OVERVIEW of the VARICELLA VIRUS

The Varicella zoster virus is a DNA virus of the herpes group. It causes about 3.9 million cases of chickenpox yearly in the United States. This equates to approximately 500 million dollars in health care costs and lost wages. Even though most of these cases occur in healthy children under the age of 10, are self-limited and are uncomplicated, each year the virus is responsible for approximately 364,000 physician office visits, 9,000 hospitalizations and 100 deaths. Most of these deaths have occurred in children who were otherwise healthy. Approximately 5%-10% of children remain susceptable until they are adults, when the viral infection is potentially much more severe. Currently, adults account for only 2% of the infections but almost 50% of the deaths. Furthermore, recent reports indicate that the number of susceptable adults is increasing, most probably secondary to the recent increase in adult immigrants from tropical countries, where the children are not as susceptable because of the heat sensitive nature of the virus.

Moreover, the varicella zoster virus, like the other herpes viruses, has the capacity to remain in the body. Following the primary infection, this virus gains access to sensory nerve ganglia where it establishes a latent infection. This latent infection causes no further symptoms in most people, but in about 15% the virus will become re-activated and cause a secondary infection called zoster or shingles.

After the resolution of this secondary infection, a post-herpetic neuralgia can occur. This is thought by some physicians to be one of the most intractable problems of the elderly because of the lack of treatment modalities that appeciably relieve the symptoms.

THE VARICELLA VIRUS

The recurrent infections of varicella have been recognized since ancient times. Steiner demonstrated in 1875 that chicken pox was caused by an infectious agent when he inoculated volunteers with the vesicular fluid from a patient with acute varicella. At the end of the 19th century, varicella was reliably distinguished from the smallpox virus. In 1888, von Bokay demonstrated the relationship between varicella and herpes zoster when he exposed susceptable children to patients with zoster. Thomas Weller in 1954 isolated the varicella zoster virus from the vesicular lesions of both chicken pox and zoster.

PATHOGENESIS

The varicella virus enters the body via the conjunctivae and the respiratory tract. It requires host to host tramsmission because of it's short survival time outside of the body. Replication is believed to occur at the site of entry and in regional lymph nodes. It's primary viremia occurs after approximately 4-6 days, during which the virus disseminates to the sensory ganglia, liver, spleen and other organs. Following further replication in these organs, a secondary viremia develops during which the skin is infected. The virus can be isolated from the mononuclear cells of an infected person approximately 5 days prior to and up to 1 to 2 days following the appearance of the rash.

CLINICAL FEATURES

Incubation

The average incubation period for the varicella virus is 14-16 days. In immunocompromised patients this period can be prolonged and can last up to 28 days following the administration of varicella zoster immune globulin.

Prodrome

In adults the incubation period is followed by by 1 - 2 days of fever and malaise. Children typically have no prodrome and their first sign of infection may be the rash.

Rash

The rash usually appears on the scalp and spreads to the trunk and extremities. This pruritic generalized rash rapidly progresses from being macular to papular to vesicular. These lesions are usually 1 - 4mm in diameter, contain clear fluid and have an erythematous base. They are on the patient's trunk primarily but can involve the oropharynx, repiratatory tract, vagina, conjunctiva and the cornea. The vesicles routinely rupture and become purulent before they dry and crust. Over the course of the rash, multiple crops of lesions continue to appear. Therefore, the trunk of a patient with chickenpox can potentially have several crops, each in a separate stage of evolution. In healthy children, 2 - 4 successive lesions may have up to 200-500 lesions.

Clinical course

The clinical course in healthy children is generally mild with malaise, pruritis and fever up to 102 degrees for 2 to 3 days. Respiratory and gastrointestinal complaints are typically absent. However, the disease is usually more severe and prolonged with higher complication rates in children with leukemia, lymphoma or HIV. This is also true for adults who become infected. The most common complications include secondary bacterial infections of skin lesions, dehydration, pneumonia, and central nervous system involvement.

Zoster

Recovery from the primary varicella infection results in lifetime immunity. However, as mentioned before, the virus remains dormant in the sensory nerve ganglia and may reactivate later and cause herpes zoster or shingles. Factors associated with this reactivation include aging, immunosuppression, intrauterine exposure to varicella or infection at < 18 months. Again, the immunocompromised patient may have a more severe illness with dissemination causing generalized skin lesions and CNS, pulmonary and hepatic involvement.

The rash of varicella zoster generally is unilateral and in the dermatomal distribution supplied by a dorsal root or extramedullary cranial nerve sensory ganglia. Most often this involves the patient's trunk or the area supplied by the fifth craial nerve. Prior to the appearance of vesicles, there are few systemic symptoms but the patient may experience pain and paresthesia in the involved area. After the resolution of the vesicles, a post-herpetic neuralgia can occur and can last up to one year after the zoster episode.

OVERVIEW of VACCINES

The routine immunizing against measles, mumps, rubella, invasive Haemophilus, tetanus and poliomyelitis in the United States has been very effective. According to data from the CDC, the incidence of these diseases in the United States has been reduced approximately 97%. Other vaccines for organisms such as pertussis, hepatitis A and B and pneumococcus have not proven to be as effective. Efforts are currently underway for developing vaccines against organisms such as respiratory syncitial virus, rotavirus, tuberculosis and HIV and just recently has a vaccine for the varicella-zoster virus been released.

HISTORY of the VACCINE

Efforts to find a vaccine against the varicella-zoster virus were begun in 1966 by Merck, Sharp and Dohme Research Laboratories of West Point, Pa. In 1972, Mishiaki Takahashi, MD., of Osaka University, isolated the varicella virus from a 3 year old boy and named it Oka (after the boy). It was not until 1981 that Merck decided to abandom work on it's other vaccine candidates and begin work with the "Oka" vaccine. Therefore, this vaccine became known as the Oka/Merck live vaccine.

After growing the virus out in a number of different cell lines, the virus was attenuated and vaccine tested. Studies showed this vaccine to be very effective and safe in healthy as well as immunocompromised children. Breakthrough reactions were rare, but when they did occur they were were very mild when compared to the naturally occuring disease.

In 1983, a problem developed when the production lots of the vaccine were tested. In vaccinated leukemic children, there were more vesicular lesions as compared to the investigational vaccine. Therefore, trials were discontinued until this problem could be solved. The Merck scientists later discovered that the difference between the investigational and production vaccines was in the way that the virus was harvested from the infected cells. The original technique had been changed in order to increase the yield of viable virus obtained from each cell culture. However, this change resulted in a reduction of the actual amount of viral antigen per dose, making it less effective. Ultimately, the original methods were resumed and new trials were undertaken.

In 1990 the vaccine was presented to the FDA for approval.

The FDA in turn called for more clinical trials for safety and efficacy to be conducted. One particular study assured that the vaccine did not induce an autoimmune response to DNA since the virus is cultured in human cell lines. Other studies were to rule out the possible presence of other adventitious agents in the vaccine.

Ironically, when the FDA did give it's initial approval, there was not enough of the vaccine to put on the market. Therefore a license was not applied for and ultimately a new facility had to be constructed to produce the vaccine in quantity. On March 17, 1995, the FDA finally approved the varicella vaccine, called Varivax, but the testing of the virus is far from over. Postmarketing surviellance will be of necessity because there are so many concerns and unanswered questions about this vaccine. The three sites currently set up for surveillance by the CDC's National Immunization Program are : Travis County, Texas, West Philadelphia, Pa. and Los Angeles County, Ca.

CURRENT RECOMMENDATIONS for the ADMINISTRATION of the VACCINE

The Redbook Committee of the American Academy of Pediatrics, the American Academy of Family Practice, and the CDC's Advisory Committee on Immunization Practice have all recommended the wide spread use of this vaccine under following guidelines.

Children less than 1 year of age should not recieve the vaccine.

Children 12-18 months of age should recieve the vaccine universally. The vaccine is administered to these infants in a single 0.5ml subcutaneous dose in the anterior lateral thigh (in older children it can also be given in the outer aspect of the deltoid). Currently, the vaccine cannot be given in the same syringe as the MMR vaccine. However, the vaccine can be given using a separate syringe and a separate site at the same time the MMR immunization is given.

Children 18 months to 12 years of age who are still susceptable should still recieve the vaccine universally as a one-shot catch up dose. This dose is given in the same manner and at the same dose as with the younger children.

Patients aged 13 years and older should still recieve the vaccine but they require a two dose catch-up program. Each shot is still only 0.5ml given subcutaneously, but they are given these one to two months apart. In the case of non-compliant patients who have recieved the first but not the follow-up vaccination, the program does not require starting over. These patients need only to recieve their second shot.

Contraindications to vaccination with Varivax include:

-the vaccine should not be given to children who are immunocompromised, either secondary to disease or the administration of steroids at doses equal to or greater than 2mg/kg/day of prednisone in children less than 22 pounds or 20mg/day in patients greater than 22 pounds. There is however a research protocal available for administration of the vaccine to children with acute lymphocytic leukemia.

-the vaccine should not be given during pregnancy secondary to the teratogenic effects of the virus. The varicella virus causes a fetal varicella syndrome in about 2% of infected pregnant women. However, people who are non-immune to varicella and are living with a pregnant person, should recieve the vaccine. This would serve to decrease the chances of the pregnant person coming in contact with the wild virus.

-patients with previous anaphylactic reactions to neomycin.

-patients who have recieved immune globulin in the past 5 months.

-patients who have intercurrent moderate to severe diseases (not including URI, diarhea or otitis media).

SAFETY of the VACCINE

Clinical trials have shown this to be a very safe vaccine with very few adverse effects. Approximately 25% of the patients had pain, swelling and erythema at the injection site initially and only 5% developed a sparse generalized maculopapular or vesicular rash within one month of immunization. The incidence of this rash in children with leukemia was closer to 50%. There was no increase of these adverse effects or reactivation of the disease when the vaccine was accidentally given to people already immune to varicella.

Transmission of the virus from healthy immunized children to other children, either immunocompromised or close household contacts, is thought to be possible but has not yet been reported. On the other hand, vaccinated leukemic patients who developed a rash have spread the disease to otherwise healthy contacts. These disease episodes were much less severe than the naturally occurring disease, with the development of a significantly fewer number of vesicular lesions.

This vaccine does confer protection against naturally occuring varicella in family contacts, if given within 3 days of exposure. However, household exposure to the naturally occuring varicella less than five years after vaccination has resulted in mild disease in about 20% of children and 27% of adolescents and adults. Mild disease is defined as less than 50 vesicular lesions.

EFFICACY of the VACCINE

After one injection, the seroconversion rate was about 97% in children 1-12 years old and approximately 79% in 13-17 year olds. In a study done in the United States using 214 vaccinated children, about 95% had antibodies 6 years after their immunization. Another study done in the United States showed that of the 40 vaccinated adults, 82% had antibodies against the virus 7-13 years later. A study involving people that were vaccinated in Japan with an only slightly different oka virus strain detected antibodies up to 20 years later.

Over the many years of clinical trials, the breakthrough rate of chickenpox in vaccinated patients has remained close to 4%. The attack rate of naturally occuring varicella in unimmunized individuals is about 8-9% annually. Therefore, even with the breakthrough reactions, the vaccine has caused a 50-70% reduction in cases. In 1991, the breakthrough rates were reduced even further to less than 1% using newly developed vaccines with higher potencies. Futhermore, when these breakthrough reactions do occur, the disease is usually very mild as compared to the naturally occuring disease.

The vaccine does not seem to increase the incidence of zoster and some studies show that it may even be protective against it. After a follow up period as long as ten years, only 8 cases of zoster in about 9,000 vaccinees have been reported. This incidence rate is similar to that after natural infection.

Problems

Unfortunately, the rate of seroconversion does not necessarily correlate with protection against the disease. For example, even if a child is vaccinated and responds appropriately immunologically, this does not necessarily mean that he is protected. This has caused much confusion and is the reason that seroconversion is greater than 95% but the efficacy of the vaccine is only 70-90%.

As with all vaccines, in order to have greatest efficacy, the vaccine must be used universally. This may prove to be difficult secondary to many reasons. First, since Varivax is a monovalent vaccine it will need to be delivered in combintion with already existing vaccines to improve compliance. Studies are currently in progress using a combined measles-mumps-rubella-varicella vaccine. Second, physicians also feel that distribution and storage of the vaccine will also be a major problem. Because the concentrated vaccine requires refrigeration at -15 degrees celcius, the vaccine is not available in England due to their physicians not having routine availabilty of refrigeration. In addition to this, once the concentrated vaccine is reconstituted it must be used within 30 minutes or discarded. This will most certainly increase the cost to the physician for providing the vaccine.

COST of the VACCINATION PROGRAM

Vaccine 70-90% effective in preventing chickenpox and therefore could save as much as 384 million annually in direct and indirect costs. The cost of a single dose of varicella vaccine costs $41.41 if ordered directly from Varivax. At LSUMC, the vaccine is currently non-formulary and costs $44.00 a dose.