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Immunoprophylaxis for travellers
230 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. 64. No. 2.
1970.
IMMUNOPROPHYLAXIS
FOR TRAVELLERS*
5. P. BAIRD In modern times, when travel by high speed aircraft has become commonplace, no country is separated from another by more than a few hours and the world can be encircled well within the shortest incubation period of the quarantinable diseases. It seems prudent for those whose work may entail international travel at short notice to be immunized well in advance so that immunity will be established and recovery from transient ill effects will be complete before the journey commences. Such people may come to us for advice, so that knowledge of immunization procedures, with the possession of standard reference documents, schedules of requirements, international certificates and maps is essential (BAIRD, 1965). Detailed and accurate up to date information is given in the paper by Dr. D. A. Cannon in the Transactions, 63, 867. T h e q u a r a n t i n a b l e diseases are most important in international travel since, if the requirements of the International Sanitary Regulations (1966) are not complied with, restrictive quarantine, isolation or surveillance may be enforced by the health services of the country visited. These regulations are amended from time to time by another WHO publication, "Vaccination certificate requirements for International Travel," the latest issue being dated 1 January 1970. International Certificates are required only for cholera, yellow fever and smallpox. It is important to remember that a person travelling from a non-infected country requires protection against some of these conditions before his visit. But if he starts from, or passes through, any of the countries regarded as areas of endemic infection, certificates of protection will be required at his destination or on return to his starting point. I need hardly remind you that the spread of epidemics may alter international requirement--cholera is the most recent example. Containment or eradication of disease may cause relaxation o f s u c h requirements in the future. Regulations tend to be most stringent in the "yellow fever receptive areas" which are defined as the areas in which the virus of yellow fever is not known to exist but where the presence of Aedes aegypti or other potential vector of yellow fever would permit its development if introduced (International Sanitary Regulations, 1966). The use of yellow fever vaccine in mass campaigns has produced such a high protection rate that the human disease has practically disappeared from areas in which campaigns have been carried out thoroughly. H o w much longer will such vaccination be an international requirement? In 1958 the World Health Organization decided that prevention and eradication of smallpox throughout the world, by large-scale vaccination and surveillance in the endemic areas, was practicable. Although initially, during the first few years of this campaign, the world incidence of smallpox appeared to rise, this Was due to better and more complete r6porting. But whereas in 1967 there were 120,000 recorded cases, in 1968 the number had dropped to 79,000. In 1969 the total cases are estimated at under 40,000 and several endemic countries have been freed of the disease. *Reproduced in part by courtesy of the Editor, Worm Medical Journal.
J. P. BAIRD
231
Much of this success results from employing the foot operated jet injectors and the multiple puncture technique with a bifurcated needle. Field workers can perform many hundreds of vaccinations daily. At this rate smallpox may disappear in the next few years.
Immunoprophylaxis When we consider the present situation with regard to protecting travellers, as distinct from complying with international health regulations, we find the following position (WHO, 1964). 1. Vaccines and immunizing procedures may be advocated at present for the travellers in respect of the following--plague, cholera, yellow fever, smallpox, typhus exanthematicus, typhoid and paratyphoid fevers. 2. Similar procedures are used at present or are being developed for the following worldwide diseases:--adenovirus infections, influenza, °measles, °mumps, *poliomyelitis, diphtheria, pertussis, °staphylococcal infections, tetanus, °tularaemia, *tuberculosis, O,Q fever, °*brucellosis, °*leptospirosis, °*rabies. To this group should be added the tick-borne encephalitides. Many of the procedures in Groups 1 and 2 have been in everyday use for years (since 1798 in the case of Jennerian vaccination) and the only changes have been in purification or improvement in manufactnre of the vaccine, or in combining them so that several can be given in one injection, or in improved technique or route of administration. Others are comparatively new and untried. In addition to the quarantinable diseases, newcomers to the tropics, especially young people, are at risk from diphtheria, poliomyelitis, tetanus and tuberculosis. Therefore protection for travellers must always be considered, if not already complete. If vaccines produced by growth of the virus in tissues other than the traditional ones, for example in the brains of suckling mice, are confirmed to be safe and effective, this procedure may be used more frequently. Newer methods of insertion are being explored. Intradermal insertion has been used successfully for some time, the best example being the combined typhoid-paratyphoid-tetanus vaccine used in adults and older children (Memo on Immunological Procedures, 1968). Cholera vaccine has become available in a form suitable for intradermal use and an oral vaccine is under trial. Others will eventually become available in the intradermal form, but much immunological research on each vaccine is required to ensure that this route produces an immunity as strong and lasting as the subcutaneous route. The effectiveness of immunity with a non-infectious antigen often depends on the insertion of a sufficient quantity rather than on the route of administration. If an agent causes local or systemic reactions of any severity, efforts are made to minimize such reactions by using smaller doses intradermalty. With certain vaccines this method does not produce an adequate immunological response as a primary or "priming" dose, particularly in respect of persistence of antibody, but the method may be adequate for subsequent reinforcing doses. Understanding of tissue and cellular immunity has resulted from research and its importance as opposed to humoral or serological indicator reactions is increasingly appreciated. For example in respiratory infections the immune factors found in *Of special importance in Tropical countries. °These diseases involve a special form of risk, occupational hazard or exposure.
232
SYMPOSIUM O N I M P O R T E D DISEASE
bronchial secretions or cells are more relevant to protection than, and may vary widely from, the serological antibodies. When live attenuated infectious antigens are used, contact with the cells or tissues of the host is required to allow multiplication to take place--oral administration of Sabin poliovirus to allow colonization of the intestinal tract is the best example. Unconventional routes of administration may well be developed in the future and instead of the injection route we may be giving antigen by sublingual, intranasal or oral routes, or even by aerosol spray to the respiratory tract (WHO, 1964).
Complications, "accidents", untoward effects Much thought and research has been devoted to the reduction of untoward reactions to immunization and these must always be borne in m i n d . Akhough major complications are few, their effects may be disastrous, and are often exaggerated in the lay mind out of all proportion to the numerical incidence. Routine smallpox vaccination of populations at very low risk, for example in Great Britain, has been abandoned as a compulsory measure and widespread vaccination of a population during a limited smallpox epidemic is not generally undertaken since more harm than good may result from neurological and other complications (SPILLANEand WELLS, 1964; BUTLERand BENSON, 1965). Susceptible persons Certain susceptible persons tend to show an abnormal response and it is important to try to pick them out before immunization. Certain groups--young children and pregnant women--are well known. A careful preliminary history may give a warning in other cases--sensitivity to a previous immunization, history or presence of eczema or other skin disease, or a history of fits or other abnormalities of the central nervous system. I f oral vaccine is to be given, acute intercurrent infection is a bar, as is diarrhoea or intestinal dysfunction (MINISTRY Or HEALTH, 1963). Especially prone to react severely are people with any constitutional disease, particularly of the "auto-immune" or collagen groups, or of the type associated with quantitative or qualitative alterations in serum gamma globulin. An "iatrogenic" group at risk are patients receiving steroids or other immunosuppressive therapy. In this context experience in the Dutch Army is worth noting. Anti-vaccinial gamma globulin (2 ml. dose) is given to recruits at the same time as primary vaccination and has reduced the incidence of nervous system complications from 1 : 4 0 0 0 to 1 : 30,000 (NANNING, 1962). What are the future possibilities? The schedules and programmes recommended at the present time have been formulated at the cost of much thought, time and money, and in the present state of our knowledge are obligatory. They may however err on the side of caution. Many of them were criticized by an Expert Committee of the World Health Organization in 1964, who considered that they are often the combined product of administrative convemence, traditional practice and indeed chance (WHO, 1964). Adequate and careful immunological studies had played only a small part in determining these schedules. Careful observations, study and research were recommended by WHO into the following aspects: 1. Choice of route of insertion 2. Combination of antigens 3. The best age for immunization 4. Dosage, timing and the sequence of antigens
J. P. BAIRD
233
5. Reporting of untoward effects 6. Abnormal individual responses 7. Development of new vaccines To further this work a WHO reference centre for immunoglobulins was created in 1964, and in 1967 a WHO Centre for study of immunology was completed and linked with similar laboratories in the United Kingdom, the United States of America, Czechoslovakia and other countries. It is probably true to say that the discipline of immunology, with new information, ideas and techniques arising from research, has been one of the fastest growing sciences in the past decade. Knowledge has of course led to advances in organ transplantation or has been stimulated by the requirements of such surgical techniques. The major problem facing WHO at the moment is how best to bring these recent advances rapidly to bear upon the problems of clinical medicine and immunoprophylaxis. New vaccines and immunizing procedures are being developed or are contemplated for: Rickettsial diseases, other than typhus exanthematicus and Q fever, trachoma, treponematoses, amoebiasis, leishmaniasis, malaria, trypanosomiasis, and certain hen minthic diseases. P r o t o z o a l diseases. In the past, eradication or control by attack with chemotherapy upon parasites and insecticides upon vectors has produced satisfactory results. However, with resistance to drugs and insecticides presenting an increasing problem and with governmental ban upon several well known insecticides, perhaps methods of immunization will become more important, and we should "think forward" in this respect. The immunology of plasmodia, leishmaniae, trypanosomes and entamoebae is being studied by many Fellows of this Society. I-Ielminthie diseases. No immunological methods for preventing these conditions in man have yet been successful, but certain experimental work on animals suggests that efficient vaccines could be developed. Rats have been immunized against Taenia taeniaeformis infection by intraperitoneal inoculation of prepared material from the adult worms, and also passively protected by intraperitoneal inoculation of serum from immune animals. Monkeys have been exposed to gradually increasing doses of cercariae of S. japonicum and have been shown to become immune to schistosomiasis. Cercariae of S. mansoni treated with ~°Co have been used to protect mice against schistosomiasis. Irradiated larvae of the lung worm (Dictyocaulus viviparus) produced a most efficient vaccine against the lung disease in cattle. Irradiated filarial larvae injected into man cause certain immune reactions. May we not hope for an efficient vaccine against filariasis, and schistosomiasis in man? REFERENCES BAIRD, J. P. (1965). World reed. J., 12, 176. BUTLER,N. R. & BENSON,P. F. (1965). Br. reed. J., 1, 841. International Sanitary Regulations (1966). WHO, Geneva, Memorandum on Immunological Procedures (1968). London: H.M.S.O. MINISTRY OF HEALTH(1963). Active Immunization against Infectious Diseases. London: H.M.S.O. NANNING, W. (1962). Bull. Wld. Hlth Org., 113, 197. SPILLANE, J. D. & WELLS, C. E. C. (1964). Brain, 87, 1. WORLD HEALTH ORGANIZATION(1964). Research in immunology. Tech. Rep. Ser., No. 286.
Vol. 64. No. 2.
1970.
IMMUNOPROPHYLAXIS
FOR TRAVELLERS*
5. P. BAIRD In modern times, when travel by high speed aircraft has become commonplace, no country is separated from another by more than a few hours and the world can be encircled well within the shortest incubation period of the quarantinable diseases. It seems prudent for those whose work may entail international travel at short notice to be immunized well in advance so that immunity will be established and recovery from transient ill effects will be complete before the journey commences. Such people may come to us for advice, so that knowledge of immunization procedures, with the possession of standard reference documents, schedules of requirements, international certificates and maps is essential (BAIRD, 1965). Detailed and accurate up to date information is given in the paper by Dr. D. A. Cannon in the Transactions, 63, 867. T h e q u a r a n t i n a b l e diseases are most important in international travel since, if the requirements of the International Sanitary Regulations (1966) are not complied with, restrictive quarantine, isolation or surveillance may be enforced by the health services of the country visited. These regulations are amended from time to time by another WHO publication, "Vaccination certificate requirements for International Travel," the latest issue being dated 1 January 1970. International Certificates are required only for cholera, yellow fever and smallpox. It is important to remember that a person travelling from a non-infected country requires protection against some of these conditions before his visit. But if he starts from, or passes through, any of the countries regarded as areas of endemic infection, certificates of protection will be required at his destination or on return to his starting point. I need hardly remind you that the spread of epidemics may alter international requirement--cholera is the most recent example. Containment or eradication of disease may cause relaxation o f s u c h requirements in the future. Regulations tend to be most stringent in the "yellow fever receptive areas" which are defined as the areas in which the virus of yellow fever is not known to exist but where the presence of Aedes aegypti or other potential vector of yellow fever would permit its development if introduced (International Sanitary Regulations, 1966). The use of yellow fever vaccine in mass campaigns has produced such a high protection rate that the human disease has practically disappeared from areas in which campaigns have been carried out thoroughly. H o w much longer will such vaccination be an international requirement? In 1958 the World Health Organization decided that prevention and eradication of smallpox throughout the world, by large-scale vaccination and surveillance in the endemic areas, was practicable. Although initially, during the first few years of this campaign, the world incidence of smallpox appeared to rise, this Was due to better and more complete r6porting. But whereas in 1967 there were 120,000 recorded cases, in 1968 the number had dropped to 79,000. In 1969 the total cases are estimated at under 40,000 and several endemic countries have been freed of the disease. *Reproduced in part by courtesy of the Editor, Worm Medical Journal.
J. P. BAIRD
231
Much of this success results from employing the foot operated jet injectors and the multiple puncture technique with a bifurcated needle. Field workers can perform many hundreds of vaccinations daily. At this rate smallpox may disappear in the next few years.
Immunoprophylaxis When we consider the present situation with regard to protecting travellers, as distinct from complying with international health regulations, we find the following position (WHO, 1964). 1. Vaccines and immunizing procedures may be advocated at present for the travellers in respect of the following--plague, cholera, yellow fever, smallpox, typhus exanthematicus, typhoid and paratyphoid fevers. 2. Similar procedures are used at present or are being developed for the following worldwide diseases:--adenovirus infections, influenza, °measles, °mumps, *poliomyelitis, diphtheria, pertussis, °staphylococcal infections, tetanus, °tularaemia, *tuberculosis, O,Q fever, °*brucellosis, °*leptospirosis, °*rabies. To this group should be added the tick-borne encephalitides. Many of the procedures in Groups 1 and 2 have been in everyday use for years (since 1798 in the case of Jennerian vaccination) and the only changes have been in purification or improvement in manufactnre of the vaccine, or in combining them so that several can be given in one injection, or in improved technique or route of administration. Others are comparatively new and untried. In addition to the quarantinable diseases, newcomers to the tropics, especially young people, are at risk from diphtheria, poliomyelitis, tetanus and tuberculosis. Therefore protection for travellers must always be considered, if not already complete. If vaccines produced by growth of the virus in tissues other than the traditional ones, for example in the brains of suckling mice, are confirmed to be safe and effective, this procedure may be used more frequently. Newer methods of insertion are being explored. Intradermal insertion has been used successfully for some time, the best example being the combined typhoid-paratyphoid-tetanus vaccine used in adults and older children (Memo on Immunological Procedures, 1968). Cholera vaccine has become available in a form suitable for intradermal use and an oral vaccine is under trial. Others will eventually become available in the intradermal form, but much immunological research on each vaccine is required to ensure that this route produces an immunity as strong and lasting as the subcutaneous route. The effectiveness of immunity with a non-infectious antigen often depends on the insertion of a sufficient quantity rather than on the route of administration. If an agent causes local or systemic reactions of any severity, efforts are made to minimize such reactions by using smaller doses intradermalty. With certain vaccines this method does not produce an adequate immunological response as a primary or "priming" dose, particularly in respect of persistence of antibody, but the method may be adequate for subsequent reinforcing doses. Understanding of tissue and cellular immunity has resulted from research and its importance as opposed to humoral or serological indicator reactions is increasingly appreciated. For example in respiratory infections the immune factors found in *Of special importance in Tropical countries. °These diseases involve a special form of risk, occupational hazard or exposure.
232
SYMPOSIUM O N I M P O R T E D DISEASE
bronchial secretions or cells are more relevant to protection than, and may vary widely from, the serological antibodies. When live attenuated infectious antigens are used, contact with the cells or tissues of the host is required to allow multiplication to take place--oral administration of Sabin poliovirus to allow colonization of the intestinal tract is the best example. Unconventional routes of administration may well be developed in the future and instead of the injection route we may be giving antigen by sublingual, intranasal or oral routes, or even by aerosol spray to the respiratory tract (WHO, 1964).
Complications, "accidents", untoward effects Much thought and research has been devoted to the reduction of untoward reactions to immunization and these must always be borne in m i n d . Akhough major complications are few, their effects may be disastrous, and are often exaggerated in the lay mind out of all proportion to the numerical incidence. Routine smallpox vaccination of populations at very low risk, for example in Great Britain, has been abandoned as a compulsory measure and widespread vaccination of a population during a limited smallpox epidemic is not generally undertaken since more harm than good may result from neurological and other complications (SPILLANEand WELLS, 1964; BUTLERand BENSON, 1965). Susceptible persons Certain susceptible persons tend to show an abnormal response and it is important to try to pick them out before immunization. Certain groups--young children and pregnant women--are well known. A careful preliminary history may give a warning in other cases--sensitivity to a previous immunization, history or presence of eczema or other skin disease, or a history of fits or other abnormalities of the central nervous system. I f oral vaccine is to be given, acute intercurrent infection is a bar, as is diarrhoea or intestinal dysfunction (MINISTRY Or HEALTH, 1963). Especially prone to react severely are people with any constitutional disease, particularly of the "auto-immune" or collagen groups, or of the type associated with quantitative or qualitative alterations in serum gamma globulin. An "iatrogenic" group at risk are patients receiving steroids or other immunosuppressive therapy. In this context experience in the Dutch Army is worth noting. Anti-vaccinial gamma globulin (2 ml. dose) is given to recruits at the same time as primary vaccination and has reduced the incidence of nervous system complications from 1 : 4 0 0 0 to 1 : 30,000 (NANNING, 1962). What are the future possibilities? The schedules and programmes recommended at the present time have been formulated at the cost of much thought, time and money, and in the present state of our knowledge are obligatory. They may however err on the side of caution. Many of them were criticized by an Expert Committee of the World Health Organization in 1964, who considered that they are often the combined product of administrative convemence, traditional practice and indeed chance (WHO, 1964). Adequate and careful immunological studies had played only a small part in determining these schedules. Careful observations, study and research were recommended by WHO into the following aspects: 1. Choice of route of insertion 2. Combination of antigens 3. The best age for immunization 4. Dosage, timing and the sequence of antigens
J. P. BAIRD
233
5. Reporting of untoward effects 6. Abnormal individual responses 7. Development of new vaccines To further this work a WHO reference centre for immunoglobulins was created in 1964, and in 1967 a WHO Centre for study of immunology was completed and linked with similar laboratories in the United Kingdom, the United States of America, Czechoslovakia and other countries. It is probably true to say that the discipline of immunology, with new information, ideas and techniques arising from research, has been one of the fastest growing sciences in the past decade. Knowledge has of course led to advances in organ transplantation or has been stimulated by the requirements of such surgical techniques. The major problem facing WHO at the moment is how best to bring these recent advances rapidly to bear upon the problems of clinical medicine and immunoprophylaxis. New vaccines and immunizing procedures are being developed or are contemplated for: Rickettsial diseases, other than typhus exanthematicus and Q fever, trachoma, treponematoses, amoebiasis, leishmaniasis, malaria, trypanosomiasis, and certain hen minthic diseases. P r o t o z o a l diseases. In the past, eradication or control by attack with chemotherapy upon parasites and insecticides upon vectors has produced satisfactory results. However, with resistance to drugs and insecticides presenting an increasing problem and with governmental ban upon several well known insecticides, perhaps methods of immunization will become more important, and we should "think forward" in this respect. The immunology of plasmodia, leishmaniae, trypanosomes and entamoebae is being studied by many Fellows of this Society. I-Ielminthie diseases. No immunological methods for preventing these conditions in man have yet been successful, but certain experimental work on animals suggests that efficient vaccines could be developed. Rats have been immunized against Taenia taeniaeformis infection by intraperitoneal inoculation of prepared material from the adult worms, and also passively protected by intraperitoneal inoculation of serum from immune animals. Monkeys have been exposed to gradually increasing doses of cercariae of S. japonicum and have been shown to become immune to schistosomiasis. Cercariae of S. mansoni treated with ~°Co have been used to protect mice against schistosomiasis. Irradiated larvae of the lung worm (Dictyocaulus viviparus) produced a most efficient vaccine against the lung disease in cattle. Irradiated filarial larvae injected into man cause certain immune reactions. May we not hope for an efficient vaccine against filariasis, and schistosomiasis in man? REFERENCES BAIRD, J. P. (1965). World reed. J., 12, 176. BUTLER,N. R. & BENSON,P. F. (1965). Br. reed. J., 1, 841. International Sanitary Regulations (1966). WHO, Geneva, Memorandum on Immunological Procedures (1968). London: H.M.S.O. MINISTRY OF HEALTH(1963). Active Immunization against Infectious Diseases. London: H.M.S.O. NANNING, W. (1962). Bull. Wld. Hlth Org., 113, 197. SPILLANE, J. D. & WELLS, C. E. C. (1964). Brain, 87, 1. WORLD HEALTH ORGANIZATION(1964). Research in immunology. Tech. Rep. Ser., No. 286.