Exploring the Seasonal Drivers of Varicella Zoster Virus Transmission and Reactivation

Kevin M. Bakker; Marisa C. Eisenberg; Robert Woods; Micaela E. Martinez

Disclosures

Am J Epidemiol. 2021;190(9):1814-1820. 

In This Article

Abstract and Introduction

Abstract

Varicella zoster virus (VZV) is a herpesvirus that causes chickenpox and shingles. The biological mechanisms underpinning the multidecadal latency of VZV in the body and subsequent viral reactivation—which occurs in approximately 30% of individuals—are largely unknown. Because chickenpox and shingles are endemic worldwide, understanding the relationship between VZV transmission and reactivation is important for informing disease treatment and control. While chickenpox is a vaccine-preventable childhood disease with a rich legacy of research, shingles is not a notifiable disease in most countries. To date, population-level studies of shingles have had to rely on small-scale hospital or community-level data sets. Here, we examined chickenpox and shingles notifications from Thailand and found strong seasonal incidence in both diseases, with a 3-month lag between peak chickenpox transmission season and peak shingles reactivation. We tested and fitted 14 mathematical models examining the biological drivers of chickenpox and shingles over an 8-year period to estimate rates of VZV transmission, reactivation, and immunity-boosting, wherein reexposure to VZV boosts VZV-specific immunity to reinforce protection against shingles. The models suggested that the seasonal cycles of chickenpox and shingles have different underlying mechanisms, with ambient levels of ultraviolet radiation being correlated with shingles reactivation.

Introduction

Herpesviruses are unique in that they are able to cause recurring disease due to cycles of latency and reactivation. Initial infection requires close contact, which typically occurs through salivary/respiratory or sexual transmission. Varicella zoster virus (VZV), one of the 8 herpesviruses that infects humans, presents as chickenpox during primary infection and causes shingles upon reactivation. Reactivation of herpesviruses is highly complex at the molecular level, and the conditions favoring reactivation remain relatively unknown, though ultraviolet (UV) radiation is suspected to induce suppression of VZV cellular immunity.[1] In animal models, trauma and stress can induce reactivation,[2] while human herpes simplex cold sores have been shown to correlate with fatigue and UV radiation levels,[3,4] and reactivation of Epstein-Barr virus from infected B-cells is thought to occur when the cells respond to unrelated infections.[5]

Most countries do not include herpesvirus diseases within their disease notification systems, and those that do typically report only chickenpox. VZV transmission, in the form of chickenpox, is well studied relative to other herpesviruses and is known for its explosive annual springtime outbreaks worldwide.[6] There have been recent advances in understanding VZV reactivation at the molecular level;[7,8] however, how this translates to the epidemiology of shingles reactivation remains unknown. Global VZV seroprevalence has been reported to be above 90% in children and adolescents,[9–11] and nearly all individuals are infected with VZV in the absence of vaccination. Although latent VZV is highly prevalent, only 10%–30% of individuals will ever experience a symptomatic reactivation of VZV expressed as shingles.[12,13]

We aimed to shed light on herpesvirus transmission and reactivation by leveraging available data on chickenpox and shingles. We used data from Thailand, where VZV is endemic, the VZV vaccine is not required, and concurrent chickenpox and shingles notifications exist. Such data are rarely available, and we know of no other such data set in existence. We obtained data on cases at the national and regional scales from publicly available monthly clinical case reports that were supplemented with annual age-specific incidence data, spanning 2003–2010.[14] These data allowed us to focus modeling efforts on understanding the temporal dynamics of transmission and reactivation in the absence of human intervention. Although a great deal is known about chickenpox seasonality, there has been little work examining the seasonal dynamics of shingles, particularly at the population level. We took advantage of simplifying modeling assumptions in order to focus attention on our main areas of interest: 1) the seasonality of VZV transmission and reactivation and 2) immune boosting. For chickenpox, age-stratified contact patterns play a role in structuring the age-specific incidence in vaccinated populations.[15] However, because of the high rate of transmission of the pathogen and lifelong immunity against chickenpox, in the absence of vaccination (as in Thailand), simple models with homogeneous contact rates have been shown to be sufficient in capturing chickenpox dynamics.[16] Immunity-boosting has been shown to be a vital component of understanding shingles dynamics in theoretical models.[17]

In order to supplement our case notification data, we also collated data on national and regional UV radiation levels.[18,19] We did this because other herpesviruses have been identified that reactivate from latency when exposed to increased levels of UV radiation.[3,4] Here, we wanted to examine whether elevated UV radiation levels increased shingles incidence. In order to test hypotheses regarding seasonal transmission, boosting of immunity, and UV radiation exposure, we built a suite of 14 mechanistic models to test various drivers of VZV transmission and herpes zoster reactivation.

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