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Smallpox vaccine and its stockpile in 2005
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Smallpox vaccine and its stockpile in 2005 Isao Arita
Smallpox vaccine was the most important tool in the successful eradication of smallpox. In 1980, this achievement made it possible for all nations to cease smallpox vaccination. However, the threat of smallpox bioterrorism has made it necessary to reconsider the need for vaccination. Over the past 3 years, many nations have set up action plans for use in the event of such an attack. The setting up of these plans was not simple. Several factors needed to be considered, including the judgement of risk, vaccine complications, conventional vaccines versus new vaccines, optimal stockpile of smallpox vaccine, and its use for different target populations in different emergency situations. Here, I review measures taken by the USA, Japan, and other nations, and discuss likely national and global efforts in 2005 and subsequently, in view of the fact that half of the world’s population is now apparently unvaccinated and that this proportion will increase with time.
Introduction In 1980 the World Health Assembly (WHA) declared that “smallpox eradication has been achieved throughout the world and that there is no evidence that smallpox will return as an endemic disease” (figure 1). Consequently, all nations stopped their routine smallpox vaccination programmes. Now, after a quiet period of two decades, followed by the September 11 terrorist attack in 2001, we have begun to debate how we should use smallpox vaccine to defend against or respond to possible epidemics caused by the deliberate release of smallpox virus. This is a threat not only to developed nations, but also on a continental or global scale. I worked as a medical officer for the WHO smallpox eradication programme from 1962 to 1985, a period that saw three stages—planning, implementation, and certification. Thinking about the programme then and now, one may say that the history of smallpox eradication is in fact that of smallpox vaccination. Vaccination had a critical role in the fate of the programme and, at this time, it does so again, as we face the extraordinary challenges posed by a potential bioterrorist attack. In this paper, I review briefly the history of smallpox vaccine in the course of control or eradication programmes and discuss the possible use of smallpox vaccine in dealing with bioterrorism.
Lancet Infect Dis 2005; 5: 647–52 IA is Chairman, Agency for Cooperation in International Health (ACIH), Kumamoto City, Kumamoto, Japan. Correspondence to: Dr Isao Arita, Agency for Cooperation in International Health, 4-11-1 Higashi-machi, Kumamoto City, Kumamoto 862-0901, Japan. Tel +81 96 367 8899; fax +81 96 367 9001; [email protected]
of the 20th century. Among the more than 30 different strains in use in the 1960s, the Lister and New York City Board of Health (NYCBH) strains were generally found to be the least pathogenic of the effective vaccines, and many manufacturers began to use these strains. However, nationwide surveys in the 1960s in the USA revealed the occurrence of serious complications among primary vaccinees and revaccinees to be, respectively, 266 and 10 per million vaccinees.2 Not surprisingly, WHO global smallpox eradication was strongly supported by the developed states, in part because of their realisation that the only way to eliminate such
Since Jenner’s time, vaccination against smallpox was seen to be highly efficacious—eg, the introduction of vaccination in France in the early 19th century increased the average life span by 15 years.1 However, it gradually became known that the vaccine could produce serious complications such as generalised eczema, progressive vaccinia, and post-vaccinal encephalitis. The frequencies of these complications varied substantially depending upon the vaccinia strains in use by different vaccine manufacturers. Reports from the Netherlands, Germany, and Austria documented ratios of postvaccinal encephalitis that ranged from 350 to 1200 cases per million vaccinees. Research to find less pathogenic vaccinia strains was most intensive during the first half http://infection.thelancet.com Vol 5 October 2005
WHO
Smallpox vaccine—its history of efficacy and safety
Figure 1: The cover of the WHO magazine, World Health, at the time of the 33rd World Health Assembly’s declaration that smallpox eradication had been achieved
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complications and deaths would be to eradicate smallpox globally. The 1980s WHA recommendation to stop vaccination was therefore welcomed by the world community.
Attenuated vaccines Since early last century, vigorous attempts have been made to derive less pathogenic strains of vaccinia virus by serial passage of candidate strains in tissue culture. Strains tested included CV1-78 and CV-11 in the USA, DIs and LC16m8 in Japan, and modified vaccinia Ankara (MVA) in Germany. None have proved sufficiently immunogenic to warrant further investigation except MVA and LC16m8, both of which showed reduced reactogenicity. LC16m8—produced by 45 serial passages of the Lister strain in primary rabbit cells at 30oC—is a replicating strain, while MVA— developed by 572 serial passages of Ankara strain in chick embryo fibroblasts—is not. MVA was developed to be the first stage in a two-stage vaccination procedure with Lister strain vaccination following a month after administration of MVA. In a study of neurological toxicity in a monkey model, LC16m8 was the least pathogenic among various vaccinia strains (eg, NYCBH, Lister, and CV1-78).3 A relatively large number of clinical studies were done with LC16m8 during the 1970s.4 Studies of the response of various vaccines revealed that, among the replicating strains, LC16m8 produced the least marked reactions in terms of erythema and induration, and the smallest proportion of children with febrile reactions. Of some 50 000 children vaccinated with LC16m8 in 1973–74, detailed clinical observations of 10 578 children revealed one case of eczema, three cases of convulsions, and eight cases of generalised vaccinia; all were mild. It was not clear whether the convulsions were related to the vaccine. In a study by encephalography of vaccinees with different strains, those with LC16m8 were the least affected. In a follow-up experimental immunisation of 100 000 children in Chiba prefecture, Japan, between 1974 and 1976, there were no reports of severe complications despite promulgation of a law providing compensation for people with vaccine complications (S Hashizume, retired President of the Association of Biological Manufacturers of Japan, personal communication). Studies with animal models showed that LC16m8 vaccination protected animals from challenges with rabbitpox5 and mousepox.6 Another study of monkeys challenged by monkeypox virus showed the protective ability of vaccination with LC16m8.7 LC16m8 lacks the ps/hr gene (later known as B5R) that affects plaque size and growth in Vero cells and is present in the parent Lister strain.8,9 However, immunogenicity has been tested in three animal models, providing protection and a good serological response in all. Extensive clinical studies also showed good take and high immunogenicity.4 648
In terms of immunogenicity, the response of MVA was never adequately tested at the time but recent studies indicate that the strain produces a reasonably good immune response in various animals, including immunodeficient mice and monkeys.10,11 The use of MVA for the vaccination of immunocompromised individuals would be worth considering since it is non-replicating. In challenge virus studies in monkeys using monkeypox— the human clinical manifestation of which resembles smallpox (figure 2)—the vaccine appeared to protect monkeys reasonably well but further studies are needed. The basic problem in evaluating any of the attenuated vaccinia strains is that they have never been tested with a natural challenge, since they have been developed after the eradication of smallpox. Is the protection level offered by LC16m8 similar to the Dryvax or conventional calf-lymph vaccines used in the eradication programme in human beings? The answer is unknown at present, but it can be safely assumed LC16m8 is as effective in light of the animal studies discussed above, as well as clinical studies. In summary, clinical studies of large numbers of vaccinees in the 1970s support the finding that LC16m8 vaccine is the least pathogenic of all vaccines using replicating viruses. Depending on national policy, its use may include immunisation of a population before smallpox has been detected, or populations at risk of smallpox infection. The only contraindication would be immunocompromised individuals, where there may be a role for MVA.
National stockpiling of vaccine Today, because of the threat of bioterrorism, many national health services have developed biodefence measures. Smallpox is regarded as one of the most serious threats because it is a lethal disease that can be transmitted from person to person. A former official of the then Soviet Union biodefence research laboratories12 reported that various methods of attack were being studied late in the last century, including the use of mechanically produced aerosol, attacks on public transport, and the use of genetically engineered variola viruses. There was also a shift in potential targets from defence forces to the public, which could result in damage to both health and socioeconomic factors. In case of an emergency or for preparedness, the potential population for smallpox vaccination can be divided into three groups: (1) the healthy general public without a known contact history with a smallpox patient; (2) individuals with contraindications to vaccination (eg, in the USA, atopic dermatitis, pregnancy, immunosuppressive disease or treatment, infants, elderly people, those with certain cardiac risk factors, and the families of those with contraindications—at least 25% of the general population); and (3) medical and public-health personnel who have a high probability of being in contact with a smallpox patient should an outbreak occur. http://infection.thelancet.com Vol 5 October 2005
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In the USA, since 2001, more than half a million military personnel and some 40 000 medical and publichealth staff considered to be at highest risk have been vaccinated. However, the original goal of immunising half a million high-risk medical and public-health staff has failed because of the concerns of local medical and public-health leaders about the occurrence of vaccine complications and a perception that the risk of a smallpox bioterrorist attack was very low.13 An additional concern was the occurrence of myopericarditis after vaccination in about one in 10 000 primary vaccinees.14,15 This complication was only reported twice during the whole of the global eradication programme, first among vaccinees in Australia between 1960 and 197616 and second in 1968, when minor cardiac complications were reported among US military personnel.17,18 The vaccine used in the post-September 11 vaccination effort had been produced in 1978 and had been kept in a deep freezer, and was the same as had been used in the USA for many decades. Three factors related to concerns about myopericarditis may account for the failure of the vaccination effort. Before 1980, virtually all children were given primary vaccination before school entry; thus, virtually all adults who received vaccination were revaccinees, and hence at less risk of cardiac problems. Moreover, electrocardiograms and enzyme studies are often needed to confirm the diagnosis the myopericarditis, which is generally mild and transient, consisting of fever, malaise, and some substernal chest pain. Physicians who practised during the 1960s now generally believe that most vaccinees presenting with such symptoms would not have been subjected to special diagnostic measures but would have been reassured and told to return if the problem persisted. Finally, the public, as well as health personnel, have become less tolerant of possible risks associated with taking any vaccine. The US smallpox vaccination programme, except in the military, has now been suspended, with emphasis now placed on improving national readiness to respond rapidly and effectively should an outbreak occur. This change in policy has influenced that of other developed nations. The current stockpile of vaccine in the USA consists of about 95 million doses of calf-lymph vaccine produced by Wyeth Laboratories and Aventis Pasteur. Only about 8 million doses are licensed. An additional 200 million doses of Vero tissue cell culture vaccine produced by Acambis and Baxter Laboratories using the NYCBH strain19 are available, although this vaccine is currently in phase III studies, in preparation for licensing. The clinical trials of the Acambis vaccine are proceeding slowly because of the cases of myopericarditis that have occurred. Licensure before early 2006 seems unlikely. In the meantime, the vaccine has been packaged and is available for emergency use. An attenuated MVA vaccine is also under study and is expected to begin production http://infection.thelancet.com Vol 5 October 2005
WHO
Stockpiling in the USA
Figure 2: Similar exanthem in patients infected with (A) smallpox virus and (B) monkeypox virus on day 7 of exanthema
in 2005 or 2006, assuming the required clinical studies are satisfactory. Thus, there may be stockpiles of three types of smallpox vaccines: first generation (conventional vaccine), second generation (tissue culture vaccine) and third generation (attenuated strain). How these might be developed is still to be decided. Additionally vaccinia immune globulin will be stockpiled to cope with cases of complications.
Stockpiling in Japan In Japan, the only stockpiled vaccine strain is LC16m8; thus the Japanese stockpile is perhaps the only stockpile today consisting solely of an attenuated tissue culture vaccine. This vaccine was licensed in Japan more than 20 years ago, but further research continues. A study is continuing to ensure the genetic stability of LC16m8, and may further augment the safety of the vaccine.20 The quantity currently available is sufficient to deal with an emergency. Whether the vaccine would be safe enough to use for some or all of those with contraindications is not known. Further studies are urgently needed. Determining vaccine efficacy in monkeys with monkeypox would be most useful if the studies were done in parallel with studies of MVA, Acambis tissue culture vaccine, and Lister calf-lymph vaccine for the purpose of comparison. The results of such a study would be useful not only to Japan but also to international preparedness.
Stockpiles in other nations In the European Union, the Netherlands has initiated stockpiling of calf-lymph vaccine, the efficacy of which proved the same as during the smallpox eradication campaign. The quantity is enough to vaccinate the entire 649
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population and an emergency vaccination programme that is designed to vaccinate the population in 4 days has been established (A Plantinga, Senior Project Manager Vaccine Development, Netherlands Vaccine Institute, WHO Collaborating Centre for Smallpox Vaccine, personal communication). At least 40 other nations have stockpiles of vaccine, much of which is the conventional calf-lymph vaccine kept in suitable storage (DA Henderson, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MA, USA, and Center for Biosecurity, University of Pittsburgh Medical Center, PA, USA, personal communication). In addition to the USA and the Netherlands, Denmark, France, Germany, Israel, Singapore, and the UK have sufficient stockpile to cover all of their own population or more. Thus, at present, 800 million doses of vaccine or more exists worldwide. In terms of production capacity, manufacturers in Denmark, Germany, Japan, the Netherlands, and Russia may produce some 300–350 million doses a year. In 2005, the world population is estimated to be 6 billion, thus the size of the current vaccine stockpile is about 10% of the global population. At present, it is difficult to assess the optimal worldwide stockpile size needed to deal with smallpox bioterrorism. However, one thing is apparent—if such an event occurs, nations of limited preparedness in Africa, Asia, and South America would be mostly affected because of rapid transmission resulting from international travel and an ever increasing unvaccinated population. It is assumed that pre-emptive mass vaccination is not being practised throughout the world. Some incidental vaccination of defence personnel on a limited scale and of personnel of poxvirus research or surveillance laboratories may be taking place, but details are unknown.
International stockpile by WHO During the smallpox eradication programme in the 1970s, WHO established the international smallpox vaccine stockpile from donations by member states, and a quality control system in collaboration with WHO International Reference Centre in the Netherlands and the regional centre in Canada. All the vaccine batches in use for the global programme were tested for safety and efficacy according to WHO minimum requirements. Surprisingly, when it first started, only 30% of batches tested met WHO standards, but in 3 years this situation had improved to 80%. Seed lots containing the Lister strain, together with working reference preparations, were also supplied to many manufacturers. This international coordination to improve the quality of vaccine stocks had a substantial role in the success of the smallpox eradication programme.21 In view of past experience, together with the fact that many poor nations lack stockpiles, especially in Africa, WHO has agreed to develop an international stockpile of smallpox vaccine, both calf-lymph and tissue culture, with bifurcated 650
needles. Such vaccine should contain a minimum of 107·7 plaque forming units (pfu)/mL.22 This stockpile will consist of a small stock of 5 million doses in Geneva and emergency arrangements for selected donor states to supply 200 million doses when it is needed. The system was reviewed at the 2005 WHA, who agreed to implement the plan. During the smallpox eradication programme, the potency of the vaccine was determined to be 108 pfu/mL. At that time, vaccine batches with titres below this after heat stability testing for 4 weeks at 37oC were rejected. Now, the titre of the stockpile is recommended to be 107·7 pfu/mL. Since the vaccine would be mainly needed in tropical zones of states with limited resources in a global or regional emergency, the departure from a titre that proved effective in the eradication of smallpox should be further examined by WHO and the international scientific community from the view points of maintaining the required potency in tropical areas, better take rate versus complications, managing aspects of emergency operation, and cost. The results of such examination should be reflected in future WHO recommendations. Bifurcated needles are unquestionably the best device for vaccine administration. However, the suggested number of punctures by bifurcated needles now varies in different countries. For instance, some recommend three punctures for primary vaccination, and 15 punctures for revaccination, others 15 punctures for both. After extensive studies during the smallpox eradication programme, 15 punctures were used in both primary and revaccination, with a vaccine titre of 108·0 pfu/mL. Today, if implemented, three punctures with 107·7 pfu/mL would mean that actual inoculum would be one log lower than that of the standard method during the eradication programme. Is the change significant or not? It would be desirable for WHO to recommend a standard method—as they did during the eradication programme—because many nations will have difficulty making a decision. Finally, we should not ignore the cost. During the eradication programme, one dose cost one cent. Now the costs of tissue culture and attenuated vaccines are exceedingly high. Further, if the shelf life of the stockpile is short, the cost increases proportionally. It will be important for WHO to find a solution, as the WHO stockpile essentially aims to prevent the establishment of smallpox endemicity in developing countries in Africa, Asia, and South America.
Research topics Much research was done on smallpox vaccine during Jenner’s time, in the years afterwards when control was the goal, and during the eradication campaign. Since eradication, it has not been possible to do a field trial for assessment of the actual protection of human beings from natural smallpox infection. One alternative would http://infection.thelancet.com Vol 5 October 2005
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be to use animal models; another is to develop a surrogate animal model—eg, transgenic mice for variola virus, as has occurred with poliomyelitis.23 This would not be easy, but may be essential. Recently, a study reported a DNA vaccine that protected monkeys against monkeypox virus.24 There is interest in the production of a tissue culture vaccine because “it has far higher quality in terms of purity and freedom from unwanted agents than the vaccine of animal skin origin”.25 However, tissue culture vaccines may be associated with similar complications as the vaccine used in the eradication programme, because it uses vaccinia strains such as the Lister strain or the NYCBH strain. In their guidelines for the development of vaccinia-based vaccines for smallpox immunisation, the European Agency for the Evaluation of Medicinal Products state that: “Indeed, production on tissue culture supposes adaptation of the virus strain to that cell substrate and the effect of such an adaptation on immunogenicity and safety of a vaccine should be studied”.25 On these bases, the relevant studies on the tissue culture vaccine Acambis 1000 have been done in the USA.19 Acambis 2000 is still being studied, but is now in the US stockpile for emergency use. Another way to select the smallpox vaccine for a national stockpile would be to rely on the vaccine that has proved to be effective, such as calf-lymph vaccine. This vaccine has proven efficacy and potency during stockpile, and, as shown by experience at the WHO, should be satisfactory over 20 years. Tissue culture vaccine may not last that long, as suggested by a preliminary study done by a WHO collaborating centre.26 As a result of this study, the Netherlands opted to produce the calf-lymph vaccine for their stockpile. Notably, choice of vaccine type for stockpiling is an important subject for research and national consideration.
Conclusions Smallpox vaccine has made a great contribution to the reduction of human misery and death. However, the frequent occurrence of severe vaccine complications has caused concern. Substantial efforts are now being made to reduce or minimise the risk, including the development of attenuated vaccines. Meanwhile, the success of smallpox eradication in 1980 led to the termination of smallpox vaccination. Now, however, global threats of terrorism make the return of smallpox vaccine a necessity. Vaccine stockpiles are needed. Conventional vaccine strains are apparently being used in most countries, but attenuated vaccines should also have an important role in programmes. There are two promising attenuated strains—MVA and LC16m8. Both require more studies, which may best be carried out through international collaboration under the leadership of WHO. The WHO vaccine stockpile should be promoted by member states, http://infection.thelancet.com Vol 5 October 2005
since we cannot ignore the global risk. It has also been proposed that Japan should take a lead in promoting research on biodefence, especially with regard to the smallpox threat, because of its advanced research and biotechnical enterprise. It is important that we now prepare to cope with the steadily increasing level of susceptibility to smallpox in the world population. In 50 years time, if no vaccinations are done, more than 90% of the world’s population will be unvaccinated. The situation would be more dire and dangerous than at any time in history. Even before Jenner’s time, a large proportion of the adults were immune, since they were survivors of earlier epidemic smallpox. Research is essential, although this is handicapped because the target illness has been eradicated. Perhaps the first priority should be a completely new vaccine based on genetics or proteo-mix technology; the second should be rapid diagnostic techniques; and, finally, new therapeutic substances. This order is based on experience of interrupted smallpox transmission during the eradication programme. Experience in dealing with HIV has taught us the difficulties of controlling a viral pandemic with drugs. If we had a preventive vaccine we would be in a much better position. Conflicts of interest I declare that I have no conflicts of interest. Acknowledgments The preparation of this paper was assisted with research funding from the Ministry of Health, Labour and Welfare, Japan, in the fiscal year of 2004. I thank D A Henderson, F Fenner, and A Plantinga for valuable advice as well as updated technical information, and S Hashizume and A Hartmann for further technical comments on LC16m8 and MVA, respectively. I thank H Inasaki for her administrative assistance in the preparation of this paper. References 1 Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: WHO, 1988: 245–76. 2 Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis 1970; 122: 303–09. 3 Morita M, Aoyama Y, Arita M, et al. Comparative studies of several vaccinia virus strains by intrathalamic inoculation into cynomolgus monkeys. Arch Virol 1977; 53: 197–208. 4 Yamaguchi M, Kimura M, Hirayama M. Vaccination research group research report: Ministry of Health and Welfare special research: post-vaccination side effects and research regarding treatment of complications. Rinsho to Uirusu 1975; 3: 269–79 (in Japanese). 5 Empig C, Perret-Gentil M, Dermody T, et al. The attenuated vaccinia-Lister vaccine LC16m8 protects rabbits from lethal rabbitpox challenge. 7th Annual Conference on Vaccine Research; Arlington, VA, USA; May 24–26, 2004. Abstract S32. 6 Empig C, Schriewer J, Buller RML. The attenuated vaccinia-Lister vaccine LC16m8 protects mice from aerosolized ectromelia challenge. 7th Annual Conference on Vaccine Research; Arlington, VA, USA; May 24–26, 2004. Abstract LB2. 7 Saijo M, Ami Y, Nagata M, et al. Study on protection of monkeys from monkeypox by LC16m8 smallpox vaccine. Annual Meeting of the Japanese Society for Virology; Japan; Nov 21–23, 2004. Abstract 3D09 (in Japanese). 8 Takahashi-Nishimaki F, Funahashi S, Miki K, Hashizume S, Sugimoto M. Regulation of plaque size and host range by a vaccinia virus gene related to complement system proteins. Virology 1991; 181: 158–64.
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Smith GL, Vanderplasschen A, Law M. The formation and function of extracellular enveloped vaccinia virus. J Gen Virol 2002; 83: 2915–31. Wyatt LS, Earl PL, Eller LA, Moss B. Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc Natl Acad Sci USA 2004; 101: 4590–95. Earl PL, Americo JL, Wyatt LS, et al. Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature 2004; 428: 182–85. Alibek K. Smallpox: a disease and a weapon. Int J Infect Dis 2004; 8 (suppl 2): S3–8. Board on Health Promotion and Disease Prevention; Institute of Medicine, Review of the Centers for Disease Control and Prevention’s smallpox vaccination program implementation: letter report 2. Washington, DC: The National Academies, 2003. Arness MK, Eckart RE, Love SS, et al. Myopericarditis following smallpox vaccination. Am J Epidemiol 2004; 160: 642–51. Eckart RE, Love SS, Atwood JE, et al. Incidence and follow-up of inflammatory cardiac complications after smallpox vaccination. J Am Coll Cardiol 2004; 44: 201–05. Feery BJ. Adverse reactions after smallpox vaccination. Med J Aust 1977; 2: 180–83. Price M, Alpers J. Acute pericarditis following smallpox vaccination. Papua New Guinea Med J 1968; 11: 30–33. Centers for Disease Control and Prevention. Update: cardiac and other adverse events following civilian smallpox vaccination–United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52: 639–42.
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Monath TP, Caldwell JR, Mundt W, et al. ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain) – a second-generation smallpox vaccine for biological defense. Int J Infect Dis 2004; 8 (suppl 2): S31–44. Kidokoro M, Tashiro M, Shida H. Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8. Proc Natl Acad Sci USA 2005; 102: 4152–57. Arita I. Standardization of smallpox vaccines and the eradication programme – a WHO perspective. Dev Biol Stand 1999; 100: 31–37. WHO. Report of the meeting of the Ad Hoc Committee on Orthopoxvirus Infections. Geneva: WHO, 2004; WHO/CDS/ CSR/ARO/2004.3. Abe S, Ota Y, Koike S, et al. Neurovirulence test for oral live poliovaccines using poliovirus-sensitive transgenic mice. Virology 1995; 206: 1075–83. Hooper JW, Thompson E, Wilhelmsen C, et al. Smallpox DNA vaccine protects nonhuman primates against lethal monkeypox. J Virol 2004; 78: 4433–43. The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use. Note for guidance on the development of vaccinia virus based vaccines against smallpox. London: CPMP, 2002. CPMP/1100/02. Christian PD, Scoggins T, Minor PD. Stability studies on the candidate replacements for the new international standard for smallpox vaccine. WHO/BS/04.1990. Expert Committee on Biological Standardization; Geneva, Switzerland; Nov 15–19, 2004.
http://infection.thelancet.com Vol 5 October 2005
Smallpox vaccine and its stockpile in 2005 Isao Arita
Smallpox vaccine was the most important tool in the successful eradication of smallpox. In 1980, this achievement made it possible for all nations to cease smallpox vaccination. However, the threat of smallpox bioterrorism has made it necessary to reconsider the need for vaccination. Over the past 3 years, many nations have set up action plans for use in the event of such an attack. The setting up of these plans was not simple. Several factors needed to be considered, including the judgement of risk, vaccine complications, conventional vaccines versus new vaccines, optimal stockpile of smallpox vaccine, and its use for different target populations in different emergency situations. Here, I review measures taken by the USA, Japan, and other nations, and discuss likely national and global efforts in 2005 and subsequently, in view of the fact that half of the world’s population is now apparently unvaccinated and that this proportion will increase with time.
Introduction In 1980 the World Health Assembly (WHA) declared that “smallpox eradication has been achieved throughout the world and that there is no evidence that smallpox will return as an endemic disease” (figure 1). Consequently, all nations stopped their routine smallpox vaccination programmes. Now, after a quiet period of two decades, followed by the September 11 terrorist attack in 2001, we have begun to debate how we should use smallpox vaccine to defend against or respond to possible epidemics caused by the deliberate release of smallpox virus. This is a threat not only to developed nations, but also on a continental or global scale. I worked as a medical officer for the WHO smallpox eradication programme from 1962 to 1985, a period that saw three stages—planning, implementation, and certification. Thinking about the programme then and now, one may say that the history of smallpox eradication is in fact that of smallpox vaccination. Vaccination had a critical role in the fate of the programme and, at this time, it does so again, as we face the extraordinary challenges posed by a potential bioterrorist attack. In this paper, I review briefly the history of smallpox vaccine in the course of control or eradication programmes and discuss the possible use of smallpox vaccine in dealing with bioterrorism.
Lancet Infect Dis 2005; 5: 647–52 IA is Chairman, Agency for Cooperation in International Health (ACIH), Kumamoto City, Kumamoto, Japan. Correspondence to: Dr Isao Arita, Agency for Cooperation in International Health, 4-11-1 Higashi-machi, Kumamoto City, Kumamoto 862-0901, Japan. Tel +81 96 367 8899; fax +81 96 367 9001; [email protected]
of the 20th century. Among the more than 30 different strains in use in the 1960s, the Lister and New York City Board of Health (NYCBH) strains were generally found to be the least pathogenic of the effective vaccines, and many manufacturers began to use these strains. However, nationwide surveys in the 1960s in the USA revealed the occurrence of serious complications among primary vaccinees and revaccinees to be, respectively, 266 and 10 per million vaccinees.2 Not surprisingly, WHO global smallpox eradication was strongly supported by the developed states, in part because of their realisation that the only way to eliminate such
Since Jenner’s time, vaccination against smallpox was seen to be highly efficacious—eg, the introduction of vaccination in France in the early 19th century increased the average life span by 15 years.1 However, it gradually became known that the vaccine could produce serious complications such as generalised eczema, progressive vaccinia, and post-vaccinal encephalitis. The frequencies of these complications varied substantially depending upon the vaccinia strains in use by different vaccine manufacturers. Reports from the Netherlands, Germany, and Austria documented ratios of postvaccinal encephalitis that ranged from 350 to 1200 cases per million vaccinees. Research to find less pathogenic vaccinia strains was most intensive during the first half http://infection.thelancet.com Vol 5 October 2005
WHO
Smallpox vaccine—its history of efficacy and safety
Figure 1: The cover of the WHO magazine, World Health, at the time of the 33rd World Health Assembly’s declaration that smallpox eradication had been achieved
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complications and deaths would be to eradicate smallpox globally. The 1980s WHA recommendation to stop vaccination was therefore welcomed by the world community.
Attenuated vaccines Since early last century, vigorous attempts have been made to derive less pathogenic strains of vaccinia virus by serial passage of candidate strains in tissue culture. Strains tested included CV1-78 and CV-11 in the USA, DIs and LC16m8 in Japan, and modified vaccinia Ankara (MVA) in Germany. None have proved sufficiently immunogenic to warrant further investigation except MVA and LC16m8, both of which showed reduced reactogenicity. LC16m8—produced by 45 serial passages of the Lister strain in primary rabbit cells at 30oC—is a replicating strain, while MVA— developed by 572 serial passages of Ankara strain in chick embryo fibroblasts—is not. MVA was developed to be the first stage in a two-stage vaccination procedure with Lister strain vaccination following a month after administration of MVA. In a study of neurological toxicity in a monkey model, LC16m8 was the least pathogenic among various vaccinia strains (eg, NYCBH, Lister, and CV1-78).3 A relatively large number of clinical studies were done with LC16m8 during the 1970s.4 Studies of the response of various vaccines revealed that, among the replicating strains, LC16m8 produced the least marked reactions in terms of erythema and induration, and the smallest proportion of children with febrile reactions. Of some 50 000 children vaccinated with LC16m8 in 1973–74, detailed clinical observations of 10 578 children revealed one case of eczema, three cases of convulsions, and eight cases of generalised vaccinia; all were mild. It was not clear whether the convulsions were related to the vaccine. In a study by encephalography of vaccinees with different strains, those with LC16m8 were the least affected. In a follow-up experimental immunisation of 100 000 children in Chiba prefecture, Japan, between 1974 and 1976, there were no reports of severe complications despite promulgation of a law providing compensation for people with vaccine complications (S Hashizume, retired President of the Association of Biological Manufacturers of Japan, personal communication). Studies with animal models showed that LC16m8 vaccination protected animals from challenges with rabbitpox5 and mousepox.6 Another study of monkeys challenged by monkeypox virus showed the protective ability of vaccination with LC16m8.7 LC16m8 lacks the ps/hr gene (later known as B5R) that affects plaque size and growth in Vero cells and is present in the parent Lister strain.8,9 However, immunogenicity has been tested in three animal models, providing protection and a good serological response in all. Extensive clinical studies also showed good take and high immunogenicity.4 648
In terms of immunogenicity, the response of MVA was never adequately tested at the time but recent studies indicate that the strain produces a reasonably good immune response in various animals, including immunodeficient mice and monkeys.10,11 The use of MVA for the vaccination of immunocompromised individuals would be worth considering since it is non-replicating. In challenge virus studies in monkeys using monkeypox— the human clinical manifestation of which resembles smallpox (figure 2)—the vaccine appeared to protect monkeys reasonably well but further studies are needed. The basic problem in evaluating any of the attenuated vaccinia strains is that they have never been tested with a natural challenge, since they have been developed after the eradication of smallpox. Is the protection level offered by LC16m8 similar to the Dryvax or conventional calf-lymph vaccines used in the eradication programme in human beings? The answer is unknown at present, but it can be safely assumed LC16m8 is as effective in light of the animal studies discussed above, as well as clinical studies. In summary, clinical studies of large numbers of vaccinees in the 1970s support the finding that LC16m8 vaccine is the least pathogenic of all vaccines using replicating viruses. Depending on national policy, its use may include immunisation of a population before smallpox has been detected, or populations at risk of smallpox infection. The only contraindication would be immunocompromised individuals, where there may be a role for MVA.
National stockpiling of vaccine Today, because of the threat of bioterrorism, many national health services have developed biodefence measures. Smallpox is regarded as one of the most serious threats because it is a lethal disease that can be transmitted from person to person. A former official of the then Soviet Union biodefence research laboratories12 reported that various methods of attack were being studied late in the last century, including the use of mechanically produced aerosol, attacks on public transport, and the use of genetically engineered variola viruses. There was also a shift in potential targets from defence forces to the public, which could result in damage to both health and socioeconomic factors. In case of an emergency or for preparedness, the potential population for smallpox vaccination can be divided into three groups: (1) the healthy general public without a known contact history with a smallpox patient; (2) individuals with contraindications to vaccination (eg, in the USA, atopic dermatitis, pregnancy, immunosuppressive disease or treatment, infants, elderly people, those with certain cardiac risk factors, and the families of those with contraindications—at least 25% of the general population); and (3) medical and public-health personnel who have a high probability of being in contact with a smallpox patient should an outbreak occur. http://infection.thelancet.com Vol 5 October 2005
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In the USA, since 2001, more than half a million military personnel and some 40 000 medical and publichealth staff considered to be at highest risk have been vaccinated. However, the original goal of immunising half a million high-risk medical and public-health staff has failed because of the concerns of local medical and public-health leaders about the occurrence of vaccine complications and a perception that the risk of a smallpox bioterrorist attack was very low.13 An additional concern was the occurrence of myopericarditis after vaccination in about one in 10 000 primary vaccinees.14,15 This complication was only reported twice during the whole of the global eradication programme, first among vaccinees in Australia between 1960 and 197616 and second in 1968, when minor cardiac complications were reported among US military personnel.17,18 The vaccine used in the post-September 11 vaccination effort had been produced in 1978 and had been kept in a deep freezer, and was the same as had been used in the USA for many decades. Three factors related to concerns about myopericarditis may account for the failure of the vaccination effort. Before 1980, virtually all children were given primary vaccination before school entry; thus, virtually all adults who received vaccination were revaccinees, and hence at less risk of cardiac problems. Moreover, electrocardiograms and enzyme studies are often needed to confirm the diagnosis the myopericarditis, which is generally mild and transient, consisting of fever, malaise, and some substernal chest pain. Physicians who practised during the 1960s now generally believe that most vaccinees presenting with such symptoms would not have been subjected to special diagnostic measures but would have been reassured and told to return if the problem persisted. Finally, the public, as well as health personnel, have become less tolerant of possible risks associated with taking any vaccine. The US smallpox vaccination programme, except in the military, has now been suspended, with emphasis now placed on improving national readiness to respond rapidly and effectively should an outbreak occur. This change in policy has influenced that of other developed nations. The current stockpile of vaccine in the USA consists of about 95 million doses of calf-lymph vaccine produced by Wyeth Laboratories and Aventis Pasteur. Only about 8 million doses are licensed. An additional 200 million doses of Vero tissue cell culture vaccine produced by Acambis and Baxter Laboratories using the NYCBH strain19 are available, although this vaccine is currently in phase III studies, in preparation for licensing. The clinical trials of the Acambis vaccine are proceeding slowly because of the cases of myopericarditis that have occurred. Licensure before early 2006 seems unlikely. In the meantime, the vaccine has been packaged and is available for emergency use. An attenuated MVA vaccine is also under study and is expected to begin production http://infection.thelancet.com Vol 5 October 2005
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Stockpiling in the USA
Figure 2: Similar exanthem in patients infected with (A) smallpox virus and (B) monkeypox virus on day 7 of exanthema
in 2005 or 2006, assuming the required clinical studies are satisfactory. Thus, there may be stockpiles of three types of smallpox vaccines: first generation (conventional vaccine), second generation (tissue culture vaccine) and third generation (attenuated strain). How these might be developed is still to be decided. Additionally vaccinia immune globulin will be stockpiled to cope with cases of complications.
Stockpiling in Japan In Japan, the only stockpiled vaccine strain is LC16m8; thus the Japanese stockpile is perhaps the only stockpile today consisting solely of an attenuated tissue culture vaccine. This vaccine was licensed in Japan more than 20 years ago, but further research continues. A study is continuing to ensure the genetic stability of LC16m8, and may further augment the safety of the vaccine.20 The quantity currently available is sufficient to deal with an emergency. Whether the vaccine would be safe enough to use for some or all of those with contraindications is not known. Further studies are urgently needed. Determining vaccine efficacy in monkeys with monkeypox would be most useful if the studies were done in parallel with studies of MVA, Acambis tissue culture vaccine, and Lister calf-lymph vaccine for the purpose of comparison. The results of such a study would be useful not only to Japan but also to international preparedness.
Stockpiles in other nations In the European Union, the Netherlands has initiated stockpiling of calf-lymph vaccine, the efficacy of which proved the same as during the smallpox eradication campaign. The quantity is enough to vaccinate the entire 649
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population and an emergency vaccination programme that is designed to vaccinate the population in 4 days has been established (A Plantinga, Senior Project Manager Vaccine Development, Netherlands Vaccine Institute, WHO Collaborating Centre for Smallpox Vaccine, personal communication). At least 40 other nations have stockpiles of vaccine, much of which is the conventional calf-lymph vaccine kept in suitable storage (DA Henderson, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MA, USA, and Center for Biosecurity, University of Pittsburgh Medical Center, PA, USA, personal communication). In addition to the USA and the Netherlands, Denmark, France, Germany, Israel, Singapore, and the UK have sufficient stockpile to cover all of their own population or more. Thus, at present, 800 million doses of vaccine or more exists worldwide. In terms of production capacity, manufacturers in Denmark, Germany, Japan, the Netherlands, and Russia may produce some 300–350 million doses a year. In 2005, the world population is estimated to be 6 billion, thus the size of the current vaccine stockpile is about 10% of the global population. At present, it is difficult to assess the optimal worldwide stockpile size needed to deal with smallpox bioterrorism. However, one thing is apparent—if such an event occurs, nations of limited preparedness in Africa, Asia, and South America would be mostly affected because of rapid transmission resulting from international travel and an ever increasing unvaccinated population. It is assumed that pre-emptive mass vaccination is not being practised throughout the world. Some incidental vaccination of defence personnel on a limited scale and of personnel of poxvirus research or surveillance laboratories may be taking place, but details are unknown.
International stockpile by WHO During the smallpox eradication programme in the 1970s, WHO established the international smallpox vaccine stockpile from donations by member states, and a quality control system in collaboration with WHO International Reference Centre in the Netherlands and the regional centre in Canada. All the vaccine batches in use for the global programme were tested for safety and efficacy according to WHO minimum requirements. Surprisingly, when it first started, only 30% of batches tested met WHO standards, but in 3 years this situation had improved to 80%. Seed lots containing the Lister strain, together with working reference preparations, were also supplied to many manufacturers. This international coordination to improve the quality of vaccine stocks had a substantial role in the success of the smallpox eradication programme.21 In view of past experience, together with the fact that many poor nations lack stockpiles, especially in Africa, WHO has agreed to develop an international stockpile of smallpox vaccine, both calf-lymph and tissue culture, with bifurcated 650
needles. Such vaccine should contain a minimum of 107·7 plaque forming units (pfu)/mL.22 This stockpile will consist of a small stock of 5 million doses in Geneva and emergency arrangements for selected donor states to supply 200 million doses when it is needed. The system was reviewed at the 2005 WHA, who agreed to implement the plan. During the smallpox eradication programme, the potency of the vaccine was determined to be 108 pfu/mL. At that time, vaccine batches with titres below this after heat stability testing for 4 weeks at 37oC were rejected. Now, the titre of the stockpile is recommended to be 107·7 pfu/mL. Since the vaccine would be mainly needed in tropical zones of states with limited resources in a global or regional emergency, the departure from a titre that proved effective in the eradication of smallpox should be further examined by WHO and the international scientific community from the view points of maintaining the required potency in tropical areas, better take rate versus complications, managing aspects of emergency operation, and cost. The results of such examination should be reflected in future WHO recommendations. Bifurcated needles are unquestionably the best device for vaccine administration. However, the suggested number of punctures by bifurcated needles now varies in different countries. For instance, some recommend three punctures for primary vaccination, and 15 punctures for revaccination, others 15 punctures for both. After extensive studies during the smallpox eradication programme, 15 punctures were used in both primary and revaccination, with a vaccine titre of 108·0 pfu/mL. Today, if implemented, three punctures with 107·7 pfu/mL would mean that actual inoculum would be one log lower than that of the standard method during the eradication programme. Is the change significant or not? It would be desirable for WHO to recommend a standard method—as they did during the eradication programme—because many nations will have difficulty making a decision. Finally, we should not ignore the cost. During the eradication programme, one dose cost one cent. Now the costs of tissue culture and attenuated vaccines are exceedingly high. Further, if the shelf life of the stockpile is short, the cost increases proportionally. It will be important for WHO to find a solution, as the WHO stockpile essentially aims to prevent the establishment of smallpox endemicity in developing countries in Africa, Asia, and South America.
Research topics Much research was done on smallpox vaccine during Jenner’s time, in the years afterwards when control was the goal, and during the eradication campaign. Since eradication, it has not been possible to do a field trial for assessment of the actual protection of human beings from natural smallpox infection. One alternative would http://infection.thelancet.com Vol 5 October 2005
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be to use animal models; another is to develop a surrogate animal model—eg, transgenic mice for variola virus, as has occurred with poliomyelitis.23 This would not be easy, but may be essential. Recently, a study reported a DNA vaccine that protected monkeys against monkeypox virus.24 There is interest in the production of a tissue culture vaccine because “it has far higher quality in terms of purity and freedom from unwanted agents than the vaccine of animal skin origin”.25 However, tissue culture vaccines may be associated with similar complications as the vaccine used in the eradication programme, because it uses vaccinia strains such as the Lister strain or the NYCBH strain. In their guidelines for the development of vaccinia-based vaccines for smallpox immunisation, the European Agency for the Evaluation of Medicinal Products state that: “Indeed, production on tissue culture supposes adaptation of the virus strain to that cell substrate and the effect of such an adaptation on immunogenicity and safety of a vaccine should be studied”.25 On these bases, the relevant studies on the tissue culture vaccine Acambis 1000 have been done in the USA.19 Acambis 2000 is still being studied, but is now in the US stockpile for emergency use. Another way to select the smallpox vaccine for a national stockpile would be to rely on the vaccine that has proved to be effective, such as calf-lymph vaccine. This vaccine has proven efficacy and potency during stockpile, and, as shown by experience at the WHO, should be satisfactory over 20 years. Tissue culture vaccine may not last that long, as suggested by a preliminary study done by a WHO collaborating centre.26 As a result of this study, the Netherlands opted to produce the calf-lymph vaccine for their stockpile. Notably, choice of vaccine type for stockpiling is an important subject for research and national consideration.
Conclusions Smallpox vaccine has made a great contribution to the reduction of human misery and death. However, the frequent occurrence of severe vaccine complications has caused concern. Substantial efforts are now being made to reduce or minimise the risk, including the development of attenuated vaccines. Meanwhile, the success of smallpox eradication in 1980 led to the termination of smallpox vaccination. Now, however, global threats of terrorism make the return of smallpox vaccine a necessity. Vaccine stockpiles are needed. Conventional vaccine strains are apparently being used in most countries, but attenuated vaccines should also have an important role in programmes. There are two promising attenuated strains—MVA and LC16m8. Both require more studies, which may best be carried out through international collaboration under the leadership of WHO. The WHO vaccine stockpile should be promoted by member states, http://infection.thelancet.com Vol 5 October 2005
since we cannot ignore the global risk. It has also been proposed that Japan should take a lead in promoting research on biodefence, especially with regard to the smallpox threat, because of its advanced research and biotechnical enterprise. It is important that we now prepare to cope with the steadily increasing level of susceptibility to smallpox in the world population. In 50 years time, if no vaccinations are done, more than 90% of the world’s population will be unvaccinated. The situation would be more dire and dangerous than at any time in history. Even before Jenner’s time, a large proportion of the adults were immune, since they were survivors of earlier epidemic smallpox. Research is essential, although this is handicapped because the target illness has been eradicated. Perhaps the first priority should be a completely new vaccine based on genetics or proteo-mix technology; the second should be rapid diagnostic techniques; and, finally, new therapeutic substances. This order is based on experience of interrupted smallpox transmission during the eradication programme. Experience in dealing with HIV has taught us the difficulties of controlling a viral pandemic with drugs. If we had a preventive vaccine we would be in a much better position. Conflicts of interest I declare that I have no conflicts of interest. Acknowledgments The preparation of this paper was assisted with research funding from the Ministry of Health, Labour and Welfare, Japan, in the fiscal year of 2004. I thank D A Henderson, F Fenner, and A Plantinga for valuable advice as well as updated technical information, and S Hashizume and A Hartmann for further technical comments on LC16m8 and MVA, respectively. I thank H Inasaki for her administrative assistance in the preparation of this paper. References 1 Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: WHO, 1988: 245–76. 2 Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis 1970; 122: 303–09. 3 Morita M, Aoyama Y, Arita M, et al. Comparative studies of several vaccinia virus strains by intrathalamic inoculation into cynomolgus monkeys. Arch Virol 1977; 53: 197–208. 4 Yamaguchi M, Kimura M, Hirayama M. Vaccination research group research report: Ministry of Health and Welfare special research: post-vaccination side effects and research regarding treatment of complications. Rinsho to Uirusu 1975; 3: 269–79 (in Japanese). 5 Empig C, Perret-Gentil M, Dermody T, et al. The attenuated vaccinia-Lister vaccine LC16m8 protects rabbits from lethal rabbitpox challenge. 7th Annual Conference on Vaccine Research; Arlington, VA, USA; May 24–26, 2004. Abstract S32. 6 Empig C, Schriewer J, Buller RML. The attenuated vaccinia-Lister vaccine LC16m8 protects mice from aerosolized ectromelia challenge. 7th Annual Conference on Vaccine Research; Arlington, VA, USA; May 24–26, 2004. Abstract LB2. 7 Saijo M, Ami Y, Nagata M, et al. Study on protection of monkeys from monkeypox by LC16m8 smallpox vaccine. Annual Meeting of the Japanese Society for Virology; Japan; Nov 21–23, 2004. Abstract 3D09 (in Japanese). 8 Takahashi-Nishimaki F, Funahashi S, Miki K, Hashizume S, Sugimoto M. Regulation of plaque size and host range by a vaccinia virus gene related to complement system proteins. Virology 1991; 181: 158–64.
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