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March, 1995
Vol.25, No.3
BCG : DO WE HAVE AN ALTERNATIVE
Vaccination is generally used as a form of immunopro
phylaxis, so tliat administration of the vaccine even a
long time before exposure to the wild-type infectious
organism should afford protection. Since effector T
and B cells are short-lived, a prime requisite for a
vaccine is to generate immunological memory.1 In the
case of organisms such as mycobacteria which are
obligate intracellular pathogens and which elicit
granulomatous tissue reactions, artificial immunisation
with live bacteria is required to induce protection.213
The only existing vaccine against tuberculosis is the
BCG (Bacille Calmette - Guerin), an attenuated strain
of M.bovis and it is mandatory or officially recom
mended in 182 countries or territories. Under the
Expanded Programme on Immunisation (EPI) started
by the Government of India in 1978, BCG is recom
mended to be given to all infants 3-9 months after
birth.4
History of BCG Vaccine
The history of BCG vaccination and the trials
conducted to assess its effectiveness in humans have
been reviewed by many workers.5;10 BCG, the biletolerant, attenuated strain of M.bovis, was isolated by
Calmette and Guerin.11 Ox-bile was originally added
to these cultures to prevent clumping of bacilli. This
led to the fortuitous observation that growth in the
presence of bile also resulted in attenuation or gradual
loss of virulence. Such attenuated organisms will
multiply only to a limited extent in the animal or human
body and can bring about an increase in the resistance
of the host to a subsequent fully virulent infection by
the same or other antigenically closely related organ
isms. Calmette further attenuated this strain by cul
tivation of the organism on a potato-glycerol-bile medium
for 230 serial transfers between the years 1908 and
4918.
The bacilli resulting from this attenuation have
never been cloned. The original strain of BCG has been
lost and has been replaced by a variant while it was
being transferred serially on artificial culture media at
the Pasteur Institute12 and have since been maintained
by many different laboratories, using many different
methods. As a result, the BCG strains used today are
not bacteriologically identical.13-14 In 1966, a WHO
Expert Committee on Biological Standardisation adopted
a series of recommendations for the production of BCG
vaccine.I5.These recommendations stated that the vaccine
should be freeze-dried, and that the vaccine strain
should be maintained by the seed-lot-system vyhereby
no vaccine is produced from a seed more than 12
passages removed from a primary freeze-dried lot.
Such a method of maintenance was soon adopted by
........... —
...... ........................ -......... '
most laboratories and this eliminated the possibility of
more attenuated variants in later BCG vaccine lots.16
and Guerin.18 Scepticism concerning the safety an.
efficacy of BCG vaccine, and the Lubeck disaster m
which 72 of 240 children vaccinated with BCG died
BCG Vaccine Production in India
as a result of being fed a batch of vaccine containing
virulent
tubercle bacilli, delayed the acceptance of
In India, the BCG Vaccine Laboratory was started
BCG.
A
series of controlled trials were begun in the
in Madras in 1948 for the production of BCG vaccine
for use in India and also for supply to some of the , 1930s. Despite inconsistent results from the trials.
WHO encouraged widespread dissemination of BCG
neighbouring countries. Since 1966, Danish strain
^vaccines, starting in the 1950s.7 By the 1970s, BCG
1331 is being used here for the preparation of both the
became the most widely used vaccine in the world.
liquid and the freeze-dried BCG vaccines, based on the
About 3 billion doses have been given in the last four
seed-lot-system17.
decades, and more than 70 per cent of the world’s
For preparing the liquid and freeze-dried vaccine,
children now receive BCG.5-19
the BCG Laboratory, Madras, uses the method followed
Between the years 1935 and 1955, at [east eight
at the State Serum Institute, Copenhagen, but using
controlled
trials were conducted to <assess the efficacy
Sauton potato medium for maintaining the BCG strain.
of
BCG
vaccine
against tuberculosis. The protective
The prepared vaccine is tested for purity by Ziehlefficacy obtained ranged from rone to 80 per cent
Neelsen .smear for acid fast bacilli, and by culture on
(Table).8
nutrient broth, thioglycollate medium and Sabouraiid’s
agar medium. Total bacterial count and the number
Table: Protective efficacy of BCG vaccine against tuber
of culturable particles in the preparation are estimated.
culosis
Biological tests are carried out in guineapigs to estimate
Population group
Period of intake
Protective
thedegreeofvirulenceoftheBCG vaccine, allergenicity
efficacy
(%)
and safety. In addition to the above tests, in the case
of the freeze-dried vaccine, tests are carried out to
North American Indians
1935-1938
80
estimate residual moisture and heat stability. Both
Chicago infants
1937-1948
75
types of vaccines are to be stored at refrigeration
Georgia school children
1947
None
temperature, protected from light. Under these con
Illinois children
1947-1948
None
ditions of storage, the liquid vaccine can be used for
Puerto Rico
1949-1951
31
4 weeks from the date of manufacture while the freeze- . general population
/ dried vaccine can be used for 3 months.
• Georgia and Alabama
1950
14
general
population
BCG can be administered intracutaneously, orally,
British children
1950-1952
78
by scarification or by multiple puncture. The most
South
Indian
1950-1955
31
widely used method of administration is by intracutarural population
neous injection. The dose is usually 0.1 ml and the
site of injection is the upper arm. In the newborn, the
dose used is 0.05 ml. The liquid BCG vaccine prepared
The South Indian Trial
by the BCG Laboratory, Madras, is to be administered
A study was smarted in Chingleput, south India, in
by an intracutaneous injection of 0.1 ml of the vaccine
1968 in an attempt to avoid the methodologic errors
containing 0.075 mg (moist weight) of BCG. The
that might have affected previous trials.10-20-21 The south
freeze-dried vaccine prepared here is reconstituted by
Indian BCG trial was organised by the Indian Council
the addition of sterile distilled water or sterile saline
of Medical Research (ICMR) in collaboration with the
to contain 0.1 mg (moist weight) in 0.1 ml of vaccine
WHO and Centre for Disease Control (CDC), US
which is given intracutaneously.
Public Health Services. The intake for the study started
in 1968 and was completed in 1971, including about
Efficacy of BCG Vaccine
2.6 lakh participants out of a population of 3.6 lakhs.
BCG was used successfully in humans for the first ' The entire population of all ages was eligible and
time in [921 by Weil-Halle, a colleague of Calmette
tuberculin reactors were not excluded, in contrast with
34
previous trials. Two BCG strains, Copenhagen and
Paris, were tested at two doses, 0.1 mg and 0.01 mg.
Neither of the vaccines, whether in full or reduced
dosage, had given any protection against the bacillary
form of pulmonary tuberculosis as assessed over a 7.5
year follow up period. No data are available from the
■ study to evaluate protection in children. Very little
disease was observed in the period immediately after
infection.22 Incidence peaks were absent in young
children and in young adults but the incidence increased
logarithmically with age.
The findings of the south Indian trial were disappoint
ing. The ICMR convened an expert committee meeting
to scrutinise the trial methodology, wherein it was
agreed that no errors in the conduct of the field op
erations or in the data processing could have been so
serious as to invalidate the results.10 In the first meeting
of the ICMR/WHO Scientific Group23 it was stated that
the data obtained in this trial are unique and of great
importance for tropical countries, and should be con
sidered as the starting‘point for further intensive in
vestigations into the epidemiological, bacteriological
and immunological problems related to BCG vaccine
and tuberculosis, as well as studies to test certain
hypotheses, eg, that the immune response of the popu
lation was unusual, that the vaccine were inadequate
to confer immunity, that the south Indian variant of M.
tuberculosis acted as an attenuated immunising agent,
and that mycobacteria other than M. tuberculosis may
have partially immunised the study population.
Explanations for the Varying Efficacy of BCG
The explanations and hypotheses for the varying
efficacy of BCG have been discussed in detail5-7. BCG’s
varying efficacy due to interactions with the immune
responses to other mycobacterial infections still re
mains one of the most popular explanations. Palmer and
associates24-25 showed in animal experiments, and in
studies of US navy personnel, that infections with
certain non-tuberculous mycobacteria could impart some
protection against infection with the tubercle bacillus
and such naturally acquired protection could mask any
protection due to BCG vaccination, partially or totally.
This explanation was criticised l?y Hart26 as being
inadequate to explain all the differences between the
various BCG vaccine trials. Comstock et aP1 also coui l
not find any evidence for lowered protection by BCG
in those with intermediate levels of tuberculin reactiv
ity, and this was thought to be due to non-tuberculous
mycobacterial infection, in the Puerto Rico trial.
In the 1980s, Rook, Stanford and associates28'30
proposed that exposure to non-tuberculous mycobacte
ria (NTM) can result in two types of cell-mediated
responses, the ‘Listeria type’ and the ‘Koch type’.
Which of these two types of responses is evoked de
pended, among other factors, on the mycobacterial
species inducing the response and the immunomodulating
cells and the pathway brought into play. They further
proposed that the ‘Listeria type’ of response enhances
the protective effect of subsequent vaccination with
BCG while the ‘Koch type’ response opposes the pro
tective effect of BCG. Once Koch-like responsiveness
is present, this blocks subsequent recognition of further
species by Listeria-like responses. BCG vaccination of
a person with a pre-existing Koch-like response will
temporarily boost this response, but completely fail to
reconvert to Listeria-like responsiveness or induce
protection from pathogenic challenge. According to
them, this is. likely to have been the situation in the
south Indian trial.31-32
Investigations carried out since then have been able
to produce some evidence supporting the hypothesis
that infection with NTM induces a protective response
and does not interfere with the immunity produced by
BCG. Attempts to demonstrate that prior infection with
any of the mycobacteria induced a suppressive effect
against BCG have failed.33’36
The study population in the south Indian BCG trial
was characterised by a very high prevalence of nonspe
cific sensitivity.37 Further, nearly 20 per cent of the
NTM obtained from sputum samples of subjects in this
area belonged to the Mycobacterium avium-intracellularescrofulaceum (MAIS) complex.38 and a recent study on
the isolation profiles of environmental mycobacteria
present in soil, water and dust samples, and sputum
samples of symptomatics in this area has shown that
isolates belonging to the MAIS complex are predomi
nant in waler, dust and sputum samples while organisms
of the M.fortuitum complex are predominant in soil
samples.39
The hypothesis that oral immunisation with M. avium
intrace.'Iulare complex might induce tolerance which
35
might interfere with the immune response to subsequent
BCG immunisation was studied at the Tuberculosis
Research Centre (TRC)40 in guineapigs challenged with
M.tuberculosis, and. it was found that there was no
interference with the protective immunity induced by
BCG. A later study using intradermal route showed
that while there was no interference with the immunity
due to BCG by prior exposure to NTM on the early
course of challenge infection, modulation could be
taking place during the later course.41
The variation in the efficacy of BCG has also been
attributed to the differences between the BCG prepa
rations.42-43 Another view is that BCG is more effective
• in stopping haematogenous spread of the bacteria as
occurring in primary progressive disease and endog
enous reactivation versus exogenous reinfections.44 Other
explanations include the genetic or physiological dif
ferences between the trial populations.
More recently, another explanation for the varying
efficacy of BCG has been proposed based on the ob
servation that a subgroup of the population may be
actually adversely affected by vaccination.45 Several
trials include in the assessment many subject with weak
initial tuberculin sensitivity, due either to environmen
tal mycobacteria’, infection or to infection with
M.tuberculosis. While it is accepted that vaccine
efficacy may be moderately reduced in the former
subgroup, it has been postulated that the lattar subgroup
may be at risk of reactivation of tuberculosis soon after
vaccination perhaps from focal reactions due to en
hancement of their weak sensitivity. The low levels of
efficacy in several trials, and the early adverse effect
in the south Indian trial are broadly consistent with this
hypothesis.
In a search for identifying the correlates of vaccineinduced protective immunity, more than 70000 subjects
in northern Malawi were skin tested with soluble an
tigens of the tubercle and leprosy bacilli, and then
followed up for 5 years for tuberculosis and leprosy
incidence. Incidence rate ratios were calculated to compare
subjects with different levels of prior skin test sensi
tivity.16 It was found that delayed type hyper-sensitivity
to mycobacterial antigens has different implications for
tuberculosis and leprosy: low level hypersensitivity,
probably attributable to environmental mycobacteria,
was associated with protection, but persistent vaccine
associated hypersensitivity to mycobacterial antigens
.36
was not a correlate of vaccine derived protection against
mycobacterial diseases.
.
BCG Vaccination and HIV Infection
With regard to BCG vaccination in HIV infected
individuals, there are reports of BCG abscesses in HIV
seropositives, and of disseminated infection due to BCG
in at least one case given BCG.47 However, in all these
cases,, the infection could be successfully treated.
Since the risks and known consequences of natural
infection with tubercle bacilli are likely to be more
serious than the risks associated with live attenuated
vaccines, the WHO has recommended that all asymptomatic"
HIV infected children should receive all standard vac
cines both live and inactivated; and those with symp
toms of AIDS Related Complex (ARQ/AIDS should
receive all vaccines other than BCG. However, in_
developing countries like India, where extensive HIV
testing is not possible the WHO Expert Group has
recommended that all infants should continue to receive
immunisation against all the major preventable dis
eases.48
There is no evidence that BCG activates HIV in
fection.49 Further, it has been observed that the inci
dence of disease due to M.avium intracellulare (MAI)
in AIDS patients varies from region to region and it
has been postulated that this difference is the result of
a protective effect of neonatal BCG vaccination.5,1 In
the USA, 30 per cent of patients with AIDS develop
MAI disease in contrast to only 10 per cent of AIDS
patients in Sweden. This difference in incidence be
tween the two countries could be due to BCG vacci
nation: most Swedish patients with AIDS would have
received BCG in infancy while those in the USA would
be unvaccinated. This is further supported by the fact'
that over 50 per cent of AIDS patients in Netherlands,
where BCG vaccination is not given, developed disease
due to MAI or M.scrofulaceum. Also, in a limited
follow up of HIV infected individuals at the TRC.
Madras, it has been found that while a few HIV infected
- individuals developed disease due to M.tuberculosis no
case has been encountered so far with disease due to
MAI (Tuberculosis Research Centre - Unpublished
observations). It has been suggested that MAI disease
in AIDS is not due to direct infection but that it arises
from long standing silent foci of MAI in the lymphatic
tissue of the patient.51 It is possible that neonatal BCG
vaccination prevents overt infection by MAI and may
therefore prevent inapparent persisting infection of
lymphoid tissue thus removing the internal reservoir of
these bacilli from which AIDS-related MAI disease
may arise later in life.52
BCG as an Immunopotentiating Agent
The widespread use of BCG has demonstrated its
safety and its potent immunogenicity. This has also
led to its suggested use as a carrier to vaccinate against
other diseases.53'54 BCG and other mycobacteria are
highly effective adjuvants. It is one of the few
vaccines that can be given at birth, and with a single
dose it induces long-lived immune responses. Till now,
nearly 3 billion vaccinations have been carried out
using BCG with a long record of safe use in man. There
is also a worldwide distribution network with experi
ence in BCG vaccination. The adjuvant properties of
BCG and its cell wall components have previously been
made use of in experimental vaccines. Mixtures of .
BCG and schistosomal antigens have been used success
fully to protect mice in a model of schistosomiasis.55
Mixture of muramyl dipeptide, which is one of the
mycobacterial cell wall components that contributes to
the adjuvant properties, and killed simian immunodefi
ciency virus (SIV) has been shown to provide partial
protection against SIV infection in monkeys.56 Mix
tures of BCG and killed M.leprae have been used in
large scale trials to assess the efficacy of this leprosy
vaccine candidate.57
Recombinant BCG and BCG as a Multiple Vaccine
Vehicle
Recently developed genetic engineering techniques
for mycobacteria have provided the means for the
introduction and expression of foreign genes in BCG.53-58
Recombinant BCG vaccine vehicles can induce immune
H-esponses to foreign proteins produced by the bacillus,
indicating that BCG can act simultaneously as an ad
juvant and as a vehicle to produce and deliver specific
antigens to the immune system. A BCG recombinant
may provide a longer lasting immunity to a pathogen
than a simple mixture of BCG and the antigen because
the antigen continues to be produced by BCG multi
plying in the host.
There is no ready answer for the question whether
there is an alterqative for BCG vaccine for protection
against tuberculosis. It is possible to improve the
protective efficacy of the existing BCG vaccine against
tuberculosis by using the tools of genetic engineering
even though very little has been achieved in this di
rection to date. Such an approach requires a full
understanding of the factors important in the virulence
of M.tuberculosis, pathogenesis of tuberculosis, and
protective response against,tuberculosis. Genetic de
letion or modification of mycobacterial virulence fac
tors or the addition of appropriate mycobacterial an
tigens important for protection might improve the ef
fectiveness of BCG as an antituberculosis vaccine.
CONCLUSION
'I
Fine and Rodrigues7 state that several factors, es
pecially the differences in BCG strains and regional
differences in mycobacterial ecology, in addition to
differences in trial methods, have all contributed to the
observed variation in BCG’s efficacy. They conclude
that despite our inability to predict its precise effect,
BCG is still judged worthwhile in many countries
because there is a possibility that the vaccine might
provide reasonable levels of protection against childhood forms of the disease in most populations.7 Recent
retrospective studies of BCG vaccine efficacy among
newborns and children have reported a protective
effect against all forms of tuberculosis ranging from 17
to 90 per cent, and protection against tuberculous
meningitis and against cavitary, miliary and bone and
joint tuberculosis has been estimated to be 75 per cent
or greater.5961 BCG vaccine, when effective, apparently
does not prevent infection but interferes with the
haematogenous spread of tubercle bacilli, thus reducing
the risk of severe primary disease and its compli
cations/'0 A meta-analysis of 14 trials and 12 case
control studies showed that (he protective effect of BCG
against tuberculosis was 51 and 50 per cent respec
tively.62 Combining data from 7 trials reporting on
deaths from tuberculosis, the relative risk for death
among the vaccinated was 0.29 (71 % protective effect).
Five case-control studies reporting on tuberculous
meningitis showed a 64 per cent protective effect, and
3 case-control studies reporting efficacy of BCG in
preventing disseminated tuberculosis showed a 78 per
cent protective effect. The conclusion was that BCG
reduces the risk for active tuberculosis on an average
by 50 per cent, and the risk for tuberculosis death,
meningitis and disseminated tuberculosis. The fact that
37
-
BCG provides variable though significant protection
against leprosy increases its value in those countries
with high prevalence of leprosy.63
It has been concluded that vaccination alone at
I least with the present vaccine, cannot substantially
influence the epidemiological situation but should be
continued for children when its use is justified for
prevention.w4 BCG vaccination of the newborn usually
prevention/
protects against serious forms of tuberculosis, is safe
and cheap and should be used in developing countries,
including India, where tuberculosis is more prevalent.’
In such highly endemic areas,
due to
areas, due
to the
the frequent
frequent
occurrence
of exogenous reinfection
and also udue to [|the
e
*------- -- ------j
|: waninff
nf r°teCtive effect ____
t
I?/"2 //,
over .the
years after vaccination, BCG vaccination of the newborn may not offer
protection in the later years of life when revaccination,
perhaps
pemapb at
ai the
me school going age, may have to be
considered. In developed countries with low preva
lence of tuberculosis, BCG should be given to high risk
groups such as immigrants, their newborn, contacts of
patients with tuberculosis and hospital staff.65
1.
Ada, G.L. The immunological principles of vaccination
Lancet. 335: 523, 1990.
2.
Lagrange, P.H., Hurtrcl, B. and Slack, J.L. Vaccines against
mycobacteria and other intracellular multiplying bacteria.
Ann Inst Pasteur/Immunol. 136D: 151, 1985.
4.
Mackaness, G.B. Cellular resistance to infection. J Exp Med
116: 381, 1962.
Sokhcy, J., Bhargava, I. and Basu. R.N. In: The Immunisation
Programme in India: A Handbook for Medical Officers.
Government of India. Ministry of Health and Family Welfare
New Delhi, 1984.
5. .j Fine, P.E.M. BCG
BCG vaccination
vaccination against
against tuberculosis
tuberculosis and
and
leprosy. P.r Med Bull, 44: 691, 1988.
6.
7.
Fine, P.E.M. The BCG story: Lessons from the past and
'l^P^'cn'ions forthe future. Rev Infect Dis. 1] (Suppl 2): 5353
Fine, P.E.M and Rodrigues, L.C.
Lancet. 335: 1016, 1990
H. Calmette A. and Guerin.. C. Sur quclqucs proprielcs
bacille tubercluleux cultive sur la bile. CR Acad Sci 1
1456, 1908.
12. Guerin, C. In: BCG Vaccination Against Tuberculosis
p 48 RoscnthaI- LlltIc- Brown, Boston, Massachussets. 19
13. Frappier, A., Portclance, V., St Pierre, J. and Parissct,
BCG strains! Characteristics and relative efficacy. In: Stc.
of Immunisation in Tuberculosis Ed. E.C. Chambcrlay
Fogarty Int Cent Proc 14, Washington, 1972, p. 157
14. Milstein, J.B. and Gibson, J.J. Quality control of BCG v
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that may influence vaccine effectiveness and safety Wh
EP1/GEN/89: 3, 1989.
15. WHO Expert Committee on Biological
FStandardisation. I
quircments for dried BCG Vacci
—ine.. WHO Tech Rep Ser. 3<
23. 1966.
16. Collins. F.M. Tuberculosis. In: Bacterial Vaccines Ed.
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Kothari Book Depot. Bombay, India, 1972. p. 495.
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3.
10. Ten Dam, H.G. PResearch on BCG vaccination. Adv Tul
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atypical mycobacteria on P"''
BCG vaccination
and tuberculosis
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V* »
.> I.1
Am Rev Respir Dis. 94. 553, 1966.
w
wvjiv
8.
Luelmo. F. BCG vacindtion. A/n Rev Respir Dis. 125: 70.
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26. Hart. RD. Efficacy and applicability of mass BCG vaccination
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9.
Smith, D.W. BCG. In: The Mycobacteria (Part B). Eds. G.P.
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38
28. Rook, G.A.W. The importance to the International Union
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31. Shield, M.J. The importance of immunologically effective
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New York, 1983. p.43.
33. Collins, F.M. Kinetics of the delayed hypersensitivity re- ,
sponse in tuberculous guincapigs and mice tested with several
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47. Von Reyn, C.F., Clements, C.J. and Mann, J.M. Human
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51. Good, R.C. Opportunist pathogens in the genus Mycobacteri
um. Ann Rev Microbiol, 39: 347, 1985.
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36. Smith, D., Reeser, P. and Musa, S. Docs infection with
environmental mycobacteria suppress the protective response
to subsequent vaccination with BCG? Tubercle, 66: 17,1985.
52. Grange, J.M. Is the incidence of AIDS-associated Myco
bacterium avium intracellulare disease affected by previous
exposure to BCG, M.tuberculosis or environmental mycobac
teria? Tuberc Lung Dis, 75: 234, 1994.
37. Narain, R., Vallishayce, R.S. and Vcnkalcsha Reddy, A. Value
of dual testing with PPD-S and PPD-B. Indian J Med Res,
68: 204, 1978.
53. Aldovini, A. and Young, R.A. Humoral and cell mediated
immune responses to live recombinant BCG-H1V vaccines.
Nature, 351: 479, 1991.
38. Paramasivan, C.N., Govindan, D., Prabhakar, R.,Somasundaram,
P.R., Subbamrnal, S. and Tripalhy, S.P. Species level iden
tification of non-lubcrculous mycobac'cria from south Indian
BCG trial area during 1981. Tubercle, 66: 9. 1985.
54. Young, D.B. and Cole, S.T. Leprosy, tuberculosis and the new
genetics. J Bacleriol, 175: 1, 1993.
39. Kamala, T., Paramasivan, C.N., Herbert, D.. Venkalesan, P.
and Prabhakar, R. Isolation and identification of environ
mental mycobacteria in the Mycobacterium bovis BCG trial
area of south India. Appl Environ Microbiol, 60: 2180, 1994.
40. Narayanan, S., Paramasivan, C.N., Prabhakar, R. and Nara
yanan, P.R. Effect of oral exposure of Mycobacterium avium
inlracellulare on the protective immunity induced by BCG.
J Biosci, 10: 453, 1986.
55. Pcarle, E.J.. James. S.L., Hicny, S.. Lanar. D.E. and Sher,
A. Induction of protective immunity against Schistosoma
mansoni by vaccination with Schistosoma paramysin (Sm97).
a nonsurface parasite antigen. Proc Natl Acad Sci USA, 85:
5678, 1988.
56. Desrosiers, R.C., Wynad, M.S., Kodama, T., Ringler, D.J ,
Arthur, L.O., Schgal, P.K., Letvin, N.L., King, N.W. and
Daniel MD. Vaccine protection against simian immunodefi
ciency virus infection. Proc Natl Acad Sci USA, 86: 6353,
1989.
39
57. Bloom, B.R. Learning from leprosy: A perspective on immu
nology and the third world. J Immunol, 137: 1, 1986.
BCG vaccine in the prevention of tuberculosis: Mcla-analysis
of the published literature. J Am Med Assoc, 271: 698, 1994.
58. Jacob, W.R., Tuckman, R. and Bloom. B.R. Introduction of
foreign DNA into- mycobacteria using a shuttle plasmid.
Nature, 327: 532, 1987.
63. Ponnighaus, J.M., Fine. P.E.M., Sterne, J.A.C.. Wilson. R.J.,
Msosa. E., Grucr, P.J.K., Jenkins. P.A.. Lucas, S.B., Liomba.
N.G. and Bliss. L. Efficacy of BCG vaccine against leprosy
and tuberculosis in northern Malawi. Lancet. 339: 636, 1992.
59. Padungchan, S.» Konjanarat, S.. Kasiratta, S., Daramas. S.
and ten Dam, H.G. The effectiveness of BCG vaccination
of the newborn against childhood tuberculosis in Bangkok:
Bull WHO, 64: 247, 1986.
60. Snider, D.E. Jr., Rieder, H.L., Combs, D., Bloch, A.B.,
Hayden, C.H. and Smith M.H.D. Tuberculosis in children.
Pediatr Infect Dis J, 7: 271, 1988.
64. Styblo, K. Overview and epidemiologic assessment of the
current global tuberculosis situation with an emphasis on
control in developing countries. Rev Infect Dis, 11 (suppl 2):
S339, 1989.
•
65. Citron, K.M. BCG vaccination against tuberculosis: Inter
national perspectives. Br Med J, 306: 222, 1993.
61. Tidjani, O., Amedomc, A. and ten Dam, H.G. The protective
effect of BCG vaccination of the newborn against childhood
tuberculosis in an African community. Tubercle, 67: 269.
1986.
This write-up has been contributed by Dr. C.N. Paramasivan,
Dy. Director (Sr. Grade), Dr. Daniel Herbert, Research
62. Colditz, G.A., Brewer. T.F., Berkey. C.S.. Wilson. M.E..
Burdick, E., Finebcrg, H.V. and Mostcllcr. F. Efficacy of
I
Officer and Dr. R. Prabhakar,
Research Centre, Madras.
Director, Tuberculosis
DIRECTOR/.TE GENERAL OF HEALTH SERVICES
NIRMAN BHAVAN, NEW DELHI 110 011
No.T-18020/6/80-TB
From?
The Director General of Health Services
To
All Directors of Health Services
of States/Union Territories
26th Aug.,1980
Sir,
Sub: The new policy of BCG vaccination in the National
Tuberculosis Control Programme
As you are aware, the BCG vaccination programme has been in operation in our country for the last 30 years, The vaccination was
initially offered to all persons negative to tuberculin tests and
later to all persons in the 0-19 years age group without any tuber
culin test. The strategy of BCG vaccination programme was to cover
the entire susceptible population initially by a mass campaign and
thereafter to maintain the protective effect of BCG vaccination in
the community by covering the young population added by new births
regularly through the general health services.
To make BCG vaccination routinely available in the general health
service, therefore, the BCG vaccination policy of the country was
revised about three years back and it was decided that:
1) The mass BCG vaccination teams should be disbanded and the
technicians of these teams should be posted in Primary_Health Centres
and sub centres for training of all the para-medical workers in the
rural areas in the technique of BCG vaccination.
2) In future, BCG vaccination will be performed by the multi
purpose health workers like basic health workers, ANMs, etc. in
their respective areas of responsibility under the expanded pro
gramme of immunization.
-
—
3) The multipurpose workers will cover the infants within 3-9
months of their birth rather than immediately after birth, as
tuberculin conversion after vaccination immediately after birth has
been found to be unsatisfactory and BCG vaccination within 3-9
months after birth is operationally convenient for the multipurpose
workers in the EPI, as this can be performed at the time of giving
any of the thru-, doses of DPT vaccine.
4) In urban an.-as where BCG vaccination of the new boms imme
diately after birth has been in operation for a number of years
because the new horns are available in the maternity institutions
immediately ~ft- r the mother’s confinement, and once the mother
leaves the hospit.il, it is difficult to contact the child,new born
vaccination imm-dJ -itely after birth may continue.
The recently published results of the BCG trial of the ICMP in the
x Chingleput district have created some doubt in the minds of various
members of the profession about the use of BCG vaccination. The
results have shown that BCG vaccination failed to prevent emergence
of infections pulmonary tuberculosis cases in the vaccinated group
in the trial. However, the direct benefit of BCG vaccination is in
the reduction of the incidence of clinical forms of tuberculosis
diseases following upon primary infection, like miliary tuberculosis,
meningeal tuberculosis, bone and joint tuberculosis, tuberculosis
lymph adenitis, etc. The Chingleput study has not provided any
definite evidence, one way or the other, regarding effectiveness of
2
BCG in preventing such clinical d
’
diseases
after primary infection,
°ther/cientific BCG studies suggest that’enoGgh
.
--- protection
is indeed conferred by BCG vaccia■•,
•
y
vaccination
against
these types
of cli—
nical tuberculosis manifestations
“tazaj that are mostly prevalent in
infants and children.
All
BCv vaccination therefore continues unchanged.
Obi th^. para-medical workers in the rural areas who are going to be
tifnTEM^XulZh
S
thC ExPanded Programme of Immunizavaccination
The bO
trained in the technique of BCG
rr
The training methodology has already been circulated
Duof^India. letter NO.18011/1/77-PH dated 24.5.1977.
I t
fo y-1
"I S
S
x' ~
in the
the vl£v th?n X-n g0Gfbag° grouPs first and gradually go down to
pu™s?o>
! the new boms. This has been done with the
va^inatllnPfi ^ly traln?n9 the Para-medical workers for intradermal
i'^tb
th very thln skins of the new horns and infants and
also in the process of such training, to cover the backlog of un
aviil2bl°d1^latiODlin the 0-19 ylars age group that
avc.liable in -the rural areas.
district
°f immmization is implemented in any
should be in target age group to be covered under the programme
ul_. be all the infants within 3-9 months of their birth as oer
the recommended immunization schedule.
P
?r?QS Where new borT1 3CG immunization immediately after
f,r a’lon9 time, the same may be^ont^ued
tor operational convenience.
arla*9ha™0inSfiotbh eOVefed ™der BCG vaccination in urban and rural
cular
clearly explained in this Directorate cirthi Imo; TB Off,:
2^-2.78, that has been circulated to all
Centres in ii? Ib If 2
Directors of Training and Demonstration
centres in all the States and U.Ts.
One BCG vaccination ;performed properly within the first year of
lite is considered to be adequate,
<
. /as
the protection afforded lasts
for several years. Revaccination at subsequent
years of life is
therefore not being considered at present.
*
3CqV?St you to kindly bring the above instructions
to the
nonbin
.po^sons engogod in BCG vaccination and others responsible^ for implementati on < f the EPI in your State including
paediatricians. District and State TB and EPI Officers, PHC
Medical Officers, etc.
4
Yours faithfully,
sd/~
(Dr B. Sankaran)
Director General of Health Services
o,
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WWWM»>--------------------------(Excerpt from the Paper read at the Commonwealth
.Medi cal Con fe ren ce , Calcutta, byP.V. Benjamin,
M.B.B.S., T.D.D.)
Why B.C.G. Vaccination has been allotted
such a high priority in the scheme (of
Planning Commission)is a legitimate question,
especially because this is not used exten
sively in the United Kingdom or America or
in some of the more advanced countries of
the Commonwealth. Tuberculosis has been
controlled without B.C.G. in many countries
and some eminent epidemiologists have even
questioned the wisdom of giving so much
importance to B.C.G. Vaccination as tills may,
in their opinion, distract attention from
lotlier important measures which have proved
at their value and without which tuberculosis
Mjcannot be controlled. At the outset it may
be stated that those who advocate B.C.G.
Vaccination in India do not consider that
B.C.G. alone can control tuberculosis. The}'
do not overlook the fact that B.C.G. is only
one of the measures for tuberculosis control
and that the other accepted methods such as
die provision of institutions for diagnosis,
treatment and isolation are essential and
Should not be neglected.
What India needs by way of tuberculosis
institutions is 3,000 to 4,000 clinics and
500,000 beds. As against this need we have
only 110 clinics and about 10,400 beds.
It Is estimated that about 450 crores of
rupees will be required for the establislunent
of the minimum number of institutions and
about 60 crores of rupees a year to run them.
■"Tlie present annual expenditure in the whole
of India for tuberculosis work is not more
than 2 crores of rupees. It is against tills
^background that the question of B.C.G.
Vaccination in India is to be viewed. We
are proceeding on the assumption tfiat if
B.C.G. Vaccination programme is carried out
extensively and systematically, that is, if
at least 90^ of tlie tuberculin negative
individuals in tlie country are vaccinated
^.during the next five to seven years, a
reduction in the tuberculosis morbidity and
mortality in the country to 1/2 to 4/5 of
F
I
of!/•A"'3
iV/ ,
f)
-A GJ-ulO-S L f '
frirr' iv, ~
VeP' /^Jo
j\_' A kj
what is at present can be anticipated in
about 20 years' time. But it should be
emphasised that it would be too much to
expect that B.C.G. alone can make any appre
ciable effect on the epidemiology of tuber
culosis unless it is carried out_on._a_mas^
scale and in the shortest possible time.
Where infection is widespread and tlie con
ditions for its transference from one person
to another are widely prevalent, vaccination
of a few thousands here and there cannot
materially change the trend of tuberculosis
mortality in the country as a whole, though
it will, undoubtedly, have some effect on
the small groups vaccinated. Even in Eh gland
and America it is now recognised that B.C.G.
Vaccination should be offered to groups
especially exposed to tuberculous infection
such as medical students, nurses and those
children living in tuberculous homes. In
India, as could be judged from tne tuberculin
reactions, practically the whole population
especially those who live in the cities and
urban areas are exposed to
tuberculous
in fection.
B FNJ AM I X
The author of this contribution is the
Adviser-in-T.8. to the Government of India
and Technical Adviser to the Tuberculosis
Association of India, New Delhi.
(WHS BULLETIN FOR SEPTEMBER J9 52
(3)
It is estimated that in India there are
about 170 million persons below tlie age of 20
and about 17 to 20 millions of these are in
the urban and semi-urban areas. Hie Planning
Commission has accepted the principle of mass
vaccination and has directed that the initial
effort should be made in the urban and semiurbai areas and extended whenever possible to
rural areas. To carry out this programme the
Government of India is providing the advisory
and co-ordinating staff, tuberculin and.
R.C.G. vaccine and the budget provision for
this purpose for 1952-53 is Rs. 4 laklis.
The UNICEF is providing the necessary equip
ment and the WHO the foreign personnel
needed. They have already allotted or spent
760,000 on this account. The State Govern
ments have to provide the necessary local
staff and the running expenses in their areas
and’it is estimated that JL9 to 20 laid is of
rupees per year have to be spent by all the
States on this programme. If B.C.G. Vac
cination is carried out on a mass scale and
if the programme of building institutions
is pursued simultaneously it will give the
country the immediate benefit of reducing
the incidence of the disease, thereby lesseiing the number of institutions required in
the country by about 50 to 70-%.' This will
also give time to build up the necessary
institutions. Without B.C.G. Vaccination
the prospect of tuberculosis control in
India under the present ci re instances is
very depressing, but with B.C.G., there is
hope of achieving it within a measurable time.
DOCTORS
BEDS
4
India requires 5 lakh beds for
isolation J treatment of its
5 lakh T.B. patients.
As
aqainst this only lO.UOO beds
are avai1able.
(♦) DGHS BULLETIN FOR SEPTEMBER 1952
4
Ii
To man the required number of
T.B. institutions I ndia requires
15,000 qualified Doctors.
As
aqainst this only 150 are
avai i a b 1 e.
i
c"
v
ye>
"IPr.trr.T'tw
treatment now-a-days.
r
This is specially so,
because greater advances in the medical care
of scuh people have helped much in the sal
vaging and even in the permanent cure of
patients who at one time would have considered
themselves doomed if they had been infected
by the T.B. germ.
Now, if proper treatment
and precautions are taken in time, not only
is the patient helped to recover but his
assistance is taken so that the disease is
not communic'ated to others. Thus the erst
while rapid spread is soon prevented.
The successful rehabilitation of the pa
tient when he is ready for it requires all
the skill and care of the Social Workers
concerned. On them finally rests the future
happiness of people who have faced tragedy,^
but have also been assisted to over-come it.
This they can accomplish only if they get
the full co-operation of the community and
the government of the country concerned.
The Ministry of Health at the Centre and
some at the local levels, also the T.B.
Association in India, have done much to rouse
consciousness about the social aspects of
this disease both through dissemination of
pertinent facts and the training of appro
priate personnel. They have to their credit,
as being almost one of the first Public Wel
fare Departments in India that has recognised
the importance of a team approach to the
prevention and cure of Social problems.
In the promotion of a sound Health pro
gramme which is their major responsibility
they have also included the contributions
that can be made by social workers, both by
training them and appointing them as funds
allow. It is hoped that other Departments
will soon follow their example and accept
the fact that Man is a social animal and
therefore cannot be served in water-tight
compartments. He has many more needs than
the merely physically and materially visible
ones. These social and emotional needs can
only b e adequately tended to by social workers
who are equipped with special knowledge and
skill to do so.
(8) DGHS BULLETIN FOR SEPTEMBER 19S2
Col.
C.K.
Lakshmanan,
the new
Director General of Health Services,
Government of India.
"it is obvious that India cannot find for many
years to come the finances or the personnel needed
for the anti-tuberculosis measures of the type which
has been used and found successful in the more
advanced countries of the world. We have to take
advantage of every possible preventive measures
which can be introduced in our country without
much capital outlay and which will not need a
large number of highly qualified doctors and nurses.
This is the time when B.C.G. has come to its own
and is being widely used as a preventive measure
in many countries in the world. This is a method
which can be introduced fairly quickly and at
comparatively little cost.
The country has now
the experience of over 3 years in tuberculin testing
and B.C.G. Vaccination by different groups in the
various parts of India. There is a general awareness
of the seriousness of the tuberculosis problem in
the country and there is constant demand for intro
duction of anti-tuberculosis measures. The response
for B.C.G. Vaccination has been very good, and in
fact we are at present not in a position to cope
with the demand as quickly as we would wish, though
there had been criticism and objection to this
vaccination from certain quarters."
C.K. LAKSHMANAN,
Lieut. Colonel
I
11 hl f®
TUBERCULOSIS
e?
A.C. UKIL, M.B., M.S.P.E. (Paris), F.C.C.P.,
F.S.M.F.B., F.N.I., F.A.S.
Apart from general and health education
and improvement in the standard of living
Including housing, a sound plan for the
control of tuberculosis should have the
following objectives, viz.,(l) the pre
vention of spread of tuberculosis from known
infectious cases; (2) the protection of groups
highly exposed to tuberculosis and most
likely to get the disease; and (3) the
furthering of all other preventive ami cura
tive measures including after-care and re
habilitation.
The application of protective vaccination
is meant to meet the second of the above
o bj ec ti ves • The isolation of infective
cases may be the most important method in
checking the spread of tuberculosis; but,
being a costly programme, it may not be
possible for an under-developed country like
India to provide a sufficient number of beds
for the purpose within a short period. Hence,
vaccine with a living but weakened variety
of tubercle bacillus which has proved to be
permanently harmless for man and animals, at
repeated trials extending over 20 years. The
term B.C.G. is derived from the first letters
of the name of the vaccine, which was Bacillus
of Calmette and Guerin. Hie speaker, having
been a former associate of Professor Calmette*
personally tested the -harmlessness of the
bacillus and the efficacy of the vaccine and
the findings were published in a series of
papers between 1927 and 1946. At the present
time, the methods of preparation and standardi
sation have been so perfected by skilled
workers in special laboratories solely devoted
to this work that its harmlessness is assured.
In India, the vaccine is being manufactured
according to international standards in a
special laboratory at the King Institute of
Preventive Medicine, Madras.
we have to think of a method which does not
involve a large expenditure and which can be
fairly rapidly carried out. The use of a
suitable protective vaccine against tuber
culosis naturally arises in our mind. The
only practical way so far known for producing
specific resistance against tuberculosis, even
if this resistance is not absolute, is B.C.G.
Vaccination. However, the full effectiveness
of B.C.G. Vaccination will be achieved only
if it is carried out as part of a general pro
gramme of tuberculosis control.
After working persistently for over 13
years, Drs. Calmette and Guerin, two French
bacteriologists working at the Pasteur
Institute in Paris, were able to prepare a
* From a broadcast talk given before the
A.I.R.^ Calcutta, June 7, 1952.
V-
The author of this contribution is a
Consulting Physician for Chest Diseases to
the Medical College Hospitals, Calcutta and
Chairman of Bengal Tuberculosis Association.
DGHS BULLETIN FOB SEPTEMBER 1952
(9)
I
To those who are already naturally infected
with the tubercle bacillus, usually from an
infective person in the community, it
confers a certain amount of resistance but the
dose of germs which enter the body cannot be
measured in this process. Such persons do not
require to be inoculated with the B.C.G.
Vaccine. B.C.G. Vaccine has the merit of
being given in a measured dose and whether
it has "taken" or not can be tested after 5-8
weeks. If there is a case of tuberculosis in
the house it is better to isolate the child
during this period. In case die vaccine takes
successfully., the tuberculin test becomes
positive at the end of this period. If it
proves negative, the vaccine has to be given
again. A preliminary tuberculin testis, there
fore, needed before the vaccine is given,
except in new-born babies during the first
few days after birth.
Those who have already
been infected, i.e., in whom the tuberculin
test proves positive, need not and should not
be vaccinated. The vaccine is suitable for
those wno have not been infected, i.e., in whom
the intra-dermic tuberculin test, done by
introducing a measured quantity of the pro
ducts of gpowth of the tubercle bacilli
(known as tuberculin) into the superficial
lavers of the skin, proves negative.
Immunity or resistance conferred by trie
B.C.G. Vaccine is akin to the immunity pro
duced by an attack of, for example, syphilis,
i.e., die immunity lasts so long as the human
body harbours even a small quantity of the
specif c germ or virus. Work done in various
countries in the world shows that resistance
conferred by the B.C.G. vaccine lasts for35 years during which period, if the tuberculin
test proves negative, the vaccine should be
re-administered. In the U.S.S.R.^ to whicn I
paid a visit recently, the vaccine is given
thrice before adolescence is reached, namely,
once after birth, again at the end of the
Kindergarten stage, andlastly at the commence
ment of the teen age, provided, of course,
the tuberculin test proves negative in such
cases.
The protective power of the vaccine has
oeen tested in many countries during the last
25 years or so. It has been generalLy found
that the disease rate in susceptible groups
of population has been reduced to at least
one-fifth among those receiving this vacci
nation, as compared to groups which did not
receive it. This naturally contributes to a
lowering of the general mortality rate.
If it is possible to mobilise a campaign of
inoculating the whole tuberculin-negative
population in a country, priority should be
given to (1) new born infants, particularly
in slums and tuberculous households, (2)
children in creches, schools,orphanages etc.,
(3) pupils and medical and auxiliary personnel
who are exposed to infection in nursery
schools, medical schools,hospitals or lunatic
asylums, (1) the general population, parti
cularly of younger age groups, from among
whom recruitment is made for the Police, Army,
Navy and Air services, and the factories, coal
fields and plantations, and (5) j^iugees and
those wtio come from rural areas to large
centres of population for residence, study or
employment. In Denmark, a concerted campaign
of B.C.G. vaccination has brought about a
phenomenal reduction in tuoercul ous meningitis
and miliary tuberculosis in children, in a
sharp decline in the number of older children
admitted to the children's sanatoria and in
the tuberculosis mortality rate.
The campaign was inaugurated in India in
194H with the aid of the International Tuber
culosis Campaign which is a joint enterprise
by UNICEF, V>HO, the Scandinavian Voluntary
Organizations and the Government of the
country concerned and since July 1951 with
the aid of UNICEF/W.H.O. Already nearly
millions people have been vaccinated. 11 is
hoped to cover 80^ of the tuberculin-negative
population in urban and semi-urban areas
within a period of 7 - 10 years, if all the
constituent States and the public cooperate
with the campaign. This is likely to lead,
as has happened in other countries, not only
to a reduction in tuberculous disease and
deaths but will probably effect a great
‘ PR? .
saving for the Government in limiting the
number of tuberculosis institutions in the
country. 11 is a perfectly safe method of
vaccination which does not adversely affect
the health of the individual vaccinated.
( 10) DGHS BULLETIN FOB SEPTEMBER 1952
J—
...
DIVERSIONAL THERAPY FOR TB PATIENTS
• St
1ot
a
e.
of
J
By Di vya Bhatt, B.A., M.Sc., (Boston)
ve
oe
Sir William Osler once said that the fate
of a T.B. patient depended more on what he had
in his head than what was in his chest. Ibis
fact is increasingly recognized today in the
treatment of tuberculosis. A tuberculous
patient usually passes through a long period
of heavy emotional stress arising from socio
economic factors like social stigma, separa
y
Ji
y
g
tion from the family, problems of job, edu
cation of the children, his own treatment,
etc. This affects the course of his treat
ment. Diversional Therapy deals with this
tremendous impact of mind on body, and has
for its main purpose the relieving of boredom
>1
1
2
1
i
I
1
<
I
I
and helping in the recovery of the patient by
keeping him as happy as possible, during his
treatment. This has been accepted by medical
authorities in advanced countries as an essen
tial part of treatment. It helps the patient
to divert his mind from the disease, makes
him a happy and well-adjusted person in the
hospital and thus ultimately contributes
towards his early recovery. In our country
also, the need for introducing Diversional
Therapy work is now being gradually realized
and a small beginning has been made.
the programme is introduced. A quick survey
of the patient's interests should beconducVed before introducing any new programmes and
activities.
Another factor which sometimes comes in the
way of making this programme a success is the
patient's fear of physical movement. The need
for physical rest is so much emphasised that a
patient gets almost obsessed with the fear
of movement, and even though he may be getting
physically better, he remains a mental invalid
with the consequent result that he returns to
the hospital in a state of relapse. No doubt,
rest is essential but something also must be
done to keep his mind away from dark and
depressing thoughts while he is under treat
ment to bring him back to normal life by the
time he leaves the hospital. Through the
Diversional Therapy work the patient can be
Diversional Therapy work in its initial
stages consists of introducing light, easy
recreation and crafts or games. The patients
as a rule are usually grown up men and women
with set patterns of life; and so some of them
may become more rigid because of this sudden
on-set of a terrible disease. Hence, one has
to be very care fill in introducing such a pro
gramme. The need, aptitude and interest of
every patient has to be understood first.
His suggestions have to be taken into consi
deration. Even for teaching small things he
has to be treated as a grown up person,
otherwise, it may, at times, become difficult
to get him interested in small things. There
should be a thorough understanding of what the
patient is and what he would like to do before
Mrs.
D I VYA
The
author of
Lecturer in
Delhi
the
BHATT
this
Medical
Diversional
Social
Work
at
is
a
the
Work.
She is also
Supervisor
Incharge of
School of Social
Field Work
contribution
Therapy Centre at the Silver
Jubilee Tuberculosis Hospital,
Delhi.
OCRS BULLETIN FOR SEPTEMBER 1952
I
(11)
helped gradually to over-come this fear
complex and be prepared for future life. What
the patient needs is self-confidence which
gives him a feeling of getting better. Even
tne making of a little paper flower or the
playing of a game of carrom will have a more
salutory effect on his recovery than a hundred
consoling words of the doctor.
While planning a programme it should be
kept in mind that it has to be conducted by a
trained social worker. Diversional Therapy
work should be closely integrated with social
service programme. While teaching some crafts
or conducting literacy classes, the worker
will be presented by the patient with many
personal problems. But once the relationship
between the patient and the worker is estab
lished, the patient will not hesitate to seek
a solution of these from the worker. Only a
trained social worker can competently handle
these. Unless the basic social services are
rendered, mere teaching of crafts or intro
duction of any other diversional activity
will not succeed. This is so because the
patients must be helped in the solution of
their own problems first before they can be
expected to take any interest in the Diver
sional Therapy programme.
It may however be mentioned that although
this programme is generally started with the
object of diverting the minds of the patients
from their disease by providing recreational
activities and light crafts, which may keep
them happy and well-adjusted, and thus contri
bute towards their early recovery, it can also
be developed into a vocational rehabilitation
centre. In fact as die Diversional Therapy
work develops anr1 as the patients take more
and more interest, regular vocational train
ing should be provided. Tuberculosis always
entails the problems of rehabili tationand
Rehabilitation Centres will meet a long felt
demand.
DIVERSIONAL THERAPY CENTRE, DELHI.
Diversional Therapy programme was started
by the Delhi School of Social work in co-ope
ration with the Ministry of Health, Govt, of
India in Silver Jubilee T.B.Hospital, Kingsway,
Delhi. Initially, this programme was aimed at
providing some activities for the patients
(12) DGHS BULLETIN FOR SEPTEMBER 1952
P
m
E
and thus helping them break the tedious
monotony of the mechanical hospital routine.
Before introducing any activity, contacts
are made with each patient. A rapid survey
is made. The patients are asked to fill in
the forms indicating their interests, apti
tudes, previous occupational experience and
lastly, their inclinations.
(
!
i
It will be interesting to note that this
survey itself acted as a first item on the
Diversional Therapy Programme. It was for
the first time in the history of this hos
pital that somebody took individual interest
in the patients and gave them an opportunity
to express themselves, The patients wrote
pages for one enquiry! They were so nappy
and excited!
After analysing the data, die following
activities were started for bed and ambulatory
patien ts:-
(i) A small library’ was established and
books were distributed in the wards.
(ii) Paper flower-making was introduced.
(iii) Language classes were started.
(iv) Straw-string bag making and leather
work were introduced.
(v) Embroidery, knitting and painting
etc. were also started.
To the above mentioned crafts, various
light games were added. These few activities
along with relayed music really caused a
change in the hospital atmosphere and in due
course helped in the development of more
activities like health competitions among
the patients, exhibition of articles they
were learning to make, group games and game
competition, composition of poems and cele
bration of festivals.
Whenever a patient was discharged from the
hospital, paper flower garlands were made and
offered. Farewell speeches were also given.
Whenever there was a festival, wards were
decorated wi th the various things, the patients
had leamt to make, and on Di wall day patients
kept busy preparing greeting cards for sending
to their friends in and outside the hospital.
These and many other similar activities deve
loped an initiative in patients for learning
and creating something good. It also created
interest in their surroundings and in other
I
people. For the first time they found their
minds off the disease. They became sociable.
Excitement and smiling faces were seen all
us
e.
ts
over the hospital.
ey
in
d
s
2
I
have also been extended to the Wards where
the bed patients are provided equipment for
light crafts, books, paintings and other
desired material which brings to one's mind
tiie case of a patient of this hospital suf
fering from tuberculosis of the Spine and
put in a plaster cast for 2 years.
He is
not able to sit up at all as the cast covers
him from the arm-pits down to the hips. This
Monotony was broken.
As the Diversional Therapy programme be
came more popular, need was felt for a Centre
where equipment could be housed and the
patients enabled to get together in order to
learn, to enjoy and to have their social
functions. The Ministry of Health, Govern
ment of India, kindly provided two nice
rooms for this purpose and this, together
with an increased grant, have enabled us to
form a full fledged Diversional Therapy centre
at the S.J.T.B. Hospital, where now the
patients learn tailoring, cutting, leather
work, typing, shorthand, embroidery, knitting
work, string bag making and painting. Here
also they listen to music, read newspapers and
books, play games, attend classes to learn
patient was provided with drawing and paint
ing materials and 11 is amazing to see the
beautiful pencil sketches he makes the while
he takes his treatment! He finds a tremend
ous joy in his recreation. His gloomy ex
pression has disappeared and his face glows
with happiness and pride in his work. This,
then, is what the Diversional Therapy work
can do to a t.B. patient. Joy, happiness
and, may be, a quick recovery, as well.
Before concluding, it may be mentioned
that this programme would not have been
various languages, and hold discussion
groups - thus, to laugh and chase away their
blues. FYirther developed, such a Centre
could very well become a good Vocational
Training Centre, Thus, for example, an ex
possible without th:e keen and continuouV^
interest shown by Rajkumari Amrit Kaur,
Minister for Health, she has really taken
to her heart the needs of the t.B. patients
and h,as helped very much in developing
this Diversional Therapy work.
patient who at first was a student at this
very Centre das been given the job of a
tailoring teacher. The services of the Centre
DGHS BULLETIN FOR SEPTEMBER 1952
I
(13)
BCC
By Alan Gilroy, O.B.E.,
An awareness of the increasing incidence of
Tuberculosis amongst tea estate workers found
expression at a meeting of the Assam Branch
of the British Medical Associationearly ih
i949j .when the importance of tuberculin
testing and B.C.G. vaccination was brought
to the notice of both Medical Officers em
ployed in the Tea Industry and the Indian Tea
Association. When it was learnt that the
International Tuberculosis Campaiga (ITC) was
organising a nation-wide B.C«G« campaign, the
decision to have the advantages for tea estate
populations was promptly made. The Calcutta
Committee of the Indian Tea Association
readily agreed to finance the campaign and
the Ross Institute of Tropical Hygiene,
advisers on preventive medicine to the tea
estates, agreed to organise and supervise
the work. Government agreed to allow the
I.T-C. Scandinavian team, already in Assam,
to train teams for tea estates and agreed
further to a free supply of vaccines and
equipment. Three teams were recruited in
December 1949 and were trained by Dr. 0. Hagan,
leader of the I.T-C. team. A fourth team was
added in June, 1950.
Each team consisted of two vaccinators, an
Assistant Medical Officer as leader, and a
Compounder. Personnel received the Indian Tea
Association scale of salary and allowances
and, in addition, a generous field allowance
to compensate for constant travelling.
Names of U- Teapis and Record Clerk.
Dr. R.B. Roy, L.M.F.
Team No. i:
Mr. K.P. Paul Choudhury,
Compounder.
Dr. N. Dey, L.M.P.
Team No. 2:
Mr. All Hussain, Compounder.
Tear. No.
3:
Teas No.
4:
Record Clerk:
Dr. J.K. Mach, L.M.PMr. M. Sangdem Ao,
Compounder.
Dr. S.K. Phukon, L.M.P.
Mr. Dilawar Hussain,
Compounder.
Mr. S.G. Banerjee.
(U) DGHS BULLETIN FOB SEPTEMBER 19S2
1
ririv
D.T.M.i K.
In addition to a thorougp technical training,
Dr. Hagen imbued the men with enthusiasm for
their work.
The teams' pride in the smooth
running of the campaigi, in the large number
of Mantoux tests per team and in the small
number of absentees was retained throughout.
Even the earthquake of 1950, in spite of
disrupted communications and the natural
anxieties of the teams concerning their
homes , did not delay the campaigi by as much
as a day.
The tea estate population of I .T. A. tnember-
estates numbers about 9 lakhs. It was de
cided to include all persons over the age of
1 year. It was realised that there migrt not
be much to be gained in vaccinating aged de
pendents but to have excluded them would have
led to miainderstandings.
Record cards, one for eacn person, were
distributed to es tates well before the arrival
of the teams.
The campaign had to be planned to cause a
minimum of interference with estate work es
pecially in the monsoon months wnen all avail
able labour is required for leaf plucking.
The teams agreed to start the day's work
early, and by 8 a.m., each team nad given the
Mantoux test to 1000 persons and upwards.
The Estate Managers had been advised on a
choice of site for the teams and had been
asked to put up bamboo fences so that persons
approached the vaccinators ih single file and
did no t overcrowd them.
0r.
ALAN
GILROY
The author of this contribution is the
Principal of the Ross Institute of Tropical
Hygiene, India and Pakistan Branch,
Cinnamara (Assam).
ai
w
T
t
rr
s-
Of persons taking the Mantoux test only
5.9& failed to have the test read.
The average number of Mantoux tests per
team (of 2 vaccinators) per month was 9,854.
For months on end the average per team exceeded 13,000.
g,
Jr
Records
th
The completed record cards are returned
to the Headquarters of the Ross Institute
in Assam fbr analysis where this very onerous
and tedious job is carried out by one clerk,
employed for the purpose by the I.T-A. and
whose part in the campaigi has been most im
portant.
er
1
f
1
The campaign commenced in the Sibsagar
and Cachar Districts simultaneously, 3 teams
working ir. the former and 1 in the latter.
The schedule was planned to take advantage of
the dry season to visit districts where com
munications would be difficult in the rainy
season.
r
i
The Progress
The campaign lasted almost exactly 2
years and was completed in December 1951 by
which time 8.4 lakhs of the estimated total
population of 9 lakhs had been tested.
To 31.12. 1951.
Man toux-tes ted
Positive
Vaccinated
Persons
837,61,3
426,953
361,401
The Future
Although the population of tea es tates
in Assam is a stable one, never thel ess a
certain number of "short term" recruits
arrive each year. Mantoux tests for these
people and for the infants who pass their
first birthday, are now being considered
and the importance of testing the duration
of Mantoux conversion is also borne in mind.
Very many people have contributed to the
smooth organisation and without the financial
support of the Indian Tea Association and the
ready co-operation of Estate Managers and
Medical Officers it would not have been
possible.
DGHS BULLETIN FOR SEPTEMBER 1952
I
(15)
GrOX - Be Cr Its
Rtprlnttd from Thf Indian Journal of Tubf culosis^'uL XXVlU,
July, 1^3f.
REVIEW ARTICLE
PRESENT STATUS OF IMMUNISATION AGAINST TUBERCULOSIS
G.V.J. Daily*
The discovery of the tubercle bacillus by
Robert Koch in 1882 and his classical demons
tration, in 1891, of the effect of a second infec
tion with tubercle bacilli in an already tuber
culous guinea pig, which later came to be known
as the ‘Koch phenomenon’, heralded scores
of attempts to develop a specific immunising
agent against tuberculosis, derived from the
tubercle bacillus. The attempts were indeed
inspired by the observations of Edward Jenner
who about a hundred years earlier, in 1798,
had also noticed the increased reactivity to vacci
nia virus occurring in persons who had been
previously vaccinated or who had had smallpox.
conflicting results could be the fact that the
test-systems used for testing the vaccines in
animal models varied from experimenter to
experimenter, as is seen in the varying results in
the potency assay of the same BCG vaccines in
different BCG laboratories (Smith, et al 1971).
Thus, non-viable vaccines have never been
employed though interest in these vaccines has
not ceased even to-day. Although Vole vaccine
has been shown to confer a significant degree
of protection, vaccination with Vole vaccine
causes some unpleasant reactions at the site
of vaccination and as such has never been prac
tised on any large scale. Thus, the only vaccine
that has been used, and used extensively through
In animal experiments conducted over the out the world, is the BCG (bacille Calmette
years, the immunising capacity of four distinct. Guerin), which is an attenuated variant of M.
types of ‘vaccines’ were studied: preparations bovis. BCG vaccine does not cause progressive
consisting of small numbers of living tubercle disease in man except in the extremely few
bacilli; preparations containing mycobacteria corded cases and under exceptional circumstan
that are non-pathogenic to man but pathogenic ces. it is also avirulent in experimental animals
to certain animals or birds; products of ubercle except the Syrian golden hamster.
bacilli or tubercle bacilli themseves, killed by
a variety of physical and chemical methods and
Virtually since BCG vaccine was introduced
finally, preparations containing attenuated
variants of originally virulent strains of tubercle by Calmette and Guerin in 1921, it has been a
bacilli pathogenic to man (Weiss 1959, a b, c). subject of controversy. It was introduced in
Europe at a time when Europe was just reco
The first was never widely tested and dis vering from the ravages of a war and tuberculosis
carded as too hazardous. The second i.e. several was quite common, and interest in BCG,
mycobacteria that are non-pathogenic to man, considerable. With greater Experience’ which
were shown to be ineffective until the discovery was not uniform, interest in many countries
of the effect of the Vole bacillus (Af. microti) including United States and Britain waned.
which causes naturally occurring disease among Scandinavian countries however have always
field rats (Wells, 1937) and is also pathogenic been very enthusiastic about BCG vaccination.
to certain other species of animals including the In the post second world-war years, massive
guinea pig. Vaccine prepared from the vole BCG vaccination campaigns were organised in
bacilli was shown to offer significant and a Europe through the International Tuberculosis
measurable degree of protection in man (Medical Campaign with Headquarters in Copenhagen.
Research Council, Great Brimin, 1972). 7 he Tuberculosis at that time was still relatively
first attempts to induce immunity with killed common and the privations of war had aggra
tubercle bacilli or their products were initiated vated the situation in many countries. Soon
soon after the discovery of the tubercle bacillus. alter, BCG was introduced in many developing
For instance, Daremberg in 1889 reported that countries of the world and in India, it was first
several rabbits which had been inoculated with tried out in 1948 and vaccination programme
cultures of tubercle bacilli sterilised by heating started on a large scale, as a mass campaign,
for 15 minutes at 115°C or for six hours at in 1951.
70°C survived longer after virulent challenge
infection. Later his claim was not substantiated
By 1950, even though BCG vaccination, was
by others. Since then scores of animal experi in use for nearly 30 years and several BCG
ments using non-living vaccines have been re campaigns had already started, the opinion
ported (Weiss 1959, a b, c) with conflicting about BCG in many developed countries, es
results. One of the possible reasons for these pecially Britain and United States could only be
•Tuberculosis Specialist, National Tuberculosis Institute, 8, Beilary Road, Bangalore-560 0037
lad. J. Tab.* V©L XXVlli, Na. 3
118
C VJ. BAILV
considered as lukcwar a. This was bv ,t slated
In man, nov-rycr, evidence ol the protective
by D’Arcy Hart et al as
.mederate cflect of BCG vaceination can be obtained
opinion on BCG in Britninund iu.the USA in through clinical observation, or better still,
1949 might have been summarised as follows: through
through controlled
controlled trials
trials.
Literature is
(I) it gave some protection in those specifically replete with rcooris on <
,i i J- [c^rls 011 observations and
exposed to tuberculous infection in their homes r
controlled trials but most of thVse ”winotT
or at work; (<) it could be expected, at least in considered
considered as
as statistically
statistic,illy valid
valid.
general populations with low lUndards of living
to reduce the inciThe
The. first _ controlled trial which can
dence of tuberculous disease appearing within a be
be considered
considered as
as statistically
statistically valid
valid was
was started
started
. few years of a natural first infection with tubercle by
Aronson
and
others
(1958)
in
1935
by Aronson and others (1958) in 1935. Prior
Prior to
to
Vj?l!US......... " ^Hart’ poHock and Sutherland, thi? study, most of the evidence in favour of a
protective effect of BCG in man came from cli
cii-
nical observations. Some of these observations
Opinions on the efficacy of BCG Vaccine H?L1?or?iSoI‘d tha.n I1*® ®vidcncc available for
were formed, in addition to the demonstration several
‘
* other prophylactic measures and are
of its effects in animal models, in several ways: discussed below.
Observations based on ‘experiences’ with the
use of BCG, early uncontrolled observations and The earlier observations and studies
studies on the protective effect of BCG and,
the results of controlled trials. While the Heimbeck’s studies :
first two could be considered to be easily in
One of the earliest observations and studies
fluenced by several factors, more recent observa- *BCG were those by Heimbeck in Norway,
tions indicate that conflicting results obtained
Heimbeck (Heimbeck, 1948), started
even in well controlled trials could have ln.
been due to one or more factors as yet un-identi- tuberculin testing the staff of the Oslo municifled.
42•J
PJl hospital in Norway. The hospital then had
about 2,000 beds and about 300 of those were
occupied by patients suffering from tuberculosis.
Protective Effect of BCG Vaccine
He had observed that many nurses developed
tuberculosis within a few years after joining
Though all BCG vaccine produced in the nursing. Table 1 presents the fate of the nurses
world in dozens of BCG laboratories to-day, joining in 1924, 1925 and 1926. Of the 109
comes from the original BCG cuiture produced nurses joining in 1924, 58 were tuberculin
and 5I’ ?bercul»n.negative. By the end
iub^Hn’n^^e'cominWiote^^
vary. This is because with repeated subculturing, t"‘— ’*
the genetic characteristics of BCG (or, for that i..
o.... and all the others had converted to the
negative
matter, several micro-organisms) undergo change, tuberculin positive state. Over the next few
As a result of repeated sub-culturing, the changes years whereas only ,J case of tuberculosis
lHAk BCG Producc? in one lab?ratory may not developed among the initially/ tuberculinporituberculin posi
oe the same as the changes obtained in another. tive, among
—— •«- 5! in-tially
<• tuberculin
«
the
negative
In one instance, only the morphological charac- nurses,
nurses, 18
18 cases
cases developed'
developed with
with 77 deaths?
deaths. The
The
tenstics of the bacilli may have changed with fate
fate of
of the
the cohorts
cohorts admitted
admitted in
in 1925
1925 and
and 1926
1926
no changes in the protective effect. In another, was also, similar
except for
deaths in the tuber(
- ---------------- - —
while the morphological characteristics are not culm
* ” negatives.
affected, the protective effect may have changed
considerably. It is therefore, common practice t Observing this striking fate among those
to refer to BCG produced in different laboratories initially tuberculin negative nurses, Heimbeck
as ‘strains’ of BCG. Thus, BCG produced in offered, from 1927 onwards, BCG vaccination
Madras is referred to as ‘BCG-Madras’ (strain to all tuberculin negative new entrants. He,
1331) and BCG produced in Paris as ‘BCG- however, did not compel them too much to get
Paris’(strain 1173) etc. In animal experiments, vaccinated with the result that of the 899 nurses
most strains of BCG show a higher or a lower (Table 2) admitted between 1927 and 1934, 436
protective effect measured as the survival time were tuberculin positive, 95 were tuberculin
of the animals (guinea pig, mice etc) which have negative but refused vaccination, and 368 were
been vaccinated andjater challenged, i.c. in tuberculin negative and BCG vaccinated. Wherefected,
as com as 42 cases of tuberculosis developed amone the
„ u with virulent tubercle bacilli,
.
pared to those that are not vaccinated but are 95 unvaccinated tuberculin negatives, 37 cases
only challenged. (Ladefoged, Bunch-Christensen developed among the 368 vaccinated tuberculin
and' Guld, 1970),
negatives during the following few years after
A Sa. 4*J*
-•
- ------
.
«*•
*
*
.
...
Ind. J. Tub., Vol. XXVm, No. 3
...v
PRBSBN1 STATUS OF IMMUNISATION AGAINST TUBERCL’I OSJS
1 ISi
Tahir 1
L'finibeck's observation among ituduit nuncs in Osh
Year of admission
Tuberculin Positive
■ Total
Tuberculin Negative
Cases of TB
Deaths
Total
I
I
Cases of TB
Deaths
1924
58
1
0
51
18
7
1925
42
1
0
72
26
1
1926
52
1
0
62
18
0
Table 2
Heimbeck's BCG study among student nurses in osh1927-1934
Tuberculin and BCG
status on entry
Nos.
Ccses of
Tubercu
losis
Percent
Tub. Positive
436
27
6.2
Tub. Negative, Not
vaccinated
95
-.2
4-!. 2
Tub. Negative, BCG
vaccinated
368
37
10.1
all pupils and one year after BCG vaccination
of the majority of tuberculin negatives.
The fate of the pupils is shown in a summa
rised form in Table 3. While of the 94 who were
tuberculin negative and were not vaccinated,
41 cases of primary tuberculosis occurred, among
the 106 tuberculin negatives vaccinated with
BCG, no case of primary tuberculosis occurred.
The development of progressive primary disease
is also presented. Though this is a retrospective
study, and again, not statistically fully valid,
the complete absence of primary disease among
the vaccinated is striking and can scarcely be
explained as being entirely due to bias. Indeed
the above t’vo studies gave strong indications of
the protective effect of BCG in man and provi
ded an impetus for planning statistically valid
studies to obtain irrefutable proof of the pro
tective effect of BCG.
vaccination—a reduction of about 76 percent
among vaccinated. This early observation of
Heimbcck cannot be considered as absolute
Tabic 3
proof of the protective effect of BCG mainly
Hyge s study: An Epidemic of Tuberculosis among
because the 95 ‘controls* were self-selected and
school girls during the second World War
thus the allocation was far from blind. Even
so, since the study population was all uniform
i.c. all women aged about 20 and all belonging
Students Cases of
to urban middle class families, of similar socio Status before
Progres
epidemic
exposed
economic status and exposed to similar risk of
tubercu sive Pul
losis
infection, the study can be considered as of
monary
(Primary) T.B. over
interest and provided one of the first evidences
of the protective effect of BCG in humans.
12 years
Hyge’s study :
An epidemic of tuberculosis in school girls
aged 12.-13 years, has been described by Hyge
(Quid, 1980). The epidemic occurred in a blacked
out atr-raid shelter where all the pupils were
exposed to infection b> chance. This occurred
1-3 months after routine tuberculin testing
(Mantoux 100 units) and X-ray examination of
Tub. Negative
94
41
20
Tub. Negative, BCG
vaccinated'
106
0
4
Tub. Positive, Not
vaccinated
105
1
14
Jnd, J. fob., Vol, XXVJH, No. 3
120
G.V.J. daily
The controlled trials
Controlled trials have come to be recognised
as the most reliable methods of establishing the
efficacy of therapeutic or prophylactic measures
in man and conhrm what has been studied in
antmal models as also from ‘experiences’ from
application in humans. The trials are meant to
establish not only that a curative or a prophy
lactic measure is effective, but the actual degree
of efficacy. In these trials, after the safety of the
measures is assured and ethics of the studv
examined, the hypotheses are clearly laid down,
subjects (persons) among whom the studies will
be conducted are carefully identified, the approprate design selected and meticulous care is
exercised in the follow-up of all subjects for the
same period of time. Possibly, the most impor
tant characteristic of these trials is that, neither
the person who administers a measure nor the
subject to whom it is administered decides which
measure is applied to whom. Subjects are allo
cated to the measures through a double-blind
randomised scheme.
In the BCG trials, following an appropriate
randomisation scheme, subjects arc allocated
either to ‘BOG vaccination* or to ‘no BCG
vaccination’ (controls) blindly. All the subjects
are followed-up for a specified and the same
duration oi time, to identify the new cases of
tuberculosis arising from among them. (It will
be obvious that preliminary investigations arc
carried out to exclude from analysis of the
protective effect, persons who at the time of
allocation are cither infected or are actually
suffering from tuberculosis). The protective
effect of BCG is expressed as the proportion
by which the incidence of new cases is reduced
among the vaccinate^ as compared to the con-
A very large number of BCG trials have been
reported in the literature. Most of these trials,
for one reason or another do not satisfy the
criteria mentioned above and are thus statis
tically not valid. As upto the time that the
Chmgleput study of the protective effect of BCG
vaccination was started, the studies indicated
m Table 4 can be considered as some of the
studies that are statistically valid and conducted
in the general population.
Tabic 4
JUiul's of Six conJroHet! trials of BCG vaccination Against Tuberculosis
Trial and age of
lut^ecte
Intake period
Duration of
foiled-up yn.
Vaccination
gfAUp
No. of
subjects
Cases of
tuberculosis
Protective
eflbctive%
i
North Amer.* .
Indians (9) 1*18 yrs.
1W-M
9-11
Control
BCG
PS7
1551
238 64
80
Georgia (14) 6-17 yrs.
1947
12-23
Control
BCG
2341
2498
3
5
None
1949L-51
5Hi
Control
BCG
27338
50634
73
31
93
Puerto Kko (13)
Georgia, Alabama (21)
5+yaara
Great Britan (5)
14-15| yn.
Madaoapalle (15)
Allan
1950
14
Control
BCG
17854
16913
32
26
14
1950-52
15
Control
BCG
12699
13598
240
56
78
9-14
Control
BCG
5808
5069
46
31
28
f"
1950-55
‘Figuraa In brackets indicate the reference nos. of the reports on these studies.
lad. J. TWk, Vol XXVin, No. 3
STATUS OP IMMUNISATION AGAINST TW1ERCULOS1S
The lit st of these studies was conducted
among the North American Indians (Aronson,
Arpnson and Taylor, 1958). The stucS popination was characterised by low socio economic
conditions and a high risk of tuberculous disease
At about the 10th year of follow-up the inci,
/.^culoais cases among the vaccinated
css tlian the incidence among controls.
At the time of the final follow-up i.e. at about
the ) 8th year, the protective effect wus still of
the order of 72 % since there were 42 cases of
tuberculosis among the BCG vaccinated compar
ed to 185 cases among the controls. In this study
not only the emergence of new cases was evalua
ted but also, the deaths were carefully assessed
As at the end of follow-up, there were 13 tuber
culous deaths among the BCG vaccinated
compared to 68 tuberculous deaths among the
controls giving a protection of 82%. Acid fast
bacilli could be demonstrated among 5 deaths
vaccinated and among 27 deaths that were not
vaccinated again giving a protection ra le of 82 %.
On lhc whole, this early but well conducted
study indicated a protective effect of about 80%.
J21
to be about 36% (Frimodt-Moller, Acharyulu
and Parth:isarathy, 1968).
It will thus bn observed that while animal
models almost always showed a measurable
degree of protection by BCG, experience in
humans varied considerably. In the words of
Ian Sutherland, who was always associated with
ihe MRC trial in Britain,
.the instinctive
reaction of any scientific worker, when be finds
that his results differ from those of another
scientific worker, is to mistrust the other man’s
results, and so it was not surprising that there
was a good deal of coming and going across the
Atlantic between the MRC workers and the U.S.
Public Health Service Workers, each group
prepared to be ver)' critical about the other’s
investigations. The results of this exercise have,
however, been entirely beneficial in that our
mistrust has been dispelled..,.” (Sutherland,
1971). After considerable deliberations, they
agreed that, of the many reasons that can be
associated for the lack of protective effect in
American studies, two reasons might be the most
relevant; firstly, the vaccine used in some of the
American studies could have been prepared
from poor stiains of BCG and secondly, that
infection with atypical mycobacteria prevalent
in the United States may have itself offered
some degree of protection which masked the
protection offered by BCG. When the Chingleput study was planned and started in 1968,
this was the state of knowledge regarding the
protective effect of BCG vaccination.
f
three other studies were started
in different parts of United States of America
during the late forties. In the study in Puerto
.startc^ *n ^949, the protective effect of
z nas b$cn assessed in 27,338 controls and
50,634 vaccinees. As at about 6 years the pro
tective effect was 31 % (Palmer, Shaw, and Cornstock, 1958) while at the 18th year of follow-up
it still was the same i.e. 28.7% (Comstock,
Livesay and Woolpert, 1974). The effect was
sinmar in different age groups. In another study The Chingleput BCG trial
in Georgia in a population of about 5.000 child
ren aged InlUELV*
6-17 years, no protective
Protc<*\c effect was
was v I® 1963. the Government of India took up
observed.
anri
AUkaT n .......................
th,rd Au]crican stu<ty m Georgia the question of conducting a BCG trial in India
ibAoT a very J,odcstJPr?tetf*ve effect of There
was
controversy
,
, still some
n
---------- in i.the country
about the use of BCG and it was felt that the
wXteMSW)*" Observed' (Comsto<:k
problem had to be settled by a controlled field
study under Indian conditions. The study
The Medicdl Research Council (MRC). (Tuberculosis Prevention Trial, Madras, 1980)
Great Britain carried out a study among British was planned in collaboration with the World
school leavers (all aged 14-151 years) wherein Health Organisation and the Centre for Disease
12.699 were unvaccinated and 13,598 were Control, United States Public Health Service
offered BCG vaccination (Medical Research and conducted by the Indian Council of Medical
Council, Great Britain, 1972) The protective Research as a separate project.
effect was assessed at various intervals for 15
years and it was found that it was almost cons
The study was undertaken in Trivellore
tant at about 80%. This was also true when the taluk of Chingleput district in Tamil Nadu. The
effect was assessed against different manifesta intake (i e. admission of population to the study)
tions of tuberculosis. In the same trial, another was eta: ted in July, 1968 and ccrnpleted in
section of the study subjects had been vaccinated March, 1971. During this period, a total popu
with Vole vaccine and in them also the protective lation of about 3,60.000 persons in 209 conti
effect of Vole vaccine was similar to that of guous villages and one town were registered
BCG. i.e.,about 80%. Inasmallstudyinagcncrai on individual cards. AU persons aged one month
population of about 10,000 persons in Madana- and above were offered one of two doses of
palle in South India, the protective effect as at BCG vaccination (0.01 mg or 0.1 mg) or a
about 9-14 years after vaccination was assessed placebo on a random basis. Two strains of
Ind. J. Tub., Vol. XXVm, No. 3
122
C.VJ, baily
BCG, the Copenhagen and the Paris strains were
used. At the same time, all persons aged 1 year
and above were tested with Tuberculin (PPD-S)
and an antigen prepared from an atypical
mycobacteria (PPD-B), the former, to elicit the
status of infection with
tuberculosis and the
latter to elicit infection with atypical myco
bacteria. All persons aged 10 years and above
were also X-rayed and for those in whom X-rays
showed any abnormality sputum examination
by direct smear and culture was done.
The study population was systematically
and intensively followed up by X-ray and sputum
examinations in an effort to diagnose all new
cases of pulmonary tuberculosis occurring in
the community. In addition, representative
eamplcs of population were tuberculin tested
using PPD-S in order to elicit the status of
tuberculin sensitivity after BCO vaccination.
The population was characterised by high
prevalence and incidence of tuberculous infec*.
tion as well as high prevalence of non-specific
sensitivity. The overall prevalence of tuberculous
disease (pulmonary) was also high being very
much higher in males than in females.
Table 5 presents, in brief, the main results
regarding the protective effect of BCG vaccina
tion in the prevention ot puimoiinry tuberculosis
as observed in the study.
Tabic 5
The Cklnglepiu BCG trial: Rcsitltf* (7|
Given
Standi Goes BCG dard Dose
| (0.1 mg.) BCG
(0.01 mu.)
Tuberculin reaction at i Given
I Standard
intake
.
Yean)
Placebo
i.c. in al! probability, these were definite ca^cs
of tuberculosis. The protective effect is studied
among those who were initially tuberculin
negative i.c. reacting with 0-11 mm to PPD-S.
These arc again divided into two groups, one
reacting with 0-7 mm i.c. definitely not infected
at intake and the other reacting with an indura
tion of 8-11 mm. Some of the latter could be
considered to have been infected with M. tuber
culosis. Because of the large size of the study
population the denominators can be taken as
similar. The difference observed between the
three groups do not attain statistical significance. •
Thus, BCG gave no protection against the deve
lopment of bacillary pulmonary tuberculosis in
this study. The results were similar when analysis
was done for less definite bacillary cases as well
‘ as X-ray positive but abacillary cases.
Currcat Status of Immunisation Against Tuber
culosis in India Based on the Results of WeliConducted BCG Trials
The Chinglcpul study was conducted on the
hypothesis that BCG offers protection against
tuberculosis and one of the objectives was to
measure the exact degree of protection offered
by BCG With the present result in hand it is
scientifically appropriate to examine the possible
reasons for this result.
The study was meticulously conducted and
the procedures followed were constantly monito. :?d in order to obtain accurate results. Even
so, a committee of experts was appointed to
scrutinise the methodology and it, concluded
that no errors could have been introduced. In
further discussing the possible reasons for Ihis
result in the Trial in India, one major assumption
is made. That all trials listed in Table 4 and the
persent one are scientifically valid. Only those
hypotheses that are amenable to testing are
presented.
One of the reasons put forward by the Ameri
can workers was that the low protective effects
0-7 m-n
37
37
28;o:_ observed in the trials conducted in the U.S.
were due to the masking of the protective effect
8-11 mm
14
17
17 its. of BCG by the protection afforded by previous
infection with atypical mycobacteria. Examining
the problem in animal studies, Palmer and
Long (1966) found that atypical mycobacteria
(I) Distribution of definite bacillary cases of pul
do give some protection against tuberculosis in
monary tuberculosis only.
animals.
While BCG confers about 80% pro
(ii) Results similar for les^ definite bacillary cases
tection, photochromogens confer 68%, Scoto(culture negative on one specimen only) and cases
chromogensand non-chromogcns 50% and rapid
positive on X-ray only!
growers 15%. Further, if animals which have
(iii) Nos. vuccinatc4 are similar in all three groups.
been previously infected with photochromogens,
arc injected with BCG the protection is not
The table shows the distribution of new cases additive but goes up to 80% as in the case
of pulmonary tuberculosis that were positive of BCG. Thus—in an animal study, if animals
on culture of at least two specimens of sputum arc first infected with photochromogens and
I«d. Jk Tub., Vol, XXVIII, No. 3
PRESENT .'TTA'Hjy
’MMUNlSAWf AGA1? ST TUfiERCUU-ftS
then vaccinated with BCG the protection that
will be attributable to BCG woulu b- only
12/'==(80%-68%), If what is observed in ani.nals
is true of man, then in areas with high prevalence
of non-specific mycobacteria in the environ
ment, only the residual prctcciion would be
observed in the BCG trials. As has been said
earlier, the prevalence of nonspecific sensitivity
was very high in the study area indicating a
high prevalence of environmental atypical my
cobacteria.
A rough estimate of the type (photochro
mogens, scotochromogens, etc) of environ
mental mycobacteria prevalent in the area of the
study can be obtained from cultures of sputa
collected from study subjects, usually in a
survey such as this, at their homes. From the
sputum samples collected under field conditions,
such environmental mycobacteria would be
grown as contaminants. In the over 2,00,000
sputum samples collected and cultured during
the study in nearly 6% such ccntaniinants were
grown indicating the very high prevalence of
environmental atypical mycobacteria However,
it was observed that most of the mycobacteria
were those that gave only a low degree of pro
tection. In effect, only 1 % of all the atypical
mycobacteria isolated were typed as photo
chromogens which were shown by Palmer and
Long to confer a protection close to that of
BCG. If BCG were to confer a high degree of
protection of the order of 80%, one should have
observed some residual protection in the study
population since most infections with atypical
mycobacteria would probably be caused by
organisms that confer low degree of protection.
Thus infections with atypical mycobacteria may
not, at least fully, explain the zero protection
observed m the study.
Disease occurring as a direct extension of the
first infection (primary) itself is most common
in children and the forms of disease can be
termed as childhood forms of tuberculosis. These
include, besides the primary complex complica
tions such as miliary, meningitis, bone and
joint tuberculous etc. In contrast, adult forms
of tuberculosis represented mainly by cavitating
bacillary pulmonary tuberculosis is considered
to be m.iinly a result of later endogenous reacti
vation of a healed primary complex, and not
as a result of another exogenous reinfection with
tubercle bacilli. Since Koch demonstrated that
a second infection with tubercti bacilli in a
guinea pig is far more difficult than the first, it
has occurred to most workers that much nf
adult forms of tuberculosis occurs as a result
of endogenous reactivation The role of BCG
was based on this hypothesis as it will be obvious
123
that if exogenous rein?x »en ;hc main cause
of aduit typ-j of tube..rvlosi'.,.BCG obviously
cannot help.
In Shingle; ut area, iniccticu with tubercu
losis is ye y higi. and the viru! ,:ice cf M. tuber
culosis isolated in the area is prubcbly low. If
the high incidence of tuberculous infection re
sults m exogenous, reinfection ocing tby prime
cause of adult forms of tuberculosis, BCG may
not be expected to protect -’gaimt sue’', disease.
This hypothesis appears pro,. ;si! g in explaining
the complete lack protective effect :.i Chingleput study. Attempts are being irr.'-c to investi
gate this hypothesis This is rciev-’nl r»oi only
lor the explanation of the failure ef BCG to
protect in this study but ?h:o for ’ c tubercu
losis Programme in general.
Several other hypotheses ca.i be put forward.
Two of these are: the differences in immunolo
gical responses in differzni population groups;
the effect of nutrition on immunological res
ponses in the body. While the former could
be investigated, the latter appears to bt‘ net rele
vant because one canrot classi.y the entire
population of the study area as undernourished
or malnourished. Father, tuberculin sensiti
vity, which is an immunological resoonsc to
antigens derived from the tubercle bacilli, is
not influenced by the state of nutrition in the
population. In a study by Ganapati and Chakraborty (1981) where the state of under-nutrition
was classified into 4 grades depcrd:ng on the
severity of under-nutrition,--tuberculin sensiti
vity status was similar in children in all the four
grades of undernutritiun as also in children
classified as normal.
The present status of BCG vaccination stems
from the knowledge as it stands to-day. BCG
offered no protection against pulmonary tuber
culosis. At the same time, one cannot assume
that BCG may not protect against childhood
forms of tuberculosis which were not investiga
ted in the trial. It is however quite likely that
BCG would protect against such disease for ihe
following reasons: disease forms in animal
studies, where BCG almost always conferred
a measurable degree of protection, resemble
more closely childhood forms of tuberculosis
rather than adult forms. Secondly, several
controlled trials wherein protection against
other forms of tuberculosis h3s bcm investiga
ted (Medical Research Council, 1972; Rosenthal
ct al 1961) have shown that BCG offers protection
against childhood forms of tuberculosis. It is
thus appropriate that BCG vaccination, at
present in India, is limited to the prevention of
tuberculosis in childhord.
I s£.
T”b.» '/d. riVIP, No. 3
124
o.vj.aArty
In all studies, except the small study in
/Madanapalie, whore BCG was shown to be
protective, it was demonstrated that the protec
tion was durable i.c. it lasted as long as the
follow-up of the population was continued. This
is true irrespective of the degree of protection
as evidenced in the British trial where the protec
tion was high, and Puerto Rico where the protec
tion was low. On this basis, if a good vaccination
is offered at an young age, revaccination may
not be indicated as, in those studies, protection
lasted from 15 to 20 years. Primary infection is
most frequent in the younger ages and so is
primary disease. Thus if BCG vaccination has
to be given to prevent primary dtsease> it should
be. given before primary infection occurs i.e.
in India well before the age of 5 years. After
20 years of age, primary infection is less frequent
in India and risk of primary disease even less
frequent. Revaccination is indicated only when
the first vaccination has not been satisfactory—
Le. given either with a poor vaccine with a poor
technique. It may however be remembered that
post vaccination allergy tends to wane with
time (Tuberculosis Prevention Trial, 1980) and
deciding -on revaccination on the basis of waned
post-vaccination allergy may not be quite
appropriate. In animal experiments it has b cn
' shown that BCG induced allergy wanes very
fast but can be restored by repeated tuberculin
testing. With the waning of allergy, the acquired
resistance does not wane nor, at the same time,
with restoration of allergy by repeat ‘tuberculin
test' is the acquired resistance enhanced (Magnus,
1957). In a study in children it was shown that
BCG induced allergy wanes with time but
can be restored by repeated tuberculin testing
(Guld eta). 1968). Thus, revaccination may be
practised only if a group of children vaccina
ted very early in life show poor post-vaccina
tion allergy shortly after vaccination—say bet
ween 2 to 6 months. For all practical purposes,
revaccination is not indicated if the first
vaccination has been good.
Discussed above is the status of immunisa
tion against tuberculosis in India to-day. In
developed countries, with the sharp decline of
tuberculosis, interest in immunisation has also
declined. However, developing countries like
India, which have missea those winds of
change, may have to continue their interest
in immunisation. The story of immunisation
against tuberculosis is not yet over.
2. Weiss D. Vurciimtian mainst tuberculosis nith non
living vaccines. Amer. Rte. Resp. Dts, Kl, 4, 495
(959 b).
?. Wriss, £>.: Vaccination against tuberculosis with non
living vaccines: Amer. Rev. Resp. Dis. 80, 5, 676
(1959c).
4. Wells, A.Q: Tuberculosis in wild voles. Lanett, 1,
1221,(1937),
5. Medical Research Council, Great Britain: BCG A
vole bacillus vaccines in the prevention of tuberculosis
in adolescence and early adult life. Bull. Wld. Hlth.
Orgn., 46, 371 (1972).
6. Smith, D.W., Wiefeshans, E.H., Stark, R.H. and
Hardingc G.E.: Models for the potency assay of
tuberculosis vaccines: In: Immunisation in Tubercu
losis, Fogarty Intemutional Centre Proceedings
DHEW Publication No. (NIH) 72-6B, 205 (1971).
7. Hart, P.D.A., Pollock, 7.M. and Sutherland, I:
Assessment of the first results of the Medical Research
Council’s trial of tuberculosis vaccines in adolescents
in Great Britain: In: Advances in Tuberculosis
Research, Vlll, S. Karger, Basel and New York
(1957).
8. Ladefoged, A., Bunch-Christenson, K and Quid, J:
The protective effect in banhvoles of some strains
of BCG. Bull. Wld. Hlth. Orgn., 43, 71 (1970).
9. Arons an, J.D., Aronson, C.F. and Taylor, H.C.:
A twenty year appraisal of BCG vaccination in the
control of tuberculosis. Arch. Inter. Med, 101, 881,
(1958).
10. Heimbeck, J: BCG Vaccination of nurses. Tubercle,
29, 48 (1948).
11. Guld, J: The early evidence in favour of the protective
effect of BCG in man. Document WHO/TRI/ScG/79.5
(1980) Presented at the Scientific group on vaccina
tion against tuberculosis. A joint meeting of 1CMR
and WHO, New Delhi (1980).
12. Painter, C.E, Shaw, L.W. and Comstock, G.W.:
Community trials on BCG vaccination. Amer. Rev.
Tub Pulm. Dis, 71, 877 (1958).
13. Comstock, G.W., Uvesay, V.T. and Woolpcrt, S.F:
Evaluation of BCG vaccination among Puerto Rican
Children. Amer. J. Pub. Hlth, 64, 3, 283 (1974).
14 Coms lock. G.W. and Webstar, R.O.: Tuberculosis
studies in Muscogee county, Georgia. Amer. Rev.
Resp. Dis. 100, 839 (1969).
REFERENCES
1. Writs, D.: Vaccinatiun against tuberculosis with
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