# VZV vaccine attenuation and the DNA damage response

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $664,466

## Abstract

ABSTRACT
Diseases caused by the human herpesvirus Varicella Zoster Virus (VZV) are widespread and debilitating but
can be limited by using live attenuated VZV vaccines. The varicella vaccine has been hugely successful in the
US, but many countries do not use it widely, some not at all. A high titer version of the same vaccine virus was
then developed to immunize adults to boost VZV immunity and reduce the incidence of Herpes Zoster (HZ),
the result of VZV reactivation from neuronal latency. HZ is debilitating and complicated, most often by chronic
pain that is difficult to treat. HZ remains a public health concern, because most adults harbor wild-type (WT)
VZV in their ganglia and are at risk for HZ, and the HZ vaccines have far from optimal coverage in the target
populations. The live vaccine virus, vOka, needs improvement. It can cause rashes, go latent and cause rare
cases of HZ. It is genetically heterogeneous, with hundreds of single nucleotide polymorphisms (SNPs)
occurring at different parent/vaccine allele frequencies. The basis of virus attenuation is not known. 5 SNPs are
fully or nearly fully fixed for the vaccine allele and are suspected to direct attenuation. Intriguingly, four lie in
the VZV gene encoding IE62, a critical protein that regulates expression of all VZV genes. Excitingly, our data
shows that WT VZV, through its IE62, turns on expression of the stem cell epidermal marker KRT15 in
keratinocytes and skin, while vaccine virus and its IE62 do not. We then found that KRT15 expression in our
epithelial differentiation model is required for VZV replication. Furthermore, KRT15 levels influence the
keratinocyte DNA Damage Response (DDR). Taken together, the data support a global hypothesis that IE62
upregulates KRT15 to control pro-viral aspects of the DDR. vOka is attenuated in skin because its IE62 does
not trigger the upregulation of KRT15 to regulate DDR pro-viral pathways. To test this hypothesis, Aim 1 will
seek to establish that vaccine SNPs in IE62 underlie growth attenuation in models of skin. First, we will use a
complementation assay to delineate those vaccine SNPs that prevent IE62 from boosting the replication of
vOka vaccine virus in keratinocytes. Second, we will develop WT VZV recombinants that contain ORF62
genes with vaccine SNPs, then quantify their replication in models of skin, including human skin explants. In
Aim 2, we will characterize steps of the novel IE62-KRT15-DDR pro-viral pathway that is differentially regulated
by KRT15 levels and IE62. This includes studying how the IE62 vaccine genotype influences KRT15
transcription; how KRT15 levels affect the DDR and VZV replication; and what components of the DDR are
proviral for VZV in the human epithelial differentiation model. Aim 3 will seek to determine if IE62 specific
SNPs underlie the poor reactivation phenotype of vOka from neuronal latency, using cultured human neuron
models that have successfully modeled VZV latency and experimental reactivation. T...

## Key facts

- **NIH application ID:** 10520131
- **Project number:** 1R01AI158510-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Paul R. Kinchington
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $664,466
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520131

## Citation

> US National Institutes of Health, RePORTER application 10520131, VZV vaccine attenuation and the DNA damage response (1R01AI158510-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10520131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*