Making the Case for Universal Herpes Zoster Vaccination in Older Adults

Herpes zoster (HZ, or shingles) is a painful dermatomal cluster of vesicles caused by varicella-zoster virus (VZV), the same virus responsible for chickenpox primarily in children.^1-3 Following childhood chickenpox, VZV lives within the nerve ganglion of the host for months to years. It becomes reactivated either spontaneously or by a condition that impairs the body’s immune defense mechanism.^1-3 Increasing age,³ trauma, dental or surgical manipulation,⁴ use of immunomodulatory therapies, emotional or physical stress, and malignancies are potential triggers of VZV reactivation.

While reactivation most often causes skin lesions, HZ also can erupt on the mucosa of the mouth, pharynx, larynx, and/or tongue.^4,5 Evidence also is emerging regarding the association of HZ with an increased risk of stroke, myocardial infarction (MI), and cancer.^6-8 The presentation varies by person, with nonspecific symptoms occurring mostly in older persons and immunocompromised persons.^1,2,4,5 Because older persons can present with atypical symptoms, they are most at risk of misdiagnosis,³ unnecessary laboratory testing, and delayed treatment; these situations are associated with significant personal and public health costs, especially for persons who are immunocompromised or in long-term care (LTC) settings.^9,10 For example, a study of residents of skilled nursing facilities showed a significant increase in hospitalization episodes and hospitalization days among patients with HZ compared with patients without HZ, accompanied by a significant increase in the cost of care.¹⁰

Failure to initiate treatment with antiviral therapy and lack of vaccination can increase the risk of developing such complications as postherpetic neuralgia (PHN). PHN is a serious and potentially disabling neuropathic pain syndrome that can persist for months to years with or without the appearance of HZ lesions.^1-3,11 The process by which HZ transitions to PHN remains unclear; this paucity of evidence may contribute to the delay in identifying more definitive and efficacious treatments. While current treatments include antiviral therapies and palliative analgesic, antidepressant, and neuropathic medications, vaccination remains the most promising preventive approach.^1,2,11 However, despite the benefits and availability of the live HZ vaccine, the Centers for Disease Control and Prevention (CDC) reports that less than 30% of persons eligible for the vaccine receive it.^12,13 Contributory factors to this low vaccination rate may include the 30% target vaccination rate set by Healthy People 2020;¹⁴ the recommended age of vaccine eligibility published by the CDC of 60 or older, with no explicit mention of the very high risk in persons aged 70 or older (the older old); and recommendations against vaccination in adults who have an immunocompromising condition or who are on immunosuppressive therapies.^1-3,15,16 The older old and immunocompromised groups in particular are at risk of developing the most severe complications after VZV reactivation.

Each year, approximately 1 million cases of HZ are reported in the United States,^1,17 and persons older than 50 years are most vulnerable to the increased risk of morbidity, mortality, disability, and the economic burden of this condition.^2,3,10,18 The older population is a substantial age demographic in the United States,¹⁹ and 1 in 3 older adults could develop HZ at some point, with more than 13% of such cases complicated by PHN.^17,18,20 The risk of HZ increases with age.²⁰ Hence, the goal of this article is to emphasize the need for long-term planning and to promote universal vaccination against HZ of older residents of LTC facilities, who are most affected by and at high risk of associated complications.

While efforts are ongoing to develop new treatments to alleviate HZ and its associated complications, prevention via vaccines is a more cost-effective option. Compared with placebo, the live HZ vaccine (Zostavax, Merck & Co), which was approved by the Food and Drug Administration (FDA) in 2006, has been found to reduce the occurrence of HZ by 51.3% (95% CI, 44.2-57.6) and PHN by 66.5%
(95% CI, 47.5-79.2) compared with placebo in participants aged 60 or older.²¹ The non-live, recombinant, adjuvanted HZ subunit vaccine (Shingrix, GlaxoSmithKline), FDA-approved in October 2017, has been shown to lower HZ cases by 91.3% (95% CI, 86.8-94.5) and PHN by 88.8% (95% CI, 68.7-97.1) compared with placebo in participants aged 70 or older^.22

Compared with the older unadjuvanted live vaccine, the newer adjuvanted HZ vaccine is a non-live vaccine and as such is considered safe for use even in immunocompromised persons and older residents of LTC facilities who previously would have been ineligible for HZ vaccination due to safety concerns with the live vaccine.²² Nevertheless, real-world longer-term clinical studies with large sample sizes in diverse populations are needed to rigorously assess the reactogenicity, immunogenicity, and safety profile of the live vaccine in immunocompromised persons and older residents of LTC facilities.²³

The public health and economic impact of HZ is significant.^9,10,24 The authors of a 2007 report found that the benefit of the HZ vaccine varied with age and gender (women and persons aged 70 or older benefitted more).²⁵ The authors posited that universal HZ vaccine coverage for older adults could be cost-effective if the vaccine were priced at $46 (approximately $55 in 2017 dollars).²⁵ In a 2017 report, the average US price of the vaccine was estimated to range from $320 to $471, depending on geographic location.²⁶ In a 2016 cost analysis for HZ and other vaccine-preventable diseases, Ozawa and colleagues found that approximately 9% ($782 million) of the annual US economic burden of undervaccination could be attributed to HZ.²⁷ Another 2017 study projected the 2030 costs of HZ in persons aged 65 or older at $4.74 billion if the incidence of HZ is not slowed.³ Another important consideration is the direct cost burden of HZ and PHN on older adults, especially those paying out-of-pocket for expenses not covered by insurance.^9,10,24

In adults aged 70 or older, HZ creates an additional burden because of the persistent symptoms of recalcitrant pain, itching, and sensitization from the increased neuronal response (allodynia) of PHN.^1,18,28 This significant impairment may affect the patient’s functional state and can induce problems such as mood disorder, insomnia, physical isolation, permanent disability, paralysis, and, in extreme cases, death.^29-31 The presence of multiple comorbidities,³² polypharmacy,³³ declining kidney function,³⁴ and declining liver function³⁵ further contribute to the severity of presentation, worsening the patient’s state of health and increasing the risks for falls, HZ-related emergency department visits,³⁶ and myriad cardiovascular and cerebrovascular complications.^31,37,38

Evidence suggests that stroke,^37,38 MI, and other cardiac and cerebrovascular conditions are associated with HZ.³⁸ A meta-analysis by Lian and colleagues found a significant correlation between stroke and HZ within the first 3 months of infection.³⁷ This association is related to viral migration from the nerve endings to the brain, where proinflammatory and thrombotic cytokines such as IL-6 are activated and released into the blood vessels. This activation evokes the vasoconstriction that induces stroke.^37,38 These pathophysiologic processes would suggest a greater risk of ischemic stroke than for hemorrhagic stroke, but relative risk analysis indicated a slightly higher risk of developing hemorrhagic stroke in the first month (1.70; 95% CI, 0.73-3.96) and the third month (2.05; 95% CI, 1.17-3.60) compared with ischemic stroke in the first month (1.55; 95% CI, 1.46-1.65) and the third month (1.17; 95% CI, 1.12-1.23).³⁷ Although little evidence links HZ with MI, the mechanism appears to be somewhat similar to that of stroke; more robust evidence exists for higher odds for stroke compared with MI after HZ.^37,38 Although research studies are under way, little is known about the relationship between HZ and other older age–associated diseases such as Alzheimer disease and cancer.^6-8,39

The live HZ vaccine faces challenges related to the need for freezer storage, its contraindications in immunocompromised persons, and the cost of and access to the vaccine.^12,13,25,40 In addition, there are concerns that the 1-time recommended dose of the live vaccine does not confer lifelong protection. Indeed, results of long-term effectiveness studies of the live HZ vaccine demonstrate a loss of efficacy over time. Morrison and colleagues conducted a study on the persistence of vaccine efficacy for up to 11 years in people enrolled in the original study of HZ vaccine efficacy.⁴¹ After analysis, the authors found a lack of statistically significant efficacy of the vaccine after 8 years. More recently, 176,078 members of Kaiser Permanente Southern California aged 60 or older who had been vaccinated with the live vaccine were matched to unvaccinated control individuals; vaccine efficacy decreased from 68.7% 1 year after vaccination to 4.2% 8 years after vaccination.⁴²

To address these challenges, a recent randomized controlled trial examined the efficacy of non-live recombinant VZV components (glycoprotein E and AS01B) among adults aged 70 or older.²² The study showed similar efficacy of the non-live vaccine in 2 groups, those aged 70 to 79 (90.0%) and those aged 80 years or older (89.1%). Indeed, the study showed 91.3% overall efficacy of the non-live vaccine among adults aged 70 or older (n = 16,596) compared with placebo. The effect was not limited to HZ prevention. Among those who received the vaccine and developed HZ, the vaccine prevented PHN in 88.8% of cases. These results suggest that the adjuvanted non-live vaccine provides a safer alternative for older adults and those on immunomodulatory therapy in whom the live vaccine is contraindicated.

The newer non-live vaccine offers unique advantages in the LTC population, because an episode of HZ in this population can be the beginning of a downward spiral from hospitalization to frailty, disability, and premature death. LTC residents, who previously had been excluded from receiving the live vaccine due to immunocompromising medications or conditions,^21,22 are good candidates for the new non-live vaccine, with no fear of causing disseminated zoster, although longer-time real-world data regarding safety in immunocompromised populations are still pending.⁴³

In addition to not requiring freezer storage, the non-live HZ vaccine also demonstrates immunogenicity and sustained efficacy, up to 87.9% 4 years from the time of vaccine administration.^22,41,44 Additional long-term follow-up studies in ethnically and racially diverse populations are imperative to determine whether the second HZ vaccine dose recommended by the CDC’s Advisory Committee on Immunization Practices (ACIP)¹⁵ will confer long-term protection, especially in the LTC setting.

The non-live HZ vaccine is contraindicated in persons with a history of allergic reaction to any of its ingredients, while the live HZ vaccine is contraindicated in persons with HIV/AIDS or cancer and persons on immunomodulatory therapies or corticosteroids.^16,43 The high level of risk reduction and the fewer contraindications associated with the non-live vaccine compared with the live vaccine likely informed its approval by the FDA and its recommendation by the CDC’s ACIP in October 2017.^45,46 However, the non-live vaccine’s high immunogenicity is associated with a clinically relevant downside: high reactogenicity (79.0% in non-live vaccine recipients vs 29.5% in placebo recipients) and a frequency of fever, headache, fatigue, and myalgia severe enough to interfere with activities of daily living (ADLs) in some recipients.²² These adverse effects—which may even be more serious with the second dose—may reduce vaccine uptake in the frail geriatric population, especially residents of LTC facilities who have a high risk of HZ complications.⁴³

Nursing home populations are at high risk of HZ and its complications given the profile of typical LTC residents: octogenarians with a high prevalence of cognitive impairment or dementia, multimorbidity, polypharmacy, multiple ADL dependency, recurrent hospitalizations, and immunocompromising conditions such as diabetes and malnutrition.^28,47 Approximately half of Americans would have developed HZ by age 85, and yet the efficacy of the older live vaccine was lowest in this age group, reducing the incidence of HZ by only 18% in persons aged 80 or older.^21,48 An important objective of Healthy People 2020 is to increase the proportion of vaccine-eligible adults who are vaccinated against HZ from 6.7% in 2008 to 30% by 2020.¹⁴

Given the personal and public health burden of HZ, especially in frail older adults, we advocate that all LTC providers aim for a target of 100% vaccination with the non-live HZ vaccine among nursing home/LTC residents with multimorbidity who have no contraindications to vaccination. Cost-effective prevention through vaccination^10,27,32 can help reduce the disease burden of HZ and improve quality of life of persons in this population.

Vaccinate all LTC residents with non-live HZ vaccine

Given the long-lasting and highly protective effects of the newer non-live HZ vaccine and the high incidence of HZ and severe complications among persons in the LTC setting, we propose vaccination with the non-live HZ vaccine of all LTC residents as a quality-of-care indicator in the nursing home setting, similar to the approach to vaccination against pneumococcal disease and influenza. Preventing HZ in this setting has significant potential to increase quality of life and care, decrease hospitalizations, and reduce costs.

Provide education and decision support aids 

Informed decision-making will require investment in the development and implementation of culture-appropriate vaccine decision-support aids to guide informed choices, especially among persons in ethnic minorities groups or those with low health literacy. Provision of such decision-making aids and other educational materials has the potential to address concerns and questions about safety, adverse effects, and benefits of the vaccination against HZ. 

Integrate HZ vaccination into performance-improvement strategies

Incorporating the HZ vaccination into clinical performance-improvement measures (eg, Healthcare Effectiveness and Data Information Set [HEDIS]) and pay-for-performance reimbursement models may incentivize health care providers to recommend and provide the HZ vaccine to frail residents of nursing homes.

Expand Medicare Part B coverage to include HZ vaccine

Medicare Part B covers influenza, pneumococcal, and hepatitis B vaccines as part of the preventive services on the “Welcome to Medicare” preventive visit.⁴⁹ Expanding Medicare Part B coverage to include the HZ vaccine would help eliminate the cost-sharing challenges faced by many Medicare beneficiaries.

Incorporate vaccine reminders into resident databases

Health systems, nursing homes, assisted-living facilities, hospitals, clinics, and private practices should incorporate vaccine reminders into resident databases and electronic medical record (EMR) systems to facilitate coordinated, current, and efficient communication between patients and caregivers, specialists, and primary care providers about immunization activities. Doing so would help keep track of each patient’s vaccination records. EMR systems could be used to send reminders to patients to promote vaccination adherence and to reduce missed opportunities for vaccination. 

There are potentially huge benefits for a society that embraces a prevention-first approach. Practical strategies need to be implemented to ensure an increase in vaccine uptake and adherence and a decrease in morbidity and disability associated with HZ and its sequelae, especially in the LTC setting.