Attention turns to VIG as smallpox immunization plan is announced

Expectation for IV formulation is high, but questions remain

Now that the initial phase of President Bush’s smallpox vaccination plan is scheduled to be under way, public health officials are scrambling to make sure they have enough supply of vaccinia immune globulin (VIG), the primary product available to treat complications of the smallpox vaccinia vaccination. Here are some important facts to know about VIG:

Facts about VIG

VIG is an isotonic sterile solution of the immunoglobulin fraction of plasma from people vaccinated with vaccinia vaccine. It is available only from the Centers for Disease Control and Prevention (CDC) under Investigational New Drug protocols.

VIG is effective for the treatment of eczema vaccinatum and some cases of progressive vaccinia. This information is the result of using historic controls and not a randomized controlled trial, says Inger Damon, MD, PhD, chief of the poxvirus section of the CDC in Atlanta. VIG also may be useful in the treatment of ocular vaccinia resulting from inadvertent implantation and for severe generalized vaccinia if the patient has a toxic condition or a serious underlying disease, according to the CDC. VIG is contraindicated for vaccinial keratitis because increased scarring can occur. VIG also is not recommended for mild instances of accidental implantation, mild or limited generalized vaccinia, erythema multiforme, or encephalitis post-vaccination.

In some instances, VIG has been given concomitantly with the vaccine to "prevent" complications in a susceptible person. VIG, however, cannot prevent a side effect, says Marguerite Neill, MD, associate professor of medicine at Brown University and chair of the bioterrorism work group at the Infectious Diseases Society of America. "You can’t give it to a person with eczema before the person gets vaccinated," Neill explains. Instead, VIG halts the progression of the adverse event, unless the individual has an underlying immunodeficiency. The CDC says not enough is known about the efficacy of concomitant administration to recommend its use. Furthermore, there is currently an insufficient amount of intramuscular VIG (IM-VIG) to use prophylactically when the benefits are uncertain.

The plasma used for VIG in the past contained a high titer of anti-vaccinia neutralizing antibody. Because it contained a high proportion of aggregated protein, it was administered intramuscularly as soon as possible after the onset of symptoms in an initial dose of 0.6 mL/kg of body weight, the CDC says. As much as 1-10 mL/kg were used in severe cases of eczema vaccinatum and progressive vaccinia. Because the therapeutic doses of VIG could be large, the product was given in divided doses over a 24- to 36-hour period. Doses could be repeated, usually at intervals of every two to three days, until recovery began. Data from a CDC survey indicate that VIG has been administered at a rate of 47 uses per one million primary vaccinees and two uses per million revaccinees.

The main adverse events have been local pain and tenderness, and swelling and erythema because of the IM injection. "There have been a few allergic or anaphylactic-type reactions following administration of IM or IV human IG preparations," Damon says. "Those are the significant adverse events — which are seen with certain immune globulin injections — that you need to watch for."

Now new lots of intravenous VIG (IV-VIG) are being produced that conform to intravenous standards. The CDC expects that IV-VIG most likely will be administered at a lower dose than the intramuscular preparation. In preliminary studies, IV-VIG appears to be five to 10 times as potent as IM-VIG when tested in animal models. In addition, IV-VIG has a low level of aggregated protein, allowing it to be used by either the IM or IV route.

The new formulation will be a significant improvement, Neill says. "By having an IV preparation available, we can give more. So not only is more available to give, but when it needs to be given, particularly for the conditions that take a lot, we can provide it."

The CDC says IV-VIG will require new recommendations for both dosage and preferred method of administration. Not knowing specifics about IV-VIG is a concern to some health care professionals. Of bigger concern, however, is the uncertainty of how people with weak immune systems will react to VIG. People whose immune systems have been weakened by cancer, AIDS, or other diseases are at risk for having complications from the smallpox vaccine and are supposed to be disqualified from the vaccination process.

"There are some good reasons to think that by extensively, systematically, and incredibly carefully screening people, you will weed out [the people with weakened immune systems]," Neill says. But is there a chance a totally healthy-looking person who is immunized might have a condition such as asymptomatic, undiagnosed Hodgkin’s disease? "The possibility is there, but the probability is low."

If some of these people do end up being vaccinated and experiencing complications, no one knows for sure how they will react to VIG. This concerns Jared N. Schwartz, MD, PhD, FCAP, chair of the College of American Pathologists ad hoc committee on national preparedness. He also is director of pathology and laboratory medicine at Presbyterian Health Care in Charlotte, NC. "[The reaction] would probably depend upon the dose of drugs they were on. We don’t know how effective the vaccinia immune globulin would be for these individuals. There are a lot of unknowns."

When routine smallpox vaccination among the American public stopped in 1972, not as many people were being treated with strong immunosuppressive drugs for diseases. The first AIDS cases in the United States had yet to be reported.

Schwartz says that is why a lot of health care experts are anxious about the ramifications of immunizing the general population for smallpox too quickly without a real threat. "There is no specific data for many of these questions," he notes.

The varying VIG stock

Another concern some health care professionals have, including Schwartz, is whether the CDC has a large enough stock of VIG to handle adverse effects of the smallpox vaccination. The CDC says it has sufficient IM-VIG to counter approximately 600-800 adverse events if appropriate recommendations are followed. This is enough VIG to treat the adverse reactions that would be expected to result from the vaccination of four to six million people.

"One of the real concerns relating to VIG right now is that historically, if individuals had reactions to the smallpox vaccinia vaccine, the only treatment at the time [from the 1950s through the 1970s] was to give them vaccinia immune globulin," Schwartz says. "There was a good supply then because the vast majority of the population had been vaccinated. You were able to get blood from individuals and then harvest the immune globulin."

The harvesting stopped, though, when smallpox vaccinations were discontinued. "As a result, the great concern is that if someone had a reaction right now to the vaccine, there are few doses that would be available to help decrease the symptoms," he says.

The CDC has ordered many more doses of IV-VIG and says the future supply should be more than sufficient to meet the need. Canadian drug manufacturer Cangene, for example, has contracted with the CDC to supply 100,000 doses of VIG.

"The VIG available now is adequate for the limited vaccination program presented by the president, which is a stage type of program," explains John A. Becher, RPh, chief of the CDC Drug Service. "The contract that we have with Cangene has adequate supplies of the VIG to cover any of the reactions that we statistically have put together and thought might be enough. The contract will be completed by the third quarter of 2003. Half should be done by the second quarter."

The United States may have enough supply for Americans, but what about other countries requesting our help? The Washington Post has reported that the Kuwaiti government asked the United States for the smallpox vaccine last summer "in readiness for any eventuality."

"The feeling is that if the United States is concerned enough to begin to immunize its own health care workers and military and within a year possibly make it available to the general population, maybe the threat is more real than some people believe," Schwartz says. "Of course, [other countries] want to have access for their own population in case there truly is an outbreak."

One benefit of the new smallpox immunization plan is that public health officials will now have a significant pool of individuals from which to harvest immune globulin. Schwartz continues, "It could then be used when the vaccine might need to be given to a wider portion of the general population."

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