On September 23, 2002, the CDC released its "Smallpox Vaccination Clinic Guide" (Guide) a part of the upcoming revisions of the "CDC Smallpox Response Plan and Guidelines" (Plan). (See http://biotech.law.lsu.edu/blaw/bt/smallpox.htm) The Guide sets out the operating parameters for clinics participating in a mass immunization campaign, either in specific regions or as part of a national campaign. Mass immunization is to be a back up to the selective case-finding and immunization (Ring) strategy which would only immunize contacts and contacts of contacts, but would not involve mass immunization of a community. This is a welcome document, but one that leaves very important questions unanswered. I will briefly review the general problems related to smallpox spread and immunization strategies, then review the extent to which this Guide and the CDC plan address these issues.
Smallpox was one of the great scourges of mankind. It is a rapidly progressive disease that causes ulceration of the skin and affects other organs in the body, in particular the mouth and throat. It has a 2 week incubation period before the victim develops visible lesions, then the disease runs its course in another week or so. If the victim survives, he or she will be scarred by the ulcers on the skin, hence the name smallpox from these pock marks. The disease is spread by contact with the sores, which exude virus, or through the respiratory spread of virus as the throat and mouth become infected and the victim coughs up virus. The virus particles are relatively stable and will persist on clothing and other materials which the victim has been in contact with. Well before the germ theory was developed, it was understood that smallpox infected corpses and clothing that had been in contact with smallpox victims could spread the infection. Early biological warfare saw corpses hurled into towns during sieges and infected clothing given to tribes during some of the Indian wars in North America.
The key medical facts about smallpox are that:
1) it has a high infectivity, i.e., if a person with no immunity is exposed to the virus, there is a high probability he or she will be infected;
2) it can be infectious for a few days before there are obvious skin lesions;
3) the disease or immunization for it leaves a person immune from infection for 20 or more years;
4) the disease kills about 30% of infected persons, although it is possible this would be lower if intensive medical support were available;
5) the vaccine is a live virus vaccine with the risks attendant to live virus vaccines - while the virus is vaccinia and not smallpox, it can become virulent in immunosuppressed persons;
6) the patient lives or dies within 3 weeks and there is no animal host, which means that effective control measures can rapidly stop the disease; and
7) vaccinating a person after exposure, even a few days after, will still prevent disease in most cases.
Post World War II, there was a world-wide effort to eradicate smallpox. By the 1960s smallpox was limited to a few areas of the world and by the early 1970s many countries, including the U.S., stopped routine smallpox immunizations. The last case of naturally occurring smallpox was observed in 1977. (MMWR describing the last case.) While a few selected individuals in health care, research, and the military continued to receive immunizations through the 1980s, the general population of the U.S. was either born after 1970 and not immunized or has not be re-immunized for 30 or more years and has only questionable immunity. This is true of the rest of the world as well. Thus, for the first time in human history, most of the population of the word is susceptible to a fast spreading, fatal communicable disease. Ironically, modern technology has put the entire world in the same position as the indigenous peoples in the Americas and the Pacific islands facing the first European explorers and their diseases.
This vulnerability was recognized by all smallpox experts and fueled a debate in the 1990s as to whether the last stocks of virus, maintained at the CDC and by the Russians, should be destroyed, lest they fall into terrorist hands. Unknown to these experts, the Russians were making tons of smallpox as a biological weapon. This came to light in 1993, but intelligence forces did not make the information generally available for some years later. The existence of this store, and the inability of the Russians to convincingly account for it, made discussions of destroying the last virus stocks moot. It should have made finding a genetically engineered virus fragment vaccine the first priority, but this research has only been started recently because of the delay in admitting that the Russians had uncontrolled stocks of virus.
THE IMMUNIZATION IMPERATIVE
Since 9/11 and the subsequent anthrax letters, preparing for bioterrorism has been a key part of the war on terrorism. Smallpox has to be considered as the most dangerous agent, if not the most likely one, and the only protection against smallpox is immunization.
The federal government has been incrementally refining its smallpox immunization strategy, and this discussion is based on the policy as of 25 September 2002.
The first proposal had two parts:
1) staged immunization of health care and emergency workers, starting with first responders to bioterrorism and working through to routine medical care workers; and
2) ring immunizations in the case of an outbreak.
Ring immunization strategy was developed during the smallpox eradication campaign in the 1960s and 1970s. You identify cases, which is easy to do because the disease is so visible. Then you isolate the case and immunize everyone who had contact with the case and everyone who had contact with the contacts. (Despite the revisionist history about protecting everyone's rights, this was sometimes brutal and involved bribing informers and vaccinating people without much nicety as regards consent, not to mention the isolation issues. This is not a criticism, it had to be done that way, but we should not pretend that it was otherwise.)
This works great when you have small villages in Africa or India and you are doing clean up in a mostly immune population that you can vaccinate and isolate with no concerns about their rights. It is harder to imagine this strategy in a US city - how do you do a ring immunization strategy for someone who rides downtown on the subway, shops in a mall at lunch, then goes to the office in a high rise building? Two rings and you have most of the city.
The most politically difficult assumption behind this plan is that the government is going to be able to sit on the vaccine and control who gets it if there is an outbreak or even a suspected outbreak. It will be politically impossible to deny the general public access to vaccine if there is smallpox outbreak or scare. If there is an outbreak, the hardest political decision that any president has faced will come up: do I really trust this ring system, or do I allow mass immunizations? The potential risks to the nation of using the ring system and having it fail are enormous, and the political risks are incalculable because sticking to the ring strategy will mean ignoring the public outcry for vaccine. There is little chance that the government will be able to avoid mass immunization of the U.S. population. With this political reality in mind, the CDC has just released a plan for mass immunization clinics, for either cities or the entire U.S. The objective, as reported in some news accounts, is to be able to immunize the entire population in a few days. These plans are sound approaches to the smallpox immunization problem as it existed in the United States in 1971. They do not address the key problems of 2002.
BACK IN TIME TO 1971
In fall 1971, the Clinical Research Service at Texas Children's hospital in Houston did the first grand experiment in human immunosuppression - they created the Bubble Baby. David's parents had a sex-linked genetic disease that lead their male children to be born with no immune system. David had a brother who was born earlier and died from the disease, alerting the physicians. The plan was to put David into a sterile environment at birth to see if he would develop an immune system if he could be kept alive for some months. In retrospect, there should have been more thought about what would happen if he did not, but that is easy to say after the fact. I joined this service a year or so later as a grad student. We learned a tremendous amount about a very rare and poorly understood condition - immunosuppression - from David.
I tell this tale to illustrate a point: we have lived with the medical fact of immunosuppression secondary to HIV, cancer and arthritis treatment, transplants, and other natural and iatrogenic causes for more than 20 years, and almost everyone implicitly thinks this is the way it has always been. When we did the last massive smallpox vaccine campaigns in the US, we had almost no immunosuppressed persons in the population. (Partially because they probably were the 1/1,000,000 deaths from the vaccine.)
THE REALITY OF IMMUNOSUPPRESSION
In 2002, there are at least 1% and perhaps 2% or more of the population with significant immunosuppression, either permanently or because their physician likes to treat aches and pains with Medrol Dosepaks. Smallpox immunizations pose three problems for immunosuppressed persons. First, they may not develop effective immunity. This leaves them susceptible to smallpox and a threat to others who are not immune. Second, they are at significant risk of disseminated vaccinia if vaccinated or exposed through contact with a recently vaccinated person who has picked at his/her vaccine sore. Disseminated vaccinia means that the normally benign vaccinia virus used in smallpox vaccine becomes virulent because of the patient's weakened immune system. This is a common phenomena in immunosuppressed persons in which normally benign organisms such as Pneumocystis carinii become serious pathogens. While disseminated vaccinia only poses a risk of contagion to other immunosuppressed persons, it is a serious disease with almost the same morbidity and mortality as smallpox, and a more prolonged course.
Working the numbers, 1% of 280,000,000 is 2,800,000 immunosuppressed persons. If 1/10, a conservative estimate, develop vaccine complications, that is 280,000, and if only 1/10 of those die or are permanently injured, that is 28,000, probably on the low side. The numbers that the press and the government documents continue to use are those from the 1960s world, 1/1,000,000 deaths and perhaps 10/1,000,000 serious complications. These translate to 280 deaths and 2,800 serious complications, numbers that can only be reconciled with 28,000 deaths and 280,000 complications by one assumption: that no immunosuppressed persons will be immunized. Consistent with this, the CDC's smallpox vaccine guidelines, prior to the most recent mass immunization clinic guidelines, recommend that immunosuppressed persons not be vaccinated.
Many, probably most, persons do not know they are immunosuppressed, either because they do not know they have HIV or because they have no idea of the connection between the drugs they are taking and immunosuppression. The first issue posed by non-emergency smallpox immunizations is identifying the immunosuppressed. The guidelines depend on self-identification, which may be impossible either because the patient does not know or because the patient is unwilling to admit his/status because it is linked to HIV. The second issue is whether persons who refuse immunizations must be removed from all first responder teams and, if there is an outbreak, barred from working in any capacity that would put them in contact with exposed persons. This would exclude them from health care, police, fire, and many other activities. Such exclusion may be critical to public health and safety since unimmunized persons pose a risk to themselves and others, but it is it supportable politically? None of these questions is adequately addressed in the government's recommendations on immunizing health care and emergency workers.
Ring strategy immunizations after a case of smallpox pose these questions more starkly. Persons who cannot be successfully immunized must be quarantined. The guidelines on mass immunizations recommend that such persons be quarantined for 18 days. The guidelines on quarantine facilities, however, state that only immunized persons should be put in quarantine facilities because of the chance of a missed diagnosis and because of the chance of contagion from others. More tellingly, Guide C - Isolation and Quarantine Guidelines, the CDC official guideline, does not mention immunosuppression or HIV a single time. Where should these persons go? Can they be put in the quarantine facilities, knowing that they are at high risk for smallpox should anyone in the facility develop the disease? Should they be vaccinated, knowing that they have a high risk of disseminated vaccinia?
Mass immunizations, in response to a case of smallpox, make all of these problems intractable. The number of quarantine beds suitable for isolating a case of smallpox is very small nationally. Even the largest cities have only a hand full of such beds. Isolation rooms used for cancer and transplant patients cannot be used because they are designed to protect the patient from others, not others from the patient. Converted motels and hotels have no effective air flow isolation, so anyone who is not immunized will become infected if any other quarantined persons become infected. Most critically, there will be no time to sort out who is immunosuppressed from those who are not. Immunosuppressed persons will feel tremendous pressure to accept immunization and avoid the pest house. Since the plan is to carry out the immunizations in short period, the immunizations will be done before any of the complications develop. When they do develop, they will all develop at the same time, potentially swamping the ability of the medical system to provide care.
WHAT SHOULD WE BE DOING?
The number one opportunity has been missed - in 1993, when were knew the Soviets had an uncontrolled stockpile of smallpox, we should have started work on a genetically engineered vaccine that did not use live virus. We can wait until such a vaccine is available, and run the risk of an outbreak. In an outbreak, the risk of infection spreading in the general population and killing tens of millions means that we will have to immunize everyone with little regard for their individual risk. Preventing 10,000,000 deaths at the cost of 28,000 is simple arithmetic.
A gradual mass immunization of the entire population before there is an outbreak may be the best way to protect the public health and the rights of individuals. Such a program would allow time to identify the immunosuppressed so they are not forced to choose immunization or the pest house. It would also let us learn more about the risks of the vaccine as persons with various levels of immunosuppression chose to be immunized, and it would mean that those with complications could receive optimum medical treatment. This strategy would be a logical extension of the government's staged immunization of health care and emergency workers. If, at the end of campaign, several % of the population was unimmunized, there would still be enough herd immunity to make managing an outbreak possible.
Before such a campaign is started, the government must figure out how to pay for the care of persons with complications, and how to deal with the problem of excluding unimmunized persons from certain jobs. It is critical that Congress do this with specific legislation and that this legislation completely eliminate tort litigation over vaccine complications. Ideally there will be a government compensation fund with pre-established guidelines, and, for those who want more coverage, perhaps the opportunity to purchase private vaccination insurance. Given the probable level of vaccine complications, litigation would cripple the public health system.
Edward P. Richards, J.D., M.P.H.
Katharine C. Rathbun, M.D., M.P.H
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