Confirmatory testing of NHANES specimens for varicella seroprevalence by gp-ELISA determined that the original EIA test produced false-negative results for 22.4% of specimens from participants aged 6–19 years collected between 1999 and 2004. As one would expect given the timing of implementation of the varicella vaccination program, the percentage of false-negative EIA test results increased over time between 1999 and 2004. That the percentage of false-negative results was also significantly higher for younger children than for older children likely reflects a higher proportion of children in the younger group having vaccine-induced immunity. The gp-ELISA results were posted as surplus specimen data on the NHANES website in March 2009.
Results indicate that seroprevalence among both children and adults has remained relatively stable across the two survey periods; age-adjusted seroprevalence of IgG antibody to VZV was 93.6% for 6- to 19-year-olds and 98.0% for adults aged 20–49 years (NHANES 1999–2004) compared with 90.0% and 98.1%, respectively, for NHANES 1988–1994. For children, non-Hispanic black race/ethnicity and younger age were associated with increased risk for susceptibility to varicella in both survey periods. For adults, history of live birth for females and being born in the U.S. for males were the two predictors of seroprevalence that reached statistical significance in the logistic models for the more recent NHANES period. Being married was a significant predictor of seroprevalence for men in the earlier survey period but not for the later survey period.
Varicella is a highly contagious disease caused by VZV and is transmissible by contact, respiratory secretions, and aerosolized spread.13
Prior to vaccine licensure in 1995, there were approximately four million cases of varicella each year in the U.S., which resulted in 11,000 to 13,500 hospitalizations, and 100 to 150 deaths annually.13
A live, attenuated varicella vaccine became available to the public sector in May 1996, and in July 1996 it was recommended by the Advisory Committee on Immunization Practices (ACIP) for all children aged 12–18 months (one dose), susceptible children by age 13 (two doses), people in contact with those at high risk for severe disease (family members of immunocompromised people), and adults at high risk for exposure (two doses: health-care workers, teachers, day care or institutional employees, military members, college students, adolescents and adults in households with children, international travelers, and nonpregnant women of childbearing age).5
In June 2006, ACIP voted for a universal second dose for children <13 years of age.13
Varicella vaccine induces humoral and cell-mediated immunity in more than 95% of vaccine recipients,5
and its overall effectiveness is estimated to be 70%–90% for children in post-licensure studies and clinical trials against all disease, and >95% against moderate to severe disease.13
Vaccine coverage among children aged 19–35 months increased from 25.8% in 1997 to 87.5% in 2004.14
Population-based disease surveillance data from two communities showed cases of varicella decreased by 90% from 1995 to 2005.15
Additionally, varicella hospitalizations and ambulatory visits have declined dramatically among all age groups in the U.S. since the introduction of the varicella vaccination program.16,17
As the childhood vaccination program is implemented, one might expect to see an increase in seroprevalence among the youngest children with a decline in seroprevalence in slightly older children in the absence of a fully implemented catch-up program, due to declining circulation of varicella in communities and a concomitant decrease in likelihood of exposure. That such a decline was not seen for those aged 12–19 years in this study should not be viewed as refuting this expectation. The data available for this analysis do not provide a sufficient test of how the vaccination program implementation affected seroprevalence rates, as only the 6- and 7-year-old participants from the 2003 and 2004 data collection years can be considered as having grown up in the “post-vaccine” era. Data from future NHANESs are needed to evaluate the impact of the vaccine on seroprevalence. However, varicella testing was not included in the NHANES protocol for specimens collected from 2005 through 2008.
Analysis of varicella seroprevalence estimates based on the original EIA test results for varicella IgG antibodies (as opposed to the gp-ELISA results presented in this article) would have suggested a decline in seroprevalence among those aged 6–11 years between the two survey periods (86.0% to 83.9%), but this decline would not have reached statistical significance.
Because commercially available varicella seroprevalence tests are based on EIA methods, these findings highlight the importance of maintaining accurate vaccination records, as a negative result from such a test does not necessarily indicate that the child is susceptible. In the absence of vaccination records, the commercially available assays for varicella seroprevalence currently in use are undoubtedly leading to false-negative results among vaccinated people without disease history and resulting in the unnecessary vaccination of such people (e.g., testing of vaccinated health-care workers). Though there are no safety concerns associated with vaccinating people who are already seropositive, it does result in wasted resources. Commercially available tests that more reliably detect vaccine-induced immunity would be beneficial.
This study had several limitations. Analyses of more detailed age groups or selected population characteristics within racial/ethnic subgroups were limited due to small sample sizes and, in some cases, 100% seroprevalence among people of selected strata. Several of the estimates presented, especially among adults, were unstable with very high relative SEs (>30%) and based on small numbers of varicella-negative people as noted in our tables, and should be interpreted with caution. We limited our analyses to characteristics likely to be important in the epidemiology of varicella to minimize the potential of identifying statistically significant, yet spurious associations due to multiple comparisons.18
A comparison of specimens with EIA false-negative results between vaccinated and unvaccinated individuals could not be performed, as vaccination status is not assessed in NHANES.
That the more recently collected specimens had increased false-negative results might suggest the possibility that the older samples could have experienced great degradation. This is normally an issue associated with repeated freeze-thaw cycles of specimens, which does not apply to the NHANES specimens used in this study. NHANES specimens are aliquoted at the outset and carefully controlled to minimize the number of freeze-thaw events. Additionally, even 10 or more freeze-thaw cycles would not significantly degrade IgG antibody in a serum specimen. Moreover, the comparison of conventional EIA methods to gpELISA and FAMA using specimens newly isolated from vaccinated people reveals a pronounced difference in sensitivity; EIA methods using crude antigen preparations are universally too insensitive to reliably detect seroconversion to vaccine.11