First Vaccine for Chickenpox

The days when nearly everyone spent a week of their childhood with the itchy, miserable rash of chickenpox may be on the wane. Last March 17, the Food and Drug Administration licensed a new vaccine, Varivax (varicella virus vaccine live). Commonly known as the chickenpox vaccine, it will prevent the typical cases of itchy, uncomfortable, week-long rashes and mild fevers, and the rarer cases of serious illness caused by the virus.

Although chickenpox is generally mild and not normally life-threatening, the Centers for Disease Control and Prevention estimates that there are 9,300 chickenpox-related hospitalizations and 50 to 100 deaths annually, mainly among young children.

Before receiving approval from FDA, researchers tested Varivax in about 11,000 children and adults. Scientists predict that it will be 70 to 90 percent effective in preventing the disease. Of those who did get chickenpox after vaccination, almost all had a mild form of the disease.

Adverse reactions to the vaccine were generally mild and included pain, rash, hardness, and swelling at the injection site, fever, and generalized rashes.

Mary L. Kumar, M.D., chief of pediatric infectious diseases at MetroHealth Clinic in Cleveland, tested the vaccine on about 500 children and 200 adults in the Cleveland area. She says the vaccine trials were very easy to recruit for. "We actually had people calling us," Kumar explains, adding that there was not only great interest from parents who wanted to spare their children from the disease, but also from adults in health-care professions who were concerned about getting chickenpox themselves and about infecting susceptible patients.

Will It Last?

Throughout the development of the chickenpox vaccine, there has been concern about whether the vaccine would confer lifetime immunity or simply delay infection until adulthood. When adults get chickenpox, the cases are usually more severe and the risk of complications such as pneumonia greater.

"Over the period of time it's been looked at carefully, which is about five years, we're not able to find evidence for substantial waning in immunity," says Philip Krause, M.D., senior research investigator in FDA's Center for Biologics Evaluation and Research. "It's complicated to determine how long immunity lasts, because right now people who are vaccinated are exposed to children who have [naturally acquired] chickenpox and they presumably are getting a booster effect from those repeated exposures."

"Longer is more difficult to tell," says Krause. "The only way to sort that out is going to be to see what happens after the vaccine is introduced." At FDA's request, Merck will follow several thousand vaccinated children for 15 years to determine the long-term effects of the vaccine and possible need for a booster immunization.

Shingles

As with the question of immunity, more time is needed to answer another question about the vaccine--will it cause shingles in adulthood?

Shingles is the second act of chickenpox. Once someone has had chickenpox, the virus doesn't die, it simply becomes dormant. It lingers in the body's nerve cells next to the spinal cord. Then, for reasons still not definitely known but possibly related to a weakened immune system, the virus reactivates and infects nerve fibers, causing severe pain, burning or itching. Because weakened immunity often accompanies aging, shingles usually occurs after age 50.

Can the chickenpox vaccine, which is a weakened form of the live virus, cause shingles?

"Nobody's sure what the effect will be," says Krause. "We really don't have the data to say what's going to happen in 20 to 30 years. Based on our knowledge of how the virus works and the data available so far, it doesn't appear that the rate of shingles cases in vaccinated individuals will be any greater than in the naturally infected population. There's some data in children who were immunocompromised that suggests that the vaccine may reduce the likelihood of shingles over the short term. But more data are required to determine the effect of the vaccine on shingles in healthy individuals over a lifetime."

Just One or Two Shots

A single injection of the vaccine is recommended for children ages 12 months to 12 years, while two injections four to eight weeks apart are recommended for adolescents and adults who have never had chickenpox.

"We're not really sure why teens and adults don't get immunity with one shot," says Krause. "The immune response to a single shot if you're 13 or older is not nearly as good as it is if you're younger. But two shots provide immune responses comparable to what younger people get."

For children, the vaccine has been shown to be safe and effective and can be administered at the same time as the measles, mumps and rubella vaccine. (The MMR vaccine is given at 15 months and again between 4 and 6 years or before junior high or middle school. See "Kids' Vaccinations Get a Little Easier," in the March 1994 FDA Consumer.) Public health officials hope that being able to give the chickenpox vaccine along with an already scheduled vaccine will encourage vaccination.

Vaccine Development

Varivax's development began with a sample of varicella (chickenpox) virus isolated from the blood of a 3-year-old Japanese boy in 1972. Japanese researcher Michiaki Takahashi, M.D., attenuated (weakened) the virus by growing it in different human and animal host cells. He then tested the weakened virus in children as a vaccine against chickenpox.

His tests were successful, and in 1981, Merck obtained the rights to use the "Oka" strain (named after the 3-year-old boy) to develop its own vaccine.

Merck began clinical trials of the vaccine for safety and effectiveness. But obtaining successful test results was only half the battle for Merck to bring the vaccine to market. Making enough vaccine to meet demand was the other.

Unlike other weakened live viruses used for vaccines that spontaneously emerge from cultivated cells, varicella stays in the cell.

"In the case of varicella, we have to collect the infected cells and then break them open," explains Barry D. Garfinkle, Ph.D., Merck's vice president for vaccine quality operations. "We do this using an ultrasonic device."

The ultrasound creates heat and, in this case, creates problems. Although the varicella virus is extremely virulent in its natural environment inside the human host, once it's removed from the infected cells in the lab "varicella is very, very sensitive to elevated temperatures," says Garfinkle.

"We have to use the right amount of [ultrasound] to get the virus freed but not so much that we damage the virus," says Garfinkle. "Getting those parameters correct took us a while."

To this end, Merck built a new facility in West Point, Pa., where robots handle most of the vaccine production. Garfinkle explains that using robots allows for better control of the exacting ultrasound procedure.

Merck submitted data on Varivax's safety and effectiveness to FDA in May 1993.

In January 1994, FDA's Vaccines and Related Biological Products Advisory Committee concluded that the vaccine was safe and effective. But the committee advised FDA to address several questions before making a final decision, including how to address whether vaccinating children would shift the disease to adults and whether doctors could give Varivax at the same time as other vaccines.

In January 1995, FDA presented to the committee clinical data from the manufacturer resolving those issues.

Easy to Catch

An estimated 3.7 million Americans get chickenpox each year, with more than 90 percent of cases in people younger than 15.

Chickenpox is transmitted through fluid from broken blisters and through coughing or sneezing. A person is contagious for one or two days before the rash appears until all the lesions are dried, which usually takes four to five days. The average incubation period (the time between exposure to the virus and the onset of illness) is 10 to 21 days.

Those at greatest risk for a serious case of chickenpox are people age 13 and older, and anyone with impaired immunity. Chickenpox can also be serious for fetuses and newborn babies. When a woman breaks out in chickenpox just before or after delivery, her baby may develop a severe form of the disease; as many as 5 percent of these babies die. Infection early in pregnancy may cause the fetus to develop limb abnormalities, scarring of internal organs, or damage to the central nervous system.

In addition, "there are a fair number of complications that require hospitalization of otherwise healthy children," says Kumar.

That was the case for Brittany Evans (not her real name). The only risk factor for the healthy two-and-half-year-old was her 5-year-old sister's routine bout with chickenpox two weeks before.

"Frequently in a family, the second and third cases can be more severe," explains Kumar. Siblings generally spend more time with each other than with friends and schoolmates and this gives the virus the opportunity to infect siblings when it's most virulent.

Brittany's chickenpox broke out on Friday, March 10. By the next Wednesday she was covered with blisters and running a fever of almost 105 degrees Fahrenheit.

"She had [blisters] between her fingers so bad she couldn't get her fingers side by side," says her mother. "I couldn't rub my hand along her tummy and find a spot that didn't have a blister."

Brittany was admitted to Shady Grove Hospital in Gaithersburg, Md., on March 17 (ironically, the same day the vaccine was licensed). She spent three days there to make sure she didn't become dangerously dehydrated from the high fever. Her body's own defenses finally overcame the virus, and she recovered.

On April 10, the American Academy of Pediatrics recommended the vaccine for all healthy children between the ages of 12 months and 13 years who have not had chickenpox. For children between 12 and 18 months, the academy recommends giving the chickenpox vaccine at the same time as the first measles, mumps and rubella shot. Older children should be vaccinated at the earliest convenient time.

While some doctors still question the need for vaccinating against a generally mild disease, Kumar agrees with the academy's recommendations because of the need to prevent unforeseen complications and hospitalizations.

Brittany's mom isn't a medical expert, but she says, "I never want to go through this again. My husband and I are thinking about having another child, and I'll get the next one the vaccine, without a doubt."

Isadora B. Stehlin is a staff writer for FDA Consumer.

Treating Chickenpox

Public health officials don't know yet how many children will be vaccinated since the chickenpox vaccine isn't required for school admission at this time.

In otherwise healthy children and adults, the disease should be allowed to run its course. But that doesn't mean the symptoms should be ignored. Calamine lotion applied to the lesions may offer some relief from the infamous itch of the chickenpox rash. Soaking in a cornstarch, baking soda, or oatmeal bath may also do the trick. However, because any relief is at best temporary, doctors advise parents to cut children's nails very short, since scratching can lead to secondary skin infection by bacteria on the skin, such as staphylococcus ("staph") and permanent scarring. A daily bath with soap is also recommended to clean as much bacteria off the skin as possible.

A non-aspirin pain reliever and fever reducer such as acetaminophen (Datril, Tempra, Tylenol, and others) can ease headaches, fever, or general malaise. Aspirin or any medication that contains aspirin or salicylates should never be used because of the risk of Reye syndrome, a rare but serious illness that typically strikes children and teenagers just as they appear to be recovering from the flu or chickenpox.

If a doctor visit is necessary, pediatricians usually make special arrangements to see children who might have chickenpox to avoid exposing others.

"They might see [those children] after hours or when the office isn't busy," says Mary L. Kumar, M.D., a pediatrician in Cleveland. Although diagnosis may be possible over the phone, "I like to take a look myself," she says. "Over the phone can be pretty accurate if other children in the family just had chickenpox. But there are many other rashes that can look somewhat like the varicella [chickenpox] rash, so I don't think it's easy over the phone to be certain."

During the course of the infection, the doctor should be called if the patient's temperature goes above 102 degrees Fahrenheit (39 degrees Celsius) or any fever lasts longer than four days, or if areas of the rash become very red, warm, or tender, which may signal a bacterial infection requiring antibiotics.

In February 1992, FDA approved the use of oral Zovirax (acyclovir) to treat chickenpox in otherwise healthy children. (FDA had already approved the drug to treat genital herpes and shingles.) When a patient receives oral Zovirax within 24 hours after the rash appears, the number of lesions are reduced, and average recovery time is shortened approximately one day.

However, the American Academy of Pediatrics does not recommend the use of oral Zovirax in otherwise healthy children. The academy says the medication's relief of chickenpox symptoms is minimal, it's extremely difficult to start it during the first 24 hours, and there is a potential for unforeseen dangers when treating large numbers of children who are at low risk of developing complications. The academy recommends use of oral Zovirax only in people at high risk for severe chickenpox or complications, including:

• healthy nonpregnant teenagers and adults
• children over 1 year who have chronic skin or lung disorders, or who must take aspirin daily for conditions such as arthritis
• children taking corticosteroids for conditions such as asthma.

A biological product that actually prevents infection is available for people at high risk. But the product, varicella-zoster immune globulin, or VZIG (doctors pronounce it "vee-zig"), must be administered within 96 hours of exposure, long before symptoms appear. And it serves little purpose to the otherwise healthy population because VZIG gives only temporary protection.

VZIG is prepared from the plasma of normal blood donors who have high levels of antibodies to the varicella virus, which causes chickenpox. It confers a "passive" immunization that lasts only about three months.

The Centers for Disease Control and Prevention recommend VZIG for the following

• high-risk individuals who have no immunity to chickenpox:
• immunocompromised children and adults
• newborns whose mothers came down with chickenpox five days before to two days after delivery
• premature infants exposed after birth.

VZIG may be recommended for mothers who are exposed during the first trimester. However, taking VZIG at this time only benefits the mother's health. There is no indication that VZIG can prevent the birth defects associated with the chickenpox virus.

Those at highest risk for complications are not candidates for the chickenpox vaccine. (Healthy teenagers and adults, who are considered at high risk for chickenpox complications simply because of their age, can get the vaccine.)

"People who have compromised immune systems are more likely to get worse reactions to the vaccine because it is a live virus," says FDA's Philip R. Krause, M.D. "The hope is that if enough healthy children get the vaccine there will be less natural chickenpox floating around and [high-risk] people will not be exposed."

--I.B.S.