Preventing herpes zoster through vaccination: New developments

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Herpes zoster (HZ) affects 1 million Americans every year. The disease burden is higher in immunocompromised patients. The live-attenuated HZ vaccine is effective in preventing HZ and postherpetic neuralgia and has been recommended for immunocompetent adults age 60 and older. However, because protection wanes by 10 years, a booster may be necessary. In 2015, an adjuvanted subunit HZ vaccine was shown to reduce incidence by 97%, even in the elderly, but long-term data on vaccine protection are not available. Clinical trials are under way to investigate a safe and effective vaccine for immunocompromised patients.


  • HZ continues to be an important public health problem, with substantial morbidity and economic impact. Because of the lack of effective treatment, vaccination provides the best strategy for disease mitigation.
  • Physicians can reduce the impact of HZ by educating patients about its complications and recommending immunization for all patients age 60 and older. Patients can protect themselves by seeking vaccination.
  • Vaccine protection wanes completely after 10 years, and physicians should be prepared to offer a booster dose should the Advisory Committee on Immunization Practices issue such recommendations.
  • Newer vaccines offer promise for greater efficacy, especially for the elderly. For immunocompromised patients, a safe and effective vaccine may be available in the near future.



Herpes zoster (HZ), or shingles, represents a reactivation of the varicella-zoster virus (VZV). Following primary infection, usually in childhood, the virus typically lies dormant in the dorsal root and sensory nerve ganglia for decades. The precise mechanism of reactivation is not well understood, but it is associated with a decline in cell-mediated immunity that occurs with advancing age, immune-compromising conditions such as HIV infection and cancer, or immunosuppressive therapies, including corticosteroids.1 HZ is usually a self-limited disease characterized by unilateral dermatomal rash and pain, but can cause disseminated infection in immunocompromised individuals.2

Treatment with antiviral medications within 72 hours of rash onset can reduce acute HZ symptoms.1 However, antiviral agents are only minimally effective in preventing postherpetic neuralgia, the most common complication of HZ.3 Therefore, efforts to reduce the burden of HZ morbidity have focused on prevention through vaccination.

Currently, the only shingles vaccine approved by the US Food and Drug Administration (FDA) is Zostavax (Merck), which contains the live-attenuated Oka strain of VZV at a concentration 14 times greater than that of the varicella vaccine (Varivax, Merck). The live-attenuated vaccine boosts VZV-specific cell-mediated immunity, preventing reactivation of the latent virus.

In this article, we describe the burden of disease and review recent developments in the literature on HZ vaccine, including duration of efficacy, uptake and barriers to vaccination, cost-effectiveness, and the outlook for future vaccines.


The incidence of herpes zoster in the general population is between 3 and 5 per 1,000 person-years4 and increases with age, especially after age 60 when the incidence can approach 13 to 15 per 1,000 person-years.5,6 An estimated 1 million new cases occur each year in the United States, and about 6% of patients experience a second episode of HZ within 8 years.7,8 In immunocompromised patients, the incidence of HZ is 2 to 10 times higher than in the general population.9

The incidence of HZ has been increasing for reasons that are unclear. After varicella vaccine was introduced into the routine childhood immunization schedule in 1995, it was hypothesized that the resultant decrease in primary varicella infections would remove a natural source of immune boosting and cause an increase in HZ incidence for up to 20 years.10 However, recent studies demonstrate that the observed increase in HZ incidence actually predates the introduction of varicella vaccine,11–13 and the widespread use of varicella vaccine has not resulted in an increase in the incidence of HZ.14

Other potential explanations for the rise in reported incidence include increasing awareness among patients, who might previously not have sought care and among physicians, who may be more likely to make the diagnosis. Advertisement of new treatments for HZ, including gabapentin and capsaicin, probably began to increase awareness in the 1990s, as did promotion of the HZ vaccine after its licensure in 2006.

HZ can occur in people who have been vaccinated against varicella due to reactivation of the vaccine-strain virus, but the risk is lower than after infection with wild-type varicella.15 Given that the varicella vaccine has been routinely used in children for only 20 years, the long-term effect of varicella vaccination on the incidence of HZ in elderly people is unknown.

Serious complications

HZ can cause rare but serious complications including encephalitis, herpes ophthalmicus, herpes oticus, myelitis, and retinitis.1 These can lead to long-term disability including unilateral blindness and deafness.

The most common and debilitating complication is postherpetic neuralgia, a persistent pain lasting at least 3 months, with a mean duration of 3.3 years and sometimes as long as 10 years.16 Postherpetic neuralgia occurs in 8% to 32% of patients after acute HZ,4 and the incidence increases with age, being most common after age 70. The chronic pain of postherpetic neuralgia has a significant adverse impact on patients’ quality of life, including physical disability and emotional distress.17 Some pain is intense, and anecdotal reports of patients committing suicide were included in the Advisory Committee on Immunization Practices (ACIP) recommendations regarding herpes zoster vaccine.18

HZ and its complications also impose a substantial economic burden on society.19 In a population-based study, the mean direct medical costs of HZ ranged from $620 to $1,160 (2015 dollars) depending on age,20 and the mean costs of postherpetic neuralgia were 2 to 5 times higher than that.20–22 Immunocompromised patients had costs 2 to 3 times higher than those of immunocompetent adults.23 In addition, for employed patients, HZ resulted in an average loss of 32 hours of work due to absenteeism and 84 hours due to presenteeism (ie, working while sick and therefore suboptimally).24

Assuming there are 1 million cases of HZ each year, if 8% to 32% of patients go on to develop postherpetic neuralgia, that would translate into approximately $1 to $2 billion in direct medical costs. With 60% of adult patients working,25 at an average wage of $23.23 per hour,26 HZ illness could be responsible for another $1.6 billion in lost productivity.


In 2006, the FDA approved the live-attenuated Oka strain VZV vaccine for prevention of HZ and postherpetic neuralgia in adults age 60 and older based on findings from the Shingles Prevention Study (SPS).27

The Shingles Prevention Study

This multicenter randomized placebo-controlled trial27 enrolled 38,546 immunocompetent persons age 60 and older. Subjects in the intervention group received a single dose of live-attenuated vaccine, and all participants were followed for up to 4.9 years after vaccination.

HZ occurred in 315 (1.636%) of the 19,254 participants in the vaccine group and in 642 (3.336%) of the 19,247 participants in the placebo group, an absolute risk reduction of 1.7%, number needed to treat 59, relative risk reduction 51%, P < .001. Similarly, postherpetic neuralgia occurred in 27 (0.140%) of the 19,254 vaccine recipients and in 80 (0.416%) of the placebo recipients (an absolute risk reduction of 0.276%, number needed to treat 362, relative risk reduction 66%, P < .001). The investigators calculated that vaccination reduced the overall burden of illness by 61% (Table 1).

The efficacy against HZ incidence decreased with age,28 but the efficacy against postherpetic neuralgia did not. In addition, vaccine recipients who developed HZ generally had less severe manifestations.

The safety of the vaccine was assessed for all participants in the SPS. In addition, one-sixth of SPS participants were enrolled in a safety substudy. These participants completed a detailed report card regarding all medically important events within the first 42 days. Forty-eight percent of the vaccine group and 17% of the placebo group (P < .05) experienced adverse events, primarily at the injection site. Less than 1% of all local reactions were severe.29 Serious adverse events were rare (< 2%), but occurred significantly more often in the vaccinated group.

Short-Term Persistence Substudy

Short-term efficacy of the live-attenuated vaccine (up to 7 years) was assessed in the Short-Term Persistence Substudy (STPS), which involved 14,270 of the initial participants and reported yearly and overall vaccine efficacy.30 After 5 years, the yearly efficacy against postherpetic neuralgia incidence declined to 32% and was no longer statistically significant. Efficacy against HZ incidence and burden of illness displayed the same pattern. After the end of the STPS, all subjects in the placebo group received vaccination.

Long-Term Persistence Substudy

Those in the intervention group were followed for an additional 4 years in the Long-Term Persistence Substudy (LTPS).31 Due to the lack of concurrent controls in the LTPS, the authors used regression models based on historical controls to estimate contemporary population incidence of HZ and postherpetic neuralgia for comparison.

Efficacy continued to decline over time, and by 10 years after vaccination there was no difference between vaccinated patients and historical controls in the rate of any end point (ie, efficacy declined to zero).

A trial of booster vaccination

Because many patients are vaccinated at age 60, waning immunity could leave them vulnerable to HZ and postherpetic neuralgia by age 70. A potential solution would be to give a booster dose after 10 years.

A recent phase 3 clinical trial of adults age 70 years and older found that a booster dose of live-attenuated vaccine was as safe and immunogenic as an initial dose.32 While antibody responses were similar in the boosted group and the newly vaccinated group, cell-mediated immunity was higher in the boosted group.

Because prevention of HZ is generally via cell-mediated immunity, the booster might be more effective than the initial vaccination, but clinical trials measuring actual cases prevented will be required to prove it. A booster dose is not currently recommended.

A trial of vaccination in adults 50 to 59

In 2011, the FDA extended its approval of HZ vaccine for use in adults ages 50 to 59.33

In a randomized, double-blind, placebo-controlled trial in this age group,33 the vaccine reduced HZ incidence by almost 70% (absolute risk reduction 0.614%, number needed to treat 156; Table 1), but the severity of HZ cases was not affected. There were too few cases of postherpetic neuralgia to assess the efficacy for this end point. The study followed patients for only 1.5 years after vaccination, so the duration of efficacy is unknown.

As in the older recipients, the vaccine was well tolerated; injection-site reactions and headache were the major adverse effects reported among vaccine recipients.33


Although HZ vaccine is licensed for use in adults age 50 and older, the ACIP recommends it only for immunocompetent adults age 60 and older. At this time, the ACIP does not recommend HZ vaccine in those younger than 60 because of the low risk of HZ in this age group.34

Any person age 60 or older should receive a single dose of the live-attenuated HZ vaccine subcutaneously, regardless of past history of HZ.

The vaccine is contraindicated in patients who have a history of allergic reaction to any vaccine component, immunosuppression or immunodeficiency conditions, and pregnancy. Specifically, people who will receive immunosuppressive therapies should have the vaccine at least 14 days before beginning treatment. Antiviral medications such as acyclovir, famciclovir, and valacyclovir should be discontinued at least 24 hours before vaccination and not resumed until 14 days later. Patients taking high-dose corticosteroids for more than 2 weeks should not be vaccinated until at least 1 month after therapy is completed.

In contrast, HZ vaccine is not contraindicated for leukemia patients who are in remission and who have not received chemotherapy or radiation for at least 3 months, or for patients receiving short-term, low-to-moderate dose, topical, intra-articular, bursal, or tendon injections of corticosteroids. Patients on low-dose methotrexate, azathioprine, or 6-mercaptopurine can also receive the vaccine.18

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Thoughtful vaccination

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