Meningitis Caused by the Live Varicella Vaccine Virus: Metagenomic Next Generation Sequencing, Immunology Exome Sequencing and Cytokine Multiplex Profiling.

Prashanth S Ramachandran,Ethan H Heusel,Charles Grose,Gaud Catho,Randall J Cohrs,Nicoline Schiess,David Boutolleau,John E Carpenter,Anne Wapniarski,Geraldine Blanchard-Rohner,Sonia Burrel,Bradley A Ford,Michael R Wilson,Tetsushi Yoshikawa,Wallen Jackson

doi:10.3390/v13112286

Abstract

Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3–4 weeks before onset of vaccine meningitis may be a risk factor in some cases.

Highlights

Twenty years ago, virologists at the Food and Drug Administration (FDA) carried out an analysis of antibody titers of 4631 children collected over the 4 years after varicella vaccination
Varicella vaccine meningitis presumably represents the clinical manifestations of herpes zoster of the trigeminal ganglion, whereby afferent fibers carry reactivated virus to the meninges [23,24]
One case of varicella vaccine meningitis had been described before 2006 [26], when the CDC switched their recommendation from one to two varicella vaccine doses for children (Figure 3)

Summary

Introduction

Virologists at the Food and Drug Administration (FDA) carried out an analysis of antibody titers of 4631 children collected over the 4 years after varicella vaccination. They interpreted the results as showing frequent asymptomatic reactivation of latent varicella vaccine virus in immunized children with low serum antibody titers after vaccination [1]. Subsequent epidemiologic studies have clearly shown that symptomatic reactivation as herpes zoster can occur after varicella vaccination, but the prevalence is less than that after wild-type varicella-zoster virus (VZV) infection [2]. Four cases of varicella vaccine meningitis in twice-immunized children have been reported [5]. This report provides proof-of-principle that mNGS can be used to differentiate vaccine-type from wild-type VZV strains

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Discussion

Conclusion