Research Story of the Week

Smallpox: Threat, Vaccine, and U.S. Policy
Parts I and II of a Six-Part Series

View: Parts I & II | Part III | Part IV | Part V | Part VI

View the entire series as a single PDF file.
PDF format, 36 pages, 539 kb.
Illustration
Illustration showing vaccination for smallpox. [Source: World Health Organization]

View the entire series as a single PDF file.
PDF format, 36 pages, 539 kb.

By Richard Pilch, M.D.

[The author would like to thank Dr. Raymond A. Zilinskas and Ms. Sarah Diehl for their invaluable guidance during the writing and review of this article.]


Introduction

Pursuant to concerns that Iraq and other states of proliferation concern may possess the smallpox virus and in view of the implications of September 11th with respect to homeland defense, on December 13, 2002 President Bush announced a multi-phase plan for the vaccination of certain subsets of the U.S. population against smallpox.[1] The first phase calls for (1) the voluntary vaccination, beginning late January 2003, of approximately 500,000 front-line health workers (e.g., emergency room physicians and nurses) and first responders (e.g., paramedics, firemen, and policemen) identified by the Department of Health and Human Services (HHS) and state and local governments as candidates for specialized "Smallpox Response Teams;" and (2) the mandatory vaccination by the Department of Defense (DoD) of some 500,000 military and civilian personnel who are or may be deployed in locations considered "high threat" by authorities within the U.S. intelligence community.[2] In addition, the DoD will offer voluntary vaccination to a limited number of additional personnel stationed at certain overseas embassies.

Following the initial phase, vaccinations will be extended to up to 10 million additional members of the healthcare and first responder community, again on a voluntary basis. This second phase could be completed as early as summer 2003.

Building upon this is what could be considered a third phase of vaccinations, those involving the general public, namely adult civilians who insist on being vaccinated and for whom the vaccine is not contraindicated. According to the Center for Disease Control and Prevention (CDC), options include vaccination in 2003 with the unlicensed vaccine or in 2004 once the vaccine has been licensed by the Food and Drug Administration (FDA), or alternatively with next generation vaccines by participating in ongoing clinical trials.[3]

While the president's plan ends here, additional phases of vaccination do exist, as laid out by the CDC.[4] The first of these phases (phase four overall), the "Primary Strategy: Contact Identification and Vaccination," is only set in motion in the event of a confirmed smallpox outbreak. Upon identification and isolation of the initial smallpox cases, all individuals having had face-to-face or household contact with those infected will be identified and vaccinated in the now classic "ring" approach, regardless of whether or not they are contraindicated for the vaccine. In addition, all people likely to come into contact with the individuals of this ring (i.e., household members) will also be vaccinated unless contraindicated, creating a second ring of protection around each exposed individual in order to prevent further spread of the disease should that individual later become symptomatic. Additional healthcare and response personnel may receive the vaccine at this time as well.

Phase five, the "Supplemental Strategy," is essentially a contingency plan in which, in addition to continued contact identification and vaccination, "broader" vaccination of the U.S. population is undertaken in order to increase herd immunity. Presumably, this strategy refers to nationwide mass vaccination. The Supplemental Strategy is only to be initiated under one of three circumstances: (1) the size of the first wave of smallpox cases is too great to be effectively managed by contact identification and vaccination alone; (2) no decline is seen in the number of new cases after two or more generations from the index case(s); or (3) no decline is seen in the number of new cases after approximately 30 percent of current vaccine stores has been utilized.

While information on smallpox and the smallpox vaccine is plentiful in the public domain, little has been reported on certain aspects of President Bush's vaccination strategy, specifically the decision to offer voluntary vaccinations to members of the general public, the logistics of preparing for the implementation of the Supplemental Strategy on a local level, and the consequences of the vaccination plan in terms of both financial impact and public health preparedness. In order to adequately address these points, however, a certain level of background information must be provided as well. Therefore, Part I of this series will outline the basics of smallpox. Part II will cover the smallpox vaccine, including contraindications, side effects, and availability. In Part III, the theoretical threat of the virus will be weighed against the absolute risk of the vaccine. Part IV will then address the current vaccination plan phase by phase, while Part V will focus on the Supplemental Strategy specifically. Finally, Part VI will discuss the consequences of the current vaccination plan. The ultimate goal will not be to provide a comprehensive discussion of smallpox or vaccination measures against it but rather to offer a unique look forward at the decisions and events that will face the nation in the months and years to come.

Part I. The Basics: Smallpox

In the twentieth century, smallpox killed more people than war. Despite its lethality, however, the fact that the virus can only live in humans made it vulnerable.[5] Physicians and scientists in the international community recognized that given this limitation, preventing human-to-human transmission would halt the spread of the virus and effectively eliminate it from its only reservoir. Thus, in 1967 the World Health Organization (WHO) began its global campaign to eradicate smallpox, utilizing a "surveillance-containment" ring vaccination technique that is now the basis of the CDC's Primary Strategy (phase four of the vaccination plan). A decade later, the campaign was deemed successful, and in 1980 WHO recommended the cessation of all vaccinations worldwide. Vaccinations in the United States had been discontinued in 1972. A universal and reportedly successful movement followed to destroy all remaining samples of the virus except for those held in two locations, the CDC in Atlanta and the Institute of Virus Preparations in Moscow. Later, the Moscow samples were moved to the State Research Center for Virology and Biotechnology (Vector) in Siberia. These two laboratories, the CDC and Vector, hold the only official stores of the virus today.

In the United States, the cessation of vaccinations 30 years ago has created what is effectively a virgin soil population in which previously vaccinated U.S. citizens have little if any waning immunity and those born after 1972 have none at all.[6] Historically, this type of unprotected population has not fared well against the virus. For example, when a series of events surrounding the 1519 exploits of Hernando Cortes unwittingly introduced smallpox among the virgin Aztec civilization of Mexico, the impact was so devastating that within a generation the Aztec culture, religion, and language were gone.[7] Similarly, the distribution by British forces of blankets that had been used by smallpox patients among virgin populations of American Indians during the French and Indian Wars (1754-1767) led to epidemics of the disease with case-fatality rates (the percentage of deaths among infected individuals) reportedly surpassing 50 percent in affected tribes.[8]

How does the smallpox virus generate this lethal effect?[9] First, it must gain entry into the body, which in nature--and presumably in the event of deliberate dissemination of the virus as well--generally occurs via the respiratory system.[10] Most commonly, the virus spreads from person-to-person when very small viral particles are expelled from the mouth of an infected individual and inhaled by a person nearby.[11] As a general rule, the distance between these two individuals must be less than 2 meters (approximately 6 1/2 feet) in order for this transmission to occur.[12] However, only a few virions (individual viral particles) need be inhaled to cause infection.[13]

Upon inhalation, these virions become implanted in the lining of the mouth or lungs. Normal draining of these areas then carries the virions to regional lymph nodes, which exist throughout the body and filter such drainoff in order to ensure that no foreign particles enter the bloodstream. The filtration process works, and the virions are held at bay. However, this affords the viral particles the opportunity to enter the lymph node cells and begin to replicate.

By day 3 or 4 post-infection, the virus enters the bloodstream and is carried to the spleen and bone marrow. In addition to continued replication in the lymph nodes, the virus replicates in these new areas as well, generating virtually limitless copies of itself in order to maximize its own chances of survival as a species. Around day 8 post-infection, the virus re-enters the bloodstream in force.

Up until this point, the infected individual has demonstrated no sign of infection. Unless testing has been performed, he or she has no idea the infection has taken place. This resurgence of the virus signals the approach of ill effects, however. The first symptoms usually appear by day 12 to 14 post-infection, and classically include high fever, generalized discomfort, headache, and backache.[14]

Inside the body, the virus continues to work. It finds its way to small blood vessels within the skin and beneath the lining of the mouth and enters cells in the vicinity, where it again replicates. Because this replication occurs so close to the surfaces of the skin and mouth, a rash begins to form in these areas, and with this rash comes the ability of the virus to spread to other individuals. It is the rash that occurs in the mouth that allows for this. Lesions of this rash break open and distribute the virus into the mouth and throat, after which it is exhaled in minute particles with each breath. At this point, the infected individual is most capable of spreading the virus to others, and the appearance of the rash therefore serves as an indicator that he or she has become "infectious." Though most infectious during the 7 to 10 days following onset of the rash, the individual remains capable of transmitting the virus until the rash scabs over and the last scab falls off, a process that takes about three weeks from beginning to end (if the patient survives). While most outbreaks in the 1960s and 70s averaged less than two persons infected per infectious individual according to the CDC,[15] historical data has shown that such an individual can transmit the virus to as many as 10 to 20 others.[16]

Smallpox infection carries an estimated case-fatality rate of 30 percent among unvaccinated individuals in the absence of specific therapy. Death usually occurs during the second week of the rash (the third to fourth week post-infection), most likely due to the overwhelming presence of toxic components in the blood, namely viral particles and immune complexes (viral particles bound to antibodies). Even if the victim survives, however, the effects of the virus can last a lifetime. In 1562, for example, Queen Elizabeth I of England was infected with smallpox at age 29, and though she survived the disease, she was left without hair and with a permanently scarred face, hence the heavy make-up and red wig with which she is identified today.[17]

II. The Basics: The Smallpox Vaccine

The recognition that victims who survived smallpox never contracted the disease again led very early on to the idea of deliberately infecting an individual with a mild form of the illness in order to confer immunity. The first method employed in this regard was known as "variolation," developed sometime before 1000 B.C. This process consisted of inoculating unexposed individuals--through incisions in their skin--with scabs or pus from mildly infected smallpox patients, an action that effectively reduced the fatality rate of the resulting smallpox infection from 30 percent to approximately 1 percent.[18]

In the latter half of the 18th century, physician Edward Jenner observed the clear complexion of milkmaids in the English countryside, noting that they exhibited none of the disfiguring lesions associated with a past history of smallpox. Up until this point, variolation remained commonplace as the only known approach to mitigating the effects of the disease. Jenner's observation, however, set him on the path to discovery, and what would be the creation of the first true vaccine. It turned out that the milkmaids, as a result of occupational exposure to the cowpox virus, had developed antibodies to this virus that also served to protect them against the related smallpox virus. In 1796, Jenner demonstrated that this effect could be recreated via the injection of fluid from a cowpox pustule in order to confer immunity to smallpox. Eventually, he coined the term "vaccine" (from the Latin word vacca, meaning "cow") to describe the injected substance. This cowpox vaccine is predecessor of the vaccinia vaccine used today.

Contraindications of the Vaccine

Certain populations are known to be at high risk for developing severe complications following vaccination with vaccinia vaccine. With respect to these populations, the only scenario in which the vaccine's benefits outweigh its risks is in the event of direct contact (face-to-face, household, or close, i.e., less than 2 meters) with a confirmed smallpox case. Otherwise, the dangers of the vaccine are too great to warrant its use, even if cases of smallpox appear that are remote from the high-risk individual. Pre-event voluntary vaccination is not an option. These contraindicated populations include:[19]

  1. immunocompromised persons, including individuals with HIV/AIDS or cancer, organ transplant recipients, or those receiving chemotherapy, radiation, or high-dose corticosteroids;
  2. persons with a history of eczema, whether or not the condition is mild or presently active;
  3. pregnant or breastfeeding women;
  4. infants less than 1 year old;
  5. individuals with life-threatening allergies to the antibiotics neomycin, polymyxin B, streptomycin, or tetracycline, because the major brand of currently available vaccine (DryVax) contains trace amounts of these substances;
  6. persons with acute or chronic skin conditions such as atopic dermatitis, burns, impetigo or varicella zoster (shingles) should wait until the condition resolves before being vaccinated; and
  7. persons with moderate to severe short-term illness should wait until the condition resolves before being vaccinated.

Importantly, any person who lives with a contraindicated individual should not receive the vaccine unless either that person or the contraindicated individual has for certain been exposed to the virus. Also, it is very important to note that the Advisory Committee on Immunization Practices (ACIP) has recommended against the vaccination of any individual under 18 years of age unless exposed to the virus.[20] While not a contraindication per se, this explains why President Bush's voluntary vaccination plan is only offered to general members of the "adult" public.

Side Effects of the Vaccine

Even in healthy individuals, the vaccine can be dangerous. Up to 70 percent of vaccine recipients may experience some sort of self-limited adverse reaction, for example fever or swelling of the lymph nodes.[21] Further, statistics suggest that for every million people vaccinated approximately 1,000 will experience serious complications, for example the formation of a localized or generalized rash. Some 50 vaccine recipients per million will be expected to develop life-threatening complications, and 1 to 2 healthy individuals per million vaccinated will be expected to die as a result of the vaccination. It is generally accepted that individuals vaccinated for the first time ("primary vaccinees") are at a greater risk for complications and/or death than individuals who have been vaccinated in the past. Serious complications carrying the risk of death include:

  1. tissue destruction at the site of inoculation ("progressive vaccinia," a.k.a. "vaccinia necrosum"), frequently fatal in immunocompromised individuals, hence their contraindication as discussed above;[22]
  2. widespread skin infection ("eczema vaccinatum") in individuals with pre-existing skin conditions, hence their contraindication as discussed above;[23] and
  3. inflammation of the brain ("postvaccinial encephalitis"), which occurs only in primary vaccinees at a rate of 3 cases per million.[24]

An additional point that deserves attention is that the vaccinia vaccine is made from and thus contains a living virus (the vaccinia virus, not the smallpox virus).[25] Following vaccination, this virus can be spread from one part of the body to another ("autoinoculation") or from person-to-person ("contact vaccinia") via contact with the inoculation site.

Autoinoculation occurs when, after touching the vaccination site, an individual touches or scratches another part of the body with the same hand. This action transplants the virus to the new location, where a rash develops. Importantly, transfer of the virus to the eye in this fashion can lead to severe damage and even blindness. Autoinoculation accounts for a substantial portion of the serious but not life-threatening rashes mentioned above, the remainder of which are generally caused by either entry of the virus into the bloodstream with subsequent generalized rash ("generalized vaccinia") or an allergic reaction to the vaccine itself ("erythema multiforme").

Contact vaccinia is a concern because it presents the possibility of spreading vaccinia virus from healthy, voluntary vaccine recipients to immunocompromised--and thus contraindicated--individuals. This person-to-person transmission has been documented in the past at a rate of 27 infections per million.[26] Further attention is paid to this possibility in the below discussion of the vaccination plan.

Vaccine Availability

It has been widely reported that the United States is currently in possession of enough vaccine for every American should the need arise.[27] Two brands of the vaccine compose the present stockpile:[28]

  1. Wyeth DryVax (15.4 million doses), which over the past many years has been used to vaccinate laboratory personnel at risk of exposure to the virus. Studies have shown that this vaccine can be diluted up to ten-fold and still be highly effective, thus creating a potential supply of 154 million doses.[29] However, current plans have only called for five-fold dilution of the stockpile--resulting in 77 million doses--in order to meet the nation's demands. This is the vaccine that will be used to meet the demands of the current vaccination plan, except in the event of an emergency requiring the implementation of the Supplemental Strategy and mass vaccination.[30] On October 15, 2002, DryVax was approved for licensure by the FDA.[31]
  2. Aventis-Pasteur's vaccine, the decades old supply mysteriously discovered in Pennsylvania early in 2002 (approximately 80 million doses).[32] This vaccine is not and will not be approved for licensure but will remain in what is known as IND (Investigational New Drug) status, only to be used in the event of emergency activation of the Supplemental Strategy.

The total supply of 157 million doses fails to meet the headcount of the U.S. Census Bureau, which in 2000 listed the total population as 281,421,906.[33] The author is unable to account for the remaining 124 million plus declared doses. However, the CDC has ordered an additional 209 million doses of the vaccine in contracts awarded in September 2000 to Acambis and November 2001 to Acambis/Baxter.[34] The first contract calls for the 20 year continuous production of 45 million doses of the vaccine ACAM 1000, now undergoing Phase II clinical trials.[35] The second contract calls for the production of 155 million doses of the vaccine ACAM 2000 in the shortest timeframe possible. ACAM 2000 is now undergoing Phase I clinical trials.

These and other new vaccines are under development largely because of the dangers associated with the current vaccine. Originally, viruses used in vaccine production ("first generation" vaccines) were grown in embryonated hen eggs, in other words eggs containing living cells in which the virus can replicate.[36] While this technique continues to be the major approach to such production today, improvements in biotechnology over the past many years have led to the creation of a new growth medium of living cells in which vaccines can be produced ("second generation" vaccines) called "cell culture."[37] However, because the actual product is the same, the second generation vaccines come with the same complications as their predecessors.[38] Thus with respect to the smallpox vaccine, these newer products offer little hope for improvement of the traditional side effects. Because the worst complications of the smallpox vaccine are due to replication of vaccinia virus in the vaccine recipient, research on "third generation" vaccines is focused on genetically removing this characteristic of the virus in order to create non-replicating vaccinia strains that still retain their immunizing properties.[39] The future, while bright, remains distant.


[1] In the strict sense of the word, "smallpox" is defined as the disease caused by the virus Variola major (or in very rare cases Variola minor). For the sake of simplicity, however, the term will be used to represent both the virus and its resulting disease in this article.
[2] See for example, Stevenson, R., and Stolberg, S., "Bush Lays Out Plan on Smallpox Shots as 'a Precaution,'" New York Times, December 13, 2002; "Protecting Americans: Smallpox Vaccination Program," the Center for Disease Control and Prevention (CDC) website, www.bt.cdc.gov/agent/smallpox/vaccination/vaccination-program-statement.asp.
[3] See the U.S. National Institute of Health website, http://www.clinicaltrials.gov/.
[4] See "Guide B--Vaccination Guidelines for State and Local Health Agencies," Smallpox Response Plan and Guidelines (Version 3.0), CDC website, http://www.bt.cdc.gov/agent/smallpox/response-plan/index.asp.
[5] Viruses differ from bacteria in that, because they generally consist of only a protein shell, a sequence of genetic material (DNA or RNA), and sometimes a lipid membrane, they lack the cellular machinery required for reproduction (termed "replication") and thus survival. As a result, they need to adopt the cellular machinery of a host organism in order to replicate, and are therefore inert until they get into a cell, human or otherwise. The smallpox virus is limited in its choice of hosts: it is only equipped to enter and adopt the machinery of human cells. Viruses also differ from bacteria in that they are not susceptible to antibiotics. Antibiotics specifically target bacterial structures or mechanisms; viruses do not have these features and thus are not targeted. For a given virus, treatment is limited to (1) a vaccine, given pre- or post-exposure to induce the formation of protective antibodies by the host; (2) immune globulin, a solution containing pre-formed antibodies derived from human blood; or (3) specifically designed antiviral agents, which unfortunately have limited application (e.g., cidofovir).
[6] Regarding previously vaccinated individuals, studies have shown that neutralizing antibodies against smallpox, which are believed to signify protection, decrease substantially over 5 to 10 years following vaccination, making protection 30 plus years later negligible at best. Downie, A., and McCarthy, K., "The antibody response in man following infection with viruses of the pox group, III: antibody response in smallpox," Journal of Hygiene 56 (1958), pgs. 479-487; as cited in Henderson, D. et al., "Smallpox as a Biological Weapon," Journal of the American Medical Association 281 (1999), pgs. 2127-2137.
[7] Tucker, J., Scourge: The Once and Future Threat of Smallpox (New York: Atlantic Monthly Press, 2001), pgs. 9-11.
[8] Stearn, E. and Stearn, A., The Effect of Smallpox on the Destiny of the Amerindian (Boston: Bruce Humphries, 1954); as cited in Henderson et al., "Smallpox as a Biological Weapon."
[9] While malignant and hemorrhagic presentations of smallpox do rarely occur, this discussion will be limited to the most common presentation of the disease.
[10] Access via injection will be discussed in Part III (Capability: Delivery).
[11] The virus can also be naturally transmitted via direct contact with the rash (but generally not the scabs) or via fomites such as contaminated clothes or bed linens. Transmission due to the exchange of saliva is also a possibility.
[12] See, for example, "Guide B--Vaccination Guidelines for State and Local Health Agencies," pg. B-5; http://www.bt.cdc.gov/agent/smallpox/response-plan/index.asp. This proximity limitation is not always the case, however. In 1970, for example, a hospitalized smallpox patient isolated in a single room managed to infect individuals on 3 floors of the hospital. Wehrle, P., 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 (1970), pgs. 669-679; as cited in Henderson et al., "Smallpox as a Biological Weapon." In the following discussion of Soviet smallpox development, this point will receive additional attention.
[13] For example, in animal studies during the Cold War, Soviet scientists found that fewer than 5 viral particles were required to infect half of the exposed population (denoted by the value ID50, or infectious dose in 50 percent of those exposed). Alibek, K., Biohazard (New York: Random House, 1999), pg. 115.
[14] These initial symptoms may present as early as 7 days and as late as 17 days post-infection.
[15] Milloy, S., "Smallpox Attack Exaggerated," Foxnews.com, October 5, 2001.
[16] Henderson et al., "Smallpox as a Biological Weapon," pg. 3.
[17] Tucker, Scourge: The Once and Future Threat of Smallpox, pg. 14.
[18] Tucker, Scourge: The Once and Future Threat of Smallpox, pg. 15.
[19] "Guide B--Vaccination Guidelines for State and Local Health Agencies," pg. B-6, http://www.bt.cdc.gov/agent/smallpox/response-plan/index.asp; "People Who Should NOT Get the Smallpox Vaccine (Unless they are Exposed to the Smallpox Virus)," www.bt.cdc.gov/agent/smallpox/vaccination/contraindications-public.asp.
[20] "People Who Should NOT Get the Smallpox Vaccine (Unless they are Exposed to the Smallpox Virus)," www.bt.cdc.gov/agent/smallpox/vaccination/contraindications-public.asp.
[21] McIntosh, K., et al., "Standard percutaneous (smallpox) revaccination of children who received primary percutaneous vaccination," Journal of Infectious Diseases 161 (1990), pgs. 445-448, as cited in Henderson et al., "Smallpox as a Biological Weapon."
[22] See, for example, www.bt.cdc.gov/training/smallpoxvaccine/reactions/prog_vac_path.html: "Death occurred in nearly all individuals with profound [cell-mediated immune (CMI)] defects." The T-cell deficiency seen in untreated HIV/AIDS patients is a classic example of such a CMI defect.
[23] Vaccinia immune globulin (VIG) has been found to be therapeutic against eczema vaccinatum. VIG is discussed in the context of the CDC's Primary Strategy below. Goldstein, V., et al., "Smallpox vaccination reactions, prophylaxis and therapy of complications," Pediatrics 55 (1975), pgs. 342-347, as cited in Henderson et al., "Smallpox as a Biological Weapon."
[24] Postvaccinial encephalitis carries an estimated lethality of 25 percent. Those who survive often suffer permanent neurological damage, for example paralysis. Henderson et al., "Smallpox as a Biological Weapon," pg. 10.
[25] Traditionally, live vaccines are weakened, or "attenuated," in order to reduce the potential side effects of their administration. Examples include the measles, mumps and rubella (MMR) vaccine and the oral polio (Sabin) vaccine. Despite its lingering dangers, the vaccinia vaccine is no different: it is attenuated as well.
[26] Lane J., et al., "Complications of smallpox vaccination, 1968: results of ten statewide surveys," Journal of Infectious Diseases 122 (1970), pgs.303-309, as cited in "Vaccinia (Smallpox) Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001," www.cdc.gov/mmwr/preview/mmwrhtml/rr5010a1.htm.
[27] See, for example, "Protecting Americans: Smallpox Vaccination Program," www.bt.cdc.gov/agent/smallpox/vaccination/vaccination-program-statement.asp. This point raises the issue of vaccine availability for non-U.S. citizens living in the U.S., either legally or illegally. According to the CDC, "enough vaccine exists to vaccinate every single person in the country in an emergency." While the issue appears to have been considered by policy-makers, further clarification is needed before it can be stated with certainty that such a demand can in fact be met.
[28] It should be noted that multiple strains of vaccinia virus exist and are thus available for use in vaccine production. Important here is that the strain used in all vaccines (Wyeth, Aventis, and Acambis) discussed below, the New York City Board of Health (NYCBH) strain, carries the lowest complication rate of all strains available. Wyeth Smallpox Vaccine [package insert]. Lancaster, Pa: Wyeth Laboratories Inc., 1968; Lane, J., et al., "Complications of smallpox vaccination, 1968: national surveillance in the United States," New England Journal of Medicine 281 (1969), pgs.1201-1208; both cited in Henderson et al., "Smallpox as a Biological Weapon."
[29] Efficacy (the ability to generate a therapeutic effect) of DryVax at five-fold dilution has been found to be 99 percent, while efficacy at ten-fold dilution dropped only to 97 percent. New England Journal of Medicine 346 (2002), pgs.1265-1274, as cited by Russell, P., "Smallpox Vaccine Stockpile for the United States," presented at the G7+ Global Health Security Action Group Workshop "Best Practices in Vaccine Production for Smallpox and other Potential Pathogens," September 5-6, 2002, Paul-Ehrlich-Institut, Langen (Germany).
[30] See, for example, "Optional Inoculation: Bush Says Smallpox Vaccine Program Will Be Voluntary," ABCNews.com, December 11, 2002, www.abcnews.go.com/sections/2020/DailyNews/bush_walters021211.html.
[31] This becomes a vital point in the discussion of the current vaccination plan (Part IV of this series), because the vaccination plan describes Phase 3 voluntary vaccination with an unlicensed vaccine until 2004 (though the vaccine, as noted, has in fact been cleared for licensure already).
[32] Russell, "Smallpox Vaccine Stockpile for the United States;" Roos, R., "Trials of Aventis smallpox vaccine getting underway," www.umn.edu/cidrap/content/bt/smallpox/news/avent.html.
[33] U.S. Census Bureau website, www.census.gov/main/www/cen2000.html.
[34] Monath, T., "Smallpox Vaccine: U.S. Manufacturers," presented at the G7+ Global Health Security Action Group Workshop "Best Practices in Vaccine Production for Smallpox and other Potential Pathogens," September 5-6, 2002, Paul-Ehrlich-Institut, Langen (Germany). See also: http://www.hhs.gov/news/press/2001pres/20011128.html.
[35] For more information, see www.acambis.com. Generally speaking, clinical trials are studies designed to investigate the therapeutic potential of new drugs or treatments. Phase I trials largely explore side effects; Phase II trials evaluate effectiveness; and Phase III trials test the drug in question against the current drug of choice for its intended purpose. A given drug must pass through all three phases before being approved for use by the FDA.
[36] Wyeth DryVax and the Aventis-Pasteur vaccine are examples of first generation vaccines. Embryonated eggs are particularly suited for viral vaccine production because they offer a sterile environment, have no immunologic functions (and thus don't fight off the virus being produced), and are both inexpensive and widely available. See, for example, www.medschool.lsumc.edu/Micr/COURSES/DMIP/dmex19.htm.
[37] ACAM 1000 and ACAM 2000 are examples of vaccines grown in cell culture (second generation vaccines).
[38] Midthun, K., "Regulatory Requirements for Historical and New Smallpox Vaccines," presented at the G7+ Global Health Security Action Group Workshop "Best Practices in Vaccine Production for Smallpox and other Potential Pathogens," September 5-6, 2002, Paul-Ehrlich-Institut, Langen (Germany).
[39] Ibid.: Falkner, F., "Highly attenuated vaccinia strains as safe third generation smallpox vaccines," presented at the G7+ Global Health Security Action Group Workshop "Best Practices in Vaccine Production for Smallpox and other Potential Pathogens," September 5-6, 2002, Paul-Ehrlich-Institut, Langen (Germany).


CNS Experts on the Smallpox Threat, Vaccine, and U.S. Policy:

View: Parts I & II | Part III | Part IV | Part V | Part VI

View previous Research Stories.

 

Author(s): Richard Pilch
Related Resources: CBW, Americas, Weekly Story
Date Created: January 6, 2003
Date Updated: January 13, 2003
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