Cornea Society and AAO Quality of Care Secretariat, Hoskins Center for Quality Eye Care
Herpes zoster is a serious health problem in the United States. Current estimates of new cases in the US are up to 1.2 million annually, about 20% of which are herpes zoster ophthalmicus (HZO).1 It is estimated that 1 in 3 people will have herpes zoster in their lifetime. Although it is more common and severe in immunocompromised persons, the vast majority (>90%) of patients with herpes zoster are not immunocompromised. Although the incidence of herpes zoster goes up significantly with age, starting at 40 years, the number of cases is highest in people 50 to 59 years of age.2-4 In one Centers for Disease Control and Prevention (CDC) study, the mean age of onset was 52 years.5 Risk factors for the development of herpes zoster include increased age, immunocompromised status, female gender, severe physical limitation,6 heart failure,7 traumatic brain injury,8 diabetes,1 acute kidney failure,9 and depression.10
Disease Complications and Costs
The complications and sequelae of herpes zoster can be severe and long term, even -- rarely -- resulting in death.11 The medical costs caused by herpes zoster and it complications, including direct medical care costs from acute and chronic pain, eye complications, secondary infections and neuropathies, are estimated to be $1 billion,12 with indirect costs from lost work and work productivity adding to that total, especially in younger age groups such as those 50 to 59 years of age.13
Ocular complications of herpes zoster include infectious and inflammatory anterior and posterior segment disease, neurotrophic ocular surface disease, and eyelid malposition and scar. Severe, irreversible vision loss may result from corneal opacification, glaucoma, and retinal disease.14 Approximately 20% of individuals affected by HZO experience potentially serious ocular disease, such as keratitis, uveitis, glaucoma, or neurotrophic disease. The 10-year probability of severe visual loss (20/200 or worse), a serious eyelid malposition, or chronic trichiasis developing varies between 2% and 9% depending on the treatment of the disease. Early recommended treatment with systemic antiviral therapy may decrease the incidence or severity of serious sequelae, but the likelihood of preventing complications is reduced if therapy is delayed, usually considered to be after more than 3 days of initial symptoms15 or rash. Postherpetic neuralgia is more likely in older patients, in patients with more severe acute pain and rash, and in patients with ophthalmic involvement.16,17 Systemic complications of herpes zoster include stroke, which is more common after HZO than herpes zoster in other locations,18-21 temporal arteritis,22 and possibly heart attack23,24 and depression.25
Evaluation of Current Evidence
Recent evidence seems to indicate that the age of onset of herpes zoster is decreasing, and this effect may be unrelated to herpes zoster vaccination. Two studies reported a significant 5-year decrease in the mean age of onset of herpes zoster from older than 60 years to younger than 60 years.26,27 Both studies recommended that vaccination age may need to be lowered to 50 years. The mean age of patients experiencing HZO-related ocular disease is 63 years in another publication.28
Effectiveness of Vaccinations and Recommendations of Other Organizations
Zoster Vaccine Live (Zostavax)
A randomized, controlled clinical trial demonstrated that zoster vaccine live (ZVL; an attenuated live virus vaccine; Zostavax; Merck & Co, Inc, Whitehouse Station, NJ) decreased the incidence of herpes zoster by 51% and the occurrence of postherpetic neuralgia by 66%in immunocompetent people 60 years of age and older.29 The vaccine decreased the incidence of herpes zoster by more than 60% in people 60 to 69 years of age compared with less than 40% in people 70 years of age and older. However, the effect on disease severity was greater in older persons, resulting in similar reduction in disease burden across age groups. An important limitation of ZVL is its waning effect, and models estimate nearly complete loss of efficacy by 10 years after vaccination. On the basis of this study, ZVL was approved by the United States Food and Drug Administration (FDA) in 2006 and recommended by the CDC in 2008 for immunocompetent people 60 years of age and older. The CDC also recommended herpes zoster vaccine for people with chronic medical conditions, including those affecting humoral immunity, and people who anticipate becoming immunocompromised. In the United States, the low rate of herpes zoster vaccination is a public health problem. According to 2015 CDC data, only 31% of eligible people 60 years of age and older had received a herpes zoster vaccine.30
In 2011, the FDA expanded their approval of the vaccine to include immunocompetent people 50 to 59 years of age, after it was shown to decrease the incidence of herpes zoster by 70% in this age group.31 The CDC recommendation for ZVL remains unchanged.
Recombinant Zoster Vaccine (Shingrix)
The recombinant zoster vaccine (RZV; Shingrix, Glaxo-SmithKline, Philadelphia, PA) also called the herpes zoster subunit vaccine, contains a recombinant varicella zoster virus glycoprotein E surface antigen reconstituted in a novel liposome-based adjuvant system.Aclinical trial (Zoster Efficacy Study in Adults 50 Years of Age or Older [ZOE-50]) of the RZV compared with placebo conducted outside of the United States from 2010 through 2011, the results of which were published in 2015, demonstrated that this vaccine had an efficacy of approximately 97% in all age groups.32 The results of the second part of this trial (Zoster Efficacy Study in Adults 70 Years of Age or Older [ZOE-70]), which was conducted concurrently and included participants 70 years of age and older, were pooled with ZOE-50 and showed an approximately 90% efficacy in vaccine recipients 70 years of age and older.33 The efficacy of this vaccine remained 85% against herpes zoster after 4 years. Local or acute systemic reactions, or both, interfering with normal activities occurred in more than 10% of vaccine recipients, raising concern about adherence to the 2-dose
schedule required for efficacy.34 In vitro studies report that the immune response is not inferior in people with a past history of vaccination with ZVL35 or herpes zoster36 or when given at the same time as 1 influenza vaccine.37
Food and Drug Administration Approval
The RZV was approved by the FDA in October 2017 for adults 50 years of age and older.38 This vaccine is administered intramuscularly as a 2-dose series 2 to 6 months apart. It is refrigerated and must be discarded if frozen before or after reconstitution. According to the FDA label, acute local and general reactions occur more often in people 50 to 69 years of age than in those older than 70 years, and general or systemic reactions occur more frequently after the second dose than the first dose of the 2-dose series.38
Centers for Disease Control and Prevention Recommendations
In January 2018, the Advisory Committee on Immunization Practices of the CDC recommended the RZV vaccination of immunocompetent adults 50 years of age and older, including people with a history of vaccination with ZVL at least 2 months previously.39 The CDC states that it is important to counsel patients regarding the possibility of acute local and systemic reactions and to encourage patients to complete the 2-dose series. With regard to the timing of vaccination with the 2-dose series of the RZV in people with a past history of vaccination with ZVL, the CDC notes one should consider the age at and time of vaccination with ZVL, which was less effective in preventing herpes zoster in people 70 years of age and older than in people 60 to 69 years of age, when vaccination with the RZV was studied 5 years after vaccination with ZVL.35 The CDC recommends the RZV as the preferred vaccine over ZVL because of its higher and longer-lasting efficacy across all age groups. The CDC issued no recommendations for immunocompromised persons because they were excluded from the clinical trials. According to the CDC, reporting of adverse events, using the Vaccine Adverse Events Reporting System (phone, 1-800-822-7967) and Vaccine Safety Datalink, is especially important because of the novel adjuvant that the RZV contains with high reactogenicity and immunogenicity.
People with a history of HZO may be at risk for recurrent eye disease after vaccination with the RZV, as has been reported in some cases after vaccination with ZVL.40,41 It is suggested that patients with a history of HZO should be examined by their ophthalmologist within several weeks before and after vaccination against herpes zoster, and adverse events should be reported. The optimal timing of vaccination after an episode of herpes zoster, including HZO, is not specified by the CDC. An episode of herpes zoster stimulates cell-mediated immunity for a period of time, so vaccination is not urgent. It is suggested that vaccination should be delayed after HZO until eye disease is well controlled.
Comparisons between Recombinant Zoster Vaccine and Zoster Vaccine Live
The CDC recommends the RZV as the preferred vaccine over ZVL, although there are no head-to-head studies comparing the 2 vaccines. In our opinion, if compliance with the second injection of the RZV required for efficacy is doubtful, and concern about acute local and general reactions is a barrier to RZV vaccination, ZVL is an option to consider, especially in immunocompetent adults 50 to 59 years of age, among whom ZVL reduces herpes zoster by 70% and has fewer systemic reactions.
Both the RZV and ZVL are FDA approved for individuals 50 years of age and older, but as of 2018, the CDC now recommends vaccination against herpes zoster with the RZV for immunocompetent adults 50 years of age and older. Vaccination starting at 50 years of age will reduce the burden of this disease, including chronic eye disease. Ophthalmologists should recommend strongly that patients 50 years of age and older without contraindications obtain vaccination with the RZV and should work with primary care physicians, internists, dermatologists, other medical doctors, and health care professionals to recommend vaccination strongly against herpes zoster starting at 50 years of age. Given the currently low rate of ZVL immunization in indicated age groups, advocacy by ophthalmologists may play an important role in increasing vaccination rates in the future.
- Suaya JA, Chen SY, Li Q, et al. Incidence of herpes zoster and persistent post-zoster pain in adults with or without diabetes in the United States. Open Forum Infect Dis 2014;1:ofu049.
- Yawn BP, Gilden D. The global epidemiology of herpes zoster. Neurology 2013;81:928-30.
- Ghaznawi N, Virdi A, Dayan A, et al. Herpes zoster ophthalmicus: comparison of disease in patients 60 years and older versus younger than 60 years. Ophthalmology 2011;118:2242-50.
- Insinga RP, Itzler RF, Pellissier JM, et al. The incidence of herpes zoster in a United States administrative database. J Gen Intern Med 2005;20:748-53.
- Hernandez PO, Javed S, Mendoza N, et al. Family history and herpes zoster risk in the era of shingles vaccination. J Clin Virol 2011;52:344-8.
- Liu B, Heywood AE, Reekie J, et al. Risk factors for herpes zoster in a large cohort of unvaccinated older adults: a prospective cohort study. Epidemiol Infect 2015;143:2871-81.
- Wu PH, Lin YT, Lin CY, et al. A nationwide population-based cohort study to identify the correlation between heart failure and the subsequent risk of herpes zoster. BMC Infect Dis 2015;15:17.
- Tung YC, Tu HP, Tsai WC, et al. Increased Incidence of Herpes Zoster and Postherpetic Neuralgia in Adult Patients following Traumatic Brain Injury: A Nationwide Population-Based Study in Taiwan. PLoS One 2015;10:e0129043.
- Yang WS, Hu FC, Chen MK, et al. High Risk of Herpes Zoster among Patients with Advance Acute Kidney Injury--A Population-Based Study. Sci Rep 2015;5:13747.
- Liao CH, Chang CS, Muo CH, Kao CH. High prevalence of herpes zoster in patients with depression. J Clin Psychiatry 2015;76:e1099-104.
- Bricout H, Haugh M, Olatunde O, Prieto RG. Herpes zoster-associated mortality in Europe: a systematic review. BMC Public Health 2015;15:466.
- White RR, Lenhart G, Singhal PK, et al. Incremental 1-year medical resource utilization and costs for patients with herpes zoster from a set of US health plans. Pharmacoeconomics 2009;27:781-92.
- Gater A, Uhart M, McCool R, Preaud E. The humanistic, economic and societal burden of herpes zoster in Europe: a critical review. BMC Public Health 2015;15:193.
- He Y, de Melo Franco R, Kron-Gray MM, et al. Outcomes of cataract surgery in eyes with previous herpes zoster ophthalmicus. J Cataract Refract Surg 2015;41:771-7.
- Severson EA, Baratz KH, Hodge DO, Burke JP. Herpes zoster ophthalmicus in olmsted county, Minnesota: have systemic antivirals made a difference? Arch Ophthalmol 2003;121:386-90.
- Kawai K, Rampakakis E, Tsai TF, et al. Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia. Int J Infect Dis 2015;34:126-31.
- Forbes HJ, Thomas SL, Smeeth L, et al. A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 2016;157:30-54.
- Sundstrom K, Weibull CE, Soderberg-Lofdal K, et al. Incidence of herpes zoster and associated events including stroke-a population-based cohort study. BMC Infect Dis 2015;15:488.
- Langan SM, Minassian C, Smeeth L, Thomas SL. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin Infect Dis 2014;58:1497-503.
- Nagel MA, Gilden D. The relationship between herpes zoster and stroke. Curr Neurol Neurosci Rep 2015;15:16.
- Yawn BP, Wollan PC, Nagel MA, Gilden D. Risk of Stroke and Myocardial Infarction After Herpes Zoster in Older Adults in a US Community Population. Mayo Clin Proc 2016;91:33-44.
- Gilden D, Nagel M. Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis. J Infect Dis 2015;212 Suppl 1:S37-9.
- Breuer J, Pacou M, Gauthier A, Brown MM. Herpes zoster as a risk factor for stroke and TIA: a retrospective cohort study in the UK. Neurology 2014;82:206-12.
- Wu PY, Lin CL, Sung FC, et al. Increased risk of cardiovascular events in patients with herpes zoster: a population-based study. J Med Virol 2014;86:772-7.
- Chen MH, Wei HT, Su TP, et al. Risk of depressive disorder among patients with herpes zoster: a nationwide population-based prospective study. Psychosom Med 2014;76:285-91.
- Chan AY, Conrady CD, Ding K, et al. Factors associated with age of onset of herpes zoster ophthalmicus. Cornea 2015;34:535-40.
- Davies EC, Pavan-Langston D, Chodosh J. Herpes zoster ophthalmicus: declining age at presentation. Br J Ophthalmol 2015.
- Yawn BP, Wollan PC, St Sauver JL, Butterfield LC. Herpes zoster eye complications: rates and trends. Mayo Clin Proc 2013;88:562-70.
- Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271-84.
- Williams WW, Lu PJ, O'Halloran A, et al. Surveillance of Vaccination Coverage Among Adult Populations - United States, 2014. MMWR Surveill Summ 2016;65:1-36.
- Schmader KE, Levin MJ, Gnann JW, Jr., et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis 2012;54:922-8.
- Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372(22):2087-2096.
- Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016;37(11):1019-1032.
- Neuzil KM, Griffin MR. Preventing shingles and its complications in older persons. N Engl J Med. 2016;375(11):1079-1080.
- Grupping K, Campora L, Douha M, et al. Immunogenicity and safety of the HZ/su adjuvanted herpes zoster subunit vaccine in adults previously vaccinated with a live attenuated herpes zoster vaccine. J Infect Dis. 2017;216(11):1343-1351.
- Godeaux O, Kovac M, Shu D, et al. Immunogenicity and safety of an adjuvanted herpes zoster subunit candidate vaccine in adults >/= 50 years of age with a prior history of herpes zoster: a phase III, non-randomized, open-label clinical trial. Hum Vaccin Immunother. 2017;13(5):1051-1058.
- Schwarz TF, Aggarwal N, Moeckesch B, et al. Immunogenicity and safety of an adjuvanted herpes zoster subunit vaccine coadministered with seasonal influenza vaccine in adults aged 50 years or older. J Infect Dis. 2017;216(11):1352-1361.
- GlaxoSmithKline. Shingrix [package insert]. https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm581605.pdf; 2017. Accessed June 30, 2018.
- Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67(3):103-108.
- Hwang Jr CW, Steigleman WA, Saucedo-Sanchez E, Tuli SS. Reactivation of herpes zoster keratitis in an adult after varicella zoster vaccination. Cornea. 2013;32(4):508-509.
- Jastrzebski A, Brownstein S, Ziai S, et al. Reactivation of herpes zoster keratitis with corneal perforation after zoster vaccination. Cornea. 2017;36(6):740-742.
Approved by Cornea Society Executive Committee, April 2018
Approved by American Academy of Ophthalmology Board of Trustees, June 2018
The Academy would like to acknowledge the tremendous guidance and support of Elisabeth J. Cohen, MD and Keith H. Baratz, MD.