Volume 62, Number 4Printed in the U.S.A.

INTERNATIONAL JOURNAL OF LEPROSY

Protective Effect of BCG Against Leprosy and ItsSubtypes: a Case-Control Study in

Southern Vietnam'Nguyen Van Thuc, Laurent Abel, Vu Dinh Lap, Jean Oberti,

and Philippe H. Lagrange2

Whereas BCG vaccine is given primarilyto prevent tuberculosis, several prospectivetrials have revealed its protective efficacyagainst leprosy with a degree of protectionvarying from 20% to 80% ( 8 ). A recent ad-ditional trial performed in northern Malawiestimated this efficacy at about 50% ( 17). Inthese trials, nonlepromatous types of lep-rosy constituted the large majority of inci-dent cases (93% in the Malawi study) anddefinitive conclusions concerning the pro-tective effect of BCG against multibacillary(MB) leprosy were difficult to draw ( 7 ). Dur-ing the last few years, the efficacy of BCGalso was studied by several case-controlstudies (reviewed in Table 1) which provid-ed consistent results with the prospectivetrials when considering all forms of leprosy(leprosy per se). A significant protective ef-fect of BCG against leprosy per se, varyingfrom 41% to 81%, was shown in northernMalawi ("), Brazil ( 20), Venezuela ( 6), andsouthern Malawi ( 2). This effect was esti-mated at 48% in Vietnam (') and 20% in alarge study in India ( 14), although not sta-tistically significant. More conflicting re-sults were reported when subtypes of lep-rosy were considered. In the two SouthAmerican studies (6 ' 2"), the protection wasfound to be greater among MB patients (de-fined as LL, BL, BB, and also, for the Bra-

' Received for publication on 9 May 1994; acceptedfor publication in revised form on 5 August 1994.

2 N. V. Thuc, Pharm.D.; V. D. Lap, M.D., Sectionof Directives, Dermato-Vencrcology Hospital, Ho ChiMinh City, Vietnam. L. Abel, M.D., Ph.D., INSERMU194, Hopital Pitie-Salpetriere, 91 Boulevard deI'Hopital, 75013 Paris, France. J. Oberti, M.D., Ph.D.,INSERM U65, Montpellier, France. P. H. Lagrange,M.D., Ph.D., Department de Microbiologic, HopitalSt. Louis, Paris, France.

Reprint requests to Dr. Abel.

zilian study, lepromin-negative indetermi-nate cases) than among paucibacillary (PB)patients. Conversely, in Vietnam ('), theprotective effect was near zero for lepro-matous leprosy (defined as LL and BL cases)whereas it was significant for nonleproma-tous leprosy. In southern Malawi (") theeffect of BCG for MB leprosy (also definedas BL and LL) was found not significant,although estimated at 50%. In the Indianstudy ( 14), where there were no LL cases andvery few BL cases, a significant protectiveeffect was found for borderline leprosy (de-fined as BL, BB, BT cases).

The aim of the present case-control studyis to evaluate in southern Vietnam the vari-ability of BCG efficacy according to leprosyclinical forms in a larger sample than ourprevious study (').

METI-IODSStudy area. The study was conducted in

Ho Chi Minh City, located in the south ofVietnam and representing a population ofmore than 4.4 million people. Leprosy con-trol is the direct responsibility of adminis-trative authorities at all levels, and the der-matology hospital is the center for the careof leprosy patients in the city area. Leprosydiagnosis, treatment and surveillance arcdone in accordance with the "Guide to Lep-rosy Control" by the World Health Orga-nization (WHO). With the introduction ofmultidrug therapy (MDT), the prevalencehad dropped in 1992 to just 0.2/1000 withan annual incidence rate of 6/100,000. Vol-untary reporting of new patients was themost common mode of detection.

BCG vaccine was first introduced into thesouth of Vietnam in 1954 with mass vac-cination campaigns that concentrated onboth children 1-5 years old and children of

532

62, 4^Thuc, et al.: BCG Protection Against Leprosy^533

TABLE 1. Review of the case-control studies assessing the protective effect of BCG inleprosy.

Reference Place No.cases

BCG efficacyagainst leprosy

per se

Subtypes consideredBCG efficacyin subtypes(Definition) and

no. cases

Fine, et a!. (") Northern 188 41% (I 1%-61%) None (MB) 9Malawi

Abel, et a!. ( 1 ) Vietnam 50 48% (NS)° MB (BL/LL) 34PB (remainder) 16

Efficacy near 0 for MB;at 80% (13%-96%)for PB

Muliyil, el al. ('°) India 397 20% (NS) (BT/BB/BL) 66 Efficacy of 61% (17%-(TT) 291 83%) in BT/BB/BL;(Ind.) 23 15% (NS) in TT; in-

creased risk for Ind.Rodrigues, et al. ( 21 Brazil 62 81% (63%-90%) MB (LL/BUBB/lepro-

min negative Ind.) 37PB (remainder) 25

Higher proportion ofBCG scars among PBthan among MB pa-tients

Convit, et al. ( 6 ) Venezuela 90 56% (27%-74%) MB (LL/BL/BB) 22PB (remainder) 68

Greater efficacy for MBthan for PB

Baker, et a!. ( 2 ) SouthernMalawi

145 64% (42%-77%) MB (LL/BL) 25PB (BT/TT) 113

Efficacy of 50% (NS)for MB; 73% (54%-85%) for PB

(NS) = not significant.

the first-year class in primary schools (6-8years old). Since 1964, newborns have beenincluded in the official target population.According to available records, the vacci-nation program used Saigon Pasteur Insti-tute liquid BCG and freeze-dried Canadianand Japanese BCG. However, it was notpossible to assess the respective proportionsof the BCG preparations that were actuallyused. The recommended intradermal dosewas 0.1 ml in the left deltoid region. In 1972,vaccination coverages were 70% for chil-dren of the first-year class in public primaryschools and 46% for newborns at public andprivate maternity hospitals. From 1986 to1991, 83°k of newborns in Ho Chi MinhCity were vaccinated.

Study population. Cases were randomlycollected from the file of leprosy patientsunder surveillance at the dermatology hos-pital of Ho Chi Minh City. Only patientsyounger than 25 years old were retained,because vaccination has been common onlysince 1964. A total of 177 cases were se-lected. They were subjected to a clinical andskin-smear examination and classified byexperienced physicians using the Ridley andJopling ( 18 ) classification into tuberculoid(TT), borderline tuberculoid (BT), border-line (BB), borderline lepromatous (BL), andlepromatous (LL) leprosy.

Two controls were matched with each casefor age (± 1 year), sex, ethnic group (Viet-namese/Chinese), socioeconomic status(three levels), and district area. Cases andcontrols were visited at their homes by ateam consisting of a specialized physician,an auxiliary physician, and a communityhealth worker to obtain the necessary in-formation. Exposure to BCG was evaluatedby looking for the typical scar over the del-toid region. BCG scars were read by threeindependent investigators who were blindto the study aim but not to the case or con-trol status. Controls were examined to ruleout any clinical evidence for leprosy.

Data were analyzed using the classicalstatistical methods developed for matcheddata with dichotomous exposures ( 3 ). Theodds ratio (OR) and 95% confidence inter-vals (CI) were calculated to assess the pro-tective effect of BCG against leprosy. Vac-cine efficacy was computed as 1 minus theestimated relative risk ( 22); in a relativelyrare disease, such as leprosy, the OR pro-vides a good estimate of the relative risk.

RESULTSThe distribution of leprosy cases by gen-

der and leprosy subtype is shown in Table2. As noted in other studies, the proportionof males was higher among the cases (72%)

534^ International Journal of Leprosy^ 1994

TABLE 2. Distribution of leprosy cases by^TABLE 3. Distribution of cases and con-gender and leprosy subtype.^trols by age.

GenderLeprosy subtype

TT BT BB BL LL Ind. Total

Male 27 13 42 26 17 3 128Female II 10 9 10 5 4 49Male +

female 38 23 51 36 22 7 177

Age group(Yrs)

5-10 14 2411-15 44 9416-20 70 15121-25 49 85

Cases^Controls

but there was no significant difference in thedistribution of leprosy subtype by gender

= 8.7, p > 0.1). The distribution ofcases and controls according to age is shownin Table 3. The global proportion of posi-tive I3CG scars was 61% and 66.7% amongcases and controls, respectively.

The results concerning the protective ef-fect of BCG in different leprosy forms arepresented in Table 4. When all forms ofleprosy were pooled together (leprosy perse), the protective effect (estimated at 29%)was not significant (x 2 ,,„ = 2, p = 0.16). Innonlepromatous patients (defined as 13B/BT/TT cases) the protective effect increased to42%, but was still not significant (x 2 i ,„ =3.2, p = 0.08). Since different results on theprotective effect of I3CG according to theleprosy form considered have been report-ed, the results for each of the leprosy sub-types are also presented in Table 4. In thethree unstable borderline forms of the dis-ease there was a trend in favor of a protec-tive effect of BCG; this trend did not appearin the two polar forms TT and LL. Fur-thermore, when all borderline forms werepooled together, the protective effect of BCGwas significant (x 2 , d ,- = 5.6, p < 0.02) andestimated at 52% (95% CI = 16%-73%).Among borderline patients, no significantheterogeneity of the BCG effect was foundaccording to sex, ethnic group, age, or so-cioeconomic level (Table 5). However, itwas interesting to note that the protectiveeffect of BCG did not appear in the age-group 5-10 years; none of these young pa-tients had indeterminate leprosy. It is pos-sible that some patients with early onset hadbeen vaccinated after their infection withMycobacterium leprae (during primaryschool), but there were not enough casesyounger than 10 years old to assess this hy-pothesis.

DISCUSSIONThe results of this study confirm the im-

portant variability in the protection offeredby 13CG with respect to the different typesof leprosy, and indicate that assessing theprotective effect of BCG using commonclassification, such as paucibacillary versusmultibacillary or nonlepromatous versuslepromatous leprosy, could be inappropri-ate. The odds ratio assessing the protectiveeffect of BCG varies from 0.44 (95% CI =0.19— 1.03) in the BB subtype to 3.00 (0.24-37.5) in indeterminate leprosy; its overallvalue was 0.71 (0.45-1.10) for leprosy perse. When all borderline leprosy types werepooled, the protective effect of I3CG wasfound significant with an odds ratio of 0.48(0.27-0.84). In the polar forms of leprosy,TT and LL, the odds ratio was greater than1 with large confidence intervals. BCG wasalready shown to provide a higher protec-tion for borderline leprosy than for tuber-culoid and indeterminate leprosy in India( 14 ) and in New Guinea ( 21 ). The odds ratiosobtained in the Indian study for indeter-minate, tuberculoid, and borderline formsof leprosy were close to our results with val-ues of 2.74 (0.84-8.95), 0.85 (0.59-1.22),and 0.39 (0.17-0.83), respectively; there wasno case of lepromatous leprosy in this studyand no conclusion could be drawn with re-spect to this subtype. Moreover, an in-creased number of tuberculoid leprosy casesafter BCG vaccination also has been de-scribed ( 23 ). As suggested by Muliyil, et al.( 14), it is quite possible that one single in-tradermal injection of BCG could induce aboosting effect causing a shift in the immuneresponse, and could reveal clinical immu-nopathological reactions in patients infect-ed before the vaccination. Consequently,transient forms of leprosy, such as indeter-minate forms, or subclinical forms of TT

62, 4^Thuc, et al.: BCG Protection Against Leprosy^535

TABLE 4. Effect of BCG according to different leprosy phenotypes.

Leprosy pheno ype No. sets % Cases withBCG scars ORa (95% CI) p Value

Leprosy per se 177 61.0% 0.71 (0.45-1.10) 0.16

Nonlepromatous (BB/BT/TT) 112 58.9% 0.58 (0.33-1.03) 0.08Lepromatous (BL/LL) 58 65.5% 0.90 (0.42-2.94) 0.95Ind. 7 57.1% 3.00 (0.24-37.5) 0.84TT 38 71.0% 1.10 (0.37-1.22) 0.93BT 23 56.5% 0.46 (0.15-1.38) 0.30BB 51 51.0% 0.44 (0.19-1.03) 0.08BL 36 66.7% 0.58 (0.20-1.68) 0.52LL 22 63.6% 1.37 (0.44-4.33) 0.78

Borderline (BT/BB/BL) 110 57.3% 0.48 (0.27-0.84) 0.02

OR = odds ratio.

would be at higher risk after vaccination.Such a boosting effect with BCG vaccina-tion has been observed in deer naturally orexperimentally infected with mycobacteria(12 , .) It would be important to know withaccuracy the time of clinical diagnosis ac-cording to the time of vaccination, sinceincreased risk to develop reactive formscould occur soon after the boosting effectproduced by the BCG vaccination.

Two recent studies did conclude that BCGwas able to give protection in MB leprosy(6,17 ). However, in the latter there were only9 MB cases, and in the former MB casesgrouped BB, BL, and LL patients (Table 1).Such a difference with our results could beassociated with geographical variations inthe immune spectrum of leprosy ("). Thevariability in the antigenic composition of

the BCG preparations used in the presentstudy does not appear to be a relevant factorto explain these discrepant results since arecent meta-analysis on the efficacy of BCGvaccine in tuberculosis showed that differ-ent BCG preparations and strains used inthe same population gave similar levels ofprotection ( 4 ). Another hypothesis to ac-count for this difference is the heterogeneityin the definition of the MB form with thepooling of unstable forms (borderline andunstable LL patients) with stable LL forms.The presence of unstable LL forms wasdemonstrated, for instance, in immuno-therapy studies done with a mixture of killedM. leprae and BCG that reported leprominconversions in two thirds of the Mitsuda-negative LL patients ( 5 ). A similar approachhas been performed in an ongoing family

TABLE 5. Effect of BCG in borderline patients (110 sets) hi' sex, ethnic group, age (pooledin two groups) and socioeconomic level (pooled in two groups).

No. sets % Cases withBCG scars ORa (95% CI) p Value for

heterogeneity

Sex 0.93Males 82 57.3% 0.47 (0.23-0.95)Females 28 57.1% 0.50 (0.19-1.29)

Ethnic group 0.75Vietnamese 87 56.3% 0.46 (0.24-0.89)Chinese 23 60.8% 0.54 (0.17-1.69)

Age group 0.195-10 years I^l 63.6% 1.25 (0.28-5.62)> 10 years 99 56.6% 0.41 (0.22-0.77)

Socioeconomic level 0.60Low 26 46.1% 0.42 (0.15-1.16)Intermediate/high 84 60.7% 0.51 (0.26-1.02)

a OR = odds ratio.

536^ International Journal of Leprosy^ 1994

study in Vietnam, where about one half ofMitsuda-negative LL patients did convertafter one single injection of BCG (manu-script in preparation). It is thus quite pos-sible that a) there is a great variation in theproportion of stable LL forms in differentpopulations, and b) BCG can protect againstunstable LL forms as against other unstableborderline forms; whereas it has no effectin stable LL leprosy. Under this hypothesis,the higher proportion of stable LL forms inVietnam compared to South America or Af-rica can explain the absence of protectionoffered by the BCG vaccination in Vietnam-ese patients classified as lepromatous. Anal-ogous experimental results have been re-ported already with armadillos vaccinatedby BCG ("). In this study, BCG was ableto convert the lepromin skin test in only 2of 9 Florida armadillos, and a mixture ofM. leprae and BCG did not give any betterstatistically significant results. Our study andothers ( 14 ) confirm that leprosy cannot beconsidered as a simple dichotomous dis-ease. According to the complex immunespectrum of leprosy, recommendations forstrategies to control leprosy and future vac-cine trials must evaluate separately thesevarious immunoregulated disease subtypes.

Case-control studies appear as a cheapand useful tool to evaluate the efficacy ofBCG in leprosy. The choice of controls inthis kind of study has been discussed re-cently (15' 16. 19 ). In particular, it was stressedby Nishioka and Goulart ( 16) that the con-trols chosen in the Indian ( 14 ) and the Bra-zilian ( 2") studies might have had a lesserchance of developing leprosy than the cases,since cases were more likely to have had ahousehold contact; the same can apply tothe present study. However, as noted byMuliyil, et al. ( 14 ), a higher risk of infectiondue to household contacts can be a con-founding factor only if it is also associatedwith BCG vaccination. In this type of study,it is certainly more important to choose con-trols with an opportunity to get BCG vac-cination close to cases, rather than controlswith an amount of exposure to M. lepraeclose to cases. In the present study the choiceof matching controls for age, sex, ethnicgroup, socioeconomic status and district areawas based on this principle.

Random misclassification could have oc-curred in the selection of cases and controls

and in exposure ascertainment. In particu-lar, misdiagnosis of indeterminate leprosyis possible without a skin biopsy, and ex-posure misclassification could be due to thefailure to develop a recognizable scar forcertain subjects vaccinated at birth ( 10 ).However, these phenomena would have theeffect of moving the odds ratio closer tounity and, consequently, to underestimatethe true effect of BCG. Furthermore, it wasfound in Ho Chi Minh City that the pro-portion of individuals vaccinated at birthwho failed to present a scar was less than5%, and, if this were the case, new vacci-nation was recommended for them.

In conclusion, our study finding that BCGoffers about 52% of protection against bor-derline forms of leprosy in Vietnam sup-ports the results of Muliyil, et al. ( 14) andthe hypothesis that BCG can bring about ashift in the immune response to a higherlevel of cell-mediated immunity. However,when BCG vaccination is given after pri-mary infection with M. leprae, this shiftcould be the cause of an increase in the riskof the occurrence of milder forms of thedisease. When BCG efficacy was evaluatedin other types of leprosy, no protective effectwas found in polar forms of the disease. InTT patients BCG might reinforce the pre-existing subclinical immunopathological re-actions, and in stable LL patients BCG mightbe unable to induce any protective form ofimmunity. Mass vaccination, such as theextended program of immunization that in-cludes the BCG vaccine, would have vary-ing effects within different geographic areasaccording to the relative proportion of sta-ble or unstable BCG nonresponder individ-uals.

SUMMARYA case-control study was conducted to

assess the protective effect of intradermalBCG against leprosy and its subtypes insouthern Vietnam. A total of 177 cases wereselected with a distribution by subtypes asfollows: 38 TT, 23 BT, 51 BB, 36 BL, 22LL, and 7 indeterminate. Two controls werematched with a case for age, sex, ethnicgroup, socioeconomic status, and districtarea. The odds ratio assessing the protectiveeffect of BCG varied from 0.44 (0.19-1.03)in the BB subtype to 3.00 (0.24-37.5) inindeterminate leprosy; whereas its overall

62, 4^Thuc, et al.: BCG Protection Against Leprosy^537

value was 0.71 (0.45-1.10) for leprosy perse. When all borderline leprosy types werepooled, the protective effect of BCG wasfound significant with an odds ratio of 0.48(0.27-0.84). In the polar forms of leprosy,TT and LL, the odds ratio was > 1 withlarge confidence intervals. It is possible thatBCG induces a shift in the immune re-sponse to a higher level of cell-mediatedimmunity. When BCG vaccination is givenafter primary infection with Mycobacteriumleprae, this shift could be the cause of anincrease in the risk of the occurrence ofmilder and transient forms of the disease.In TT forms BCG might reinforce the pre-existing subclinical immunopathological re-actions, and in stable LL forms BCG mightbe unable to induce any protective form ofimmunity. These results confirm the im-portant variability in the protection offeredby 13CG with respect to the different typesof leprosy, and may have important impli-cations for the design and the interpretationof vaccine trials that should take into ac-count the respective proportions of leprosyforms observed in the study region.

RESUMENSc realizO un estudio con control de casos para es-

tablecer el efecto protector del BCG intradermico con-tra la lepra y sus subtipos en Vietnam del Sur. Sc se-leccionaron 177 casos de los subtipos TT (38), 13T (23),BB (51), Bt. (36), LL (22), e indeterminado (7). Cadacaso se empatO con dos controles en cuanto a edad,sexo, grupo etnico, estatus socioeconOmico, y area deresidencia. La probabilidad de un efecto protector delBCG variO de 0.44 (0.19-1.03) en el subtipo BB a 3.0(0.24-37.5) en Ia lepra indeterminada, mientras quesu valor global fue de 0.71 (0.45-1.10) para la lepraper se. Cuando se consideraron en conjunto todos loscasos de lepra intermedia, se observO que el efectoprotector del BCG tuvo una probabilidad de 0.48 (0.27-0.84). En las formas polares de Ia lepra, TT and LL,la probabilidad fue mayor de 1.0, con grandes inter-valos de confianza. Es posible que el BCG induzca uncambio en la respuesta inmune hacia un mayor nivelde inmunidad celular. Cuando la vacuna de BCG seadministra despues de la infecciOn primaria con My-cobacterium leprae, este cambio podria ser causa deaumento en Ia frecuencia de apariciOn de las formasmoderadas y transitorias de la enfermedad. En la lepraTT, cl BCG podria contribuir a la manifestaciOn de lasreacciones lepromatosas subclinicas preexistentes,mientras que en Ia LL estable, el BCG seria incapazde inducir alguna forma de inmunidada protectora.Estos resultados confirman la importante variabilidaden la protecciOn conferida por el BCG con respecto a

las diferentes formas de la lepra, y puedan tener im-plicaciones importantes en el diseno de vacunas y enla interpretaciOn de los resultados de los programas devacunaciOn ya que êstos debcn tomar en cuenta laproporciOn de casos con las distintas formas de lepraen Ia region estudiada.

RESUME

Une etude cas-temoins a etc realisee afin d'evaleurPellet protecteur du BCG intradermique vis-a-vis deIa lepre et de ses sous-types dans Ic Sud du Vietnam.Un total de 17 cas a etc selectionne, avec la distributionpar sous-types suivante: 38 TT, 23 BT, 51 BB, 36 BL,22 LL, et 7 indeterminês. Deux temoins ont Cie ap-paries pour chaquc cas pour l'âge, le scxc, Ic groupsethnique, Ic statut socio-economique et le district.L'odds ratio evaluant l'elfet protecteur du BCG variaitde 0.44 (0.19-1.03) pour le sous-type BB a 3.00 (0.24-37.5) pour la lepre indeterminee; alors que sa valourglobale etait de 0.71 (0.45-1.10) pour la lepre commetellc. Quand tous les types de lepre borderline furentmis ensemble, I'effet protecteur du BCG fut trouvesignificatifavec un odds ratio de 0.48 (0.27-0.84). Pourles formes polaires de la lepre, TT et LL, l'odds ratioetait superieur a I avec de larges limites de confiance.II est possible que le BCG induise un glissement dansla reponse immunitaire vers un taux plus (ley& d'im-munite A mediation ceilulaire. Quand Ic vaccin BCGest administre apres une infection primaire par le My-cobacterium leprae, cc glissement pourrait etre la caused'une augmentation du risqe de developper des formesplus benignes et transitoires de la maladie. Dans lesformes TT, le BCG pourrait renforcer les reactionsimmunopathologiques subcliniques pre-existantes, etdans les formes LL stables, Ic BCG pourrait etre in-capable de produire une quelconque forme d'immuniteprotectrice. Ces resultats confirment la variabilite im-portante de protection offerte par le BCG par rapportaux differents types de lepre, et peuvent avoir des im-plications importantes pour la conception et l'inter-pretation des essais de vaccination qui devraient pre-ndre en compte les proportions respectives des typesde lepre observes dans la region d'êtude.

Acknov■ ledgment. We are very grateful to all of thepersons from the Dermato-Venercology Hospital ofHo Chi Minh City who have worked for this study: L.V. Hoa, P. H. Hai, P. A. Tuyct, H. V. Tu, N. L. D.Hien, M. T. Duong, N. T. Tien, V. H. Thai, V. C. Tam,P. X. Khoa, N. H. Phu, C. T. B. Nam, T. T. T. Thuy,and T. Tinh. This work was supported in part by grant491NS4 from I.N.S.E.R.M.

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