: (leprosies OR leprosy OR "Hansen disease" OR "Hansen's disease" OR leprae) AND
136 (chemoprophylaxis OR chemoprophylactic OR chemoprevention OR prophylaxis OR prevention OR
137 protection OR immunization OR vaccines OR vaccine OR vaccination OR vaccinated OR immunized OR
138 immunity OR immunoprophylaxis OR immunoprophylactic OR BCG OR (bacillus calmette-guerin))
139 AND (randomized OR randomised OR random OR randomly OR randomization OR randomisation OR

of
140 RCT OR rcts OR "clinical trial" OR cochrane OR pubmed OR medline). Details about the search strategy
141 for other databases can be found in Supplementary Table 2. The manual search was conducted to identify

ro
142 relevant studies by looking into references from already included papers, reviews on the topic, related
143
-p
papers in PubMed and Google Scholar's, and papers suggested through contacting authors or experts.
re
144 Study selection
145 We used EndNote 8.1 (Thompson Reuters Corporation, Stanford, USA) to exclude duplicate studies. We
lP

146 screened title and abstract of each study to select studies meeting our inclusion and exclusion criteria. At
147 least three reviewers investigated the articles for inclusion or exclusion in a blinded manner, besides, any
na

148 disagreements were solved by 4th senior author opinion. Then we retrieved full text of the articles that met
149 the inclusion criteria for further screening. The above mentioned strategy was applied the same in all; title
ur

150 and abstract screening, full-text screening, data extraction, quality assessment, and manually search
Jo

151 studies.
152 Data extraction
153 A pre-designed data extraction excel sheet was used to extract data by three independent reviewers.
154 Consensus were used to resolve any disagreement between reviewers. For data extraction, excel sheet was
155 divided into following main categories: author, year published, country, sample size, groups (intervention
156 vs control), type of chemoprophylactic intervention used (dose, duration), and outcome (new case
157 detection).
158 Quality assessment
159 Cochrane Collaboration's tool was used to assess the risk of bias, three independent reviewers performed
160 it.(22) It is composed of seven particular domains; random sequence generation, allocation concealment,
161 blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other
162 sources of bias. Discordance between reviewers was resolved by discussion, and a consultant was helping
163 to reach consensus if needed.

6
164 Statistical analysis
165 Before the analysis, we rechecked extracted data. Frequentist NMA was done to compare available
166 prophylactic interventions within a single analytical framework.(23) NMA was performed by R statistical
167 software version 3.4.3 with the help of the package "net meta" package.(24, 25) The NMA was reported
168 in accordance with the modified PRISMA guidelines for network meta-analyses.(26, 27) The efficacy of
169 each intervention outcome was assessed using p-scores where the p-scores range between 0 and 1, where
170 1 hypothesizes the best and 0 hypothesizes the worst. In all NMA placebo was selected as a reference to
171 other interventions.

172 Effect sizes were synthesized using a fixed-effect model except when there was significant heterogeneity,
173 for which the random-effects model was used. Heterogeneity was assessed with I2-test considering it

of
174 significant with I2 value > 50% or P-value < 0.10.

ro
175 Publication bias was assessed through comparison-adjusted funnel plots, in which reported as bias with

-p
176 egger test more than 0.1.(28) Sensitivity analysis was done to assess inconsistency in NMA and
177 investigate both direct and indirect evidence simultaneously,(29) through node-splitting,(30) net heat
re
178 plot,(31) and inconsistency parameter approach,(32) in which if Q diff >8 revealed high inconsistency
lP

179 with red background color, while yellow revealed a non-significant inconsistency, and white background
180 revealed strong consistency between arm comparisons.
na

181
182 Results
ur

183 Study characteristics and methodological quality

Jo

184 We identified 2953 studies after the initial search, with a total of 200 articles included for full-text review.
185 No studies were identified from the manual search. Then, an updated search revealed two papers to b
186 included over nine from old search term. Among all 11 RCTs that were included in our study from old
187 and updated search, eight were eligible to enter into NMA and four into MA (Figure 1). The total number
188 of patients in our NMA was 326,264 meeting the inclusion criteria, which comprised six different
189 chemoprophylactic, and immunoprophylactic interventions namely; BCG vaccination, heat-killed M.
190 lepraae or human M.leprae + BCG, BCG+Heat killed M.leprae, single-dose rifampin, BCG
191 revaccination, LepVax (LEP-F1+GLA-SE) with a dose of 2 mg, LepVax. (LEP-F1+GLA-SE) with a dose
192 of 10 mg, and BCG + single dose rifampin.

193 Overall, 191,265 participants were allocated to active intervention and 110,939 to placebo. The age of
194 participants ranged from 0-70 years. We could not calculate the overall proportion of participants sex-

7
195 wise because gender was not specified in all trials. Detailed characteristics and demographic data of
196 participants are further summarized in Table 1.

197 The assessment of risk of bias in individual studies is presented in Figure 2 and Supplementary Figure 1.
198 The allocation concealment, and random sequence generation bias were of mostly low risk across studies.
199 While, the incomplete outcome data, selective reporting bias, and blinding of outcomes were all of low to
200 moderate risk across studies. The blinding of participants was moderate to high risk across studies.
201 Finally, the other biases was not adequately reported. In summary, all included RCTs were rated to be
202 either low to moderate risk except for two studies only that were of high risk.(15, 18)

203 Chaudhury et al(15) revealed high risk in selection bias, as method of randomization not mentioned,

of
204 while blinding of participants and outcomes, and allocation concealment were not mentioned, in which
205 this study shared with arm BCG + Heat-killed M.leprae (HKML) only. Cunha et al(18) revealed high risk

ro
206 in random sequence generation due to a higher proportion of children in intervention arm were in schools

-p
207 located in areas that had higher incidence of tuberculosis and leprosy before the trial, while blinding of
208 participants and outcomes, and incomplete outcome data were not mentioned, in which this study shared
re
209 with arm BCG revaccination only.
lP

210 For each of the six interventions, prophylactic interventions were ranked according to P scores compared
211 to placebo and rounded them to two decimals, as given in Figure 3.
na

212 Outcomes
ur

213 The network of comparisons of different interventions is shown in Figure 3A. All interventions are
Jo

214 compared against placebo. The most effective intervention was BCG vaccination with the least risk
215 compared to placebo (RR (95%CI {P-score}; 0.48 [0.29, 0.81] {P=0.76}), followed by BCG vaccination
216 combined with SDR with nearly the same low risk of 48% {P=0.71}. These were successively followed
217 by BCG + HKML vaccine (RR 0.61 [0.29, 1.31] {P=0.57}), and SDR alone (RR 0.65 [0.22, 1.90]
218 {P=0.53}). While the least effective intervention was BCG revaccination with the highest risk compared
219 to placebo (RR 1.08 [0.36, 3.19] {P=0.23}) (Figure 3).

220 Random model was used due to presence of heterogeneity with tau^2 = 0.2964; tau = 0.5445; I^2 =
221 93.5% [87.9%; 96.6%].

222 Publication bias was found in comparisons of BCG+HKML and BCG versus placebo, with egger test =
223 0.022, while all rest comparisons were of no publication bias with egger test >0.1 (Supplementary Figure
224 2).

8
225 Net heat plot revealed that most of our arm comparisons have high consistency with white background (0-
226 0.25), with only one arm comparison of no meaningful inconsistency (BCG:PLC_
227 BCG:BCG+HKML:Plc = 0.3) of light yellow background.

228 While Node-splitting cleared that comparison between BCG and placebo was significant in direct
229 estimate, while insignificant in indirect estimate, with a direct estimate of 0.97 which gave an overall
230 significant estimate. The other two comparisons between BCG vs BCG+HKML and BCG+HKML vs
231 placebo both were the same without differences between direct and indirect estimates (Figure 4B).
232 We as well did MA for five studies that have the same two arms for better assessment, BCG versus
233 placebo, we found that BCG vaccination significantly decline the risk of leprosy infection nearly to the
234 half (RR 48.6% [28.1%-84.1%] {p-value=0.01}) (Figure 5). Random model was used due to presence of

of
235 heterogeneity with I^2 = 93.435%, p-value<0.001.

ro
236 Qualitative analysis

237
-p
We found that all sorts of prophylactic interventions demonstrated a beneficial effect compared to
re
238 placebo. BCG revaccination was least effective among all interventions that we compared in our analysis.
lP

239 Regarding the safety of these interventions, only three RCTs in our study evaluated it. Chaudhary S et
240 al(15) assessed the adverse effect of vaccination in Indian subjects and found that BCG vaccination was
na

241 associated with lymphadenitis and severe reaction at injection sites in contacts who already had received
242 BCG vaccination in their childhood. They also observed that these reactions were absent in individuals
ur

243 who were given BCG combined with human M. leprae vaccines. Cunha et al(18) reported 18 cases of
Jo

244 adverse effect with BCG vaccine (ulcer in eight cases, cold abscess in seven cases and remaining three
245 cases had axillary lymph node enlarged in size without suppuration, hot abscess showing suppuration and
246 a nodule in the site of vaccination). Duthie et al(38) reported 24 cases of adverse effects with LepVax
247 (LEP-F1 + GLA–SE) with injection-related tenderness and pain, chills, decreases appetite, fatigue,
248 headache, laceration, oropharyngeal pain.

249

250 Discussion

251 Our study compared different types of prophylactic interventions of Mycobacterium leprae infected
252 patients and people living in endemic countries. Using the network approach, multiple interventions
253 would be for systematic evaluation and offering ranking order for each preventive method to prevent
254 leprosy transmission. The collaboration of both direct and indirect evidence leads to the gaining of

9
255 statistical precision when compared with other studies, which easy our interpretation because it makes a
256 comparison between prophylaxes explicit.

257 BCG vaccine has proven to be effective in preventing disseminated tuberculosis and also it prevents
258 leprosy due to the antigen similarity of bacteria.(33) Our result showed that BCG was significantly better
259 compared to the placebo, which is consistent with the results of previous studies. Richardus et al(37) in
260 Bangladesh compared the efficacy of BCG vaccine plus a single dose of rifampin vs BCG vaccine among
261 household contacts and next-door neighbors of leprosy patients. They found out that it is difficult to
262 establish the extent to which a single dose of rifampin suppresses excess leprosy cases among contacts in
263 the year after. The results of this trial were not consistent with our analysis. In fact we found that BCG
264 vaccine plus a single dose of rifampin was the second-best prevention following the most effective

of
265 method which is the BCG vaccine and it's even better than BCG vaccine plus heat-killed M.leprae

ro
266 vaccine.

-p
267 For the prevention of the emergence of new cases of leprosy, it is crucial to trace contacts and start them
268 on chemoprophylaxis or immunoprophylaxis. This statement has been further emphasized by modeling
re
269 studies by de Matos et al and Fischer et al,(34, 35) SDR has been shown to be effective in the prevention
lP

270 of leprosy among contact in previous studies which is consistent with our analysis.(36, 37) We also found
271 that BCG revaccination is least effective for reducing the risk of transmission of this disease to contact,
na

272 which is consistent with the study by Cunha et al.(18)

ur

273 These interventions used for prophylaxis are associated with some adverse effects. The preliminary
274 results of ongoing MALTALEP study(38) showed that among contacts who received BCG vaccination,
Jo

275 0.4% of them developed leprosy within 12 weeks which may be due to technical problem results in
276 damage the vaccine and be ineffective. Our study did not have sufficient data assessing the adverse
277 effects of these interventions.

278 The internal validity of our study is supported by the following factors: first, we believe this is the first
279 comprehensive SR/NMA, up till now, comparing all these types of prophylactic interventions together to
280 detect the best prophylaxis for prevention of leprosy. Second, we conducted all our steps in strict
281 accordance with the Cochrane handbook of SR(39) and reported according to the recommendations of the
282 PRISMA statement.(21) Third, we limited our search on RCTs only to overwhelm chances of biases that
283 were uncontrolled, unmeasured, and unknown in other study designs. Finally, keeping network approach
284 to handle our analysis revealed in implementing proof to a wider range of individuals giving more reliable
285 results.

10
286 One of the main aims of the Global Leprosy Strategy 2016-2020 is early detection and treatment of index
287 cases and to minimize transmission of infection in the population. Although WHO recommends use of
288 SDR for contacts of leprosy patients, but this guideline is not implemented worldwide in clinical practice.
289 From our analysis, we think that the WHO should implement guidelines on chemoprophylaxis and
290 immunoprophylaxis for contact of leprosy patients and people living in leprosy -endemic with
291 communities.

292 Some non RCTs concluded that SDR alone had no significant priority in leprosy prevention compared to
293 BCG vaccinations.(40, 41) Truoc et al(42) found that there was no significant differences between BCG
294 alone and killed Mycobacterium + BCG in leprosy prevention.

of
295 There are some challenges in the implementation of prophylaxis to household contacts. This is because
296 leprosy is still considered stigmatizing disease in many ethnic groups in developing countries and for

ro
297 starting prophylaxis to contacts, caretakers have to breach patient confidentiality which is also a major

-p
298 ethical issue.
299 Schoenmakers and Ferreira et al,(43, 44) concluded that SDR is promising as a chemoprophylactic agent
re
300 for limiting contacts of leprosy patients from catching the disease.
lP

301 Richardus et al,(45) concluded that post-exposure prophylaxis with SDR was safe; can be added into
302 many leprosy limitation programs, in which they included leprosy post-exposure patients with
na

303 prophylaxis with single-dose rifampicin, while our study include prophylaxis in endemic or contact to
ur

304 leprosy patients not leprosy patients themselves, so we could not include this article to us. Besides,
305 Moraes et al,(46) was a comment paper, not full article, from our exclusion criteria, and there was no
Jo

306 enough biostatics data to analysis it so we could not include it in our study. We found also Ortuno et
307 al,(47) which was still protocol with no published full article for it yet, so we excluded it as from our
308 exclusion criteria.

309 Schouring et al(17) has shown that BCG vaccination at infancy reduces the risk of leprosy by 50% and
310 combined BCG vaccination -at infancy- and SDR decreases risk by 80%. We did not incorporate these
311 data in our study, because we had the goal to assess the efficacy of BCG vaccine as an intervention, not as
312 a history of talking BCG vaccination from infancy.

313 Limitations

314 Firstly, leprosy is considered one of the neglected tropical diseases (NTDs), there were not enough RCTs
315 done on this topic, which led to low number of included studies. Further RCTs needed, especially in areas
316 endemic for leprosy as Indonesia, where no trials were done to date. Although we intended to assess the

11
317 effect of combined drug and vaccine in preventing leprosy. Because data were not available, we could not
318 do it. Secondly, a study is still going with the objective of assessing the effects of combined drug and
319 vaccine.(38) Finally, two studies from 11 studies were of high risk may lead to bias in the whole meta-
320 analysis. While, all rest nine studies were rated to be either low to moderate risk. But we assessed
321 sensitivity analysis in our NMA through net splitting plot and net heat plot which revealed that our NMA
322 have strong consistency, and no differences between direct and indirect estimates.

323 Conclusion

324 BCG vaccine was the most effective prophylactic intervention and combined BCG vaccination + SDR
325 was nearly with the same efficacy of BCG alone. While BCG revaccination was the least effective

of
326 intervention. Two studies have high risk from 11 included RCTs, in which, other nine were of low to
327 moderate risk, so we call for more RCTs studies in the future to investigate leprosy, which is considered

ro
328 as NTD. Sensitivity analysis in our NMA through net splitting and net heat plot revealed that our NMA

-p
329 have strong consistency, and no differences between direct and indirect estimates.
re
330
lP

331 Author contribution: RRY were responsible for the idea with NTH. Screening and extraction was done
332 by all authors under the supervision of NTH. Analysis and interpretation of Data were done by GMT. YM
na

333 organized tasks, made tables and figures under instruction of GMT and NTH. All authors contributed to
334 the manuscript writing and approval of the final version.
ur

335 Conflicts of interest: None of the authors have any conflicts of interest to declare.
Jo

336 Acknowledgements: Thanks to Abdelrahman M Makram, Faculty of Medicine, October 6 University,

337 Giza, Egypt for his previous efforts in this study.

338 Funding sources: None.

12
339 References

340 1. Regional Office for South-East Asia WHO. Global Leprosy Strategy 2016-2020: Accelerating
341 towards a leprosy-free world. New Delhi: WHO Regional Office for South-East Asia; 2016 2016-04.
342 2. Scollard DM. Infection with Mycobacterium lepromatosis. The American journal of tropical
343 medicine and hygiene. 2016;95(3):500-1.
344 3. Hatta M, van Beers SM, Madjid B, Djumadi A, de Wit MY, Klatser PR. Distribution and
345 persistence of Mycobacterium leprae nasal carriage among a population in which leprosy is endemic in
346 Indonesia. Trans R Soc Trop Med Hyg. 1995;89(4):381-5.
347 4. Sekar B, Arunagiri K, Kumar BN, Narayanan S, Menaka K, Oommen PK. Detection of mutations
348 in folp1, rpoB and gyrA genes of M. leprae by PCR- direct sequencing--a rapid tool for screening drug

of
349 resistance in leprosy. Lepr Rev. 2011;82(1):36-45.

ro
350 5. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors
351 for developing leprosy--a population-based cohort study in Indonesia. Lepr Rev. 2006;77(1):48-61.
352 6.
-p
Ximenes RA, Gallo ME, Brito Mde F. Retreatment in leprosy: a case-control study. Rev Saude
re
353 Publica. 2007;41(4):632-7.
354
lP

7. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship,
355 age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy.
na

356 J Infect Dis. 2006;193(3):346-53.

357 8. Moet FJ, Pahan D, Oskam L, Richardus JH. Effectiveness of single dose rifampicin in preventing
ur

358 leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial.
359 Bmj. 2008;336(7647):761-4.
Jo

360 9. Noordeen SK. Long term effects of chemoprophylaxis among contacts of lepromatous cases.
361 Results of 8 1/2 years follow-up. Lepr India. 1977;49(4):504-9.
362 10. Noordeen SK, Neelan PN. Chemoprophylaxis among contacts of non-lepromatous leprosy. Lepr
363 India. 1976;48(4 Suppl):635-42.
364 11. Britton WJ, Lockwood DN. Leprosy. Lancet. 2004;363(9416):1209-19.
365 12. Rodrigues LC, Lockwood D. Leprosy now: epidemiology, progress, challenges, and research
366 gaps. Lancet Infect Dis. 2011;11(6):464-70.
367 13. Mieras LF, Taal AT, van Brakel WH, Cambau E, Saunderson PR, Smith WCS, et al. An
368 enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP++. BMC Infectious Diseases.
369 2018;18(1):506.
370 14. Convit J, Sampson C, Zuniga M, Smith PG, Plata J, Silva J, et al. Immunoprophylactic trial with
371 combined Mycobacterium leprae/BCG vaccine against leprosy: preliminary results. Lancet.
372 1992;339(8791):446-50.

13
373 15. Chaudhury S, Hazra SK, Saha B, Mazumder B, Biswas PC, Chattopadhya D, et al. An eight-year
374 field trial on antileprosy vaccines among high-risk household contacts in the Calcutta metropolis. Int J
375 Lepr Other Mycobact Dis. 1994;62(3):389-94.
376 16. Bagshawe A, Scott GC, Russell DA, Wigley SC, Merianos A, Berry G. BCG vaccination in
377 leprosy: final results of the trial in Karimui, Papua New Guinea, 1963-79. Bull World Health Organ.
378 1989;67(4):389-99.
379 17. Schuring RP, Richardus JH, Pahan D, Oskam L. Protective effect of the combination BCG
380 vaccination and rifampicin prophylaxis in leprosy prevention. Vaccine. 2009;27(50):7125-8.
381 18. Cunha SS, Alexander N, Barreto ML, Pereira ES, Dourado I, Maroja Mde F, et al. BCG
382 revaccination does not protect against leprosy in the Brazilian Amazon: a cluster randomised trial. PLoS

of
383 Negl Trop Dis. 2008;2(2):e167.
384 19. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed

ro
385 Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Karonga Prevention
386 Trial Group. Lancet. 1996;348(9019):17-24.
-p
re
387 20. Tawfik GM, Dila KAS, Mohamed MYF, Tam DNH, Kien ND, Ahmed AM, et al. A step by step
388 guide for conducting a systematic review and meta-analysis with simulation data. Tropical Medicine and
lP

389 Health. 2019;47(1):46.

390 21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and
na

391 meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

392 22. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane
ur

393 Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
Jo

394 23. Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in
395 network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3(2):98-
396 110.
397 24. Team RCJRAl, computing efs. R Foundation for Statistical Computing; Vienna, Austria: 2014.
398 2015:2013.
399 25. Rücker G, Schwarzer G, Krahn U, König J. netmeta: Network Meta-Analysis using Frequentist
400 Methods. R package version 0. 9-0. 2016.
401 26. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA
402 extension statement for reporting of systematic reviews incorporating network meta-analyses of health
403 care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-84.
404 27. Abdellatif M, Vuong NL, Tawfik GM, Nhu Nguyen DP, Van Thanh L, Elfaituri MK, et al.
405 Massage therapy for the treatment of neonatal jaundice: A systematic review and network meta-analysis.
406 Journal of Neonatal Nursing. 2020;26(1):17-24.

14
407 28. Chaimani A, Salanti G. Visualizing Assumptions and Results in Network Meta-analysis: The
408 Network Graphs Package. The Stata Journal. 2015;15(4):905-50.
409 29. Donahue KE, Gartlehner G, Schulman ER, Jonas B, Coker-Schwimmer E, Patel SV, et al.
410 Sensitivity Analyses for Network Meta-Analyses: Agency for Healthcare Research and Quality (US);
411 2018 2018/07//.
412 30. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment
413 comparison meta-analysis. Statistics in medicine. 2010;29(7-8):932-44.
414 31. Schwarzer G, Carpenter J, Rücker G. Meta-Analysis with R2015.
415 32. Salanti G, Del Giovane C, Chaimani A, Caldwell DM, Higgins JP. Evaluating the quality of
416 evidence from a network meta-analysis. PloS one. 2014;9(7):e99682.

of
417 33. Sharma P, Mukherjee R, Talwar GP, Sarathchandra KG, Walia R, Parida SK, et al.
418 Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients:

ro
419 clinical field trials with a follow up of 8-10 years. Lepr Rev. 2005;76(2):127-43.
420 34.
-p
de Matos HJ, Blok DJ, de Vlas SJ, Richardus JH. Leprosy New Case Detection Trends and the
re
421 Future Effect of Preventive Interventions in Para State, Brazil: A Modelling Study. PLoS Negl Trop Dis.
422 2016;10(3):e0004507.
lP

423 35. Fischer EA, de Vlas SJ, Habbema JD, Richardus JH. The long-term effect of current and new
424 interventions on the new case detection of leprosy: a modeling study. PLoS Negl Trop Dis.
na

425 2011;5(9):e1330.
426 36. Cartel JL, Chanteau S, Moulia-Pelat JP, Plichart R, Glaziou P, Boutin JP, et al.
ur

427 Chemoprophylaxis of leprosy with a single dose of 25 mg per kg rifampin in the southern Marquesas;
Jo

428 results after four years. Int J Lepr Other Mycobact Dis. 1992;60(3):416-20.
429 37. Nguyen LN, Cartel JL, Grosset JH. Chemoprophylaxis of leprosy in the southern Marquesas with
430 a single 25 mg/kg dose of rifampicin. Results after 10 years. Lepr Rev. 2000;71 Suppl:S33-5; discussion
431 S5-6.
432 38. Richardus RA, Alam K, Pahan D, Feenstra SG, Geluk A, Richardus JH. The combined effect of
433 chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in
434 contacts of newly diagnosed leprosy cases: a cluster randomized controlled trial (MALTALEP study).
435 BMC Infect Dis. 2013;13:456.
436 39. Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane
437 Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). 2019.
438 40. Bakker MI, Hatta M Fau - Kwenang A, Kwenang A Fau - Van Benthem BHB, Van Benthem Bh
439 Fau - Van Beers SM, Van Beers Sm Fau - Klatser PR, Klatser Pr Fau - Oskam L, et al. Prevention of
440 leprosy using rifampicin as chemoprophylaxis. (0002-9637 (Print)).

15
441 41. Feenstra SG, Nahar Q Fau - Pahan D, Pahan D Fau - Oskam L, Oskam L Fau - Richardus JH,
442 Richardus JH. Acceptability of chemoprophylaxis for household contacts of leprosy patients in
443 Bangladesh: a qualitative study. (0305-7518 (Print)).
444 42. Truoc LV, Ly Hm Fau - Thuy NK, Thuy Nk Fau - Trach DD, Trach Dd Fau - Stanford CA,
445 Stanford Ca Fau - Stanford JL, Stanford JL. Vaccination against leprosy at Ben San Leprosy Centre, Ho
446 Chi Minh City, Vietnam. (0264-410X (Print)).
447 43. Schoenmakers A, Mieras L, Budiawan T, van Brakel WH. The State of Affairs in Post-Exposure
448 Leprosy Prevention: A Descriptive Meta-Analysis on Immuno- and Chemo-Prophylaxis. Research and
449 reports in tropical medicine. 2020;11:97-117.
450 44. Ferreira SMB, Yonekura T, Ignotti E, Oliveira LB, Takahashi J, Soares CB. Effectiveness of

of
451 rifampicin chemoprophylaxis in preventing leprosy in patient contacts: a systematic review of quantitative
452 and qualitative evidence. JBI database of systematic reviews and implementation reports.

ro
453 2017;15(10):2555-84.
454 45.
-p
Richardus JH, Tiwari A, Barth-Jaeggi T, Arif MA, Banstola NL, Baskota R, et al. Leprosy post-
re
455 exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme. The
456 Lancet Global health. 2021;9(1):e81-e90.
lP

457 46. Moraes MO, Düppre NC. Leprosy post-exposure prophylaxis: innovation and precision public
458 health. The Lancet Global health. 2021;9(1):e8-e9.
na

459 47. Ortuno-Gutierrez N, Younoussa A, Randrianantoandro A, Braet S, Cauchoix B, Ramboarina S, et

460 al. Protocol, rationale and design of PEOPLE (Post ExpOsure Prophylaxis for LEprosy in the Comoros
ur

461 and Madagascar): a cluster randomized trial on effectiveness of different modalities of implementation of
Jo

462 post-exposure prophylaxis of leprosy contacts. BMC Infectious Diseases. 2019;19(1):1033.

463 48. Lwin K, Sundaresan T, Gyi MM, Bechelli LM, Tamondong C, Garbajosa PG, et al. BCG
464 vaccination of children against leprosy: fourteen-year findings of the trial in Burma. Bulletin of the World
465 Health Organization. 1985;63(6):1069-78.
466 49. Stanley SJ, Howland C, Stone MM, Sutherland I. BCG vaccination of children against leprosy in
467 Uganda: final results. The Journal of hygiene. 1981;87(2):233-48.

468

16
Figure legends
Figure 1. PRISMA flow diagram of study selection.

Figure 2. Risk of bias assessment summary.

Figure 3. Network meta-analysis for network of comparisons of different interventions in leprosy
prevention.

Figure 4. Net heat plot of network meta-analysis (A), Node-splitting of network meta-analysis (B).

Figure 5. Meta-analysis for leprosy infectious risk after BCG vaccination.

Supplementary legends

of
Supplementary Figure 1. Risk of bias assessment graph of included randomized controlled trials.

ro
Supplementary Figure 2. Publication bias of our network meta-analysis.
Supplementary Table 1. PRISMA checklist.

-p
Supplementary Table 2. Details of search terms in each database.
re
lP
na
ur
Jo

17
 Table 1. Study and patient characteristics of the included studies

Author/Year/Country Sample size Age range (years) Sex (male) Doses Follow up
N (%) (Years)
Intervention Control Intervention Control Intervention Control Intervention Control
Moet/2008/Bangladesh (8) 10857 10854 5 - ≥30 5 - ≥30 4354 (23.1) 4343 Rifampicin Placebo 4
(23.0) (600 mg for adults weighing 35 kg and over),
(450 mg for adults weighing less than 35 kg and

f
for children older than 9 years), and (300 mg for

oo
children aged 5 to 9 years)
Cunha/2008/Brazil (18) 42662 50108 7 - 14 7 - 14 20,880 (48.9) 24,530 BCG (Moreau strain) Unvaccinated 6.8

r
-p
(49.0) 0.1 ml

re
Lwin/1985/Burma (48) 13066 13176 0-14 0-14 NR NR BCG Unvaccinated 14
0.1 ml of freeze-dried vaccine

lP
Chaudhury/1994/India (15) 179 714 5 - ≥20 5 - ≥20 NR NR heat-KML of human origin, 1.6 * 107 in 0.1 ml, Unvaccinated 8
BCG (Japan), 1.5*10^5 in 0.1 ml, or a mixture

na
ur of KML , 1.6 * 107 in 0.1 ml, and BCG (Japan),
1.5 * 105 in 0.1 ml.
Sharma/2005/India (27) 24060 - 1->60 - NR NR The vaccine consisted of 1 * 109 heat killed The placebo consisted
Jo

bacilli (Mw) in normal saline for the first dose of 1/8 the dose of the
and half of the first dose, i.e. 5 * 108 bacilli for normal dose of tetanus
the second dose, given 6 months after the first toxoid
dose.
Fine/1996/Malawi (19) 1-BCG + 23307 0 - ≥60 0 - ≥60 1-BCG + (49.5) 1- BCG + KML Placebo 5–9
KML (46353) KML (47.5) BCG (Glaxo) 0.1 ml + 6 * 109 per mL Dextran matrix of
2- BCG 2-BCG (48) 2- BCG alone BCG pellet 0.1 ml
(51360) BCG (Glaxo) 0.1 ml
Bagshawe/1989/PapuaNew 2707 2649 0 - ≥15 0 -≥15 1408 (52) 1349 BCG (Japan) Unvaccinated 15
Guinea (16) (51) 0.1 ml

18
Stanley/1981/Uganda (49) 9069 10131 0 – 10 0 – 10 4099 (50) 4134 BCG (Glaxo) Unvaccinated 7
(51) 0.1 ml
Convit/1992/Venezuela (14) 14704 14409 6 – 70 6 – 70 NR NR combined vaccine consisting of 0.1 ml of BCG + Unvaccinated 6
6 * 108 M. leprae bacilli.

Duthie/2019/USA (38) 12 12 36.5 40.9 6 7 The first treatment group received a 2 mg The first treatment
LepVax (LEP-F1 + GLA–SE) dose per injection group received a 10
mg LepVax dose

f
oo
/injection
Richardus/2019/Bangladesh 7609 7379 5-44 5-44 3407 3358 BCG + single dose of rifampin BCG only

r
-p
(37)
BCG : Bacillus Calmette–Guérin; KML: killed M. leprae.

re
lP
na
ur
Jo

19
Jo
ur
na
lP
re
-p
ro
of
Jo
ur
na
lP
re
-p
ro
of
Jo
ur
na
lP
re
-p
ro
of
Jo
ur
na
lP
re
-p
ro
of
Jo
ur
na
lP
re
-p
ro
of