Annals of Emergency Medicine
Volume 55, Issue 4 , Pages A17-A19, April 2010

Rabies Reason:

CDC Panel Recommends Reduced Vaccine Dosing for Rabies Exposures

Article Outline

 

A tightening of supplies of rabies vaccine has led to a comprehensive change in public health recommendations for rabies prophylaxis, and the recommendations in turn are causing confusion and some resistance as they trickle down to emergency physicians.

Vaccine Shortages Becoming All Too Common

 

by MARYN MCKENNA

Special Contributor to Annals News & Perspective

The temporary shortage of rabies vaccines that drove the new CDC post-exposure recommendations is only one of many vaccine shortages that have revealed the fragility of vaccine manufacturing.

It isn't even the most recent: That honor goes to the H1N1 influenza vaccine. By December 31, 2009, manufacturers had shipped 99.3 million doses of the novel formula1—an amount that compares to past years' seasonal flu vaccine shipments, but was far below the 160 million doses that federal officials had predicted would be produced by October.2

Seasonal flu vaccine production has fallen short in past years as well. So have others: in 2002, the CDC recommended deferring some doses of MMR and varicella vaccines because production by the sole manufacturer, Merck & Co., was interrupted after an FDA inspection.3

Sanofi Pasteur could not meet demand when its meningitis vaccine Menactra was first introduced in 2005; the shortage continued into 2006.4 In 2007, manufacturing difficulties halted production of Merck's combined pediatric vaccine ProQuad for half a year, and at the end of that year, the company was required to recall 1.2 million doses of 2 vaccines against Haemophilus influenzae.5, 6 In 2008, Merck also faced multi-week delays filling orders for its adult shingles vaccine Zostavax.7 And by late 2009, supplies of hepatitis B vaccines made by both Merck and GlaxoSmithKline had run short.8

The various vaccines were held back for different reasons: aging technology, aging production facilities, unpredictable antigen growth and equally unpredictable market dynamics. But at base, almost all of the vaccines shared a characteristic: They were made by a single manufacturer, or by one of only a few. The shortages were demonstrations of how fragile and subject to disruption the vaccine marketplace has grown.

“For most vaccines, there are very few companies producing them—in some cases, one company—so any glitch in the manufacturing process that limits a particular company's output drastically affects supply,” said Andrew W. Artenstein, MD, chief of the department of medicine at Memorial Hospital of Rhode Island and author of Vaccines: A Biography (Springer, 2010).

Companies have left the vaccine market because the products are not revenue leaders, because they expose companies to significant liability claims, and because the largest amount of vaccines are sold to developing-world countries with smaller budgets.

“It's tough to convince companies to get into that game, and that's why many vaccines are produced by only one or two companies,” Dr. Artenstein said. “The question for them is what is the impetus to pour money into [vaccine manufacturing] when the return on investment is not what it is on, say, Lipitor.”

The new recommendation shortens the course of intramuscular shots given for post-exposure prophylaxis from 5 shots to 4. (The administration of one dose of rabies immune globulin at or near the wound, or intramuscularly if no wound is evident, remains unchanged.) The recommendation was first published in June 2009 on the Web site of the Centers for Disease Control and Prevention (CDC)'s Advisory Committee for Immunization Practices (ACIP).1 That was followed during the fall by a series of meetings between the CDC and state public health officials and specialty societies, and in late November by an article in Vaccine that laid out the evidence supporting the recommendation.2

By the end of 2009, the final step in the CDC's process for promulgating new recommendations—formal acceptance by the agency's director, followed by publication in its bulletin, Morbidity and Mortality Weekly Reports—had not yet been accomplished. But news of the change was moving slowly through emergency departments (EDs), and some physicians at least who were aware of the change were concerned by it, because the new regimen effectively asks them not to conform to the manufacturer's federally approved package insert language.

“I have given rabies prophylaxis twice in 30 years,” said Stephen Cantrill, MD, who recently retired as associate director of the department of emergency medicine at Denver Health Medical Center in low-prevalence Colorado. “With something given that infrequently, you are always going to go by what the package insert says.”

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Limited Supply 

The new recommendations were prompted by a complex set of circumstances that date back several years and revealed fault lines in vaccine manufacturing and marketing and in public health surveillance.

Only 2 rabies vaccines are sold in the United States: Imovax, made by Sanofi Pasteur, and RabAvert, made by Novartis. Both companies have faced episodic challenges. In 2004, Sanofi (a division of Aventis Pasteur) discovered live virus in one batch of its vaccine, leading to a recall and supply restrictions that stretched into 2005.3, 4, 5 Then in 2007, Novartis suspended production of RabAvert as part of plant upgrades following its purchase of Chiron Corp., a suspension that was intended to last less than a year but stretched into 2008 after the company separately received a stern warning letter from the Food and Drug Administration over sterility problems.6, 7 And in mid-2007, Sanofi took the plant where it makes Imovax offline for a 2-year renovation, after building up an inventory that would meet its historic pattern of orders for the vaccine.8

Simultaneously, however, demand for rabies vaccine was surging. “In the 1990s, we assumed that we would be able to reduce the burden of human exposures to rabies to somewhere between 8,000 and 10,000 persons per year by the year 2000,” Charles Rupprecht, MS, VMD, PhD, chief of the CDC's rabies program, said in an interview. “In fact, we know now that 35,000 to 40,000 people are exposed per year.”

That mismatch between goal and reality came about both because of an unforeseen zoonosis—the mid-1990s surge in raccoon rabies up the Eastern Seaboard—and also because public health had no way to deduce a human health prediction out of veterinary data about the surge, since potential human exposures to rabies are not a reportable disease.

The combination of increasing demand and straitened supply led to a situation throughout 2008 that Dr. Rupprecht delicately calls “a limitation—not a shortage,” a reduction of up to 50% in the usual supplies of vaccine. Across the summer and fall, pre-exposure prophylaxis for occupational risks of rabies, such as among lab workers and animal control officers, was sharply restricted. At the same time, tight controls were imposed on post-exposure prophylaxis, including a multi-step approval process involving evaluation by a state rabies official, an 800 number, an application and a password that was changed frequently to prevent abuse.9 State health departments put out statements begging residents to avoid contact with wildlife so that they would not have to be prophylaxed and use up scarce vaccine.

At the same time, the ACIP began examining whether it could ease the demand situation, by reducing how much vaccine post-exposure prophylaxis consumes. It convened a working group in early 2008 that presented its findings to the committee in February 2009. The ACIP's June 2009 vote made the working group recommendation official: Reduce prophylaxis from 5 post-exposure doses to 4.

The evidence for the group's recommendation is laid out in the Vaccine paper2 and includes multiple serosurveys of human recipients in which virus-neutralizing antibody levels peaked at day 14 of prophylaxis. (That is, after the fourth dose in a 5-dose schedule administered on days 0, 3, 7, 14 and 28, along with RIG on day 0.) Additionally, studies of immunological memory in rabies vaccine recipients revealed similar adequate antibody levels in people who had received 3 doses versus 5 doses more than 1 year post-vaccination. Animal studies in several species suggested that the key to successful prophylaxis is not length of dosing, but rather promptness in administering the first dose along with RIG.

In addition, the working group found that failures in post-exposure prophylaxis were “extraordinarily low” and tended to occur in the developing world among people receiving vaccines that are not licensed in the United States, or whose prophylaxis was delayed or did not include RIG.

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A Rare Event 

In the United States, there is no evidence of prophylaxis failures due to accidental omission of the fifth dose, either in surveys or in clinical experience. “We know that compliance with 5 doses is less than ideal,” Rupprecht said. “If we say that 3% don't finish the sequence, that means we have hundreds to thousands who have not finished. And our surveillance for rabies is good, because it is a rare event—and we found no deaths as a result of not receiving a fifth dose.”

But the decision to accept the reduced dosing brings the CDC recommendation into conflict with the existing package inserts. At the February and June ACIP meetings, representatives of Sanofi and Novartis both indicated discomfort with that.10 “”It does mean a challenge for Novartis because the FDA guidance clearly states 5 doses, and Novartis doesn't support off-label use of any of its products.” Clement Lewin, PhD, of Novartis told Elsevier Global Medical News.11

The CDC understands that the manufacturers are unlikely to change their labels, because it would require a costly re-examination of clinical data, Dr. Rupprecht said. “The FDA cannot compel a manufacturer to change a label on the basis of evidence supplied by ACIP; the request has to come from the manufacturer,” he said.

That mismatch troubles emergency physicians who have learned about the new recommendation. (The knowledge is not widely distributed; in a round-up of calls and emails to ACEP members, roughly half were not aware the dosage recommendation had changed.) Even though rabies is of very low prevalence, they said, the disease's near-uniform mortality rate loads ED visits for bites or bat exposures with emotion and anxiety, especially when the patients are children. In that setting, they said, the suggestion that the change was driven by market economics will not go over well.

“It's entirely possible that the 4-shot regimen is the correct one—but nevertheless the time to announce such a change is not during a time of national shortage,” said Thomas Benzoni, DO, of Mercy Medical Center in Sioux City, Iowa. “It's likely to cause enough wondering for people to say, ‘Let’s stick to the 5-shot regimen until we have more information.'”

Physicians may also be concerned that following the recommendation rather than the insert leaves them legally vulnerable, he cautioned: “The likelihood of any individual patient contracting rabies is unbelievably low, but the consequences of contracting it are unbelievably high. If you give the 5 shots, and the patient develops rabies, at least you can say, I did the best I could.”

Given the very low prevalence of rabies in the United States—there were no recorded cases in 2008, and an average of only 2 cases per year for decades—the number needed to treat, to prevent an actual case, is very high. In addition, the ACIP working group estimated that cutting the post-exposure regimen from 5 doses to 4 could save $11.6 million to $16.6 million in health care spending. In the midst of the health care reform debate, with so much attention being paid to costs of care, re-evaluating the prophylaxis regimen was appropriate, said Michael Heller, MD, of Beth Israel Medical Center in New York City: “What we are dealing with is very low risk and very high cost.”

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References 

  1. Centers for Disease Control and Prevention. New ACIP recommendations for human rabies postexposure prophylaxis. http://www.cdc.gov/rabies/qanda/ACIP4dose.htmlAccessed November 1, 2009
  2. Rupprecht CE, Briggs D, Brown CM, et al. Evidence for a 4-dose vaccine schedule for human rabies post-exposure prophylaxis in previously non-vaccinated individuals. Vaccine. 2009;27:7141–7148
  3. Food and Drug Administration. Notice to readers: manufacturer's recall of human rabies vaccine-MMWR. http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Recalls/ucm071303.htmApril 2, 2004;Accessed December 28, 2009
  4. Meikle J. Fears of rabies jab shortage after 7,000 doses recalled. The Guardian. April 6, 2004;
  5. Picard A. Production woes threaten supply of rabies vaccine. The Globe & Mail. February 7, 2005;
  6. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices Summary Report. http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-feb08.pdfFeb. 27-28, 2008;Accessed December 20, 2009
  7. Food and Drug Administration. Warning Letter CBER 08-01Novartis Vaccines and Diagnostics 24-Jan-08. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2008/ucm1048420.htmJan. 24, 2008;Accessed December 24, 2009
  8. Centers for Disease Control and Prevention. Rabies vaccine supply situation. http://www.cdc.gov/rabies/news/2008-07-15_RabVaxupdate.htmlJuly 15, 2008;Accessed December 20, 2009
  9. Centers for Disease Control and Prevention. Rabies vaccine supply situation. http://www.cdc.gov/rabies/news/2008-08-29_RabVaxupdate.htmlAug. 29, 2008;Accessed December 20, 2009
  10. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices Summary Report. http://www.cdc.gov/vaccines/recs/acip/downloads/min-jun09.pdfJune 24-26, 2008;Accessed December 20, 2009
  11. Tucker ME. ACIP votes to reduce recommended doses of postexposure rabies vaccine. Elsevier Global Medical News. June 24, 2009;

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Further reading 

  1. Centers for Disease Control and Prevention. 2009 H1N1 Influenza Vaccine Supply Status. http://www.cdc.gov/h1n1flu/vaccination/vaccinesupply.htmAccessed January 2, 2010
  2. McNeil D. U.S. reaction to swine flu: apt and lucky. New York Times. January 1, 2010;
  3. Shortage of varicella and measles, mumps and rubella vaccines and interim recommendations from the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. Mar 8 2002;51:190–191
  4. Yee D. Health officials brace for short supply of new meningitis drug. Associated Press. February 11, 2005;
  5. Johnson L. Merck vaccine production problem means extra shot for kids. Associated Press. May 10, 2007;
  6. Johnson L. Recall of common kids' vaccine could cause shortage, but officials say there's no health threat. Associated Press. December 13, 2007;
  7. McAuliffe M. Shingles vaccine in short supply. The Republican (Springfield, Mass.). September 6, 2008;
  8. American Society of Health System Pharmacists. Bulletin: Hepatitis B Vaccine Recombinant. http://www.ashp.org/Import/PRACTICEANDPOLICY/PracticeResourceCenters/DrugShortages/GettingStarted/CurrentShortages/bulletin.aspx?id=520December 16, 2009;Accessed January 2, 2010

 Section editor: Truman J. Milling, Jr, MD

 Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. The author has stated no such relationships exist. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement.

PII: S0196-0644(10)00114-9

doi:10.1016/j.annemergmed.2010.02.002

Annals of Emergency Medicine
Volume 55, Issue 4 , Pages A17-A19, April 2010

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