Vaccines and Preventable Diseases:

Varicella Vaccine Q&A
Clinical Questions and Answers

Varicella Questions

What kind of vaccine is varicella? What is its dosage schedule?

Two varicella virus-containing vaccines are currently licensed for use in the United States. VARIVAX® is the single-antigen varicella vaccine and ProQuad®, or MMRV, is a combination vaccine of measles, mumps, rubella, and varicella. Both vaccines contain live, attenuated virus. Children 12 months through 12 years of age should receive two 0.5ml doses of varicella-containing vaccine administered subcutaneously, separated by at least 3 months. However, if the second dose is administered after at least 28 days following the first dose, the second dose is considered valid and does not need to be repeated. Persons 13 years of age and older should receive two 0.5ml doses of the single-antigen varicella vaccine subcutaneously 4-8 weeks apart. The combination MMRV is approved for use only among healthy children 12 months through 12 years of age. MMRV is not approved for use in persons 13 years of age and older.

Can varicella-containing vaccines be given at the same time as other vaccines?

Yes, single-antigen and combination varicella-containing vaccines may be administered simultaneously with other vaccines recommended for children aged 12-15 months and 4-6 years.

How effective are the varicella-containing vaccines in preventing varicella disease?

Post-licensure, vaccine-effectiveness studies of one dose of the single-antigen varicella vaccine have shown high levels of protection (70%-90%) against any form of varicella disease and more than 90% protection against severe disease. In the randomized clinical trial of one versus two doses of single-antigen varicella vaccine administered 3 months apart, the estimated vaccine efficacy of two doses was 98%, which was significantly higher than after one dose. The two-dose regimen was 100% efficacious against severe varicella. If a vaccinated person does get varicella, it is usually a very mild case with fewer lesions (usually less than 50, which are frequently not vesicular), mild or no fever, and a quicker recovery. Persons with rash, however, are infectious.

Is waning immunity a problem with the varicella-containing vaccines?

The length of protection/immunity from varicella-containing vaccines remains unknown. Available data from follow-up of children vaccinated in prelicensure clinical trials indicate that protection from varicella vaccine lasts for at least 25 years (Japanese data) and 14 years (U.S. data). However, most of the data concerning vaccine efficacy and persistence of antibody in vaccinees are based on research that was conducted when natural varicella infection was highly prevalent and had not been affected by wide use of the vaccine. A recently published community-based study among children 12 months to 12 years of age suggests that 1 dose vaccine-induced immunity to varicella may wane over time. Experience with other live viral vaccines (e.g., measles, rubella), however, has shown that post vaccination, immunity remains high throughout life. For these vaccines, second doses are needed to cover the small percentage of people who fail to seroconvert after the first dose (primary vaccine failure). Follow-up studies are continuing to assess levels of immunity in vaccinees as disease incidence declines.

Will a booster vaccination be needed in the future?

In June 2006, the Advisory Committee on Immunization Practices (ACIP) recommended a routine two-dose vaccination program with the first dose administered at age 12-15 months and the second dose at age 4-6 years and recommended second-dose, catch-up varicella vaccination for children, adolescents, and adults who previously had received one dose. Ongoing studies and surveillance will determine the need for and, if appropriate, the timing of additional doses in the future.

How will use of varicella vaccine affect the epidemiology of the disease?

As with all vaccines, use of the varicella vaccine will affect the epidemiology of the disease. Most importantly, the incidence of disease will decline in the population. This has been most notable in two areas conducting active surveillance for varicella as sentinel sites. By 2005, varicella vaccination coverage in these sites had increased to 90% and the reduction in incidence had reached 90% and 91%. The greatest decline in incidence occurred among children ages 1-4 years. However, the decline in incidence has occurred in all age groups, including adults who previously did not have recommendations for varicella vaccine and infants less than 12 months of age who are not eligible for vaccination. This overall decline reflects the protection afforded by the vaccination program at the community level. Use of the vaccine has also affected the clinical characteristics of the illness in that a small percentage of vaccinated persons might develop a modified form of the disease. Varicella disease that develops after 42 days after vaccination (i.e., breakthrough varicella) typically is mild, with less than 50 skin lesions, low or no fever, and shorter (4-6) days duration of illness. The rash is more likely to be maculopapular rather than vesicular. Given its modified clinical presentation, breakthrough varicella illness may be more difficult to clinically recognize by both practitioners and parents.

As transmission continues to decline, decreasing circulation of wild virus will increase the likelihood that unexposed and unvaccinated children will enter adolescence and adulthood without immunity. Thus, it is increasingly important to offer vaccine to all susceptible adolescents and adults as well as children according to current recommendations. The ACIP, American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP) now recommend two doses of varicella-containing vaccines with the first dose administered at 12-15 months and the second dose at age 4-6 years and recommend second dose catch-up vaccination for children, adolescents, and adults who previously had received one dose. Children, adolescents, and adults without evidence of varicella immunity should receive two doses of varicella vaccine according to these recommendations.

Should serologic testing be done prior to vaccination?

Serologic testing is not required prior to vaccination, and the vaccine is well tolerated in persons who are immune. However, for adults without a health-care provider verification of history of varicella, serologic testing prior to vaccination may be cost effective since 70% to 90% of adults with unreliable history of varicella are actually immune.

Among vaccinated persons, commercial assays are not sensitive enough to test vaccine-induced immunity. Thus, serologic testing after vaccination is not routinely recommended.

What laboratory tests are available to determine varicella immunity prior to vaccination?

The most common commercially available test is the ELISA (enzyme-linked immunosorbent assay). This test is sensitive enough to determine immunity following natural disease but not following vaccination because some commercially available tests are not sensitive enough to detect low levels of antibody induced by vaccination. Thus, serological results obtained following vaccination must be interpreted with caution. The serology test used to determine immune response to varicella vaccine during the clinical trails, the gpELISA test, is not available commercially. A VZV latex bead agglutination assay that is more sensitive than most conventional ELISAs is now commercially available.

What adverse events are associated with varicella-containing vaccines?

Varicella-containing vaccines are very safe. In uncontrolled trials, vaccine recipients reported minor injection site complaints (20% reported pain, swelling or redness) and rashes (3%-5% reported a localized rash, and an additional 3%-5% developed a generalized varicella-like rash 5-26 days after vaccination). However, the rate of adverse events was much lower in the only randomized, controlled clinical trial conducted in children. In this trial, 1% of vaccine recipients developed injection site rash compared with 0.3% of placebo recipients, and 3.2% of vaccine recipients developed generalized rash compared with 1.7% of placebo recipients. These rashes had an average of 2-5 lesions and were likely to be maculopapular rather than vesicular. The incidence of fever did not differ between the vaccination and placebo groups.

The safety profile for the two-dose regimen was comparable to that of the one-dose regimen. Injection site complaints were slightly higher after dose two (25% versus 21%), but clinical complaints, including fever (7% after dose 1 and 4% after dose 2) and varicelliform rash (3% after dose 1 and 1% after dose 2), were lower after dose two. A comparison of MMRV to MMR given concomitantly with Varivax at separate injection sites showed that fever (22% versus 15%) and measles-like rash (3% vs 2%) occurred more often in those receiving MMRV. Fever and rash usually occurred within 5-12 days following vaccination, were of short duration, and resolved with no long-term sequelae. Pain/soreness/tenderness at the injection site was lower in persons receiving MMRV (22%) compared to those receiving MMR and Varivax (27%). Finally, studies looking at the safety of MMRV given as a second dose demonstrated that the rates of adverse events were generally lower after the second dose of MMRV than after the first dose and the incidence of varicella-like rashes was lower after the second dose of MMRV than after single dose of MMR and Varivax. No vaccine-related serious adverse experiences were reported during clinical trials.

From March 1995 to December 2005, almost 48 million doses of varicella vaccine were distributed in the US. The widespread use of the single-antigen vaccine allowed the detection of adverse events not previously described. Among all adverse events reported, 5% were classified as serious (approximately 2.2 per 100,000 doses distributed). Serious adverse events including seizures, encephalitis, pneumonia, anaphylaxis, and death have occurred., although not all of them have been laboratory confirmed as associated with the vaccine virus. Note: Reporting a serious adverse event after vaccination does not indicate a causal association between vaccination and the event. Serious adverse events (i.e., all events requiring medical attention), regardless of whether they are confirmed to have been caused by varicella virus vaccine, should be reported to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967.

For more information, visit the following site:
http://vaers.hhs.gov

Varicella ACIP Recommendations 2007:
http://www.cdc.gov/mmwr/pdf/rr/rr5604.pdf

Updated ACIP recommendations 1999:
www.cdc.gov/mmwR/PDF/rr/rr4806.pdf

ACIP recommendations 1996:
ftp://ftp.cdc.gov/pub/Publications/mmwr/RR/RR4511.pdf

For serious adverse events that occur after varicella vaccination, are there laboratory methods that distinguish the vaccine virus from the wild virus?

Yes, CDC’s National VZV Reference Laboratory (404-639-0066; vzvlab@cdc.gov) provides VZV strain discrimination testing to state and local public health organizations and to private physicians in cases of suspected adverse events following vaccination. The laboratory offers free testing for suspected adverse events such as:

• Individuals who develop more than 50 lesions 7-42 days post vaccination;
• Individuals who develop certain serious adverse experiences post vaccination including pneumonia, pneumonitis, cerebritis (encephalitis), cerebellitis (cerebellar ataxia), and aseptic meningitis;
• Individuals who develop herpes zoster post vaccination;
• Suspected cases of secondary transmission of the vaccine virus;
• Pregnant women who inadvertently receive varicella vaccine or who have been exposed to a vaccinee and who develop a varicella rash.

Because adverse events after vaccination might continue to be caused by wild-type VZV even as varicella disease declines, health-care providers should obtain event-appropriate clinical specimens (e.g., cerebrospinal fluid for encephalitis, bronchial lavage or lung biopsy for pneumonia) for laboratory evaluation, including strain identification. The National VZV Laboratory is also equipped to provide VZV serological testing and VZV diagnostic testing including strain discrimination for cases of severe disease or death believed to be related to VZV infection, for suspected breakthrough infections with VZV, and for VZV outbreaks.

What are the contraindications and precautions to varicella vaccination?

Varicella-containing vaccines should not be given to persons who are allergic to any component of the vaccine or who have had a severe allergic reaction to a prior dose of vaccine. The vaccines contain neomycin and gelatin. The single-antigen varicella vaccine does not contain preservatives or egg protein but the combination MMRV vaccines are produced in chick-embryo cultures. However, the risk for serious allergic reactions following administration of measles or mumps-containing vaccines is extremely low. The varicella-containing vaccines are not licensed for persons with blood dyscrasias, leukemia, lymphomas of any type, or malignant neoplasms affecting the bone marrow or lymphatic system. However, patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive the single-antigen varicella vaccine. Combination MMRV vaccine should not be administered to persons with primary or acquired immunodeficiency, including immunosuppression associated with human immunodeficiency virus (HIV) infections, cellular immunodeficiencies, ypogammaglobulinemia, and dysgammaglobulinemia. In 2006, ACIP altered its recommendations for the use of varicella vaccine. The committee continued to contraindicate the vaccine for persons with cellular immunodeficiences but removed the restriction on vaccination of persons with defects of humoral immunodeficiency. On the basis of safety and immunogenicity data, the ACIP recommends that physicians consider vaccinating HIV-infected children ages 12 months and older who are in CDC clinical class N, A, or B and have CD4+ T-lymphocyte percentage greater than or equal to 15% and no evidence of varicella immunity. HIV-infected children in this group should receive 2 doses of the single-antigen vaccine (Varivax®), separated by 3 months. They are encouraged to return to their healthcare provider if they experience a post-vaccination, varicella-like rash. Previously, this vaccine was recommended for children in CDC classes N1 and A1 who have age-specific CD4 percentages greater than 25% (www.cdc.gov/epo/mmwr/preview/mmwrhtml/rr4806a1.htm).

Data on the use of varicella vaccine in HIV-infected adolescents and adults are lacking, and the immunogenicity may be lower in this group of HIV-infected individuals. However, based on expert opinion in examining the risk of severe disease from wild varicella infection compared to the benefit of vaccination, vaccination (2 doses administered 3 months apart) of HIV-infected persons older than 8 years of age who are in CDC clinical class A or B and have CD4+ T-lymphocyte counts greater than 200 cells/µL may be considered.

The quadrivalent vaccine for measles, mumps, rubella, and varicella (Proquad®) should not be administered to HIV-infected children, adolescents, or adults because there are insufficient data on the safety, immunogenicity, or efficacy of this vaccine in these individuals.

In addition to the above-described individuals, the following groups of persons should not be vaccinated:

• persons taking large doses of corticosteroids (equal to or greater than 2mg/kg of body weight or a total of 20mg/day of prednisone or its equivalent for persons who weigh more than 10kg);
• persons with a moderate or severe concurrent illness;
• women who are pregnant;
• persons who have received blood products (such as whole blood or immune globulin) during the previous 3-11 months, depending on dosage; and
• persons with a family history of congenital hereditary immunodeficiency in first degree relatives unless they are known to be immunocompetent.

Caution is advised when immunizing children receiving salicylates. No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the vaccine manufacturer recommends that vaccine recipients avoid using salicylates for 6 weeks after receiving varicella-containing vaccines because of the association between aspirin use and Reye syndrome following varicella. Vaccination with subsequent close monitoring should be considered for children who have rheumatoid arthritis or other conditions requiring therapeutic aspirin.

See also Recommendations for Postexposure Prophylaxis of Varicella of Persons at High Risk for Severe Disease.

What data are available concerning transmission of varicella vaccine virus to contacts?

Available data suggest that the risk of vaccine virus transmission from healthy vaccinees is very low and occurs only if the vaccinee has a rash. With the currently licensed single-antigen varicella vaccine, there have been 5 documented cases of transmission resulting in 6 secondary infections. Four of the cases of transmission occurred from healthy vaccinated children and the fifth occurred from an immunocompetent adolescent. The risk for transmission from vaccinees who are immunocompromised may be higher.

Will post-exposure use of the vaccine prevent or modify varicella?

Yes, the single-antigen varicella vaccine may prevent or modify illness when administered within 3 to 5 days after exposure. The ACIP now recommends vaccination of persons without evidence of immunity to varicella who are eligible for vaccination as soon as possible after exposure--ideally within 3 days but possibly up to 5 days of an exposure--to prevent illness or modify disease severity. Studies have shown that vaccination administered within 3 days of exposure to rash is 90% or more effective in preventing varicella, while vaccination within 5 days of exposure to rash is approximately 70% effective in preventing varicella and 100% effective in modifying severe disease. If a person has already been infected, and the single-antigen varicella vaccine is given soon enough, disease may be modified or prevented. If exposure to varicella does not cause infection, postexposure vaccination should induce protection against subsequent exposure. No data are available on the potential benefit from administering a second dose to one-dose vaccinees following exposure. However, administration of a second dose should be considered for persons who have previously received one dose to bring them up-to-date. Finally, exposure even in a household setting does not result in transmission 100% of the time. So, if the exposed person has not been infected, vaccination will confer protection against subsequent exposures. No data are available on the use of MMRV for postexposure prophylaxis.

Can vaccination be used to control outbreaks of varicella?

Varicella vaccination is recommended for outbreak control. Varicella vaccine has been used successfully by state and local health departments and by the military for outbreak prevention and control. Persons who do not have adequate evidence of immunity should receive their first or second dose as appropriate. In outbreaks among preschool-aged children, two-dose vaccination is recommended for optimal protection. Although, optimally, outbreak control efforts should be implemented as soon as an outbreak is identified, vaccination should be offered even if the outbreak is identified late. Varicella outbreaks in some settings (e.g., child care centers, schools, institutions) can last as long as 4-5 months. Thus, offering vaccine during an outbreak may provide protection to persons not yet exposed and shorten the duration of the outbreak. Persons receiving either their first or second dose as part of the outbreak control program may be immediately readmitted to school. Those vaccinated with the first dose as part of outbreak control measures should be scheduled for the second dose as age appropriate.

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