Radhika A. Shah, BS, MS1; Allison L. Limmer, BA, BS2; Crystal E. Nwannunu, BS2; Ravi R. Patel, MD3; Uyen Ngoc Mui, MD3; Stephen K. Tyring, MD, PhD2,3

1Texas A&M University College of Medicine, Dallas, TX, USA
2Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
3Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Herpes zoster (HZ), also known as shingles, results from reactivation of the latent varicella-zoster virus (VZV), which commonly causes chickenpox in childhood. Greater than 90% of adults are infected with this virus, putting them at risk for reactivation. HZ presents as a painful, vesicular rash distributed in a unilateral and dermatomal pattern along dorsal root or cranial nerve ganglia. The rash often presents with prodromal symptoms and progresses to include clear vesicular clusters, evolving through stages of pustulation, ulceration, and crusting. HZ therapy currently involves the use of antiviral agents and pain management; however, HZ prophylaxis has been strongly recommended in older adults through vaccination with a live attenuated vaccine, Zostavax®. A new recombinant subunit vaccine, HZ/su (Shingrix®), is the subject of this review. In clinical trials, HZ/su demonstrated an overall vaccine efficacy of 97.2% among participants 50 years of age or older, indicating a significantly reduced risk of HZ in these individuals. Shingrix® was approved by the US FDA in October 2017 as HZ prophylaxis.

Key Words:
herpes zoster, rash, recombinant subunit vaccine, shingles, Shingrix, treatment, vaccine, varicella zoster virus


Herpes zoster (HZ), also known as shingles, results from reactivation of the latent varicella-zoster virus (VZV), which commonly causes chickenpox in childhood. HZ presents as a painful, vesicular rash distributed in a unilateral and dermatomal pattern along dorsal root or cranial nerve ganglia.1 This painful rash negatively affects patients’ quality of life (QoL) by impairing physical, emotional, and social functioning.2 Greater than 90% of adults are infected with this virus, putting them at risk for reactivation. Reactivation often occurs in adults over the age of 50 due to immunosenescence but can occur at any age, especially in those who are immunocompromised.1 Complications of HZ include postherpetic neuralgia, which occurs in 10-20% of patients and increases in frequency and severity with age.1,2


HZ is one of the two distinct syndromes caused by VZV. Primary disease is known as varicella infection or chickenpox, a contagious, frequently benign illness occurring predominantly among susceptible children.3 Upon resolution of primary infection, VZV establishes a lifelong latency within the cranial or dorsal root ganglia.4 Major risk factors for reactivation include older age, family history of zoster, immunosuppression, and in utero or early infancy primary varicella infection, with older age being the most significant risk factor.4 As the virus-specific T cell-mediated immune response declines or becomes impaired, the subsequent reactivation of latent VZV in the root ganglia results in a dermatomal and localized maculopapular eruption known as shingles.4 Shingles often presents with prodromal symptoms such as headache, malaise, photophobia, and skin sensations ranging from itching to tingling to severe pain.3 The erythematous maculopapular rash progresses to include clear vesicular clusters, evolving through stages of pustulation, ulceration, and crusting.3 Cutaneous healing occurs within 2 to 4 weeks of rash onset. Scarring, hypo/hyperpigmentation, and postherpetic neuralgia are common sequelae.3

Current Treatments

Current HZ therapies consider both disease prevention and acute outbreak management. Antiviral agents including acyclovir, valacyclovir, and famciclovir are FDA-approved for the treatment of active HZ.3 Valacyclovir and famciclovir are preferred to acyclovir, but all three oral drugs have been shown to reduce the duration of pain secondary to postherpetic neuralgia when compared to placebo.3 HZ is often accompanied by significant pain and discomfort; thus, acute management should include symptom control.3 Analgesia can be achieved by neural blockade, oral or transdermal narcotics, and topical anesthetics.3 Pain caused specifically by postherpetic neuralgia can also be managed with gabapentin, pregabalin, tricyclic antidepressants, and opioids.3,5 Gabapentin or pregabalin, however, are most effective when initiated during acute zoster.6

In addition to acute treatment, HZ prophylaxis is an important public health consideration. As shingles results from reactivation of latent VZV, prevention of primary varicella infection can be considered the first step in HZ prevention. Often, two doses of the live attenuated single-antigen varicella virus vaccine (Varivax®) is administered to children over 12 months of age.7,8 At the age of 50, patients can receive a live, attenuated, single-dose vaccine specifically targeted at HZ (Zostavax®).9,10 This vaccine reduces the incidence and duration of shingles and postherpetic neuralgia.9 Alternatively, a two-dose shingles vaccine was recently brought to market; it is a non-live, recombinant glycoprotein E vaccine.1,11 The virus glycoprotein is combined with an adjuvant (AS01B) and is available to adults aged 50 or older.1 This newer vaccine (Shingrix®) is the subject of this review.1,11

Phase Trials

Shingrix®, a recombinant subunit vaccine also known as HZ/su, contains the VZV glycoprotein E and the AS01B adjuvant system.1 VZV glycoprotein E is involved in viral replication and cell-to-cell spread and, for this reason, was selected as the vaccine antigen in combination with the AS01B adjuvant system, which strongly promotes humoral and CD4+ T cell-mediated immunity against recombinant proteins. Phase I and II clinical trials were previously performed in older adults and those who were immunosuppressed and demonstrated that the vaccine stimulated an immune response that persisted for at least 3 years with an adequate safety profile. Because of the positive outcomes, researchers began the ZOE-50 phase III trial to evaluate the efficacy of two doses of HZ/su in reducing the risk of HZ in adults 50 years of age or older.1

ZOE-50 was a randomized, placebo-controlled study conducted in several countries around the world. Adults who were 50 years of age or older were eligible to participate in the study unless they met certain exclusion criteria, including history of HZ, previous vaccination against VZV or HZ, or current immunosuppressive condition. The patients were randomly assigned to receive either the vaccine or placebo in a 1:1 ratio and were stratified according to region and age group. Although the appearances of the vaccine and placebo differed, those who administered the injections were not involved in any study assessment. Therefore, the study remained double-blinded. Between August 2010 and July 2011, 16,160 participants were enrolled, but 749 were excluded due to deviations from Good Clinical Practice (GCP) standards. Of the remaining participants, 95.8% (14,759) were included in the modified vaccinated cohort. The modified vaccinated cohort excluded participants who did not receive the second dose of HZ/su or who had confirmed cases of HZ within 1 month after the second dose of the vaccine. In addition, 8,926 participants were assigned to the reactogenicity subgroup (4,460 in the HZ/su group and 4,466 in the placebo group).1

The vaccine, containing 50 μg of recombinant VZV glycoprotein E, is also made up of the liposome-based AS01B adjuvant system, containing 50 μg of 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and 50 μg of Quillaja saponaria Molina, fraction 21 (QS21, a purified extract from the bark of the Quillaja saponaria tree).1 MPL specifically causes activation of innate immunity resulting in cytokine production. QS21 causes stimulation of CD4+ and CD8+ T cells and antigen-specific antibody responses.12 The vaccine and placebo (0.9% saline solution) were administered as two 0.5 mL doses into the deltoid muscle at months 0 and 2. Participants were followed for a minimum of 30 months starting 1 month after the second dose.1

In total, 408 participants reported suspected HZ, of which 244 (59.8%) were confirmed through PCR assay and the ascertainment committee. Suspected cases were defined as unilateral rashes with pain which had no alternative diagnoses. Any suspected case of HZ was examined by study investigators within 48 hours of emergence and samples were taken for virus confirmation via real-time polymerase chain reaction. Efficacy was calculated using the Poisson method. In the modified vaccinated cohort, 216 cases out of 7,344 participants of HZ were confirmed after a mean follow-up of 3.2 years, with 6 in the HZ/su group and 210 in the placebo group. Overall, the incidence of HZ per 1000 person-years was 0.3 in the HZ/su group and 9.1 in the placebo group, which demonstrated a significant overall vaccine efficacy of 97.2% among participants 50 years of age or older (p<0.001). No significant difference in vaccine efficacy was seen among the three age groups (96.6% to 97.9%).1


A subgroup designated the “reactogenicity” subgroup of participants was formed to monitor the occurrence of adverse events.1 The subgroup was made up of all participants over the age of 70, as well as a random assortment of patients aged 50-69. These patients recorded injection-site reactions including pain and swelling as well as systemic reactions including gastrointestinal upset and headache for 7 days following each dose of the recombinant vaccine. Each symptom was also graded on a scale of 0 (not present) to 3 (interfering with daily activities). Any additional adverse events were monitored for 30 days after each dose. Lastly, serious adverse events were recorded in all patients for at least 1 year after the second vaccine dose.1

Within the reactogenicity subgroup, 84.4% of HZ/su-group patients versus 37.8% of placebo-group patients reported symptoms within 7 days of vaccination. Although most symptoms were of mild-to-moderate severity, 17% of HZ/sugroup patients and 3.2% of placebo-group patients experienced grade 3 symptoms. Injection site reactions were noted in 81.5% of patients who received HZ/su and in 11.9% of patients who received placebo. Systemic reactions were recorded in 66.1% of HZ/su patients and in 29.5% of placebo patients. The most commonly reported injection site reaction was pain (79.1% of HZ/su versus 11.2% of placebo), and the most commonly reported systemic reaction was myalgia (46.3% of HZ/su versus 12.1% of placebo). Reactions had median durations ranging from 1 to 3 days, and grade 3 systemic reactions were statistically more common after the vaccine’s second dose (8.5% after second dose versus 5.9% after first dose, with non-overlapping 95% confidence intervals).1

Among all study participants, 231 serious adverse events were recorded within 30 days of vaccine administration, 103 in HZ/su-group and 128 in placebo-group patients. Adverse events were evaluated, and 4 such events (1 in an HZ/su recipient and 3 in placebo recipients) were considered related to vaccination – hypotension with syncope, mononeuritis, neurosensory deafness, and musculoskeletal chest pain. At publication, with a mean of 3.5 years of follow-up, no major safety concerns related to the vaccine were identified by either the investigators or independent monitors.1

Future Trials and Considerations

Future trials for the HZ/su vaccine included ZOE-70, a sister study to ZOE-50 that would further investigate the vaccine in subjects only ≥70 years of age, as the ZOE-50 trial was not intended to definitively assess the efficacy of the vaccine within the ≥70 age group.1 When the ZOE-70 trial was completed (September 2016), trial endpoints in the ZOE-50 trial were further analyzed and evaluated.13 The results revealed that the adjuvanted HZ/su was efficacious in reducing the risk of HZ and also postherpetic neuralgia in adults ≥70 years of age.13 In addition, the vaccine displayed similar efficacy between the two age groups studied (70-79 years of age and ≥80 years of age), indicating that there was no decline in efficacy with increasing age and that an age-independent immune response is the most likely protective mechanism of this vaccine.13 This greatly differed with the approved live attenuated vaccine (Zostavax®), which was found to decline in efficacy with increasing age.13

Further trials of the adjuvanted subunit HZ/su vaccine include current ongoing clinical trials examining the vaccine immunogenicity and safety in renal transplant recipients and evaluating HZ/su efficacy in autologous hematopoietic stem cell transplant (HSCT) recipients.14 In addition, a direct head-to-head comparison study between Zostavax® and HZ/su in the older adult population (ages 50-85) is currently underway to compare the age effect and persistence of both vaccines’ immune responses.14


Shingrix®, a new recombinant subunit vaccine, has shown a great deal of promise in the prevention of HZ in adults over the age of 50. The combination of zoster viral glycoprotein E and the AS01B adjuvant system make it a safe, efficacious option for the elderly as well as immunosuppressed individuals. In addition, by preventing HZ, individuals can avoid postherpetic neuralgia, a long-term, debilitating complication associated with HZ. Due to its demonstrated efficacy and safety, Shingrix® is now considered the first-line prophylactic vaccine for those at risk of HZ.


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  13. 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 Sep 15; 375(11):1019-32.

  14. Bharucha T, Ming D, Breuer J. A critical appraisal of ‘Shingrix’, a novel herpes zoster subunit vaccine (HZ/Su or GSK1437173A) for varicella zoster virus. Hum Vaccin Immunother. 2017 Aug 3;13(8):1789-97.

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