J. Huston McCulloch
May 17, 2002
The season finale of ER on May 16, entitled "Lockdown," involved a fictitious apparent outbreak of smallpox. Two children who had recently returned from Central Africa were brought to the ER with symptoms quickly identified by Dr. Carter as smallpox. The girl died, but her brother will apparently recover. The ER was quarantined and a CDC crew from Atlanta arrived like gangbusters within hours.
The episode left the outcome hanging. Samples sent back to Atlanta confirmed that the infection was definitely an orthopox virus, but by the end of the show, it had not yet been positively identified as smallpox. Conceivably the children merely had monkey pox, a rare disease of children in Central Africa that is primarily acquired from monekys or squirrels. It is very similar to smallpox in its symptoms, and is only occasionally passed from human to human.
Or, if several characters need to be killed off before next season because their actors defect to other scrub-operas over the summer, it may turn out to have been a full-fledged smallpox outbreak. Perhaps terrorists released smallpox aerosols in an airplane or airport they passed through. Two of the doctors already are running fevers, possibly just flu, but perhaps from when the children were brought to the ER with lesser symptoms the week before. Even Carter valiantly whipped off his goggles and mask while operating so he could save the infected boy. By next fall, the situation might have been contained in the ER, or there could have been a global epidemic that overwhelmed the CDC and led to a completely new cast.
In fact, smallpox victims are not very contagious until they are exhibiting acute symptoms, so it is unlikely that the two fevers really represent smallpox contacted from the children during their earlier visit. However, anyone passing through the waiting room on the way out of the hospital while the children were waiting to be seen on this visit could have been infected, and could set off a city-wide outbreak despite the quarantine.
Only time will tell ...
J. Huston McCulloch and James R. Meginniss
Click here for PDF version of full paper dated 1/18/02.
The full paper contains equations and technical details that are difficult to display in browser-readable format. However, the Introduction and Summary, the Concluding Remarks, and the References are plain text and are given below, along with a new Addendum on jet-injection of smallpox vaccine.
A recent study by Drs. Robert B. Belshe and Sharon Frey at the St. Louis University School of Medicine has found, using a small sample of 60 subjects, that the existing stocks of smallpox vaccine have a 95% “take” rate when administered at the standard concentration, 70% when diluted 10:1, and 15% when diluted 100:1 (Harding 2001). These figures imply that a standard dose can produce 0.95 successful takes at full strength, 7.0 successful takes at 10:1, and 15 successful takes at 100:1. The last figure would allow the existing U.S. stocks to vaccinate the approximately 170 million Americans who want immediate vaccination, with 60 million to spare, but only with an unmanageable average of 6.7 vaccination attempts per take.
The present note investigates three statistical models to infer the number of successful takes per standard dose that would occur at unobserved dilutions. The best fitting model predicts that as many as 16.7 takes per dose could be obtained at a dilution of 58.2:1. The model predicts that the 15 takes per dose that were found at 100:1 could also be obtained at 33.7:1, with only about a third as many vaccination attempts.
These results could undoubtedly be refined with the forthcoming results of the larger dilution study employing over 600 subjects that is currently in progress, but meanwhile they do suggest that dilutions on the order of 20:1, 30:1, or 40:1 could give up to double the number of takes per dose obtained at 10:1, without the excessive number of attempts required at 100:1, and hence are well worth considering and investigating with further trials.
Concluding remarks argue for the immediate vaccination, using diluted existing vaccine, of all willing Americans who are not at high risk of complications, giving first priority to medical and emergency workers, and then to those who have never been vaccinated.
Such “ring vaccination” after the fact may have worked well 30 to 40 years ago against natural outbreaks in Third World countries where mobility was limited and considerable immunity from prior infection or vaccination was already present, but will be far less successful against a deliberate attack on our highly mobile and completely susceptible society. Suppose, for example, that a small group surreptitiously released smallpox virus in aerosol form at a few crowded airports. Two weeks later, thousands of cases would simultaneously appear without warning in dozens of cities and a handful of foreign countries. If, as is not unlikely, the airports and highways are closed and entire cities are quarantined, it will be next to impossible to distribute vaccine to where it is needed, particularly if a few well-timed anthrax letters close down the postal system and parcel services, and if other calculated disturbances also add to the pandemonium. Just finding the requisite bifurcated needles would be a feat in itself (Landers 2001). O’Toole (1999) projects that existing vaccine stocks could quickly be exhausted, even in a scenario in which there are far fewer initial cases, and in which the response is ideally prompt.
After one has been exposed or when one is about to be exposed in the line of duty, a take probability of even 95%, which is equivalent to 20-cylinder Russian Roulette, will be unacceptably low. Freshly vaccinated medical and emergency workers could therefore reasonably be expected to refuse to examine potentially infected persons or to move them to quarantine centers during the first week, until after their own vaccinations prove positive. One hundred CDC immunologists, who will be expected to collect and analyze fluid samples from the first victims, have prudently had themselves pre-vaccinated (Connolly 2001), even though the CDC dictates that all other health and emergency workers must wait until after an outbreak is confirmed. After an attack occurs, no one will be satisfied with any but the highest probability of a take, and stretching existing stocks with dilution will become a moot issue.
Before an attack occurs, however, we have plenty of time to vaccinate, and revaccinate as necessary with dilute vaccine, all Americans who want to be protected. First priority should be given to medical and emergency workers, and then to those born after 1972 who have never been vaccinated, but the present study suggests that at a dilution rate of 30:1, or so, there may be adequate vaccine in stock for all who want it.
Pre-vaccinating millions of Americans will greatly reduce the rate of spread of any infection, and will create a cadre of persons who can keep the country running in the face of otherwise crippling quarantines. Getting a vaccination program underway before an attack would vastly mitigate its effects, since vaccine would already be in the hands of clinics in every city, personnel would already have the necessary training and equipment, and health and emergency workers would be among the first to be vaccinated. Just knowing that the vaccine is available nearby and flowing on a rational basis, and not locked away in a vault in a distant city, to be released at the discretion of timid bureaucrats and squabbling politicians, will enormously reduce the sense of panic that would follow any outbreak. And best of all, simply reducing America’s vulnerability to smallpox by launching such a campaign is likely to discourage anyone from using it as a weapon against us in the first place.
The CDC (2001b) has expressed concern that the high risk of complications in a few individuals with certain conditions would lead to numerous deaths if all Americans were “indiscriminately” vaccinated. These complications could lead to about one death per million vaccinations using 1960s experience, and to even more with today’s higher incidence of organ transplant recipients, cancer survivors, and HIV carriers. However, there is no reason to allow this elevated risk in a few readily identifiable individuals to delay the discriminate and voluntary vaccination of the 90% or so of Americans who are not at high risk (McCulloch 2001, Millar 2002).
Many of the complications of smallpox vaccination can be mitigated or even prevented by the administration of Vaccine Immune Globulin (VIG), a product made from the blood serum of recently vaccinated individuals (CDC 2001a). The Catch-22 is that the CDC is down to only about 600 doses of VIG (Rotz 2001) and virtually no one has been recently vaccinated. Pre-vaccinating millions of healthy Americans will create a pool of potential donors to replenish these stocks, and thereby provide a measure of protection even for those who are at high risk of complications.
Center for Disease Control Advisory Committee on Immunization Practices [CDC 2001a]. “Vaccinia (Smallpox) Vaccine,” Morbidity and Mortality Weekly Report 50, No. RR-10 (June 22, 2001). Online at http://www.cdc.gov/nip/smallox/News.htm#ACIP.
Center for Disease Control [CDC 2001b]. “Interim Smallpox Response Plan and Guidelines,” Draft 2.0, 11/21/01. Online via http://www.cdc.gov/nip/smallpox/.
Connolly, Ceci. “HHS Set to Order Smallpox Vaccine for All Americans,” The Washington Post Nov. 7, 2001. Online at http://www.washingtonpost.com/wp-dyn/articles/A51468-2001Nov6.html.
Harding, Anne. “Old Smallpox Shots Work, but Jury Out on Dilution,” Reuters news story, Dec. 18, 2001. (Report on Poster Presentation by Dr. Robert Belshe at 41st ICAAC conference in Chicago) Online at http://www.nlm.nih.gov/medlineplus/news/fullstory_5304.html.
Henderson, Donald A., T.V. Inglesby, J.G. Bartlett, M.S. Ascher, E. Eitzen, P.B. Jahrling, J. Hauer, M. Layton, J. McDade, M.T. Osterholm, T. O’Toole, G. Parker, T. Perl, P.K. Russell, and K. Tonat, for the Working Group on Civilian Biodefense. “Smallpox as a Biological Weapon: Medical and Public Health Management,” Journal of the American Medical Association 281, No. 22 (June 9, 1999): 2127-2137.
Landers, Susan J. “Smallpox Vaccine: Balancing the Benefits and the Risks,” AMNews Nov. 12, 2001. Online at http://www.ama-assn.org/sci-pubs/amnews/pick_01/hlsb1112.htm.
Leadbetter, M.R., Georg Lindgren, and Holger Rootzén. Extremes and Related Properties of Random Sequences and Processes. Springer Verlag 1983.
Lester, Will. “Poll Backs Smallpox Vaccinations,” Associated Press story, Sunday, Nov. 18, 2001. Online at http://icrsurvey.com/icr/AP_Bioterror.htm.
McCanse, Cindy. “Vaccinate against smallpox? Preposterous! But will a vaccine be there if you need it? FPReport 6, No. 5 (May 2000). Online at http://www.aafp.org/fpr/20000500/03.html.
McCulloch, J. Huston. “Vaccinating Now Could Curb Outbreak,” Letter to Editor of Wall St. Journal, Nov. 6, 2001.
Millar, J. Donald. “Free to Choose the Smallpox Vaccine,” excerpt from an article to appear in the Winter 2002 issue of Regulation, the Cato Institute Review of Business and Government. Online at http://www.cato.org/dailys/01-04-02.html.
O’Toole, Tara. “Smallpox: An Attack Scenario,” Emerging Infectious Diseases 5 (July-August 1999): 540-546.
Press, William H., Saul A. Teukolsky, William T. Vetterling, and Brian P. Flannery. Numerical Recipes in FORTRAN: The Art of Scientific Computing, Second edition, Cambridge Univ. Press, 1992.
Rotz, Lisa, in “CDC-Interim Smallpox Response Plan and Guidelines Conference Call,” CDC Office of Communication, Nov. 26, 2001. Online at http://www.cdc.gov/od/oc/media/transcripts/t011126.htm.
Stolberg, Sheryl Gay, and Melody Petersen. “U.S. Orders Vast Supply of Vaccine for Smallpox,” New York Times Nov. 29, 2001.
Details are in the following articles authored or co-authored by Dr. Millar:
Millar, J.D., R.R. Roberto, H. Wulff, H.A. Wenner, and D.A. Henderson, "Smallpox Vaccination by Intradermal Jet Injection. 1. Introduction, Background, and Results of Pilot Studies." Bulletin of the World Health Organization 41: 749-760, 1969.
Roberto, R.R., H. Wulff, and J.D. Millar, "Smallpox Vaccination by Intradermal Jet Injection. 2. Cutaneous and Serological Responses to Primary Vaccination in Children." Bulletin of the World Health Organization 41: 761-769, 1969.
Neff, J.M., J.D. Millar, R.R. Roberto, and H. Wulff, "Smallpox Vaccination by Intradermal Jet Injection. 3. Evalution in a Well-vaccinated Population." Bulletin of the World Health Organization 41: 771-778, 1969.
Millar, J.D., L. Morris, A. Macedo Filho, T.M. Mack, W. Dyal, and A.A. Medeiros, "The Introduction of Jet Injection Mass Vaccination into the National Smallpox Eradication Program of Brazil." Trop. Geogr., Med. 2389-101, 1971.
Dr. Millar is currently president of Don Millar & Associates, Inc., of Atlanta GA, and is a distinguished fellow of the Public Health Policy Advisory Board in Washington, D.C.