Acute Retinal Necrosis Caused by the Zoster Vaccine Virus
Acute Retinal Necrosis Caused by the Zoster Vaccine Virus
0 Microbiology, Virology and Infection Control (VZV Typing Laboratory), Great Ormond St Hospital , London, England
1 Infection and Immunity, University College London , England
2 Medical Ophthalmology, York Teaching Hospital NHS Foundation Trust , York, England
3 Gregory Heath
4 Virology, Leeds Teaching Hospitals NHS Trust , Leeds, England
We report acute retinal necrosis caused by the vaccine Oka strain following immunization of a 78-year-old woman with live zoster vaccine. Whole genome sequencing confirmed the ocular vOka strain to be derived from the vaccine and excluded the presence of new mutations or recombination with wild-type Varicella zoster virus.
A 78-year-old white female presented with a two-week history
of floaters in her left eye. Her medical history was noteworthy
for rheumatoid arthritis, latent autoimmune diabetes of
adulthood (anti–glutamic acid decarboxylase antibody positive), and
osteoporosis. Her medications included methotrexate 7.5 mg
orally once a week, folic acid 5 mg daily (6 days per week),
insulin (Humalog Mix 50/50 [insulin lispro protamine/insulin
lispro] 30 units s/c), and alendronic acid orally 70 mg once a week.
Her ophthalmic history was unremarkable. Six weeks before the
onset of her ocular symptoms she had received the zoster
On examination, her visual acuities were 6 of 6 and 6 of 18 in
her right and left eyes, respectively. Multiple, diffuse keratic
precipitates were present in her left cornea. Although her left eye
appeared white, there were cells (+++) in her anterior
chamber. Her intraocular pressures were within the normal range at
14 mm Hg and 18 mm Hg in the right and left eyes, respectively.
Fundus biomicroscopy confirmed cells (++) in her left vitreous
cavity associated with haze (++). A white lesion in the
superotemporal aspect of her left ocular fundus consistent with an area
of retinitis was observed (Figure 1A).
Cytological analysis of the sample of vitreous fluid revealed
reactive lymphocytes. The fluid was positive for Varicella zoster virus
DNA by real-time polymerse chain reaction (qPCR) and
confirmed by genotype-specific qPCR [
] to be the vaccine Oka strain
(vOka). Whole genome sequencing showed the virus to cluster
phylogenetically with other vOka vaccine sequences (Figure 1B).
There was no evidence of recombination with wild-type Varicella
zoster virus. Compared with the sequence of the wild-type parental
Oka (pOka) strain from which the vaccine was originally derived,
the ocular vaccine strain had 12 vaccine mutations (Figure 1C),
10 of which have previously been observed in the vOka vaccine
]. Positions K168R in open reading frame (ORF) 17 and
F374C in ORF 33 have not previously been described in any vOka
vaccine strain. However, deep sequencing of the zoster vaccine
revealed these positions to be polymorphic at frequencies of 1%
and 3%, respectively (Figure 1C). Vaccine viruses recovered from
rashes and other postimmunization complications have fewer
vaccine mutations than vOka viruses found in the vaccine
preparation itself. In particular, selection for the ancestral pOka allele is
observed at >2 of 11 specific loci [
], 8 of which were wild-type in
the ocular vaccine virus sequenced here (Figure 1C).
The patient received oral valaciclovir 2 g 3 times a day for 3
weeks, reducing down to 1 g three times a day for a total period
of 3 months before stopping altogether. In addition, she was
administered a tapering dose of topical prednisolone acetate
1% for 4 weeks and atropine 1% into her left eye to address her
secondary anterior uveitis. Her visual acuity improved from 6 of
18 to 6 of 9 within 2 weeks. The area of retinitis healed, leaving
a pigmented scar (Figure 1A).
This patient met the diagnosis of acute retinal necrosis, which
was defined by the American Uveitis Society [
] as >1 foci of
retinal necrosis, progression in the absence of antiviral
therapy, an occlusive vasculopathy with arterial involvement, and
a prominent inflammatory reaction in both the anterior and
vitreous chambers. Acute retinal necrosis is a rare
ophthalmic disease with an incidence of 0.63 per million population
per year in the United Kingdom [
]. Although classically
described in immunocompetent patients, immunodeficiency
is observed in at least 30% of cases and is associated with more
severe disease [
]. Presentation appears to be bimodal and is
dependent on the underlying etiology. Acute retinal necrosis
secondary to herpes simplex virus type 2 occurs at a mean
age of 27 years, whereas cases occurring secondary to herpes
BRIEF REPORT • CID 2017:65 (15 December) • 2123
simplex virus type 1 or herpes zoster affect older ages (mean
age, 58 years) [
Although the use of intravenous aciclovir has been regarded
as the standard treatment, currently oral valaciclovir or
valganciclovir are recommended for treatment of acute retinal necrosis
secondary to herpes simplex/zoster and cytomegalovirus,
]. An oral dose of valaciclovir 2 g three times a day has
been shown to achieve systemic levels comparable with
intravenous aciclovir [
]. For those patients with aciclovir resistance or
in whom their retinitis threatens/involves their macula or optic
nerve, intravitreal foscarnet may be injected into the affected eye
twice or thrice weekly [
]. Oral corticosteroids may be added for
patients with severe inflammation or sight-threatening disease.
Topical corticosteroids combined with cycloplegia is often
prescribed to ameliorate anterior segment inflammation. In line with
recent recommendations, aspirin was not prescribed [
Herpes zoster is a potentially devastating disease affecting
>30% of those aged >70 years, with serious complications,
mainly prolonged debilitating pain occurring in 50%. The
Zostavax vaccine, which contains the live attenuated vOka strain
of varicella zoster virus, has been shown to reduce the incidence
of shingles and post herpetic neuralgia by 51.3% and 66.5%,
]. Immunization of adults aged ≥70 years began
in the United Kingdom in 2013. Coverage reached 60%, within
2 years, and this has already resulted in significant falls in the
incidence of zoster in vaccinated cohorts (G. Amirthalingam,
personal communication). Because the vaccine contains a
live attenuated strain, its use in patients who are
immunosuppressed is contraindicated. Notwithstanding, current advice is
that immunization is safe for patients receiving low-doses of
methotrexate (<0.4 mg/kg/wk), azathioprine (<3.0 mg/kg/d),
or 6 mercaptopurine (<1.5 mg/kg/d) for the treatment of
autoimmune and inflammatory diseases [
]. Despite many hundreds
of thousands of patients having received the vaccine,
complications resulting from replication of the vaccine virus have rarely
been reported [
]. One possible but unconfirmed vOka rash
occurring within 6 weeks of immunization was reported in
clinical trials of >60 000 individuals [
]. A second fatal case
of vOka vaccine strain dissemination has also been reported in
an immunocompromised patient in whom the shingles vaccine
was contraindicated . A single case of vOka herpes zoster
following the shingles vaccine has been reported [
], but there
have been no cases of acute retinal necrosis confirmed as due to
the vOka vaccine strain in a patient deemed suitable to receive
the zoster vaccine. This case illustrates, however, the need to
consider a vaccine etiology in patients who present with
unusual symptoms and have received the zoster vaccine.
We were able to recover and sequence the whole viral
genome from the vitreous fluid. From this we proved that no
recombination between the vaccine strain and the patient’s
autochthonous wild-type virus had occurred, something that,
although theoretically possible, has to date not been described
2124 • CID 2017:65 (15 December) • BRIEF REPORT
for any vOka vaccine strain. We show that all 12 vaccine
mutations, including 2 apparently new mutations in ORFs 17 and
33, neither of which lies within domains known or predicted to
affect function of these proteins, are also present in the zoster
vaccine preparation, thus confirming that no new mutations
had occurred (Figure 1C). Despite the vaccine containing
many mixed positions (fifth row down, Figure 1C,) the ocular
virus was monomorphic (ie, single nucleotide polymorphisms
were either 100% vaccine [white cell] or 100% wild-type [black
cell] [sixth row, Figure 1C]), suggesting that it is likely to have
arisen from infection by a single virion that spread
hematogenously after immunization. Whether this strain is more
virulent is unclear. However, the ocular vOka strain had the genetic
characteristics that have previously been demonstrated to be
associated with increased likelihood of rash formation and
other postimmunization complications [
]. In particular, the
wild-type (pOka) amino acid (black cell) was present in the
ocular virus at 3 positions in IE62 that have been most strongly
associated with rash formation (P < 10−10) (Figure 1C). This
includes the leucine at position 446 in the ORF62 major
transactivating protein, which despite being mixed in vOka vaccine
preparations, is always wild-type in rashes and other
complications, implying a critical role for in vivo replication of the
In summary, we report a case of retinitis, caused by the vOka
strain following zoster vaccine, which responded well to
antiviral treatment. Although very few complications caused by
replication of the attenuated vOka strain have been reported
following the zoster vaccine, this case illustrates the need to
investigate unusual presentations occurring in recently
Acknowledgments. We acknowledge the support of the UK Medical
Research Council (MRC)/National Institute for Health Research (NIHR)
University College London (UCL) Pathogen Genomics Unit. All research
at Great Ormond Street Hospital NHS Foundation Trust and UCL Great
Ormond Street Institute of Child Health is made possible by the NIHR
Great Ormond Street Hospital Biomedical Research Centre.
Disclaimer. The views expressed are those of the author(s) and not
necessarily those of the National Health Service (NHS), the NIHR, or the
Department of Health.
Financial support. This work was supported by a New Investigator
Award from the Medical Research Foundation (UK MRC); NIHR
funding (grant NIHR-HCS-D12-03-15 to D. P. D.); and NIHR UCL/UCLH
Biomedical Research Consortium funding (to J. B.).
Potential conflicts of interest. All authors: No reported conflicts of
interest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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