On 2016 Feb 29, Gary Goldman commented:

Marin et al report a vaccine effectiveness (VE) of 81% (95% C.I.: 78-84) for the one-dose varicella vaccination protocol. [1] This figure is biased high and declines rapidly as the vaccine is widely used and exogenous boosting becomes rare. Many of the clinical trials and studies that reported VE were conducted within the first few years of the start of varicella vaccination—during a time period when vaccinees were additionally boosted by exogenous exposures to those shedding wild-type (or natural) varicella-zoster virus during annual outbreaks. Annual VE, derived from secondary family attack rate (SFAR) data among contacts aged <20 years reporting to the Antelope Valley Varicella Active Surveillance Project (VASP), demonstrated an annual increase from 87% in 1997 to 96% in 1999 (the last year that varicella displayed its characteristic seasonality), then declined to 85% and 74% in 2000 and 2001, respectively, when exogenous boosting substantially decreased. [2]

The conclusion given in the Meta-analysis by Marin et al states that several studies reported a lower risk for herpes zoster among varicella vaccinated children “and a decline in herpes zoster incidence among cohorts targeted for varicella vaccination.” [1] The later part of that statement is patently false. There are two confounders in the cited studies that contribute to this erroneous conclusion and a consideration of these confounders helps to explain why the VASP study [3] (referenced in the Meta-analysis [1]) reports that (a) the 2000-2006 HZ incidence increased by 63% among 10- to 19-year olds and (b) HZ incidence decreased by 32% from 98.3/100,000 person-years (p-y) in 2006 to 66.7/100,000 p-y in 2010, with “substantial fluctuation in annual HZ rates.” [3]

The authors of both the Meta-analysis [1] and supporting reference [3] have erroneously assumed that the HZ cases reported to the VASP represent 100% reporting completeness. However, using capture-recapture with two ascertainment sources (schools and health cares), it was demonstrated that varicella cases among 2- to 18-year-olds were under-reported by approximately 45%. [4] Likewise, it can be shown that VASP also experienced approximately 50% under-reporting of HZ cases [2], leading to the Marin et al study [3] reporting incidence rates that are one-half the actual rates. HZ incidence rates that have not been ascertainment corrected simply reflect the incidence of reported HZ cases to the VASP and not the HZ incidence rate in the community. It is invalid to compare the uncorrected VASP-reported HZ rates to those rates reported by other studies that possess much higher case ascertainment. [5]

Additionally, the >10- to 19-year-old age category consists of three different cohorts with widely differing HZ incidence rates. Marin et al [3] only considers the mean HZ incidence rate for each age category instead of stratifying by (1) those still susceptible to varicella and never vaccinated (0 cases/100,000 p-y); (2) those that have had a prior history of wild-type varicella who exhibit increasing HZ incidence rates from approximately 120 cases/100,000 p-y to 500 cases/100,000 p-y (in the absence of exogenous boosting); and (3) those vaccinated who exhibit an HZ incidence rate less than 120 cases/100,000 p-y.

In summary, unless HZ incidence rates are ascertainment corrected [5], such rates will erroneously be reported as “lower” than other studies. [1] Also, reporting the mean HZ incidence of a bimodal distribution masks the widely differing incidence rates among those vaccinated and those with a prior history of varicella. Further, this invalid mean masks the significant effects of exogenous boosting. [7] Varicella vaccination innoculates children with the Oka-strain VZV. When these children are exposed to natural varicella or herpes zoster in adults, they may additionally harbor the natural VZV strain. Both strains are subject to reactivation as HZ. This is another confounder in the reporting of HZ incidence rates. Health officials initially believed that only a single dose of varicella vaccine would provide long-term protection and have negligible impact on the incidence of HZ. These assumptions are incorrect and have led to a continual cycle of treatment and disease. The shingles (herpes zoster) vaccine now provides the boosting to postpone or suppress the reactivation of HZ in adults aged 60 years and older—a substitute for the exogenous boosting that was prevalent in the pre-varicella vaccination era at no cost. [6]

References:

[1] Marin M, Marti M, Kambhampati A, Jeram SM, Seward JF. Global varicella vaccine effectiveness: A meta-analysis. Pediatrics Feb. 16, 2016; DOI: 10.1542/peds.2015-3741. Marin M, 2016

[2] Goldman GS. Universal Varicella Vaccination: Efficacy Trends and Effect on Herpes Zoster. Int J Toxicol 2006 Sep-Oct; 25(5):313-317. Goldman GS, 2005

[3] Marin M. Civen R, Zhang J, et al. Update on incidence of herpes zoster among children and adolescents following implementation of varicella vaccination, Antelope Valley, CA. 2000-2010. Presented at IDweek 2015, October 7-11, 2015; San Diego, CA.

[4] Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA 2002; 287(5):606-611. Seward JF, 2002

[5] Hook EB, Regal RR. The value of capture-recapture methods even for apparent exhaustive surveys: the need for adjustment for source of ascertainment intersection in attempted complete prevalence studies. Am J Epidemiol 1992; 135:1060-1067. Hook EB, 1992

[6] Goldman GS, King PG. Review of the United States universal varicella vaccination program: Herpes-zoster incidence rates, cost effectiveness, and vaccine efficacy based primarily on the Antelope Valley Varicella Active Surveillance Project data. Vaccine 2013; 31(13):1680-1694. Goldman GS, 2013

[7] Guzzetta G, Poletti P, Del Vava E, et al. Hope-Simpson’s progressive immunity hypothesis as a possible explanation for herpes –zoster incidence data. Am J Epidemiol 2013; 77(10):1134-1142. Guzzetta G, 2013

On 2016 Feb 29, Gary Goldman commented:

Marin et al report a vaccine effectiveness (VE) of 81% (95% C.I.: 78-84) for the one-dose varicella vaccination protocol. [1] This figure is biased high and declines rapidly as the vaccine is widely used and exogenous boosting becomes rare. Many of the clinical trials and studies that reported VE were conducted within the first few years of the start of varicella vaccination—during a time period when vaccinees were additionally boosted by exogenous exposures to those shedding wild-type (or natural) varicella-zoster virus during annual outbreaks. Annual VE, derived from secondary family attack rate (SFAR) data among contacts aged <20 years reporting to the Antelope Valley Varicella Active Surveillance Project (VASP), demonstrated an annual increase from 87% in 1997 to 96% in 1999 (the last year that varicella displayed its characteristic seasonality), then declined to 85% and 74% in 2000 and 2001, respectively, when exogenous boosting substantially decreased. [2]

The conclusion given in the Meta-analysis by Marin et al states that several studies reported a lower risk for herpes zoster among varicella vaccinated children “and a decline in herpes zoster incidence among cohorts targeted for varicella vaccination.” [1] The later part of that statement is patently false. There are two confounders in the cited studies that contribute to this erroneous conclusion and a consideration of these confounders helps to explain why the VASP study [3] (referenced in the Meta-analysis [1]) reports that (a) the 2000-2006 HZ incidence increased by 63% among 10- to 19-year olds and (b) HZ incidence decreased by 32% from 98.3/100,000 person-years (p-y) in 2006 to 66.7/100,000 p-y in 2010, with “substantial fluctuation in annual HZ rates.” [3]

The authors of both the Meta-analysis [1] and supporting reference [3] have erroneously assumed that the HZ cases reported to the VASP represent 100% reporting completeness. However, using capture-recapture with two ascertainment sources (schools and health cares), it was demonstrated that varicella cases among 2- to 18-year-olds were under-reported by approximately 45%. [4] Likewise, it can be shown that VASP also experienced approximately 50% under-reporting of HZ cases [2], leading to the Marin et al study [3] reporting incidence rates that are one-half the actual rates. HZ incidence rates that have not been ascertainment corrected simply reflect the incidence of reported HZ cases to the VASP and not the HZ incidence rate in the community. It is invalid to compare the uncorrected VASP-reported HZ rates to those rates reported by other studies that possess much higher case ascertainment. [5]

Additionally, the >10- to 19-year-old age category consists of three different cohorts with widely differing HZ incidence rates. Marin et al [3] only considers the mean HZ incidence rate for each age category instead of stratifying by (1) those still susceptible to varicella and never vaccinated (0 cases/100,000 p-y); (2) those that have had a prior history of wild-type varicella who exhibit increasing HZ incidence rates from approximately 120 cases/100,000 p-y to 500 cases/100,000 p-y (in the absence of exogenous boosting); and (3) those vaccinated who exhibit an HZ incidence rate less than 120 cases/100,000 p-y.

In summary, unless HZ incidence rates are ascertainment corrected [5], such rates will erroneously be reported as “lower” than other studies. [1] Also, reporting the mean HZ incidence of a bimodal distribution masks the widely differing incidence rates among those vaccinated and those with a prior history of varicella. Further, this invalid mean masks the significant effects of exogenous boosting. [7] Varicella vaccination innoculates children with the Oka-strain VZV. When these children are exposed to natural varicella or herpes zoster in adults, they may additionally harbor the natural VZV strain. Both strains are subject to reactivation as HZ. This is another confounder in the reporting of HZ incidence rates. Health officials initially believed that only a single dose of varicella vaccine would provide long-term protection and have negligible impact on the incidence of HZ. These assumptions are incorrect and have led to a continual cycle of treatment and disease. The shingles (herpes zoster) vaccine now provides the boosting to postpone or suppress the reactivation of HZ in adults aged 60 years and older—a substitute for the exogenous boosting that was prevalent in the pre-varicella vaccination era at no cost. [6]

References:

[1] Marin M, Marti M, Kambhampati A, Jeram SM, Seward JF. Global varicella vaccine effectiveness: A meta-analysis. Pediatrics Feb. 16, 2016; DOI: 10.1542/peds.2015-3741. Marin M, 2016

[2] Goldman GS. Universal Varicella Vaccination: Efficacy Trends and Effect on Herpes Zoster. Int J Toxicol 2006 Sep-Oct; 25(5):313-317. Goldman GS, 2005

[3] Marin M. Civen R, Zhang J, et al. Update on incidence of herpes zoster among children and adolescents following implementation of varicella vaccination, Antelope Valley, CA. 2000-2010. Presented at IDweek 2015, October 7-11, 2015; San Diego, CA.

[4] Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA 2002; 287(5):606-611. Seward JF, 2002

[5] Hook EB, Regal RR. The value of capture-recapture methods even for apparent exhaustive surveys: the need for adjustment for source of ascertainment intersection in attempted complete prevalence studies. Am J Epidemiol 1992; 135:1060-1067. Hook EB, 1992

[6] Goldman GS, King PG. Review of the United States universal varicella vaccination program: Herpes-zoster incidence rates, cost effectiveness, and vaccine efficacy based primarily on the Antelope Valley Varicella Active Surveillance Project data. Vaccine 2013; 31(13):1680-1694. Goldman GS, 2013

[7] Guzzetta G, Poletti P, Del Vava E, et al. Hope-Simpson’s progressive immunity hypothesis as a possible explanation for herpes –zoster incidence data. Am J Epidemiol 2013; 77(10):1134-1142. Guzzetta G, 2013