Evaluation of smallpox vaccination policy*

Articles in the Upda4 series Les articles de la rubrique give a concise, authoritative, iLe point fournissent un and up-to-date survey of the bilan concis et fable de la present position in the se- situation actuelle dans le ,uuateC , , lected fields, and, over a domaine considere. Des ex-period of years, will cover perts couvriront ainsi suc- many diaerent aspects of cessivement de nombreux. the biomedical sciences aspects des sciences bio- ILe po nt / / and public health. Most of medicales et de la sante /the articles will be writ- publique. La plupart de ces ten, by invitation, by ack- articles auront donc ee nowledged experts on the rediges sur demande par les / /Zsubject. I specialisteslesplusautorises. Bulletin of the World Health Organization, 57 (1): 1-9 (1979) Evaluation of smallpox vaccination policy * I. ARITA1 & J. G. BREMAN 2 During 1978 and 1979 the Global Commission for the Certification of Smallpox Eradication will proceed with verification of smallpox eradication in 31 countries. If current surveillance activities do not discover any further cases before the end of 1979, the world will be declared smallpox free. However, the recent occurrence of two laboratory associated smallpox cases in Birmingham, England, revealed that the stocks of variola virus held in at least 12 laboratories in the world pose a real danger to the achievement of smallpox eradication and efforts are being made to reduce the number of laboratories retaining the virus to not more than 4-all WHO collaborating centres-by 1980. Scientific data indicate the unlikelihood of smallpox recurring once it has been eradicated from the human population, although further confirmatory studies are continuing. If the Global Commission verifies the eradica- tion of smallpox, continuation of smallpox vaccination will be unjustifiable in view of its severe complications, however infrequent, and the expected global savings that would result from the termination of vaccination programmes. The World Health Organization's campaign to eradicate smallpox has now reached a turning-point. Interhuman transmission of smallpox, which had continued for more than 3000 years, appears to have come to an end on 26 October 1977, when the world's last known case developed his rash in Merca, Somalia. The campaign strategy has now been directed towards verifying this apparent interruption of transmission worldwide. The Global Commission for the Certification of Smallpox Eradication, recently established by the Director-General of WHO, will appraise the progress made towards global eradication of the disease. Although two smallpox cases occurred in Birmingham, England, in August and September 1978, these were considered to be associated with a laboratory retaining variola virus and not with an endemic focus and will not affect the course of global certification. * A French translation of this article will appear in a later issue of the Bulletin. ' Chief, Smallpox Eradication, World Health Organization, Geneva. 2 Medical Officer, Smallpox Eradication, World Health Organization, Geneva. 3769 -1 2 I. ARITA & J. G. BREMAN Table 1. Number of specimens tested by WHO collaborating laboratories No. of specimens received (No. positive for smallpox) Country or territory 1973 1974 1975 1976 1977 1978 a African Region Angola - - - - 1 1 Benin - - - 1 - - Botswana 14 (5) 9 8 2 43 46 Burundi 4 3 1 - - Congo - - - - 2 1 Ethiopia 27 (4) 39 (9) 112 (32) 431 (60) 565 911 Gambia - - - 1 - - Ghana - - 1 - Ivory Coast - - 9 1 - - Kenya 2 9 (3) 2 1 147 (4) 77 Liberia - - 9 - - - Malawi 2 2 - 3 296 24 Mauritania - - 1 2 1 - Mozambique - - 4 - 62 12 Niger - - - 1 - - Nigeria - - 4 3 - 1 Rwanda 2 - - - 3 Senegal - - - 1 - Sierra Leone - - 5 3 1 - South Africa - - - - - 8 Southern Rhodesia - - - - - 15 Swaziland - - - - 1 13 Uganda - - 1 1 - 119 United Republic of Tanzania 1 - 2 - 3 77 Zaire 92 b 63 b 207 b 125 b 181 b 97 b Zambia - - 2 - 50 50 Eastern Mediterranean Region Afghanistan 4 (1) - 1 5 4 - Bahrain - - - - - 50 Democratic Yemen - - - 1 - 12 Djibouti - 7 (1) - - 17 44 Iran - - - - - 336 Iraq - - - - - 12 Kuwait - - - - - 78 Lebanon 1 - Oman - - - - _ 45 Pakistan 11 (6) 21 (11) 52 116 7 1 Qatar - - - - - 24 Saudi Arabia 1(1) - - - 22 116 Somalia - - - 56 (33) 864 (265) 1133 Sudan 9 22 9 16 14 24 Syrian Arab Republic - 1 - - - 4 United Arab Emirates - - - - - 53 Yemen 7 6 3 2 2 18 South East Asia Region Bangladesh - 1 (1) 18 (3) 183 664 - Burma - - - 12 - India 39 (9) 39 (20) 404(120) 358 977 Indonesia 3 12 - 1 - Nepal 37 (27) 48 (40) 16 (8) 5 3 SriLanka 1(1) Other Regions Italy - - - - 1 Switzerland - - - 1 Viet Nam - 1 Total 257 (54) 283 (85) 871(163) 1332 (93) 3931 (269) 3402 a As at 1 October 1978. b Monkeypox diagnosed: 1973 (3); 1974 (1); 1975 (2); 1976 (3); 1977 (6); 1978 (5). EVALUATION OF SMALLPOX VACCINATION POLICY In this article, topics of interest to public health officers directly or indirectly involved in the final phase of the global campaign are discussed under the following headings: Global certification of smallpox eradication Dangers related to variola virus stocks in laboratories Possibility of recurrence of smallpox after eradication - Farewell to smallpox vaccination. These topics are all related to re-evaluation of the need to continue routine smallpox vaccination. GLOBAL CERTIFICATION OF SMALLPOX ERADICATION During the eradication programme, 77 countries in Africa, Asia, and South America were either endemic for smallpox, or at special risk of importation which could have established or re-established endemic smallpox. Since the sensitivity of the surveillance systems in these countries was highly variable, it was decided that interruption of smallpox transmission would be confirmed only if special surveillance activities were continued for at least 24 months after the last reported case without detection of hidden foci. During the 11 years of the programme the longest period that smallpox transmission continued undetected by national authorities was 8 months, in Indonesia in 1971-72. Hence the two-year period, three times the longest delay in reporting, appears to be adequate. Fig. 1. Plan for global certification of smallpox eradication by the end of 1979. 3 I. AR1TA & J. G. BREMAN These special surveillance activities, which are still continuing in some countries, include nationwide active house-to-house searches for hidden foci, and other field surveys, such as facial pockmark surveys, to detect persons who contract the disease after the last case has been reported, and the collection of specimens from suspected smallpox cases or chickenpox cases where there is any doubt about the diagnosis. National authorities must also produce full documentation concerning the development and achievements of the national programme. Table 1 shows the increase in the number of specimens 'tested after 1976 as the certification activities progressed. By September 1978, 46 countries (28 in Africa, 8 in Asia, and 10 in South America) had already been certified free of smallpox following visits by specially constituted Inter- national Commissions, entrusted by WHO with the task of independent evaluation of the eradication status in each country. Further, in order to appraise worldwide interruption of smallpox transmission, a group of public health experts composed of virologists and epidemiologists, and known as the Global Commission, was formed by WHO in early 1978. This group is proceeding with the work required in the 31 countries where smallpox eradication has not yet been certified (Fig. 1). Special attention is directed to surveillance in the Horn of Africa, where the world's last endemic smallpox case was found, and where the nomadic movement of the population makes surveillance difficult. DANGERS RELATED TO VARIOLA VIRUS STOCKS IN LABORATORIES Currently, the only known source of variola virus, and thus the only potential for future smallpox epidemics, resides in laboratories retaining stocks of the virus. Since 1975, WHO has requested the authorities of all countries and territories in the world to provide information about which laboratories maintain variola virus stocks; 180 of 181 countries and territories have responded, Democratic Kampuchea being the only exception. A review of the world's literature since 1950 was also undertaken to identify the laboratories that had conducted variola virus studies, and a list of the world's diagnostic laboratories that might have worked with variola in the past was reviewed. Thus, more than 600 laboratories have been contacted, either by WHO or by national health authorities. In India, where a number of laboratories had conducted diagnostic work for smallpox, national and WHO programme staff visited all such laboratories to examine the stocks. During these world- wide surveys, 76 laboratories with variola virus were identified; of these, 64 have voluntarily destroyed their stocks or transferred them to a WHO collaborating centre, leaving at least 12 laboratories currently retaining variola virus. Security measures for laboratories with variola virus stocks were formulated by a group convened by WHO in 1977, and these consist essentially of physical delineation of clean and contaminated areas within a smallpox laboratory, which is itself completely separated from the outside environment, and elimination of the chance that live virus can be transferred from the contaminated to the clean areas or to the exterior. There are restric- tions on the personnel allowed to work in the laboratory, whatever their vaccination status. The importance of strict control was shown in 1973 in London. Two persons died of smallpox after being infected by a laboratory worker, herself infected in a laboratory. At the time of writing, the laboratory-associated infection in Birmingham in August 1978 was still under official enquiry; one very mild secondary case (the patient's mother) occurred among the contacts under surveillance. The outbreak was quickly contained by 4 EVALUATION OF SMALLPOX VACCINATION POLICY 5 prompt and intensive surveillance and containment measures initiated by the United Kingdom health authorities. Of the 12 laboratories currently retaining variola virus, 5 are WHO collaborating centres (1 each in Japan, Netherlands, United Kingdom, USA, and USSR) and at least 7 are non-designated laboratories (2 each in the Federal Republic of Germany and USA, 1 in South Africa, and more than one laboratory with this virus in China). The episode in August 1978 in Birmingham emphasizes that the number of laboratories retaining variola virus should be reduced to the minimum, since maintaining the virus, even with safety measures, involves a degree of risk. The World Health Assembly recom- mended that all non-designated laboratories destroy their stocks of variola virus or transfer them to a WHO collaborating centre, considering that the practical benefit for the global eradication of smallpox of maintaining the virus in these laboratories appeared to be very low, weighed against the risk. The WHO collaborating centres themselves are now engaged in diagnostic work on field specimens collected from smallpox suspects in the countries where certification activities are underway. Also, in these laboratories important research activities are continuing under maximum safety measures to confirm that certain animal poxviruses are in fact distinct from variola virus and therefore will not pose a problem to the global programme. Thus the maintenance of the virus for these activities under maximum safety measures at the WHO collaborating centres appears still to be beneficial to the programme. However, of the five WHO collaborating centres, one or two may consider transferring the virus to one of the other centres in the near future. The goal ofWHO is to reduce the number of such collaborating centres to no more than 4 by early 1980. The question may arise whether the total destruction of variola virus in all laboratories would be desirable. One argument in favour of this is that it would eliminate the danger of biological warfare, or terrorist activity, employing variola virus. To minimize these possibilities national authorities should enforce stringent security measures in laboratories holding variola virus. Currently the potential benefits of keeping the reference strains of variola virus in only a few WHO collaborating centres outweigh the risks. POSSIBILITY OF SMALLPOX RECURRING AFTER ERADICATION The global smallpox eradication programme was initiated in the epidemiological belief that man was the sole host of variola virus and that no animal reservoir existed. The yellow fever eradication campaign, initially conducted with promising results, had received a severe setback from the discovery of disease that originated from an animal reservoir. Research during the smallpox eradication programme has investigated the possibility of reinfection from an animal reservoir after eradication of the disease from the human population. Several aspects of this research are discussed below. Field observations on smallpox transmission Since monkeys are susceptible to experimental variola virus infection, a review was undertaken in 1968 to find definite evidence of smallpox outbreaks in monkeys.a Except a ARITA, I. & HENDERSON, D. A; Smallpox and monkeypox in non-human primates. Bulletin of the World Health Organization, 39: 277-283 (1968). 6 I. ARITA & J. G. BREMAN for the occurrence of smallpox in orang-utangs in the Jakarta Zoo in 1949, associated with a nearby outbreak in man, there had not been any well-documented smallpox outbreaks in wild monkeys. Furthermore, smallpox had not been reintroduced into the Philippines or Central America, where monkeys are plentiful, since human transmission of the disease was stopped in these areas several decades ago. During the eradication programme, these findings have been convincingly substantiated. Nowhere in smallpox endemic areas has an outbreak been documented for which a non- human source of infection has been proved. During the last 12 months of the campaign, before the last cases were detected on the Indian subcontinent and in Africa, all localities with smallpox outbreaks were investigated. The infection was almost always shown to result from close face-to-face contact with other smallpox patients. Only in 1-5% of outbreaks was the source not identified, but these outbreaks were near localities where other known cases had occurred, so it is most likely that the epidemiological investigations were incomplete. In rare instances, airborne infection has been postulated, as at a hospital in Meschede, Federal Republic of Germany in 1970.a Here the virus was thought to have been transmitted by air flow from one ward to another, since close patient contact did not occur. The question of variola virus remaining latent in human cadavers has been of concern to some health workers. Reference has been made to a few outbreaks of smallpox occurring in England in the 18th century following the contact of unsuspecting persons with exhumed cadavers in graveyards. These are poorly documented events and must be viewed in the light of the fact that smallpox was endemic in England at the time. During the eradication campaign, vigorous efforts have been made to trace the sources of infection and there has not been any evidence of smallpox infection caused by this mode of transmission in any of the countries where smallpox has been rampant during the last several decades. Laboratory studies on poxvirus isolates from smallpox patients or smallpox suspects Since 1967, more than 10000 specimens have been collected from smallpox suspects or other patients with " fevered rash ". Specimens have come mainly from the tropical areas of Africa, Asia, and South America and all have been tested by WHO collaborating centres for poxvirus diagnosis and research. Variola virus has been isolated from ap- proximately 10% of these specimens, confirming that the suspect cases were in fact smallpox. In rare instances a poxvirus other than smallpox has been isolated from specimens. Lenny virus was isolated from a person with severe vesicular disease resembling small- pox that occurred in eastern Nigeria in 1969.3 Laboratory studies indicated that this isolate could be a hybrid of smallpox virus and vaccinia. No similar episode has occurred since and there was no evidence of continuing transmission of this virus in humans in the area. Monkeypox virus has caused 35 sporadic cases of smallpox-like disease in man in West and Central Africa between 1970 and 1978. African mammals, possibly non-human primates or rodents, are suspected of being the reservoir of this poxvirus. In only 2 cases has secondary transmission possibly occurred between humans and notably there has been no evidence of continued spread. a WEHRLE, P. F. ET AL. An airborne outbreak of smallpox in a German hospital and its significance with respect to other recent outbreaks in Europe. Bulletin of the World Health Organization, 43: 669-679 (1970). b BOURKE, A. T. C. & DUMBELL, K. R. An unusual poxvirus from Nigeria. Bulletin of the World Health Organization 46: 621-623 (1972). EVALUATION OF SMALLPOX VACCINATION POLICY 7 Vaccinia virus (smallpox vaccine virus) has been isolated from persons with generalized vaccinia infections following vaccination, or from specimens contaminated with smallpox vaccine as a result of poor specimen-collection technique. There is no evidence to suggest the presence of this virus in the natural environment. These findings reconfirm that variola virus caused the clinical and epidemiological features of the disease entity-smallpox-and that this virus was maintained by the human population. The virus is genetically stable, although strains with different pathogenicity to man have been recognized (i.e., variola major and variola minor). Laboratory studies on poxvirus isolates from animals Special attention has been paid to whether variola virus, or any virus resembling it, has been isolated from animal specimens. In addition to cowpox, camelpox, ectromelia, and rabbitpox, animal poxviruses include the recently identified whitepox virus,a monkeypox virus, Turkmenia virus,b gerbilpox virus c and raccoonpox virus;d none of these viruses appears to cause smallpox-like transmission in man. With the exception of whitepox virus, all are easily distinguishable from variola virus by laboratory tests. Six whitepox virus isolates have been recorded since 1964: two were from monkey kidney tissue culture in a laboratory in the Netherlands in 1964 (the monkeys had been shipped from Malaysia, but they may have been in contact with African monkeys during transportation) and four were from animal specimens from Zaire-two from non-human primates and two from rodents (these animals were captured in the Equator Region of Zaire where human monkeypox has occurred). The importance of whitepox virus is that it cannot be distinguished from variola virus by current laboratory tests. In the Equator Region, however, the last known smallpox case was recorded in 1970 and intensive sur- veillance in the past 8 years has found no evidence of recurrence. If whitepox virus had been identical to variola virus it could have emerged to cause smallpox in inhabitants of these areas. The fact that neither whitepox virus nor smallpox virus has been associated with human disease in these areas since 1970 makes one conclude that whitepox virus differs from variola virus in some manner yet to be determined. Special studies The viability of virus on inanimate objects, such as fragments of smallpox scabs remaining inside houses in previously endemic areas, has caused concern since it was reported in 1968 that virus remained viable in scabs kept at room temperature on a shelf in a European laboratory for over 13 years.e More recent experiments, measuring virus decay under tropical conditions, showed that infected scabs having between 104 and 107 virions per gram lost 1 log of titre every 3 days at 35°C and 65% humidity.f Considering the climate in tropical areas, it is estimated that virus concentration in scabs may decrease to a non-infective level within 3 weeks. Furthermore, experience during the last 11 years a ARITA, I. & HENDERSON, D. A. Monkeypox and whitepox viruses in West and Central Africa. Bulletin of the World Health Organization, 53: 347-353 (1976). b MARENNIKOVA, S. S. Field and experimental studies of rodent infections caused by poxviruses. Bulletin of the World Health Organization (in press). C LOURIE, B. ET AL. Isolation of poxvirus from an African rodent. Journal of infectious diseases, 132: 677-681 (1975). d THOMAS, E. K. ET AL. Further characterization of raccoonpox. Archives of virology, 49: 217-227 (1975). e WOLFF, H. L. & CROON, J. J. A. B. The survival of smallpox virus (variola minor) in natural circumstances. Bulletin of the World Health Organization 38: 492-493 (1968). f HuQ, F. Effect of temperature and relative humidity on variola virus in crusts. Bulletin of the World Health Organization, 54: 710-712 (1976). 1. ARITA & J. G. BREMAN is that there have not been any smallpox outbreaks that could not be epidemiologically linked to other human cases or to a laboratory source. Variolation is the practice of inoculating material taken from skin lesions of patients with active smallpox into the skin of healthy persons to protect them from the disease. The danger of epidemics related to this practice has been evaluated. Samples of variolators' stocks have been collected from Afghanistan, Ethiopia, and Pakistan during the last 10 years. Of21 specimens, 17 did notgrow variola virus despite the fact that electron microscopy showed several specimens to contain numerous poxvirus particles. Four specimens, all from Afghanistan, were positive for viable virus when tested 4-9 months after the collection of specimens by variolators, but Afghanistan has maintained freedom from smallpox for 5 years since the last case was recorded. In Ethiopia and Benin, where variolation was also practised, it was observed that the practice ceased oice smallpox outbreaks stopped. There are no scientific data indicating the possible mutation of a poxvirus to variola virus; genetic studies on variola virus currently being conducted by WHO collaborating centres may add light to this problem. Currently, DNA analysis of animal poxviruses does not suggest that there are any parental viruses that could mutate to variola virus. Furthermore, epidemiological experience indicates that mutation of poxviruses to variola virus is unlikely. Despite the presence of various animal poxviruses in many of the previously endemic countries, smallpox, once eradicated from the human population, has never returned spontaneously. Additionally, smallpox was absent for a long period -perhaps several thousand years-in the Americas (North, Central, and South) and Australia before it was introduced to these vast continents, in the 16th century in the Americas and in the 18th century in Australia. Assuming that species of poxvirus existed in contact with human population in these continents, mutation of certain poxviruses to variola virus might have occurred in these continents; but, history indicates that it did not. Fig. 2. Countries where routine smallpox vaccination was not obligatory on 31 October 1978. 8 EVALUATION OF SMALLPOX VACCINATION POuCY 9 Assessment of risk Evaluation of the risk of recurrence of smallpox after eradication suggests that such a recurrence is unlikely, and that the eradication of smallpox does, in fact, represent the extinction of the most devastating human pathogen in the natural environment. However, since eradication of a human disease has never occurred before, a cautious scrutinizing view must be taken. The problems that require further study include the biology of white- pox virus, ecology of monkeypox virus, serological identification of specific antibodies to variola and other poxviruses, and further characterization of certain animal poxviruses. Identification of specific antibodies to variola and certain other poxviruses will be useful for the identification of the type of poxvirus infection when only serum is available. This will become more important in the future when animal poxvirus infections will predominate, although in low frequency, and when the features of smallpox have been forgotten by clinicians and public health workers. FAREWELL TO SMALLPOX VACCINATION A survey on the complications of smallpox vaccination conducted in the USA in 1968 revealed that one fatal complication occurred among approximately one million primary vaccinees. The " New York Board of Health " vaccinia strain, which is in use in the USA, appeared to be one of the safest strains. Some countries in Europe and Japan reported somewhat higher rates of complications than those reported for the USA. Assuming that each year at least 200 million children throughout the world are still being given primary vaccination, it could be estimated that fatal complications occur in at least 200 children each year. This is unjustifiable if there is no smallpox. If eradication is confirmed, it would be a logical conclusion that routine smallpox vaccination could be universally terminated, considering the unlikelihood of a recurrence of smallpox. Such a termination of smallpox vaccination would result in an annual saving of approximately US $1000 million in global health expenditure. At the end of October 1978, 42 countries had already declared routine smallpox vaccination to be no longer compulsory (Fig. 2) and the list is growing. According to the International Health Regulations, smallpox vaccination certificates are no longer required from any traveller, since currently there are no infected areas. However, 69 countries still ask for vaccination certificates from travellers. These countries are encouraged to alter the policy.a Although WHO has supplied vaccine free of charge for the smallpox eradication campaign, this supply may be terminated in consultation with the countries concerned in 1980 if the Global Commission certifies eradication. WHO has already begun to build up a vaccine reserve and efforts are being made, in collaboration with donor countries, to establish a permanent reserve sufficient to vaccinate 200-300 million persons. The sites for the stockpile are in Geneva, New Delhi and a third site yet to be designated. Vaccine will be kept at -20°C to assure its stability with no loss of potency over 15 years. Vaccine potency and stability will be monitored regularly and it is likely that the period of 15 years will be extended. This reserve is for any unexpected emergencies and is mainly for develop- ing countries. Developed countries are encouraged to retain vaccinia seed strains and their own vaccine stocks. a Up-to-date requirements as regards vaccination are given in Vaccination certificate requirements for inter- national travel. Situation as on I Jamwary 1979. Geneva, World Health Organization, 1979 (revised annually).