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W O R L D H E A L T H ORGANIZATION

EXECUTIVE BOARD Twenty-ninth Session

Provisional agenda item 2.11

ORGANISATION MONDIALE DE LA SANTE

EB29/9 С/

1 December 1961 ORIGINAL: ENGLISH

THE MEDICAL RESEARCH PROGRAMME OF WHO FROM I958-I96I

Report

The Director-General has the honour to present to the twenty-ninth session of the Executive Board a report on the Medical Research Programme of WHO from I958-I96I which is annexed to the present document. The Board may wish, after consideration, to transmit this report to the Fifteenth World Health Assembly with whatever observations it may wish to make.

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W O R l ¿ D H E A L T H ORGANIZATION

ORGANISATION MONDI^

DE LA SANTE

THE MEDICAL RESEARCH PROGRAMME OF WHO

I958-I96I

REPORT B Y THE DIRECTOR-GENERAL

Geneva, 15 September 1961

MHO/AD/66.6I

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CONTENTS

Page

INTRODUCTION . 1 COMMUNICABLE DISEASES 8

Virus Diseases 8 Tuberculosis 19 Leprosy 26 Treponeraatoses 28

Enteric Diseases 32

Zoonoses 35 Bilharziasis . 39

Onchocerciasis and Filariases in General 斗 8

Other Parasitic Diseases * 5 )

Malaria 58 INSECTICIDE RESISTANCE AND VECTOR CONTROL 75

ANTIBIOTICS 81 IMMUNOLOGY 84 BIOLOGICAL STANDARDIZATION 85

CANCER 87 CAFiDIOVASCULAR DISEASES 91

HUMAN GENETICS • • • 98

NUTRITION Ю0 RADIATION HEALTH -

ANNEX 1 List of research projects 107 ANNEX 2 List of meetings of ACMR scientific groups and other scientific

advisory bodies of the Medical Research Programme of WHO 127

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INTRODUCTION

This report is based upon one presented by the Director-General to the Third Meeting of the Advisory Committee on Medical Research in June 1961 which was prepared to fulfil the wish of the Committee • The Committee felt that such a

statement would help them to understand more clearly the total research effort of W H O In this document, after a brief survey of the development of the research

activities of the Organization,there are summaries of the results of work in 175 projects during 1958-1961. Annex 1 contains a list of the titles of these research projects•

The details of the Organization! s research programme and its development

especially since 1958 have been published in the Official Records of W H O . H o w e v e r , a brief outline miglit help to put its achievements into perspective.

Early research policy

One of the functions of WHO contained in its Constitution (Article 2 (n) ) is

"to promote and conduct research in the field of health". The Second World Health Assembly"1* in 19斗9 laid down the guiding principles that should be applied in the

organization of research under the auspices of the World Health Organization.

Later World Health Assemblies and subsequent sessions of the Executive Board indicated the directions that WHO'S research activities might follow and stressed that research and co-ordination of research were essential functions of the

Organization,

WHO should encourage, support and co-ordinate work in existing national institutions and should not consider the establishment of its own international research institutions. 2

1 WHA2.19

¿ WHA2.19^ W H A 2 0 2 and EB7.R15 and ША7.52

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First priority should be given to problems related to WHO's programme and research should be part of the duty of field teams supported by W H O .1 Support for research should be oriented to encourage the assumption of responsibility for its continuance by local agencies Л

W H O should assist and encourage free communication between national research centres and should be particularly interested in research of an international 2 character. 3

Member States with suitable research resources were urged to co-operate with 4

W H O in research programmes applicable to international health and in striving to overcome the shortage of highly trained medical research workers in the world. lis w a s also stressed that WHO should keep in close touch with other specialized agencies interested in research in fields related to health.

Expansion of W H O1s research activities 5

The Eleventh World Health Assembly in June 1958 agreed that WHO could

"profitably expand its role in research" and asked the Director-General to study the role of WHO in research and to prepare a plan with costs • This was done with the assistance of a grant of .$ 300 000 from the United States Government. The Twelfth б World Health Assembly in May 1951 accepted this plan and upon it the research

programme of W H O has been developed. The Advisory Committee on Medical Research (ACMR) was established "to provide the Dire с tor- General with the necessary scientific advice in relation to the research programme". The Special Account for Medical

Research xvas established to receive voluntary contributions in any form and $ 500 000

1 WHA2.19

p

EB8.R34

) E B 1 3 . R 7 8 , VJHA7.52

\

WHA7.52

5 WHA11.35 б WHA12.17

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were added to the regular working budget for i960 for the medical research programme in that year. The Special Account has received contributions of $ 5〇〇 000 in i960 and 1961 from the United States Government and the National Institutes of Health of the United States Public Health Service have supported some of WHO's research programmes to the sum of. $ 48〇 000 annually (August 1961) •

The Intensified WHO Medical Research Programme"^"

The planning of the Intensified WHO Medical Research Programme, as it was originally called, was financed from the grant from the United States Government and was started Ъу two groups of internationally recognized leaders in the medical sciences which met in Geneva in August and October 1958. These groups recommended that the research programme of Ш 0 should be primarily concerned with the solution of problems needing international co-operation and with the solution of major problems where local

action is inadequate. It was recommended that Ш 0 should be concerned mainly with supporting the expansion of work in world health problems especially those related to W H Ofs programmes and with the development of medical research generally and particularly in countries where it was just commencing. To implement these recommendations WHO should assist in training and in the exchange of research workers, in planning of research, in developing methods widely applicable and in giving financial support•

The second group in addition stressed the importance of standardization of materials techniques, definitions e t c .

WHO in research, as it does in its other spheres, should act through existing national organizations and encourage their maximal development, WHO cannot avoid supporting research in basic problems since these will arise from practical needs•

1 Off. R e c . Wld Hlth Org. 9 5 , Annex 5

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There are certain broad indications for international co-operation in the

solution of medical problems• Among these are those in which all or many countries are involved such as in human genetics or many communicable diseases, in which

epidemiological studies are needed to reveal differences in frequencies or severity as steps towards finding causes and undertaking prevention, in which problems of limited extent are to b e studied because their solution may have wide implications, i n w h i c h problems need investigation in countries which cannot undertake the necessary investigations and in w h i c h internationally acceptable standards of various kinds are r e q u i r e d .

T h e planning period

Since the m e e t i n g s of these two groups in 1958^ WHO has called together scientific groups on research on different subjects^ consisting of 6-8 specialists of whom one or two should have wider interests and experience. U p to the end of 196l, 3 8 of these h a v e m e t and the subjects dealt with are given in Annex 2 . The recommendations of previous W H O expert committees and study groups were taken into account. Each scientific group reviews all the aspects of its particular subject and reports on

w h a t w o r k is being done and what WHO might take u p . These reports, which are restricted d o c u m e n t s , are to the Director-General who presents them to the A C M R . The ACMR reviews the recommendations in these reports and advises the Director-General what work it feels W H O m i g h t support j taking into account the problems in the particular field which need s o l u t i o n and their relation to WHO'S total research programme and financial resources.

T h e A C M R has m e t in October 1 9 5 9 , June i960 and June I 9 6 I . A report of the w o r k of the research programme of the OrganjLza,"tion was presen."fced. iso "the lasis meeting of the A C M R . T h e Committee endorsed the programme and expressed satisfaction with the progress that had b e e n made-

T y p e s of activity

W H O' S medical research activities have consisted of:

(1) Collaborative research undertaken by investigators in national institutes or laboratories u p o n the request of WHO and which for the most part implements the recommendations of the Advisory Committee on Medical R e s e a r c h . The projects comprising this w o r k are listed in Annex 1 . A few applications for financial support of research have been received from individual investigators and three grants have b e e n a w a r d e d .

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(2) Services to research comprise a large proportion of WHO'S activities and include international reference centres^ establishment of biological standards^

standard nomenclatures5 techniques, substances, preparations e t c . Some of this work is indicated in Annex 1•

(3) Training of research workers and exchange of research workers commenced in I96I and nine of the former and five of the latter have received grants to enable them to w o r k w i t h experienced investigators in countries other t h a n their o w n . These fourteen workers came from four of the W H O r e g i o n s , namely Europe ( 7 )

Eastern Mediterranean ⑷ , A f r i c a (1) and South-East Asia ( 2 ) . T h e studies h a v e b e e n undertaken in countries in three regions^ namely the Americas (斗 ) ,E u r o p e (7)^

Eastern Mediterranean (2) and one from the Eastern Mediterranean w e n t to America and E u r o p e . The subjects were concerned w i t h Communicable Diseases (8),

Cardiovascular Diseases (3)5 Nutrition (1), Genetics (1) and Geographical Pathology ( 1 ) .

Fields of research

The branches of medical science in which W H O has b e e n , or is active and which are reviewed in this report are given in the following T a b l e 1 .

TABLE 1 . NUMBER OF PROJECTS IN T H E DIFFERENT FIELDS OP R E S E A R C H

1 Subject Number of Projects

Communicable diseases

V i r u s diseases 16

1 Tuberculosis 19

1 Leprosy 10

Treponematoses 12

Enteric diseases 4

Zoonoses 6

Bilhcirziasis 8

Onchocerciasis and filariases 5

Malaria 23

Insecticide resistance and vector control 22 1 0 )

Antibiotics 2

Immunology 1

Biological standardization 10

Cancer 13

Cardiovascular diseases 5

H u m a n genetics 4

Nutrition 6

Radiation health 9

7 2 175

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D i s t r i b u t i o n of r e s e a r c h s u p p o r t e d

W H O is g i v i n g s u p p o r t t o a n u m b e r of collaborating w o r k e r s in institutes and l a b o r a t o r i e s i n a l l p a r t s of the w o r l d w h e r e t h e r e are adequate facilities (Table 2)

S i n c e W H O ' S g e n e r a l p r o g r a m m e h a s d e v e l o p e d as assistance to governments u p o n t h e i r r e q u e s t i t f o l l o w s t h a t m u c h of WHO,s w o r k and past research w a s orientated to c o u n t r i e s r e q u i r i n g a s s i s t a n c e . T h e p r e s e n t r e s e a r c h programme continues t h i s o r i e n t a t i o n . F o r t h i s r e a s o n , a large p a r t of W H O ' S support is d e v o t e d to

i n v e s t i g a t i o n s w h i c h a l t h o u g h t h e y may b e carried o u t in more d e v e l o p e d countries a r e a l s o o f g r e a t i n t e r e s t t o r a p i d l y d e v e l o p i n g o n e s .

I n t e r n a t i o n a l r e f e r e n c e centres a n d other services to research are m a i n l y b a s e d u p o n i n s t i t u t e s i n m o r e d e v e l o p e d c o u n t r i e s b e c a u s e i n such institutions research is a c t i v e a n d f a c i l i t i e s a r e a v a i l a b l e . T h i s i s , h o w e v e r , by force of circumstance a n d w h e r e p r a c t i c a l , as w i t h t h e r e f e r e n c e centre for cardiomyopathies in Uganda,

t h e y m a y b e in t h e t r o p i c s .

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TABLE 2 . DISTRIBUTION OF RESEARCH PROJECTS I N COUNTRIES AND TERRITORIES B Y W H O R E G I O N S *

Number of projects

N u m b e r of projects

AFRICA EUROPE

Cameroons (Southern) 1 Belgium 2

Federation of Rhodesia & Nyasaland 1 Czechoslovakia 11

Kenya Denmark 15

Liberia 2 Finland 1

M a l i 1 France 11

Nigeria 8 Germany s

South Africa 4 Hungary 2

Tanganyika 4 Ireland 2

Uganda 4 Italy- о

Upper V o l t a 2 Malta 1

Netherlands 5

AMERICAS Norway 2

Argentina 1 Poland

Brazil 9 Romania 2

Canada 1 Sweden h

Guatemala ) Switzerland 2

Guiana (British) 1 USSR 2

Jamaica 1 United Kingdom of G r e a t B r i t a i n 3 8

Mexico 3 and Northern Ireland

Puerto R i c o ) Yugoslavia 4

USA 3 3

Venezuela 4 SOUTH-EAST ASIA

Costa R i c a 1 B u r m a i

India 17

EASTERN MEDITERRANEAN

Israel 6 W E S T E R N PACIFIC

Lebanon 1 Australia 2

Tunisia 2 Japan 8

UAR (Egypt) 2 Malaya 2

Philippines 1

Singapore 1

W e s t New G u i n e a 1

T o k e l a u Islands "i

*

The total of projects numbered in Table 2 exceed 175 (see Table 1) because seme projects are active in more than one c o u n t r y .

It will be seen from Table 2 "fchat the 175 research projects involved, w o r k in 5 ) countries. Further details w i l l be found in the List of Research Projects - Annex 1 .

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C O M M U N I C A B L E D I S E A S E S

V I R U S D I S E A S E S

1 . I N T R O D U C T I O N .

T h e v i r u s r e s e a r c h p r o g r a m m e is b a s e d U p o n the recommendations of the S c i e n t i f i c G r o u p on V i r u s R e s e a r c h w h i c h m e t in Geneva in O c t o b e r 1 9 5 8,a n d the

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r e с o m m e n d a t i o n s o f t h e A C M R i n 1 9 5 9 • T h e p r i n c i p l e f i e l d s , n a m e l y , r e s p i r a t o r y

v i r u s e s ^ e n t e r o v i r u s e s , a r t h r o p o d - b o r n e v i r u s e s , smallpox and trachoma are a l l r e l a t e d t o i m p o r t a n t w o r l d - w i d e public h e a l t h a c t i v i t i e s . In all of these fields e p i d e m i o l o g i c a l s t u d i e s h a v e b e e n e n c o u r a g e d and the e s t a b l i s h m e n t of reference c e n t r e s , i n t e r n a t i o n a l , r e g i o n a l and n a t i o n a l , is an important service to r e s e a r c h , a s is t h e d e v e l o p m e n t of standard m e t h o d s and p r e p a r a t i o n s . R e f e r e n c e laboratories a l s o h a v e a n i m p o r t a n t p a r t to p l a y in the t r a i n i n g of r e s e a r c h w o r k e r s . In all t h e s e f i e l d s raany i n v e s t i g a t i o n s h a v e b e e n supported and the first results of some of t h e s e are p r e s e n t a w a i t i n g p u b l i c a t i o n ,

2 • R E F E R E N C E L A B O R A T O R I E S

T h e v a l u e o f r e f e r e n c e l a b o r a t o r i e s in f a c i l i t a t i n g progress in the elucidation of v i r u s d i s e a s e p r o b l e m s is clear^ a n d the e s t a b l i s h m e n t and support of these

l a b o r a t o r i e s i s , ancl w i l l b e , one of W H O1 s m a i n contributions in the v i r u s field p a r t i c u l a r l y d u r i n g p e r i o d s , such as the p r e s e n t , w h e n m a n y viruses are b e i n g i s o l a t e d a n d i d e n t i f i e d f o r the f i r s t t i m e , and w h e n the relationship of some of t h e m to h u m a n d i s e a s e s is n o t fully u n d e r s t o o d . The functions of these laboratorie h a v e a l r e a d y b e e n d e s c r i b e d to the A d v i s o r y C o m m i t t e e .

I n the l i s t b e l o w a r e g i v e n the r e f e r e n c e laboratories w h i c h h a v e already been e s t a b l i s h e d a n d t h o s e f o r w h i c h n e g o t i a t i o n s are in progress are indicated as

" p r o p o s e d " •

2 . 1 I n f l u e n z a c e n t r e s

...

V/orld I n f l u e n z a C e n t r e N a t i o n a l 工institute f o r M e d i c a l Research^ L o n d o n 工rrterna/tional 工nfruenza C e n t r e f o r the Americas厂 C o m m u n i c a b l e D i s e a s e s

C e n t r e , G e o r g i a , U n i t e d S t a t e s of A m e r i c a

I n a d d i t i o n t h e r e a r e 59 n a t i o n a l i n f l u e n z a centres and 10 W H O influenza o b s e r v e r s in 斗8 c o u n t r i e s .

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2.2 Centres for respiratory virus diseases other than influenza

International Reference C e n t r e , N a t i o n a l Institute for M e d i c a l R e s e a r c h , L o n d o n , and S a l i s b u r y , W i l t s .

The Ivanovski 工nstitute, Moscow (proposed)

S o u t h African Institute for M e d i c a l R e s e a r c h j, Johannesburg

A laboratory in the United States of America^ to be d e s i g n a t e d . 2 . 3 Poliomyelitis regional centres

The Americas

W e s t e r n Europe Eastern Europe Africa

South-East A s i a

W e s t e r n Pacific

Eastern Mediterranean

2.4 Other enterovirus centres W o r l d Reference Centre

Africa

Eastern Europe

D e p a r t m e n t of Epidemiology and Public H e a l t h , Y a l e U n i v e r s i t y , N e w H a v e n , U n i t e d S t a t e s

of A m e r i c a

Institut P a s t e u r , Paris

工nstâtirbe for Poliomyelitis R e s e a r c h , Moscow

Poliomyelitis R e s e a r c h F o u n d a t i o n , J o h a n n e s b u r g D e p a r t m e n t of Bacteriology^ U n i v e r s i t y of

M a l a y a , Singapore

N a t i o n a l Institute of H e a l t h , T o k y o

V i r u s R e s e a r c h Laboratory^ T h e H e b r e w University^

Jerusalem

D e p a r t m e n t of Virology^ B a y l o r U n i v e r s i t y , H o u s t o n , Texas^ U n i t e d States of A m e r i c a

(set up in 1 9 6 1 )

S o u t h A f r i c a n Institute for M e d i c a l R e s e a r c h , Joliàrïrîé sbur g

Institute for Poliomyelitis R e s e a r c h and Institute for V i r u s P r o p h y l a x i s , M o s c o w

(proposed)

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2 . 5 C e n t r e s f o r a r t h r o p o d - b o r n e viruses

A f r i c a E a s t A f r i c a n V i r u s R e s e a r c h 工restitute,

E n t e b b e

E a s t e r n E u r o p e E n c e p h a l i t i s L a b o r a t o r y5 I n s t i t u t e of V i r o l o g y , M o s c o w (proposed)

W e s t e r n E u r o p e N a t i o n a l I n s t i t u t e for M e d i c a l R e s e a r c h M i l l H i l l , L o n d o n , N . W - 7 (proposed)

A u s t r a l i a T h e J o h n C u r t i n S c h o o l of M e d i c a l R e s e a r c h , T h e A u s t r a l i a n N a t i o n a l U n i v e r s i t y ,

C a n b e r r a , A . C . T . (proposed) T h e A m e r i c a s A laboratory to be d e s i g n a t e d

T h e n e e d f o r r e f e r e n c e l a b o r a t o r i e s w i l l increase r a p i d l y in the n e x t decade a n d p r o g r e s s i v e i n c r e a s e s in f i n a n c i a l support w i l l be n e c e s s a r y to enable them t o c a r r y o u t t h e i r d u t i e s . T h e e s t a b l i s h m e n t of standard r e a g e n t s , particularly s e r a,i s u r g e n t b e c a u s e u p o n i t d e p e n d s a r a t i o n a l approach to the question of c l a s s i f i c a t i o n of v i r u s e s .

J . R E S P I R A T O R Y V I R U S E S

T h e p r o g r a m m e c o v e r s i n f l u e n z a v i r u s e s and also the other respiratory v i r u s e s . I n f l u e n z a

T h e c o l l e c t i o n a n d d i s t r i b u t i o n of i n f o r m a t i o n on i n f l u e n z a v i r u s e s isolated in t h e i n f l u e n z a c e n t r e s a n d o t h e r laboratories from outbreaks c o n t i n u e s , and the v a l u e of e a r l y i n f o r m a t i o n on the type and sub-type of v i r u s e s isolated is fully a p p r e c i a t e d b y t h e c e n t r e s and b y g o v e r ñ m e n t s .

H i s t o p a t h o l o g i c a l s t u d i e s on i n f l u e n z a

P r o f e s s o r J . M u l d e r a n d D r H e r s of L e i d e n , N e t h e r l a n d s , h a v e b e e n studying f o r s o m e y e a r s t h e p a t h o l o g y of primary i n f l u e n z a l pneumonia and secondary b a c t e r i a l p n e u m o n i a in h u m a n b e i n g s , u s i n g m o d e r n h i s t o l o g i c a l m e t h o d s i n c l u d i n g f l u o r e s c e n t a n t i b o d y t e c h n i q u e s . T h e y are also s t u d y i n g experimental infections in mice and f e r r e t s . T h e s t u d i e s h a v e a l r e a d y "thrown l i g h t on the basic pathology of influenza

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infection of the cells of the respiratory t r a c t and on the relation b e t w e e n i n f l u e n z a virus and b a c t e r i a l i n v a d e r s . The w o r k (in c o l l a b o r a t i o n w i t h D r D . A . J . Tyrrell., M e d i c a l R e s e a r c h C o u n c i l C o m m o n Cold R e s e a r c h U n i t , S a l i s b u r y , U n i t e d K i n g d o m , ) on mice w i l l soon be published and the study of m a t e r i a l from h u m a n b e i n g s and experimentally-infected ferrets c o n t i n u e s . T h e publications w i l l include n u m e r o u s colour photographs and the h u m a n studies w i l l be published as an A t l a s of I n f l u e n z a l H i s t o p a t h o l o g y .

3,1.2 Laboratory study of strains of influenza v i r u s from h u m a n and a n i m a l sources T h e study of' strains of influenza v i r u s from h u m a n and a n i m a l sources is s t i l l in progress in the laboratories of D r W e r n e r H e n l e in Philadephia a n d P r o f e s s o r

R a s k a in P r a g u e . S o far only swine v i r u s e s h a v e shown substantial c r o s s - a n t i g e n i c i t y w i t h h u m a n s t r a i n s .

3.2 O t h e r respiratory viruses

3.2.1 I n t e r n a t i o n a l R e f e r e n c e Centre

Emphasis in 1960 w a s on the e s t a b l i s h m e n t of the I n t e r n a t i o n a l R e f e r e n c e C e n t r e for R e s p i r a t o r y V i r u s D i s e a s e s other than i n f l u e n z a . B y a g r e e m e n t vzith the B r i t i s h Medical R e s e a r c h C o u n c i l , the Centre w a s established jointly a t the N a t i o n a l I n s t i t u t e for M e d i c a l R e s e a r c h , M i l l Hill, L o n d o n , and the M e d i c a l R e s e a r c h C o u n c i l C o m m o n C o l d R e s e a r c h U n i t , S a l i s b u r y , W i l t s h i r e • T h e functions of the Centre are s i m i l a r to t h o s e of other reference c e n t r e s .

3 - 2 . 2 E p i d e m i o l o g i c a l studies of r e s p i r a t o r y v i r u s infections

S u p p o r t is given to the important studies on volunteers w h i c h h a v e b e e n in progress a t S a l i s b u r y for some y e a r s . T h e conditions of i s o l a t i o n a t S a l i s b u r y

are available a t few other research c e n t r e s . T h e s e studies include the i n v e s t i g a t i o n of the pathogenicity of newly-isolated strains of v i r u s , the iinraunological r e s p o n s e s they induce and the clinical syndromes they cause•

T h e respiratory virus programme in the n e x t five y e a r s w i l l be m a i n l y c o n c e r n e d w i t h the d e v e l o p m e n t of reference services^ including standardized r e a g e n t s . S u p p o r t w i l l be given to epidemiological studies on the new viruses (for example a t the C o m m o n Cold U n i t at S a l i s b u r y ) and to studies on the role of viruses in r e s p i r a t o r y illness in c h i l d r e n , and in special groups such as soldiers and. m i n e r s .

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斗• ENTEROVIRUSES

T h e programme includes poliomyelitis viruses and the other enteroviruses.

4 . 1 Poliomyelitis

T h e W H O programme on polioxnyelitis v/hich commenced in 1953 to study certain aspects of epidemiology and to give assistance to countries in vaccination

programmes w i l l be revised because of the changes brought about by the widespread vaccination w i t h inactivated and attenuated vaccines. The programmes of development of poliomyelitis and other enteroviruses w i l l be developed as a single programme.

4 . 1 . 1 Spread of poliomyelitis viruses by the respiratory route

T h o u g h opinion at present favours the spread of poliomyelitis vir»us by the alimentary route5 the older theory of respiratory spread cannot be disregarded.

P r o f e s s o r M e e n a n in D u b l i n is studying this question. He has pointed out that infectivity appears to Ъэ greatest in the early stages of the disease when virus is present in the t h r o a t . If virus can be demonstrated in the throats and in the saliva of cases in the early stages of illness this would support the hypothesis.

T h s studies5 w h i c h include the titration of the virus in the saliva, are still in p r o g r e s s .

4.1.2 F i e l d trials of live poliovirus vaccine in Costa Rica

A study by Professor J^ R . Paul and D r D . Horstmann is in progress in Costa R i c a on the spread of the vaccine strains of virus in home contacts in village

c o m m u n i t i e s . The preliminary results showed that about one-third of the vaccinated children excreted enteroviruses^ including polioviruses. The efficacy of the

vaccination measured by virus excretion and by serological responses was low. The study continues v^ith special reference to inference between enteroviruses and to possible changes in the virulence of the vaccine viruses after excretion.

斗• 1 • 3 W i l d poliomyelitis viruses in countries using inactivated vaccines and countries using attenuated vaccines (proposed)

Some countries for the next f'〕w years w i l l use mainly inactivated vaccines and some mainly attenuated vaccines. The difference in the type of vaccines provides an opportunity for a comparison of the prevalence of the three serotypes of v i r u s in the different countries and a plan has been drawn up for the collection of information by the regional poliomyelitis laboratories and^ it is hoped^ by some n a t i o n a l laboratories. T h i s study can probably be made at no special cost to W H O .

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一 1 3 -

4 . 1 Л Immediate identification a n d p r e s e r v a t i o n for future study of s t r a i n s of poliovirus from paralytic cases in the v a c c i n a t e d ( p r o p o s e d )

T h e E x p e r t Committee on P o l i o m y e l i t i s w h i c h m e t in J u n e i960 p o i n t e d o u t that a t p r e s e n t there is n o reliable m e t h o d of d i s t i n g u i s h i n g "wild" s t r a i n s of v i r u s from v a c c i n e - d e r i v e d s t r a i n s , b u t that t e c h n i c a l advances may m a k e s u c h a

d i f f e r e n t i a t i o n possible in the f u t u r e . T h e C o m m i t t e e therefore r e c o m m e n d e d t h a t strains of v i r u s from paralytic cases i n the v a c c i n a t e d a n d t h e i r c o n t a c t s be c o l l e c t e d , typed a n d t h e n stored f o r future study• T h e r e g i o n a l p o l i o m y e l i t i s centres h a v e "been asked to indicate to w h a t e x t e n t t h e y can i m p l e m e n t these p r o p o s a l s a n d to give e s t i m a t e s of c o s t s .

4 . 2 O t h e r enterov i ruse s

The e s t a b l i s h m e n t of an i n t e r n a t i o n a l r e f e r e n c e c e n t r e in 1 9 6 1 f o r entero- v i r u s e s (excluding p o l i o m y e l i t i s ) , u n d e r the d i r e c t i o n of P r o f e s s o r J . L . M e l n i c k , D e p a r t m e n t of V i r o l o g y , B a y l o r U n i v e r s i t y , H o u s t o n , Texas, and of a r e g i o n a l

reference l a b o r a t o r y , u n d e r D r J . H . S . G e a r , a t the S o u t h A f r i c a n I n s t i t u t e for M e d i c a l R e s e a r c h , Johannesburg^ m a r k s a n o t h e r step f o r w a r d in W H O' S p r o g r a m m e on enterovirus i n f e c t i o n s •

4 , 2 . 1 E n t e r o v i r u s e s in the t r o p i c s

A study of e n t e r o v i r u s i n f e c t i o n in the t r o p i c s h a s b e e n c o m m e n c e d b y

Professor C o l l a r d , I b a d a n , and. D r M a c n a m a r a , Y a b a , N i g e r i a . T h e y w i l l investigate the prevalence of e n t e r o v i r u s e s in the l o c a l p o p u l a t i o n s a n d the r e l a t i o n of

enteroviruses t o c l i n i c a l i l l n e s s . I n this study the e p i d e m i o l o g y of a r t h r o p o d - b o r n e virus infections is also b e i n g i n v e s t i g a t e d .

5- I M M U N O L O G I C A L A N D H A E M A T O L O G I C A L S U R V E Y S A N D S E R U M R E F E R E N C E B A N K S

I m m u n o l o g i c a l surveys of c o m m u n i t i e s or of s p e c i a l groups h a v e o f t e n b e e n made in the p a s t . T h e s e surveys h a v e u s u a l l y b e e n c o n c e r n e d w i t h only one communicable d i s e a s e . T h e Study G r o u p on I m m u n o l o g i c a l and H a e m a t o l o g i c a l S u r v e y s emphasized t h a t the u s e f u l n e s s of the sera c o l l e c t e d c o u l d b e g r e a t l y increased if s u r v e y s w e r e p l a n n e d f o r the sera to be a l s o u s e d f o r h a e m a t o l o g i c a l ^ n u t r i t i o n a l a n d b i o c h e m i c a l e x a m i n a t i o n s . T h i s f u l d involve v e r y l i t t l e e x t r a c o s t . T h e b l o o d m i g h t also b e u s e d f o r genetic s t u d i e s . T h u s t h e s e d i f f e r e n t interests should be co-ordinated, in p l a n n i n g such s u r v e y s . W H O m i g h t c o - o r d i n a t e the w o r k and re suits ^ e s p e c i a l l y w i t h r e s p e c t to i t s own t e a m s .

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Moreover the preservation of a portion of each sample would enable examinations t o be made w h i c h would provide retrospective information on the changing patterns of infection over the y e a r s . Re-examination of specimens when hitherto unrecognized viruses were isolated and identified would be very useful. T o carry out these recommendations it was necessary first to establish "serum reference banks" in which the samples could be satisfactorily stored.

A W o r l d Serum Reference B a n k has been established at Yale University, with Professor J . R . Paul as Director, and regional reference banks have been, established under D r J . H . S . Gear at the National Institute for Medical Research, Johannesburg^

and Professor K . H a s k a at the Institute of Epidemiology and Microbiology^ Prague.

W H O has provided fre e z e-drying equipment for the preparation of the specimens, storage cabinets and index systems^ and has supported studies on the most satisfactory methods of freeze-drying the s e r a .

The programme of serum reference banks and the collection of sera requires careful p l a n n i n g . The use of the unused portions of sera collected for specific purposes has already been mentioned but these sera are seldom from random samples of the population. If it were possible^ at reasonable cost., to obtain periodically sera from true random samples of population in different parts of the world, the examination of such sera at intervals would be of considerable practical importance, e . g . in the epidemiology of influenza.

The collection of sera presents many practical problems, particularly from the younger age-groups, froin whom the most useful information is likely to be obtained.

Sources of sera must be carefully selected so that systematic collections can be continued over the long periods required.

These problems have been discussed w i t h the directors of the serum banks.

6 . ARTHROPOD-BORNE VIRUSES

Following recommendations of the Scientific Group on Virus Research, which met in Geneva in N o v e m b e r 1958,and the Scientific Group on Research on Birds as

Disseminators of Arthropod-borne Viruses, which met in Geneva in March 1959> a programme on arthropod-borne virus research was prepared and presented to the first session of the ACMR in October 1959- The programme was recommended for general support.

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T h e W H O a r t h r o p o d - b o r n e v i r u s r e s e a r c h programme is aimed at:

(1) increasing.the knowledge on a r t h r o p o d - b o r n e viruses;

(2) establishing the importance of each v i r u s or g r o u p of v i r u s e s as p r o d u c e r s of h u m a n disease;

(3) d e t e r m i n i n g how e n v i r o n m e n t a l changes b y a l t e r i n g the d i s t r i b u t i o n and m o v e m e n t of h o s t s and v e c t o r s , c a n influence the e c o l o g y of v i r u s e s ;

(4) e s t a b l i s h i n g , t h r o u g h a b e t t e r u n d e r s t a n d i n g of these p r o b l e m s , . effective measures of c o n t r o l , or a t l e a s t l e a r n i n g h o w to a v o i d man m a d e errors w h i c h may lead to d a n g e r o u s o u t b r e a k s of d i s e a s e .

I n S e p t e m b e r i960 a S t u d y G r o u p on A r t h r o p o d - b o r n e V i r u s e s m e t w h i c h r e c o m m e n d e d p r a c t i c a l w a y s of i m p l e m e n t i n g the p r o g r a m m e . T h e f i r s t step w a s the o r g a n i z a t i o n of a system of r e f e r e n c e l a b o r a t o r i e s . A r e g i o n a l r e f e r e n c e laboratory h a s already b e e n d e s i g n a t e d in A f r i c a .

S u p p o r t h a s b e e n g i v e n to the V i r u s R e s e a r c h I n s t i t u t e , E a s t A f r i c a H i g h • C o m m i s s i o n , E n t e b b e , for studies of a r t h r o p o d - b o r n e v i r u s e s as a g e n t s of u n d i a g n o s e d .fevers i n t r o p i c a l p o p u l a t i o n s . T h i s I n s t i t u t e is a l s o a c t i n g a s a r e g i o n a l

reference centre in A f r i c a . T h e V i r u s U n i t of the D e p a r t m e n t of B a c t e r i o l o g y , 工badan U n i v e r s i t y College H o s p i t a l , N i g e r i a , in c o - o p e r a t i o n w i t h the V i r u s R e s e a r c h I n s t i t u t e of the W e s t A f r i c a n C o u n c i l f o r M e d i c a l Research^, N i g e r i a , is r e c e i v i n g s u p p o r t f o r studies on the public h e a l t h importance of a r t h r o p o d - b o r n e v i r u s e s i n t r o p i c a l p o p u l a t i o n s . T h e s e studies also include i n v e s t i g a t i o n s o n the d i s t r i b u t i o n and importance of the e n t e r o v i r u s e s as p r o d u c e r s of d i s e a s e in t r o p i c a l p o p u l a t i o n s . T h e D e p a r t m e n t of M i c r o b i o l o g y a t the J o h n C u r t i n S c h o o l of M e d i c a l R e s e a r c h ,

A u s t r a l i a n N a t i o n a l U n i v e r s i t y , is r e c e i v i n g s u p p o r t f o r studies on the e p i d e m i o l o g y of a r t h r o p o d - b o r n e v i r u s e s in the A u s t r a l a s i a n r e g i o n .

A s p a r t of this W H O l o n g - t e r m c o l l a b o r a t i v e programme^ the B o m b a y N a t u r a l H i s t o r y S o c i e t y h a s e s t a b l i s h e d s e v e r a l field s t a t i o n s in the K u t c h d i s t r i c t of the S a u r a s h t r a Peninsula^ I n d i a , f o r n e t t i n g , r i n g i n g a n d b l e e d i n g m i g r a t i n g b i r d s a n d c o l l e c t i n g t h e i r e c t o p a r a s i t e s d u r i n g the sprir^g a n d a u t u m n of i 9 6 0 . S i m i l a r studies b y the L o n d o n S c h o o l of H y g i e n e and T r o p i c a l M e d i c i n e w e r e m a d e in t h e spring of 1961 in southern S p a i n a l o n g the route of b i r d s m i g r a t i n g from E u r o p e to A f r i c a and vice v e r s a . -

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N e w r e f e r e n c e l a b o r a t o r i e s w i l l be d e s i g n a t e d to complete the n e t w o r k and as s o o n a s a s u i t a b l e l a b o r a t o r y is a v a i l a b l e , a W o r l d R e f e r e n c e C e n t r e w i l l also be d e s i g n t e d . C o - o r d i n a t i o n of the w o r k of these l a b o r a t o r i e s a n d C e n t r e w i l l be e n s u r e d b y p e r i o d i c e x c h a n g e v i s i t s b y m e m b e r s of "the s t a f f s to "the labora "tories,

a n d b y m e e t i n g s of t h e d i r e c t o r s of the r e f e r e n c e laboratories^ S c i e n t i f i c m e e t i n g s o f w o r k e r s i n t h i s f i e l d c o n s i s t i n g of v i r o l o g i s t s , e n t o m o l o g i s t s , zoologists and e p i d e m i o l o g i s t s w i l l b e c o n v e n e d to a n a l y s e r e s u l t s o b t a i n e d , a n d to advise on f u r t h e r r e s e a r c h a c t i v i t i e s . R e c e n t l y a g r o u p of A m e r i c a n w o r k e r s h a s p r o d u c e d a n a r t h r o p o d - b o r n e v i r u s c a t a l o g u e w h i c h is s t i l l i n c o m p l e t e . F o l l o w i n g r e c o m m e n d a t i o n s of t h e S t u d y G r o u p w h i c h m e t i n S e p t e m b e r ^ this catalogue w i l l be completed and if n e c e s s a r y W H O w i l l u n d a r t a k e i t s m a i n t e n a n c e and d i s t r i b u t i o n .

T h e p o s s i b i l i t y o f a s s i s t i n g w e l l - e q u i p p e d o r n i t h o l o g i c a l s t a t i o n s to d e v e l o p v i r o l o g i c a l s t u d i e s o n m i g r a t i n g b i r d s is b e i n g c o n t e m p l a t e d and some p r o j e c t s w i l l b e i m p l e m e n t e d -

7 . S M A L L P O X

B e c a u s e of the n e e d of a p o t e n t and stable v a c c i n e a s the f i r s t r e q u i r e m e n t f o r a s u c c e s s f u l e r a d i c a t i o n p r o g r a m m e , W H O i n i t i a t e d s p e c i a l studies s e v e r a l y e a r s a g o . T h e s e s t u d i e s h a v e r e s u l t e d i n a pí^óductton-method w h i c h ensures the supply of a free-ZLe^dried v a c c i n a o f h i g h p o t e n c y a n d s t a b i l i t y .

F u n d a m e n t a l t e c h n i c a l k n o w l e d g e f o r the e r a d i c a t i o n of s m a l l p o x is n o w a v a i l a b l e . T h e r e a r e , h o w e v e r , s t i l l m a n y p r o b l e m s in n e e d of c l a r i f i c a t i o n i n e p i d e m i o l o g y ,

i m m u n o l o g y , p a t h o g e n e s i s a n d t h e r a p y , as w e l l a s i n r e l a t i o n t o the a d m i n i s t r a t i v e a s p e c t s o f t h e o r g a n i z a t i o n a n d e v a l u a t i o n of e r a d i c a t i o n c a m p a i g n s . A solution of t h e s e p r o b l e m s w i l l e n a b l e m o r e e f f e c t i v e m e a s u r e s to be t a k e n to combat the d i s e a s e , a n d w i l l i n c r e a s e t h e p a c e of the c a m p a i g n for the w o r l d - w i d e e r a d i c a t i o n of s m a l l p o x .

S p e c i a l s t u d i e s w e r e c a r r i e d o u t in M a d r a s i n the s p r i n g of i 9 6 0 . P u r p o s e s of the p r o p o s e d s t u d i e s are as follows:

1 . T o d e t e r m i n e the v a l u e of v a c c i n i a h y p e r i m m u n e g a m m a - g l o b u l i n in the p r e v e n t i o n of s m a l l p o x a f t e r k n o w n e x p o s u r e .

2 . T o s t u d y v i r u s d i s s e m i n a t i o n b y t a k i n g a i r s a m p l e s in the e n v i r o n m e n t of a s m a l l p o x h o s p i t a l .

T o d e t e r m i n e t h e i n f e c t i v i t y of c a s e s i n the p r e - e r u p t i v e and e r u p t i v e p h a s e s of t h e d i s e a s e -

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T o establish antibody levels of sera from samples of the vaccinated adult p o p u l a t i o n .

W H O assistance w a s given to D r A . W . D o w n i e , Professor of B a c t e r i o l o g y a t the University of L i v e r p o o l , and D r H . Kernpe, Professor and H e a d of the D e p a r t m e n t of Pediatrics a t the University of C o l o r a d o , to v i s i t Madras for six w e e k s to study these p r o b l e m s . The results of the Madras studies may be summarized as follows:

(a) A substantial reduction in the incidence of smallpox could be obtained b y the administration of hyperimmune gamma-globulin to intimate family contacts•

(b) V i r u s w a s absent from mouth-washings d u r i n g the first and second d a y s of fever but w a s found occasionally on the third d a y . V i r u s w a s increasingly frequent on sixth and seventh d a y s b u t in m o s t patients a f t e r the twelfth d a y virus could n o t be found by the technique u s e d . V i r u s w a s p r e s e n t in greatest amounts in those patients w h o showed numerous lesions in the m o u t h , particularly on the tongue and lips, irrespective of the general severity of the d i s e a s e .

(c) Approximately 10 per c e n t , of the sera of the adult population tested i n Madras h a d little or n o neutralizing activity^ despite the fact t h a t the b l o o d came from persons w i t h good scars from primary v a c c i n a t i o n s .

(d) V i r u s w a s found in air samplings in locations presumably h e a v i l y contaminated v/ith variola virus only once in a t t e m p t s .

(e) A comparison of dried smallpox vaccine w i t h fresh Indian buffalo calf lymph vaccine in revaccination showed conclusively that after the dried p r e p a r a t i o n there were approximately twо-and-a-half times more successful takes than a f t e r the lymph preparation.

Studies on the epidemiology, immunology, pathogenesis and therapy of smallpox w i l l be continued in Madras^ and in other suitable p l a c e s . T o concentrate

facilities for these studies in M a d r a s , a smallpox research u n i t is b e i n g established a t the Infectious Diseases H o s p i t a l , T o n d i a r p e t . I t w i l l receive t e c h n i c a l advice and support from the Department of Bacteriology^ University. of L i v e r p o o l and the Department of Pediatrics, University of C o l o r a d o .

Further research on the production of high-quality freeze-dried vaccine w i l l also be supported..

Studies on methods to evaluate results of vaccination campaigns in areas w h e r e such campaigns are taking place are b e i n g p l a n n e d . Random samples of the p o p u l a t i o n s

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v a c c i n a t e d d u r i n g t h e m a s s \ a c c i n a t i o n campaign w i l l be revaccinated in order to a s s e s s t h e s t a t u s of i m m u n i t y of the p o p u l a t i o n a f t e r the c a m p a i g n . F i n a n c i a l p r o v i s i o n f o r t h e s e s t u d i e s h a s b e e n made •

8 • T R A C H O M A

A W H O S c i e n t i f i c G r o u p on T r a c h o m a R e s e a r c h m e t in 1959 and made recommendations f o r a c o m p r e h e n s i v e r e s e a r c h p r o g r a m m e . A second Scientific G r o u p is to m e e t in A u g u s t 1 9 6 1 to r e a p p r a i s e the s i t u a t i o n a n d to r e p o r t to the E x p e r t C o m m i t t e e w h i c h

i s t o b e h e l d i m m e d i a t e l y a f t e r w a r d s .

T h e m a i n r e s e a r c h a c t i v i t i e s of W H O in t r a c h o m a are in e t i o l o g y , epidemiology^

i m m u n o l o g y a n d t h e r a p y . S u p p o r t h a s b e e n g i v e n to the T r a c h o m a 工nstitute, Algiers^

f o r r e s e a r c h on t i s s u e culture m e t h o d s and on electronic m i c r o s c o p y studies of the d i f f e r e n t p h a s e s of v i r u s g r o w t h and to the H e b r e w University of J e r u s a l e m for w o r k o n n e u t r a l i z a t i o n t e s t s a n d f l u o r e s c e n t a n t i b o d i e s - The i s o l a t i o n and characterization o f l o c a l s t r a i n s of t r a c h o m a v i r u s and the systematic laboratory screening of

t h e r a p e u t i c a g e n t s are c o n t i n u i n g in the m i c r o b i o l o g i c a l laboratory of the Ophthalmic C e n t r e,T u n i s * A p r e l i m i n a r y • survey is b e i n g supported in trachoma in T a i w a n w h e r e t h e p r e v a l e n c e is h i g h a n d w h e r e facilities for investigation are g o o d . T h i s is in c o l l a b o r a t i o n w i t h the U S N a v a l M e d i c a l R e s e a r c h U n i t N o . 2 . T h e r a p e u t i c trials are a l s o i n p r o g r e s s .

W o r k o n t r a c h o m a w i l l i n c r e a s e in the n e x t five y e a r s . T h e precise activities to b e u n d e r t a k e n b y W H O w i l l d e p e n d on the fields n o t fully covered b y n a t i o n a l i n v e s t i g a t o r s and o n p r o g r e s s in the d i f f e r e n t i a t i o n of strains of the v i r u s and on v a c c i n e p r o d u c t i o n and t e s t i n g . It m u s t be stressed that, because of marked regiona]

d i f f e r e n c e s in the c l i n i c a l , e p i d e m i o l o g i c a l and m i c r o b i o l o g i c a l a s p e c t s of trachoma a n d a s s o c i a t e d i n f e c t i o n s ^ the r e s u l t s of studies in d i f f e r e n t countries cannot be p o o l e d t o g i v e a v a l i d c o m p o s i t e picture of t h i s d i s e a s e . T h u s combined multidisci- p l i n a r y r e s e a r c h on the p r o b l e m i n one a r e a is n e e d e d . S i m i l a r l y the standard criteria a n d m e t h o d o l o g i e s a r e n e e d e d w h i c h w i l l p e r m i t comparative studies in other areas w i t h c o n t r a s t i n g p a t t e r n s of d i s e a s e . T h i s b r o a d e r field of research is one w h i c h the O r g a n i z a t i o n i s t e c h n i c a l l y w e l l - f i t t e d to a s s i s t a n d w h i c h w i l l be incorporated in t h e p r o g r a m m e of c o l l a b o r a t i v e studies in T a i w a ne

( L i s t of r e s e a r c h p r o j e c t titles, p a g e s 1 0 7 - 1 0 8 )

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- 19 -

TUBERCULOSIS

1 , INTRODUCTION

W H O1 s research effort in the field of tuberculosis is largely aimed at developing and perfecting measures for the control and eventual eradication of the d i s e a s e .

A relatively high priority has b e e n given to the improvement of the diagnostic tools, particularly to the development of a more specific tuberculin test and to the simplification of the methods for the bacteriological diagnosis of tuberculosis^

permitting this diagnostic method to be extended even to areas w i t h limited laboratory facilities.

W h i l e there is no doubt as to the general protective effect and usefulness of BCG vaccination^ the world-wide application of this prophylactic has raised certain

problems requiring research. One concerns its protective value in the many tropical areas where the population shows a h i g h prevalence of low-grade non-specific

tuberculin sensitivity. Another problem is the increased need for standardization and quality control of B C G v a c c i n e . I t is expected that the introduction of freeze- dried preparations v/ith their superior keeping qualities w i l l contribute to the solution of this problem. A more long-range undertaking is the search for an immunogenic fraction of the tubercle bacillus which would n o t have the allergizing effect of BCG vaccine and thus would n o t destroy the diagnostic value of the tuberculin t e s t .

The large-scale use of modern antituberculosis drugs in the developing countries has met with many difficulties and a number of projects are under v/ay to determine the most effective, economic and acceptable chemotherapy and chemoprophylaxis under the conditions prevailing in these countries»

A prerequisite for the effective utilization of preventive and curative measures is a good knowledge of the epidemiological behaviour of t u b e r c u l o s i s . R e s e a r c h in this direction is being undertaken both in countries where the p r e s e n t objective is the systematic reduction of tuberculosis as w e l l as in countries w h e r e the present objective is complete eradication of tuberculous infection•

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- 2 0 -

2 • T H E M Y C O B A C T E R I A

I n 1 9 5 7 and 19585 W H O w a s conducting surveys on the prevalence of tuberculosis in s o m e c o u n t r i e s of A f r i c a . I t soon became evident t h a t b a c t e r i o l o g i c a l examination b y d i r e c t m i c r o s c o p y of s p u t u m specimens is n o t a reliable diagnostic procedure as it u s u a l l y o n l y can d e t e c t t u b e r c l e b a c i l l i in p a t i e n t s suffering from cavitary

t u b e r c u l o s i s a n d e x p e c t o r a t i n g large n u m b e r s of b a c i l l i 一 10 000-100 000 rods per m l of s p u t u m . I n s p u t a c o n t a i n i n g scanty a c i d - f a s t b a c i l l i , the only e f f i c i e n t technique i s c u l t u r i n g of p a t h o l o g i c a l s p e c i m e n s . E x a m i n a t i o n by culture could n o t be made in the f i e l d o w i n g to the l a c k of w e l l - e q u i p p e d laboratories• S p u t u m specimens vrere t h e r e f o r e d i s p a t c h e d to l a b o r a t o r i e s in E u r o p e f o r examination b y c u l t u r e . H o w e v e r , c o n t r a r y t o e x p e c t a t i o n s , t h e yield from cultures w a s n o t h i g h e r t h a n t h a t from

m i c r o s c o p i c e x a m i n a t i o n s m a d e in the f i e l d . I n f a c t , there w e r e instances w h e r e s p e c i m e n s d e m o n s t r a t i n g a c i d - f a s t rods on d i r e c t microscopy failed to show any growth c u l t u r e e v e n in p a t i e n t s n o t r e c e i v i n g c h e m o t h e r a p y .

I n v e s t i g a t i o n s c a r r i e d o u t by W H O in 1958 revealed t h a t the r e a s o n for this poor y i e l d on c u l t u r e w a s t h e a d v e r s e effect of storage and t r a n s p o r t on the v i a b i l i t y of m i c r o - o r g a n i s m s . O n the o t h e r hand,, e x a m i n a t i o n b y culture, although a complicated p r o c e s s , is b e c o m i n g i n c r e a s i n g l y n e c e s s a r y f o r diagnostic and therapeutic purposes i n d e v e l o p i n g c o u n t r i e s . T h e r e f o r e5 the only solution to this problem appeared to be t o d e v e l o p simple c u l t u r e t e c h n i q u e s that could be employed u n d e r limited laboratory c o n d i t i o n s •

I t h a s o f t e n b e e n the e x p e r i e n c e , in survey programmes^ t h a t sputuni specimens c o l l e c t e d i n the f i e l d h a v e to b e transported for long d i s t a n c e s to r e a c h e v e n the n e a r e s t l a b o r a t o r y . T h i s r a i s e d the question of preserving tubercle b a c i l l i in p a t h o l o g i c a l s p e c i m e n s . I n t h i s connexion^ only certain preliminary e x p e r i m e n t s h a v e b e e n c a r r i e d o u t t o s t u d y the e f f e c t of light,temperature^ and storage on the v i a b i l i t y of t u b e r c l e b a c i l l i .

E x a m i n a t i o n in v a r i o u s E u r o p e a n laboratories of p a t h o l o g i c a l specimens received f r o m d i f f e r e n t p a r t s of t h e w o r l d showed t h a t m y c o b a c t e r i a other t h a n tubercle

bacilli, s u c h as m y c o b a c t e r i a a v i r u l e n t to g u i n e a - p i g s and other a t y p i c a l mycobacteria v i r u l e n t f o r mice, a r e f r e q u e n t l y encountered in t r o p i c a l and subtropical a r e a s .

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- 2 1 -

I t was considered to be of great interest to study the .geographical distribution of these so-called atypical mycobacteria and at the same time to standardize methods of classifying mycobacteria.

In addition to these major research projects, certain other studies have been carried out to improve culture techniques^ e . g . the N a O H . H C l method of treating pathological specimens proved detrimental to tubercle bacilli although it kept down the number of contaminations. Preliminary research showed that the addition of certain ammonium quarternary bases resulted in much better growth w i t h o u t at the same time increasing the contamination r a t e .

The purpose of the research programmes in the field of mycobacteria is to develop simple and practical methods of bacteriological examination that could b e applied in the developing countries and also in international campaigns.

These studies form an integral part of the Organization1 s tuberculosis control programme^ as the results of bacteriological examination are the only conclusive evidence of the disease•

M o s t of these experiments are still in progress^ b u t there is already enough indication that a lyophilized medium^ that could be prepared in one place and that has a long expiry d a t e , could profitably be employed for the culturing of tubercle b a c i l l i . This would bring about a considerable simplification of culture t e c h n i q u e s . Other experiments have shown the need for uniformity in classification procedures and also for setting up standard procedures and criteria for d r u g r e s i s t a n c e .

The possible recruitment of extra W H O staff would depend very largely on the future development of these projects, although it is n o t at present envisaged that such recruitment w i l l be n e c e s s a r y .

In addition to projects already begun^ it is suggested that studies on the following new subjects should be undertaken during the n e x t five years: (1) immuno- genic and allergenic fractions of mycobacteria; (2) isolation and use of mycophages for the classification of atypical mycobacteria; (3) simple technique for d r u g

sensitivity determination of mycobacteria; (4) epidemiology and prevalence of drug- resistant mycobacteria, in developing countries.

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- 2 2 -

3 . T U B E R C U L I N T E S T I N G OF D O M E S T I C ANIMALS

T h e t u b e r c u l i n t e s t continues to provide the b e s t available evidence of

t u b e r c u l o u s i n f e c t i o n in m a n . H o w e v e r , in many parts of the w o r l d,e s p e c i a l l y in t r o p i c a l r e g i o n s , m a n y p e r s o n s e x h i b i t low-grade tuberculin allergy n o t caused b y i n f e c t i o n b y Myсо. t u b e r c u l o s i s • T h i s phenomenon greatly hinders attempts t o obtain a c l e a r e p i d e m i o l o g i c a l picture in such c o u n t r i e s . Considerable efforts have been m a d e t o d e v e l o p m o r e s p e c i f i c forms of tuberculin, b u t the results are still far from s a t i s f a c t o r y , a l t h o u g h some improvement h a s b e e n o b t a i n e d . A new field of approach

.•í *

w a s t h e r e f o r e c o n s i d e r e d w o r t h e x p l o r i n g , n a m e l y , that of tuberculin testing of d o m e s t i c a n i m a l s . T h e a d v a n t a g e in this approach is that the test reactions could b e c o r r e l a t e d w i t h a d e t a i l e d anatomical examination^ so t h a t the chances of discovering t h e c a u s e s of s u c h n o n - s p e c i f i c reactions are much g r e a t e r .

T h e p u r p o s e s of t h e s e activities are: (1) to obtain knowledge on the causes of n o n - s p e c i f i c t u b e r c u l i n s e n s i t i v i t y in h u m a n s , and (2) to develop a low-dose tuberculin t e s t t h a t could b e s p e c i f i c for cattle as w e l l , thus avoiding uneconomical destruction o f c a t t l e .

T h i s p r o g r a m m e is c l o s e l y related to the problems of zoonoses w h i c h are under i n v e s t i g a t i o n b y t h e V e t e r i n a r y Public H e a l t h U n i t .

T U B E R C U L O S I S I M M U N I Z A T I O N A N D TUBERCULIN A L L E R G Y

A n u m b e r of s t u d i e s are carried out in order to test and improve the reliability of m e t h o d s of s t a n d a r d i z a t i o n and quality control of B C G v a c c i n e . The same studies are a l s o t o some e x t e n t concerned w i t h the b i o l o g i c a l differences between various B C G s t r a i n s . M e t h o d s of "viable counts" have already been investigated and have t u r n e d o u t t o give d i f f e r e n t results in d i f f e r e n t l a b o r a t o r i e s . Studies of

e x p e r i m e n t a l i m m u n i t y in m i c e are n o w u n d e r way; mice w o u l d be particularly suitable f o r r o u t i n e c o n t r o l of v a c c i n e because they are much cheaper than guinea-pigs^ b u t w i t h p r e s e n t t e c h n i q u e s the experiments are more difficult and the results more v a r i a b l e v/ith- m i c e .

T h e d u r a t i o n of a l l e r g y after B C G v a c c i n a t i o n of h u m a n beings has been examined in a n u m b e r of studies i n D a n i s h s c h o o l c h i l d r e n , a n d it h a s b e e n shown that the allergy

is p r a c t i c a l l y c o n s t a n t o v e r the first five y e a r s,a p p a r e n t l y irrespective of the o r i g i n of the v a c c i n e . A slight w a n i n g may occur b u t only if n o tuberculin testing is c a r r i e d out ; a s i n g l e low-dose tuberculin t e s t is enough to reinforce tke allergy t o i t s o r i g i n a l s t r e n g t h .

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A n u m b e r of studies have shown the B C G p r o d u c t from a particular laboratory (Tokyo) to be remarkably heat-stable and studies are now under w a y of the d u r a t i o n

(over five y e a r s ) of allergy obtained w i t h such vaccine after exposure to 3 7 С and 50°C for several w e e k s .

Studies carried out by W H O a l l over the w o r l d d u r i n g the l a s t 10 y e a r s h a v e demonstrated a peculiar difference in the p a t t e r n of tuberculin sensitivity; in most regions individuals are either strongly allergic or n o t a l l e r g i c , b u t in many places in the tropics there is a very large p r o p o r t i o n of people w i t h w e a k t u b e r c u l i n s e n s i t i v i t y . T h e origin and meaning of this , !low-grade allergy" is u n k n o w n , b u t there are indications that it m i g h t r e p r e s e n t a degree of immunity so t h a t B C G vaccination m i g h t be of limited v a l u e , or u s e l e s s , in such p e r s o n s • T h e m o s t

promising w a y of finding out w o u l d be to conduct a controlled t r i a l of the i m m u n o g e n i c effect of B C G in a population w i t h this kind of a l l e r g y . E f f o r t s are n o w made to find a suitable place for such a controlled t r i a l .

There are two important m e t h o d s of B C G vaccination^ namely,, i n t r a d e r m a l vaccination and oral v a c c i n a t i o n . I n t r a d e r m a l injection is g e n e r a l l y considered the m o s t e f f i c i e n t and is the only m e t h o d used in W H O - s pons ored B C G p r o g r a m m e s # - O r a l vaccination h a s p r a c t i c a l advantages in d e c e n t r a l i z e d p r o g r a m m e s and h a s a g a i n gained some ground in r e c e n t y e a r s , s i m u l t a n e o u s l y w i t h new d e v e l o p m e n t s in the production and application of o r a l v a c c i n e . Comparative studies of o r a l a n d

intradermal v a c c i n a t i o n are t h e r e f o r e intended^ f i r s t concerning the a l l e r g i c e f f e c t a n d i f p o s s i b l e f o l l o w e d a t a l a t e r s t a g e b y a c o m p a r i s o n o f t h e i m m u n o g e n i c e f f e c t in a h u m a n p o p u l a t i o n .

S e v e r a l laboratories are a t p r e s e n t trying to d e v e l o p a non-living v a c c i n e , and a small scientific group w i l l be gathered in 1962 to review the s i t u a t i o n . W h e n s u c h a vaccine h a s b e e n shov/n to be immunogenic in animals and i n n o c u o u s , a t r i a l in a h u m a n population w i l l be i n d i c a t e d .

T h e low-grade sensitivity m e n t i o n e d above represents a s e r i o u s problem in the diagnostic u s e of the tuberculin t e s t . A special tuberculin p r e p a r a t i o n h a s b e e n developed in r e c e n t years in the T u b e r c u l o s i s 工mmunization R e s e a r c h C e n t r e , C o p e n h a g e n w h i c h gives promise of a b e t t e r d i s c r i m i n a t i o n b e t w e e n persons v/ith h i g h - g r a d e a n d

persons w i t h low-grade s e n s i t i v i t y . W o r k is continued in the l a b o r a t o r y to f u r t h e r split this faction and in the field to study the specificity r e l a t i v e to other

tuberculin preparations•

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5.. CHEMOTHERAPY AND CHEMOPROPHYLAXIS

T h e introduction of effective antituberculosis drugs^ particularly isoniazed^

h a s revolutionized the approach to the control of tuberculosis. However, although in the last 10 years extensive clinical trials have been made of different chemo-

therapeutic regimens the problem of the best treatment under the conditions prevailing in the le s s -de ve lopecl parts of the world is still far from solved.

T h i s and r e l a t e d problems have been taken up by the Tuberculosis Chemotherapy Centre in Madras (South India), of which W H O is a nia j or sponsor. Since its start in 1956 the Centre h a s conducted"a series of controlled trial s designed to define the value of domiciliary chemotherapy in a population living under adverse socio-economic c o n d i t i o n s . One important finding is that home treatment with isoniazid plus PAS is as effective as h o s p i t a l treatment with the same combination drugs and another t h a t the contacts of patients under domiciliary treatment are not exposed to any special risk of i n f e c t i o n . Different forms of home treatment are also "being porripared and it appears from the first results that the combined regimen is more satisfactpry than isoniazid alone.

A two-year controlled study of domiciliary treatment with isoniazid in ”suspect"

cases (X-ray positive^ sputum negative) has recently been completed by the Chemotherapy P i l o t Project in Tunis'. The data from this study are currently being analysed. A four-year follow-up is planned.

A particular problem of domiciliary chemotherapy in its present form is that it requires daily self-administration of drugs - Such regular self-administration is d i f f i c u l t to ensure and depot-drugs w i t h prolonged action requiring only intermittent administration w o u l d therefore present a considerable practical advantage. Preliminary studies on the preparation of such drugs have been started at the Institute of

P h a r m a c o l o g y , University of Naples•

Adequate management of chronic advanced cases of tuberculosis is of considerable public health importance in view of their usually high degree of infectiousness. A trial designed to assess the value of long-continued chemotherapy with massive doses of isoniazid or its reputedly less toxic methansulfonate derivative in the management of such cases w a s started in Czechoslovakia i n i960 with technical guidance from W H O . F r o m early results it seems that continued chemotherapy substantially reduces

infectiousness even in cases which are isoniazid-resistant.

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- 25 -

In recent years it is becoming progressively evident from controlled experiments that isoniazid under certain conditions may be of use in the so-called secondary chemoprophylaxis of tuberculosis^ i . e . the use of antituberculosis drugs in those v/ho are infected, as demonstrated b y a significant reaction to the tuberculin t e s t , b u t w h o have no pathognomonic signs or symptoms of tuberculous d i s e a s e . T h e b e n e f i t of such disease chemoprophylaxi s and its acceptability in a community w i t h a serious tuberculosis problem and limited resources h a s b e e n investigated b y the Chemotherapy Pilot Project in T u n i s .

6 . TUBERCULOSIS EPIDEMIOLOGY AND METHODS FOR T H E C O N T R O L A N D ERADICATION OF TUBERCULOSIS

Community-wide studies of the epidemiology of tuberculosis a n d of the relative impact of different antituberculosis measures have long b e e n promoted b y VJHO.

One such study devoted to the problems of a developing community is b e i n g conducted b y the Field R e s e a r c h S t a t i o n in M a d a n a p a l l e , S o u t h India• R e s u l t s from the first seven years (1950-1957) have s h o w n , inter a l i a , t h a t 9

〇 per c e n t , of a l l

active cases occur among persons aged 2 0 years and over and that i t may be profitable v^here resources are limited to concentrate mass X - r a y examination on t h a t age-group

(which constitutes about one-half of the t o t a l p o p u l a t i o n ) . I t has also appeared that hospitalization of the bacillary cases may n o t be an effective control measure in a community where the average income is very low and w h e r e loss of income even for short periods may be s e r i o u s . T o o many people refuse to accept or to continue hospital t r e a t m e n t . Trials of home treatment w e r e therefore included in the p r o j e c t in 1 9 5 8 . The project w h i c h w a s started in 1950 as a joint undertaking of the

Government of 工ndia9 W H O and the U n i o n M i s s i o n Tuberculosis Sanatorium became in 1958 the responsibility of the Indian C o u n c i l of M e d i c a l R e s e a r c h . T h e p r o j e c t w i l l be reviewed in the n e a r future to determine to w h a t extent and for h o w long W H O a s s i s t a n c e is r e q u i r e d .

The epidemiology of tuberculosis in an advanced country v/ith a low and d e c l i n i n g incidence of the disease is the subject of a long-range study started by the D a n i s h Tuberculosis Index in 1950 w i t h assistance from W H O . T h i s study w h i c h includes the total adult population of D e n m a r k h a s already provided valuable d a t a for the planning of eradication p r o g r a m m e s . One important finding is t h a t i t is possible b y a simple examination (t-uberculin testing and chest p h o t o f l u o r o g r a p h y ) tc subdivide the populatic.

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i n t o g r o u p s w i t h markedly d i f f e r e n t r i s k s o f developing tuberculous disease and t o

pinpoint relatively small high-risk groups on which preventive efforts can be c o n c e n t r a t e d . The D a n i s h Tuberculosis Index receives an annual grant from WHO ifhich^ it is expected^ w i l l be continued, u p to the end of 1964 to permit completion

o f t h e s t u d y .

T h e health authorities of Czechoslovakia have shown considerable interest in p r o m o t i n g tuberculosis eradication and a small-scale pilot study of methods suitable for rapid reduction of tuberculosis infection and disease has been planned in

consultation w i t h WHO- The study is to be conducted in a limited area of Czechoslovak!

by the Institute for Epidemiology and Bacteriology, Prague •

(List of research project titles^ pages 109-111)

LEPROSY

i • INTRODUCTION

T h e Leprosy U n i t w a s set up in November 1 9 5 8 . A Scientific Group on Leprosy R e s e a r c h w a s convened in February 1959 which reviewed the gaps in our knowledge and recommended a w i d e programme of research. The recommendations of the Study Group were reviewed in the first session of the АСШ. Several projects aimed at obtaining the transmission of human leprosy to laboratory animals and at the growth of M . leprae in culture media^ have b e e n initiated and some trials of leprosy drugs as v/eli as

studies cf leprosy prevention^, and epidemiological investigations, are now in progress.

2 . R E S E A R C H ON T H E MICROBIOLOGY OF LEPROSY has been given first priority because .the transmission of M . leprae to laboratory animals and the cultivation of this

m i c r o - o r g a n i s m w o u l d e n a b l e m a n y p r o b l e m s t o b e s o l v e d, a n d w o u l d h a v e c o n s i d e r a b l e

impact on leprosy research and leprosy control.

T o this end) W H O has:

( i ) o r g a n i z e d t h e r e g u l a r s u p p l y o f i c e d b i o p s i e s o f h u m a n l e p r o s y t o l a b o r a t o r i e .

interested in the cultivation and transmission of human leprosy to laboratory animals;

(ii) supported research on the transmission of human M . leprae to different rodents :

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