Is the level of varicella-zoster virus IgG associated with symptomatic status of genital herpes simplex virus infection? A case-control study

Background

Herpes, caused by herpes simplex virus (HSV), is a common and widespread infection. The variation in prevalence of either HSV1 or HSV2 infection varies in countries with prevalences of HSV1 ranging from 84% in Bulgaria to 52% in Finland and for HSV2 ranging from 14% in Germany to 4% in England. ¹ The worldwide prevalence of both types of HSV is 60%–90% at the age of 50.^2,3 HSV is responsible for the majority of genital ulcer disease (GUD). HSV2 infects approximately 536 million people worldwide ⁴ and is associated with an increased susceptibility to other sexually transmitted infections (STIs), including HIV. Despite significant efforts, there has been limited progress in the effectiveness of genital herpes screening and prevention strategies over the past decade.^5,6

Varicella zoster zirus (VZV) glycoprotein E (gE) shares structural similarities with its counterpart in HSV. ⁷ These similarities stem from their common evolutionary ancestry within the Herpesviridae family. Both gE proteins play crucial roles in viral pathogenesis and immune evasion,^8,9 facilitating viral spread within the host.

Current research suggests that the VZV vaccine, which primarily targets VZV gE among other viral components, induces a robust and long-lasting host immune response. The vaccine prompts the production of specific antibodies and memory T-cells, contributing to durable immunity against VZV. This sustained immune protection has been observed to last for several decades after vaccination, effectively reducing the risk of VZV reactivation and disease, including herpes zoster (shingles). This remarkable longevity of vaccine-induced immunity raises intriguing possibilities for harnessing similar mechanisms to combat other herpes viruses, including HSV, and warrants further investigation.

Notably, research has uncovered an interesting phenomenon: an increase in antibody levels against HSV-deoxyThymidine Kinase (dTK) during VZV infections. ¹⁰ The virus-encoded thymidine kinase for both HSV and VZV is a target for future treatments. ¹¹ This finding raises the prospect of developing a comprehensive treatment approach that could target a broad spectrum of human herpes viruses (HHV) within the alpha subfamily.

Our case-control study aims to elucidate the relationship between elevated VZV IgG levels and the asymptomatic carriage of both HSV1 and HSV2. By doing so, we hope to provide valuable insights into the potential of the VZV vaccine as a candidate for managing recurrent HSV infections.

Methods

Results

The average age of the 110 participants was 37 years (range: 21–65 years), with similar age distributions in the HSV1 and HSV2 groups. Among the participants, 67 had HSV1, 84 had HSV2, and 39 had both infections. Twenty-five of the participants were on outbreak therapy (n = 15) or long term suppression therapy (n = 10) at the time blood was taken.

Out of the 110 participants, 18 had never been diagnosed with genital herpes and never had an outbreak; a few other patients were never formally diagnosed but did have previous outbreaks. All individuals who never had an outbreak and never diagnosed were recruited due to a history of prior contact with recurrent herpes partners and diagnosed by blood sample, 9 of them being HSV1 only, the others being HSV2 or had both infections. Twenty-three patients out of 110 had a positive genital swab at the time of recruitment. All others may have been diagnosed elsewhere or diagnosed on clinical examination alone, so diagnosed was confirmed by blood sample.

Each group (HSV1, HSV2 and any HSV together) were analysed separately. Supplementary Tables 1, 2, 3, and 4 provide additional demographic data and detailed results for HSV1, HSV2, and both infections combined. The main findings are summarized below.

For HSV1 (n = 67, 36 were male, 41 were symptomatic (25 females, 16 males)) the average VZV IgG titre was 2049.0 IU/mL for the asymptomatic group (n = 26) and 1078.5 IU/mL for the symptomatic group (n = 41; p = 0.001).

For HSV2 (n = 84, 44 were female, 67 were symptomatic (41 females 26 males)) the average VZV IgG titre was 2373.9 IU/mL for the asymptomatic group (n = 17) and 1219.0 IU/mL for the symptomatic group (n = 67); p ≤ 0.00001).

For any HSV infection (n = 110, if patient has HSV1&2 then only set of demographic data was analysed (duplicates removed)) the average VZV IgG titre was 2011.2 for the asymptomatic group (n = 32) and 1166.5 for the symptomatic group (n = 78; p ≤ 0.00001), see Figure 1 for graphical representation for all three sets of data.OPEN IN VIEWER

No association was found between age, ethnicity, number of children, number of outbreaks, length of outbreaks in the previous year or time since diagnoses and VZV IgG level, please see supplementary tables 1, 2, 3 & 4.

Discussion and conclusions

This pioneering study marks the first demonstration of a compelling association between VZV IgG levels and the symptomatic status of HSV. While other investigations have hinted at the potential of VZV vaccination in addressing HSV, our research underscores the relevance of VZV IgG levels as a pivotal factor in understanding and potentially managing recurrent HSV infections. Other studies have indicated the possibility of treating HSV with VZV vaccination.^12–14

It is worth acknowledging certain limitations in our study. Many participants presented with genital HSV symptoms during recruitment, some of whom had asymptomatic partners, albeit the exact proportion of such cases remains unrecorded. This situation may introduce self-selection and recall biases. Additionally, a subset of patients were under various forms of suppression therapy, either for outbreaks or continuous management. However, considering that existing medical knowledge does not associate VZV IgG titers with HSV symptomatic status, we believe these biases have minimal impact on our findings. Notably, while acyclovir consumption directly affects the efficacy of the VZV vaccine, it does not significantly influence VZV IgG titers, ensuring the robustness of our results. Furthermore, the uniform processing of all VZV samples on the Diasorin Liasion and HSV blood samples on the Hologic Panther platform, with VZV reported in standard International Units (IU), minimizes the likelihood of substantial discrepancies across different diagnostic platforms in potential future studies.

In this study, HSV status confirmation primarily relied on serum samples, utilizing HSV IgG analysis, which may not be the most precise method. HSV status was only recorded as positive or negative, and the actual titre level should have been noted to see if there was an association with patients VZV IgG titre for assessing overall strength of the immune system. HSV titre level should be recorded in future studies. However, the sensitivity and specificity of most platforms surpass 90%, a level deemed acceptable for our study's purpose of detecting associations. One noteworthy omission in our study was the lack of recording HSV titers, representing an opportunity missed to explore the relationship between HSV IgG titers and VZV IgG titers, potentially yielding more comprehensive insights into the discovered association.

Prior research has shed light on the VZV vaccine's capacity to elevate IgG titers, increase the percentages of VZV-specific memory T-cells and memory B-cells, in transplant patients.^1,15 This suggests that IgG titers may serve as indicators of T-cell function, extending beyond their role as mere antibodies. Additionally, the concept of trained immunity gains prominence, hinting at broader cell-mediated immune effects applicable to human herpes viruses and other viral infections.

While we acknowledge the potential role of age-related T-cell mediated immunity decline in initial HSV outbreaks among older individuals, our study lacked the necessary power to establish a concrete association between age and declining VZV IgG titers. Future investigations should carefully consider age-related VZV IgG decline as a potential confounding factor, particularly in studies assessing the efficacy of the VZV vaccine. Age restrictions, either focusing on younger or older populations, can mitigate this potential source of bias.

In the United States, VZV vaccination is predominantly administered during childhood, typically completed by age 6.^1,16 Nevertheless, research indicates that the immunological response to VZV vaccination is weaker compared to natural infection, affording approximately 20 years of protection ¹⁷ rather than the typical 50 years. This disparity in vaccine uptake across different demographic groups, especially minority populations, in previous decades may have contributed to a higher burden of HSV infections, including in pregnancy and neonatal cases. ¹⁸ While our study did not detect significant associations between ethnicity, number of children, or age and HSV status, we attribute this to limited statistical power. Future, larger-scale studies will be better equipped to address these factors comprehensively.

Looking ahead, a feasibility study is planned to explore the potential use of the VZV vaccine as a treatment for HSV. This endeavour holds the promise of unravelling further insights and novel strategies in the ongoing battle against recurrent HSV infections.

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material