Vaccines for postexposure prophylaxis against varicella (chickenpox) in children and adults

For the current issue of the Journal, we asked Dr Jane McDonald to comment on and put into context the Cochrane Review on vaccines for postexposure prophylaxis against varicella in children and adults.

Background

The prevention of varicella (chickenpox) using live-attenuated varicella vaccines has been demonstrated both in randomized controlled trials (RCTs) and in population-based immunization programs in countries such as the United States and Australia. Many countries do not routinely immunize children against varicella and exposures continue to occur. Although the disease is often mild, complications, such as secondary bacterial infection, pneumonitis and encephalitis, occur in approximately 1% of cases, usually leading to hospitalization. The use of the varicella vaccine in individuals who have recently been exposed to the varicella zoster virus has been studied as a form of postexposure prophylaxis (PEP).

Methods

Search methods:

The CENTRAL (2014, Issue 1), MEDLINE (1966 to March week 1, 2014), EMBASE (January 1990 to March 2014) and LILACS (1982 to March 2014) databases were searched, in addition to unpublished trials registered on the ClinicalTrials.gov and WHO International Clinical Trials Registry Platform websites.

Selection criteria:

RCTs and quasi-RCTs examining varicella vaccine for PEP compared with placebo or no intervention. Outcome measures included efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse events following vaccination.

Data analysis:

Two review authors independently extracted and analyzed data using Review Manager (Cochrane Community, United Kingdom).

Results

Three trials involving 110 healthy children who were siblings of household contacts were identified. The included trials varied in study quality, vaccine used, length of follow-up and outcomes measured and, as such, were not suitable for meta-analysis. High or unclear risk of bias were identified in two of the three included studies. Overall, 13 of 56 (23%) vaccine recipients developed varicella compared with 42 of 54 (78%) placebo (or no vaccine) recipients. Of the vaccine recipients who developed varicella, the majority experienced only mild disease (with <50 skin lesions). In all three trials, most participants received PEP within three days following exposure; too few participants were vaccinated four to five days postexposure to ascertain the efficacy of vaccine given >3 days after exposure. No included trial reported on adverse events following immunization.

Conclusions

These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. We identified no RCTs involving adolescents or adults. Safety was not adequately addressed.

The full text of the Cochrane Review is available in The Cochrane Library: Macartney K, Heywood A, McIntyre P. Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD001833. DOI: 10.1002/14651858.CD001833.pub3.

EXPERT COMMENTARY

This Cochrane review examines the utility of using varicella vaccines as PEP in exposed susceptible children and adults. Unfortunately, only three trials that involved healthy children met the study criteria for review. The limited studies that were appropriate for review demonstrated that using the varicella vaccine as PEP in children following household or close contact of a known case was effective in preventing varicella. In those who did develop varicella lesions despite vaccine, mild disease was observed. In the studies reviewed, the vaccine was generally given within three days of exposure.

Varicella is extremely contagious and the risk for transmission to someone with no immunity is high. An index case with varicella is considered to be contagious one to two days before the rash develops, until all of the lesions are crusted over. Transmission within a household is >90%; therefore, protection of susceptible contacts is important.

The live-attenuated varicella vaccine was licensed in Canada in 1998. In 1999, the National Advisory Committee on Immunization recommended universal varicella vaccination at 12 to 18 months of age. By 2005, every province was funding one dose of the vaccine. The vaccine is currently available as a univalent vaccine, or in combination with the measles, mumps and rubella vaccine (1).

The effectiveness of one dose of vaccine is estimated to be 70% to 90%, with 95% protection against severe disease (2). Breakthrough disease, when it does occur, is typically mild, with many fewer lesions than in unvaccinated children. Children with breakthrough infection are also less infectious (3). In 2006, the Centers for Disease Control and Prevention’s Advisory Group on Immunization Practices recommended two doses of varicella vaccine to address the issue of primary vaccine failure and also the issue of waning immunity. The National Advisory Committee on Immunization followed suit with a recommendation in 2010 for a two-dose schedule (4). After two doses of the vaccine, the effectiveness rises to 98%.

Every province in Canada, with the exception of Quebec, which will begin in 2016, has a vaccination schedule that includes two doses of varicella vaccine, most starting at 12 months of age, followed by a second dose at 18 months, or four to six years. The ideal timing of the second dose is unknown. Children ≥13 years of age have a less robust immune response and, therefore, should always receive two doses of varicella vaccine with a minimum of six weeks between doses. Children with selected milder immunodeficiences (asymptomatic or mildly symptomatic HIV infection with a good CD4 count, children with acute lymphoblastic leukemia in remission) should receive two doses of univalent varicella vaccine (because the measles, mumps and rubella vaccine has a much higher titre of varicella virus).

The use of varicella vaccine in susceptible children after a significant exposure has been recommended in the United States and Canada since 2000. However, the logistics of implementing this may not always be so straightforward.

When a practitioner must decide how to proceed after a varicella exposure, there are several considerations. First, the diagnosis of varicella in the index case needs to be verified. If the diagnosis is believed to be likely, then the actual exposure should be evaluated to determine if it is significant. Generally, a significant varicella exposure would include a household contact or, being in the same room for >1 h with a case of varicella, although some experts consider shorter periods of time to be significant if the contact is face-to-face. If the exposure is judged to be significant, then the age and vaccination status of the exposed child needs to be assessed. In terms of susceptibility to infection, children who have received only one dose of the varicella vaccine should be considered potentially susceptible. Infants <12 months of age do not require PEP because these infants are generally protected by maternal antibody.

Giving the vaccine within three days of exposure is ideal for all unimmunized children and for those who have only ever received one dose of vaccine (provided that the first dose was >28 days ago), assuming that there are no vaccine contraindications. If this is not feasible, there are limited data to suggest that vaccine may remain effective up to five days after exposure. If the vaccine is given as PEP, the family should understand that it may not completely protect against disease but will still probably lessen the severity of varicella. For children receiving their first-ever dose of vaccine, a second dose should be given at an appropriate follow-up time.

For more severely immunocompromised children, varicella vaccine is contraindicated and, varicella zoster immune globulin (VZIG) should be given, ideally, within 96 h of exposure and, possibly, up to 10 days postexposure.

Another strategy, if >96 h have passed after exposure, is prophylaxis with acyclovir or valacyclovir beginning seven to 10 days after exposure, and continuing for seven days. There are very limited data regarding the utility of this approach; however, it may be useful, particularly in the case of an immunocompromised child if VZIG is not available (5).

The use of postexposure varicella vaccine has been recommended for several years in Canada. The widespread use of a two-dose schedule will be helpful in limiting the number of children that would require this. However, recent immigrants and those with unknown or inadequate documentation of vaccination or disease will need to be evaluated in a timely fashion postexposure for this strategy to be effective.