Shingrix: Excellent Vaccine Against Shingles

SUMMARY

• Shingles (herpes zoster) is a common disease that causes a rash and pain.
• The risk of encountering shingles increases dramatically with age.
• Shingrix (RZV) by GlaxoSmithKline is the only vaccine that provides unequivocally powerful and reliable protection against shingles.
• Once vaccinated with Shingrix, immunity against shingles lasts for 10 years or even longer.
• The pharmaceutical industry continues to look for options to improve the protective performance of Shingrix.

 

WHAT HAPPENED

The efficacy of the Shingrix (RZV) vaccine in preventing herpes zoster is maintained for at least ten years following vaccination.

Shingrix is a vaccine indicated for the prevention of herpes zoster and postherpetic neuralgia (PHN).

The preventive protection provided by Shingrix is comparable to, or even exceeds, 90% and lasts for many years, regardless of age (in individuals without compromised immunity).

The inactivated recombinant Shingrix vaccine, developed by GlaxoSmithKline, is administered intramuscularly in two doses, with an interval of two to six months between them.

Prior to the availability of Shingrix, only one vaccine was available to prevent shingles: live attenuated Zostavax (ZVL) by Merck & Co. The immunization efficacy of Zostavax is mediocre, with a reduction in the risk of disease development of only 51% and a reduction in the risk of postherpetic neuralgia of only 67%.

 

WHY IT MATTERS

In individuals who have experienced chickenpox (varicella), usually during childhood, the virus that caused the infection persists in the neurons of the dorsal root ganglion and cranial nerves. Reactivation of the latent (dormant) varicella zoster virus (VZV; human herpesvirus 3, HHV3; human alphaherpesvirus 3) results in another form of the infection, shingles (herpes zoster).

The likelihood of developing shingles increases as T cell immunity declines. Consequently, those at risk include the elderly and individuals with weakened immune systems [1], as well as those with chronic diseases such as chronic obstructive pulmonary disease (COPD), diabetes mellitus, or asthma [2].

The disease, which affects approximately one-third of the population in some form [3] [4] [5] [6], is characterized by a range of symptoms, including pain (e.g., stinging, tingling, itching, numbing, throbbing, and oversensitivity) and a dermatomal distribution of blistering skin eruptions [7] [8] [9] [10].

The rash associated with shingles typically resolves within two to four weeks. However, in one-fifth of patients, persistent postherpetic neuralgia (PHN) can occur months or years after the skin lesions have healed.

Among many other complications: herpes zoster ophthalmicus, Ramsay Hunt syndrome (herpes zoster oticus), myelopathy, aseptic meningitis, encephalitis, polyneuropathy (including Guillain–Barré syndrome), polyradiculitis, vasculopathy, acute retinal necrosis, and progressive outer retinal necrosis.

The treatment of shingles, which should be initiated within 72 hours of disease onset, involves the administration of systemic antiviral drugs, including valaciclovir, famciclovir, aciclovir, brivudine, foscarnet, and amenamevir.

 

HOW IT WORKS

Shingrix (GSK1437173A) is an inactivated recombinant subunit vaccine combining the varicella zoster virus (VZV) envelope glycoprotein E (gE) antigen and the AS01_B adjuvant system to improve immunologic response [1] [2] [3].

The immune system’s exposure to the gE protein stimulates the production of antibodies against it, thereby generating adaptive immunity against VZV.

The proprietary AS01_B adjuvant, encapsulated in a liposomal formulation, comprises 3-O-desacylated 4′-monophosphoryl lipid A (MPL) from Salmonella minnesota and saponin molecule (QS-21) purified from the plant extract of Quillaja saponaria.

MPL, which functions as an agonist of toll-like receptor 4 (TLR), stimulates antigen-presenting cells (APCs) through activation of innate immunity. QS-21 acts as a stimulator of innate pathways in monocytes. Liposomal formulation offsets the intrinsic hemolytic activity of QS-21 and also enhances antigen presentation compared to the AS02 emulsion formulation [4] [5] [6] [7] [8] [9].

 

AVAILABILITY

Shingrix (RZV) was first made available for sale in Canada in mid-October 2017 [1].

In the United States, Shingrix has received FDA approval twice. The first approval was granted in late October 2017 for the prevention of shingles among individuals aged 50 years and older [2]. Subsequently, in late July 2021, Shingrix was approved for the same indication in individuals aged 18 years and older who are at risk of developing shingles due to immunodeficiency or immunosuppression due to disease or therapy [3].

In Europe, Shingrix secured similar marketing authorizations from the European Medicines Agency (EMA) in late March 2018 and late March 2020 [4].

 

BIG MONEY

While GlaxoSmithKline traded 2.96 billion pounds ($3.67 billion) worth of Shingrix (RZV) vaccine in 2022, its sales in 2023 were 3.45 billion pounds ($4.27 billion).

Shingrix was able to cross the $1 billion sales bar instantly: a year after its launch.

The remarkable demand for Shingrix is nothing compared to Zostavax (ZVL), which, having debuted in May 2006, failed to become a blockbuster: interest peaked in 2014, when it brought Merck & Co. $765 million.

Given the superior superior efficacy of Shingrix, the sunset of Zostavax was imminent. In mid-November 2020, Merck & Co. ceased its promotion in the United States, the primary market for any pharmaceutical product [1].

The story has a downside as well. In due course, Gardasil / Gardasil 9 by Merck & Co. displaced Cervarix by GlaxoSmithKlein from the U.S. human papillomavirus (HPV) vaccination business. Thus, while the former achieved global sales of an impressive $3.94 billion in 2023, the latter’s global sales amounted to a modest 117 million pounds ($145 million).

 

EFFECTIVENESS

The ZOE-50 (ZOSTER-006, NCT01165177) and ZOE-70 (ZOSTER-022, NCT01165229) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trials involved more than 31,000 individuals aged ≥ 50 and ≥ 70 years, respectively, and followed-up for a median of 3.1 and 4.0 years after vaccination with Shingrix (RZV). The results demonstrated a high shingles preventive efficacy of Shingrix, as evidenced by the following findings [1] [2] [3] [4]:

• ≥ 50 years: 97% (95% CI [hereafter]: 94–99)
• ≥ 60 years: 98% (93–100)
• ≥ 70 years: 91% (87–95)
• ≥ 80 years: 91% (80–97).

Shingrix was similarly successful in preventing the development of postherpetic neuralgia (PHN):

• ≥ 50 years: 100% (77–100)
• ≥ 60 years: 100% (41–100)
• ≥ 70 years: 89% (69–97)
• ≥ 80 years: 71% (−52, 97).

Shingrix demonstrated efficacy in the prevention of shingles-associated complications other than PHN, such as vasculitis, stroke, and disseminated, ophthalmologic, neurologic, or visceral disease. The prophylactic efficacy was 94% (60–100) and 92% (43–100) in individuals aged ≥ 50 and ≥ 70 years, respectively [5].

Shingrix reliably prevented the development of shingles for a long time after immunization, successfully overcoming the problem of aging of the immune system and providing durable protection regardless of age. Thus, following vaccination with Shingrix, the preventive shield was maintained for at least 3 years in individuals aged ≥ 50 years [6] [7]. Vaccine efficacy over a median of 7 years was 91% (88–93), while the level of protection varied as follows: 98% → 93% → 92% → 90% → 85% → 85% → 84% [8].

• In contrast, the efficacy of Zostavax (ZVL) vaccine for the prevention of herpes zoster in individuals aged ≥ 50 years declined rapidly, reaching 68% (65–70) in the first year following vaccination, 47% (44–50) during the second year, and 32% (15–45) after eight years [9].

A long-term follow-up of participants (n>7000) in the ZOSTER-049 (NCT05371080) phase 3 (randomized, open-label, multicenter, international) clinical trial revealed that immunity against herpes zoster persisted for an extended period at a relatively high level following vaccination with Shingrix [10]. The indicators of sustained protective efficacy are as follows:

• ≥ 50 years: 80% (74–85) between 6 and 11 years after vaccination
• ≥ 50 years: 82% (63–92) in the 11th year after vaccination
• ≥ 70 years: 73% (63–81) between 6 and 11 years after vaccination.

The ZOSTER-002 (NCT01610414; #1) and ZOSTER-039 (NCT01767467; #2) phase 3 (randomized, double-blind, placebo-controlled, multicenter, international) clinical trials invited adult (18 years and older) patients (n=1721 and n=515) with weakened immune systems (immunocompromised) who, respectively, underwent an autologous hematopoietic cell transplantation or with hematologic malignancies (multiple myeloma, non-Hodgkin’s B-cell lymphoma, chronic lymphocytic leukemia, etc.) [11] [12].

The protective efficacy of Shingrix was:

• ≥ 18 years (#1): 68% (55–78)
• ≥ 50 years (#1): 67% (53–78)
• ≥ 18 years (#2): 87% (44–99).

The efficacy of Shingrix in the task of preventing postherpetic neuralgia (PHN) is as follows:

• ≥ 18 years (#1): 89% (23–100)
• ≥ 50 years (#1): 88% (10–100).

The NCT02581410 phase 3 (non-randomized, open-label, multicenter) clinical trial confirmed that Shingrix was successful in preventing shingles among individuals previously vaccinated with the alternative vaccine Zostavax [13] [14].

The NCT01954251, NCT02045836, NCT03439657, and NCT02052596 phase 3 (randomized, open-label, multicenter, multicenter, international) clinical trial have demonstrated that Shingrix can be co-administered without any problems with other vaccines, including the influenza vaccine Fluarix, the pneumococcal vaccine Pneumovax 23 or Prevnar 13, and the tetanus, diphtheria, and pertussis vaccine Boostrix. No evidence of reciprocal interference with the immune response by the antigens contained in these vaccines has been found [15] [16] [17] [18]. Co-administrated vaccines is appropriate to inject into different anatomical sites [19] [20].

The ZOSTER-026 (NCT01751165) phase 3 (randomized, open-label, multicenter, international) clinical trial showed that the second (boost) dose of Shingrix can be given equally 2 or 6 months after the first dose [21].

 

ALTERNATIVES

As of October 2017, SKYZoster, a vaccine developed by a local SK Bioscience, is available in South Korea for the prevention of shingles in individuals aged 50 years and older [1].

The protective efficacy of the live attenuated vaccine SkyZoster (NBP608) is comparable to that of Zostavax (ZVL) by Merck & Co. [2].

In 2022, Skyzoster held 54% of the Korean market, with Zostavax holding the remaining 46% [3].

However, in 2023, the first year of Shingrix (RZV) availability, things changed dramatically. The GlaxoSmithKline vaccine instantly captured 44% of sales, leaving Skyzoster and Zostavax with 30% and 26% each. It is noteworthy that the clinical adoption of Shingrix was not hindered by its relatively high price of 500,000 won ($365), which is higher than the 150,000 won ($110) price of Skyzoster and the 170,000 won ($125) price of Zostavax [4].

In January 2023, China approved the first domestically developed vaccine to prevent shingles. The live attenuated vaccine was developed by Changchun BCHT Biotechnology [5].

 

MEANWHILE

In early 2024, Curevo Vaccine, backed by Korea’s CG Biopharma, notified the successful clinical validation of amezosvatein (CRV-101), an investigational adjuvanted subunit vaccine based on varicella zoster virus (VZV) glycoprotein E (gE) that has been directly compared to Shingrix (RZV) [1].

In the phase 2 clinical trial NCT05304351, the vaccine candidate amezosvatein demonstrated non-inferior prophylactic efficacy against shingles and an improved safety profile.

According to Curevo, despite the high level of protection against herpes zoster conferred by Shingrix, its uptake among those in need of the vaccination remains low. Consequently, it is estimated that two-thirds of Americans are not immunized against herpes zoster, while in Europe, China, and globally, less than 5% of those at risk of developing shingles have received Shingrix. One of the key issues is the tolerability of the GlaxoSmithKline vaccine. It has been reported that approximately 20%–30% of individuals who receive the first dose of Shingrix do not proceed with a second dose due to adverse events (AEs).

GlaxoSmithKline’s own studies have demonstrated a high prevalence of adverse events (AEs) following Shingrix administration. These include pain (80% on average), redness (38%) or swelling (27%) at the injection site, myalgia (47%), fatigue (47%), headache (40%), shivering (29%), fever (22%), nausea, vomiting, diarrhea, or abdominal pain (18%) [2]. Nevertheless, the AEs did not result in as high a failure rate for the second dose of Shingrix as Curevo assures [3] [4].

 

PIPELINE

Pharmaceutical companies are not giving up hope of coming up with new preventive vaccines that are more effective than Shingrix (RZV) in protecting against shingles and its complications.

In the fourth quarter of 2024, China’s Beijing Luzhu Biotechnology plans to submit an application for approval of LZ901, a recombinant shingles vaccine based on the varicella zoster virus glycoprotein E (gE) in a tetrameric form and backed by classical adjuvant aluminum hydroxide [1] [25].

China’s Jiangsu Recbio Technology is developing REC610, a recombinant gE vaccine with a proprietary BFA01 adjuvant, which is positioned as an improved version of Shingrix’s AS01_B adjuvant [2] [3] [4] [5].

China’s CanSino Biologics is collaborating with the UK’s Barinthus Biotherapeutics, formerly Vaccitech, on the development of VTP-400 (ChAdOx1-VZV, CS-2032, CSB-016), a shingles vaccine based on the chimpanzee adenovirus vector (ChAdOx1) encoding gE antigen [6].

China’s Immorna Biotechnology is optimistic about the potential efficacy of JCXH-105, a shingles vaccine based on self-replicating RNA (srRNA) encoding gE antigen [7] [8] [9].

China’s Maxvax Biotechnology is investigating a recombinant gE vaccine with a proprietary adjuvant, MA105, which is composed of polyinosinic:polycytidylic acid (Poly I:C) functioning as an agonist of toll-like receptor 3 (TLR3), a saponin molecule (QS-21) derived from the plant extract of Quillaja saponaria, and lipid molecules [10] [11].

Korea’s CHA Vaccine Research Institute is studying CVI-VZV-001, a recombinant gE vaccine with a proprietary adjuvant, L-pampo, which is an agonist of toll-like receptors 1/2 and 3 (TLR1/2 and TLR3) [12] [13] [14].

Korea’s EuBiologics relies on a recombinant shingles vaccine whose nanoliposomal particles display the gE antigen to the immune system together with the adjuvants EcML and CoPoP, which are monophosphoryl lipid A (MPL) from Escherichia coli and cobalt-porphyrin-phospholipid (CoPoP), respectively [15].

Korea’s GeneOne Life Science is working on the DNA shingles vaccine GLS-5100 (VGX-5100). Its underlying DNA plasmid encodes varicella zoster virus glycoprotein E (gE) and the immediate early (IE) 63 and IE62 proteins, as well as the adjuvants interleukin 7 (IL-7) and interleukin 33 (IL-33) [16] [17].

Korea’s EyeGene is investigating EZ-HZ, a recombinant gE vaccine with adjuvant CIA05, an agonist of toll-like receptor 4 (TLR4) [18].

Dynavax Technologies is engaged in clinical validation of Z-1018, a recombinant gE vaccine adjuvated with CpG 1018, which is a toll-like receptor 9 (TLR9) agonist, and optional aluminum hydroxide [19].

Not to be forgotten, of course, is mRNA technology, with BioNTech and Pfizer are testing BNT167 and Moderna is trying its hand at mRNA-1468. Academic institutions in China have developed Zosal and mgE@Syn-LNP. All these mRNA shingles vaccines encode the gE antigen [20] [21] [22] [23] [24].