Current status of immunisation for herpes zoster

ABSTRACT

Herpes zoster (HZ) is increasingly common in the aging and is experienced by approximately one in three people in their lifetime. It is also relatively common in immune-compromised people. Acute HZ causes severe pain, reduced quality of life and severe complications, including prolonged pain, or postherpetic neuralgia (PHN), and ocular zoster, which may rarely progress to blindness. In severely immune-compromised people disseminated zoster may affect the brain and liver. A second-generation vaccine, the Recombinant Zoster Vaccine, consisting of recombinant viral glycoprotein E and the Adjuvant System 01 (AS01B), now offers >90% efficacy against HZ and associated complications in immune-competent people. Efficacy persists above 80% for 11 years. In severely immune-compromised patients, the vaccine is safe with efficacy and/or immunogenicity of 68–87%. There is also excellent immunogenicity for those on JAK inhibitors and corticosteroid therapy. The vaccine offers a paradigm for successful and durable immunization in the aging and immune-compromised.

Introduction

Information on Recombinant Zoster Vaccine (RZV) from detailed analysis of the original phase 3 trials and new studies are continually being reported. In particular, the durability of the vaccine’s high efficacy has been remarkable, especially in aging people, and the 11-year results have just been reported. Furthermore, RZV provides a paradigm for highly efficacious, durable vaccines in the aging. The adjuvant AS01B is now being used in other licensed vaccines for the aging population, such as for respiratory syncytial virus. This review focuses on updating recent progress with RZV in the context of past seminal results.

Relevant epidemiologic and clinical aspects of herpes zoster in immune-competent people

After initial infection, Varicella zoster virus (VZV) spreads to the dorsal root or trigeminal nerve ganglia via blood or retrogradely from cutaneous nerves¹ and remains latent there for life. During age-dependent decline in immunity, referred to as immunosenescence, or immunosuppression caused by disease or drugs, the virus reactivates from these sites to cause Herpes zoster (HZ). The virus causes inflammation at the dorsal root ganglion and along the nerve as it is transported to the skin dermatome. This results in neuritic pain, which may be severe, and a characteristic papulovesicular rash in the innervated dermatome.² This pain may persist beyond 90 days after onset of the rash as postherpetic neuralgia (PHN) in 12% of people over 50 years of age (YOA) and 17% of people over 70YOA.^3,4 Reactivation is controlled by specific immunity, especially T-cell mediated immunity. This declines with advancing age, starting over 50YOA. Immunosenescence predisposes to an increasing incidence of HZ, ranging from 3–5 per 1000 person years for the general adult population to >10 per 1000 person years for those over 70YOA, in almost all countries. Overall, one in three people have a lifetime risk of HZ and this increases to one in two over the age of 85 years.^5,6 Another major complication is ophthalmic zoster (HZO) which results from HZ in the first division of the trigeminal nerve. It occurs in 4–20% of HZ and the incidence increases with age. 50% of people with HZO develop ocular disease and it can cause blindness, albeit rarely. 25% develop recurrent or chronic disease.^6–9 Indeed, recurrent HZ may recur in all dermatomes. It usually commences about one year after the first episode and reaches an incidence of about 6 to 8% over eight years in the other dermatomes.¹⁰

Herpes zoster in immunocompromised patients

The risk of HZ is increased in people who are moderately to severely immunocompromised. This includes those with hematologic or other malignancies, those undergoing hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), those with HIV infection and immunosuppression and those receiving immunosuppressive drugs such as 20 mg/day or more of prednisolone or equivalent for over two weeks.^11,12 The incidence and severity of HZ increases proportionately with the degree of immunosuppression.

Highly immunocompromised patients receiving allogeneic or autologous HSCT have a very high incidence of HZ at 8 to 21% in the first two years after HSCT.¹³ They are also at increased risk of visceral dissemination. In SOT recipients HZ incidence was reported as 22 to 32 per 1000 person years and in patients with a solid tumor receiving chemotherapy incidence is ~14 per 1000 person years. Prior to the use of antiretroviral therapy, the risk of HZ in people with HIV infection was ~32 per 1000 person years, 10-fold higher than in age matched populations. Now in treated patients, it is still 2–3-fold higher than age-matched populations, especially if the CD4+ T cell counts remain below 200 cells/mL. HZ complications are increased threefold and include PHN.¹² Patients being treated for autoimmune diseases with immunosuppressive drugs and biologicals including disease modifying antirheumatic drugs (DMARDs, e.g., for rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis) are moderately immunocompromised and also at increased risk of HZ. In particular, JAK inhibitors lead to a fivefold increase in risk, much higher than other DMARDs.¹⁴

Vaccines for herpes zoster

The hypothesis that T cell immunity could be boosted in aging people by varicella vaccine was proven by proof-of-concept studies and led to successful trials of the more concentrated live attenuated zoster vaccine (ZVL),¹⁵ essentially, the first-generation vaccine for HZ. Although 51% efficacious against HZ and PHN in people over 60YOA, efficacy declined with age (41% in those > 70YOA) and over time (4–32% in all those over 60 YOA over 8 years).^16–18

The recombinant zoster vaccine (RZV)

The recombinant zoster vaccine (RZV or Shingrix) is now the only HZ vaccine available in many countries and has been the only vaccine recommended for moderately and severely immunocompromised patients.

RZV consists of a single viral surface protein, glycoprotein E, and the AS01B adjuvant system. Glycoprotein E (gE) is essential for viral replication and is abundant in VZV infected cells.^19,20 It is the major target for antibody and cellular immune responses to VZV during infection and is efficiently produced by recombinant technology.^10,21 AS01B consists of monophosphoryl lipid A (MPL, a toll-like receptor 4 agonist) and QS-21 a saponin, all encased within a liposome. After intramuscular injection, RZV drains rapidly to the axillary lymph nodes and initiates a cascade of multiple immune cell types and cytokines to stimulate anti-gE antibodies and T cells.^22–24 The adjuvant is crucial for the vaccine’s marked immunogenicity and efficacy.

RZV efficacy, immunogenicity and safety in immunocompetent people immunogenicity

Phase 1 and 2 clinical trials showed that RZV stimulated strong humoral and CD4 T cell responses to gE in adults aged 50 years or older, including those aged over 70 years. AS01B was critical for optimal responses, especially in people over the age of 70 years, where it increased the proportion of those with CD4 T-cell responses from 10 to 90%. The first dose of RZV induces a partial T cell response, but two doses 2–6 months apart are needed for this to be optimal.^25,26

Efficacy of RZV

Two large randomized, placebo-controlled phase 3 trials, the Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50) and Zoster Efficacy Study in Adults 70 Years of Age or Older (ZOE-70), were conducted in 29,300 immunocompetent adults to determine efficacy of RZV in preventing HZ and PHN.^27,28 Approximately half received RZV and half placebo, with good demographic matching. These trials were run in parallel at the same study sites in 18 countries, allowing pooling of results. Trial participants were followed for development of HZ and/or PHN for 3.2 years for ZOE50 and 3.7 years for ZOE70.^27,28 The ZOE-70 study markedly increased the number of participants with PHN.²⁷ RZV had an efficacy of >91% against HZ, even in people aged over 80 years. Follow-up studies showed this efficacy to be durable. Overall efficacy over 11 years was 87% for those >50 YOA and 84% for those >70YOA. Annual efficacy at year 11 was 82% and 72% for those >50 and >70YOA, respectively (Figure 1).^29–31 This shows RZV to be the most efficacious and durable vaccine yet for the aging. Two retrospective vaccine effectiveness studies, using databases, confirmed the high effectiveness of RZV, although slightly lower in one (86% and 70%, respectively) likely due to the reliability of databases for diagnosis (e.g. defining HZ according to antiviral drug use). One of them showed a decrease in effectiveness of 13% (to 56%) if only a single dose was administered.^32,33

Figure 1.

Studies of the durability of the recombinant zoster vaccine.

Follow-up studies of the long-term efficacy of RZV ZOE-50/70: original pivotal phase 3 trials of RZV over four years in participants aged over 50 years, pooled with those over 70 years. LFTU: long-term follow-up study over 6 years. Efficacy: vaccine efficacy in years 1, 4, 6 and 11 after last of two immunizations. The last two represent year 1 and year 6 of the LFTU study.

RZV efficacy against PHN

RZV vaccine efficacy against PHN was 91% in adults aged 50 years or older and 89% for those aged 70 years or more, using pooled data from the ZOE-50 and ZOE-70 trials.^26,27 This efficacy against PHN was due solely to prevention of HZ. Follow-up analysis of these trials showed attenuation of acute pain and pain medication to be reduced during breakthrough cases of HZ in immunized patients.³⁴ The numbers needed to vaccinate with RZV to prevent one case of HZ was 8–11 and of PHN was 39–53.³⁵ RZV also significantly protected against other complications of HZ, including ocular HZ, disseminated disease and neurological disease, including vasculitis and stroke, and visceral disease. Unlike certain other vaccines for the aging, efficacy against HZ was not reduced in those patients with frailty or multiple comorbidities, which are common in those over 70.^36,37

Reactogenicity and safety of RZV

Vaccine reactogenicity is local at the injection site or systemic. Injection site reactions were much more frequent in RZV than placebo recipients in the first seven days after RZV administration (82% vs 12%).²⁸ Pain was the most common local reaction (79% of RZV recipients). Systemic reactions, the commonest being myalgia and fatigue, were also more frequent in RZV than placebo recipients (66% vs 30%). Reactogenicity diminished with older age. Vaccine recipients are more concerned about reactions preventing normal daily activity, which were defined as severe or ‘grade 3’ local and systemic reactions. They occurred in 9.5% and 11% of RZV recipients, respectively. However, overall reactions to RZV lasted only one to three days and less for grade 3 reactions (1–2 days). Nevertheless, 95% of recipients returned for a second dose, including 91% of recipients with grade 3 reactions. Therefore, such reactogenicity was tolerated by most recipients. Grade 3 reactions were similar in incidence after the first and second doses; however, only a third of those with such reactions after the first dose experienced them after the second dose.³⁸ In addition, there was only a weak association between such reactogenicity and good RZV immunogenicity.³⁹ Such dissociation suggests the potential for future vaccine modification to retain immunogenicity and reduce reactogenicity, especially at the injection site.

In ZOE-50 and ZOE-70, 14650 adults aged 50 years or older received RZV, with a similar number administered placebo. The incidence of serious adverse events (10.1% vs 10.4%) and fatalities (4.3% vs 4.6%) were similar between vaccine and placebo recipients and are therefore attributable to the aging population rather than the vaccine.^27,28,40 The low incidence of potential immune-mediated diseases was also similar between vaccine and placebo recipients (1.1% vs 1.3%). This is important as theoretical concerns have been raised about the potential immune effects of new immunomodulating adjuvants. However, an epidemiologic community-based study showed an extremely low incidence (3 per million recipients) of Guillain–Barré syndrome in the first 42 days after each dose of RZV. This incidence is similar to that of influenza and adenovirus vectored vaccines.⁴¹

RZV was also safe when administered five years after natural herpes zoster (physician documented) and induced anti-gE antibody in more than 90% of patients aged 50 years or over.⁴² It was equally immunogenic and safe when administered to patients five years after ZVL compared to unimmunized recipients.⁴³ The latter results are important in countries where there is high ZVL coverage. This has led to recommendations from National Immunisation Technical Advisory Groups (NiTAGs) in several countries for RZV to be given at one year or more after natural HZ or ZVL. In other countries, including the USA, RZV is recommended soon after full recovery from HZ. However, a recent retrospective study in the USA reported a small but significant increase in recurrent ocular HZ when patients received RZV within 56 days after an episode of ocular HZ.⁴⁴ This study needs to be confirmed but, in the interim, has led to recommendations in the USA for RZV administration to be delayed after ocular HZ. In most other countries where the recommendation is to wait one year after a prior episode of HZ, this is not an issue.

Coadministration with other vaccines

RZV is safe, and immunogenicity is similar after coadministration with unadjuvanted inactivated seasonal influenza, pneumococcal (PPV23), COVID-19 RNA and diphtheria-tetanus-pertussis (DTaP) vaccines.^45–47

RZV efficacy, immunogenicity and safety in immunocompromised people

The immunogenicity, safety, reactogenicity and/or efficacy of RZV in moderately to severely immunocompromised patients was examined in five phase 2 and 3 clinical trials.^48–52 Two doses of RZV were given one to two months apart, with follow up 12 months later to patient cohorts with either autologous HSCT, SOT, hematologic malignancy or with solid tumors receiving chemotherapy. In patients with hematological malignancies, including chronic lymphatic leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma and myeloma, and aged 18 years or older, RZV was administered during or after chemotherapy. 73% of this cohort were aged over 50 years. After RZV, significantly increased T cell responses were observed in 84% of patients and gE antibody responses in 60% of them. In a post-hoc analysis, vaccine efficacy against HZ was 87%.⁴⁸

However, in the largest phase 3 trial, 1846 patients received RZV, 50 to 70 days after autologous HSCT for acute myeloid leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma or multiple myeloma. The immune responses to RZV were excellent: 89% showed significant T cell responses and 71% significant gE antibody increases. Vaccine efficacy against HZ was 68%, against PHN 89%, against other complications 78% and hospitalization 85%. In patients receiving rituximab for B-cell lymphomas and chronic lymphocytic leukemia, vaccine efficacy was similar.⁴⁹

In patients undergoing SOT, 64% had a T-cell response and 74% a gE antibody response.⁵⁰ Immune response to RZV was lowest in patients with solid tumors receiving chemotherapy: a T cell response was observed in only in 46%, but 92% had a gE antibody response.⁵¹

Patients with HIV infection were stratified into three subgroups by CD4+ T-cell count. They received three vaccine doses at zero, two and six months, and were followed up for 18 months. In this cohort RZV induced excellent T-cell and gE antibody responses which persisted until the end of the study, with no effect of antiretroviral therapy. The third dose did not improve the immune responses.⁵²

Where patients cannot be administered RZV immediately after induction of immunosuppression, antiviral prophylaxis for HZ with valaciclovir or famciclovir should be continued until immune responses are restored. Therefore, in the HSCT trials the first dose of RZV was administered 50 to 70 days after transplant and the second dose one to two months later. The peak of antibody and T cell responses occurred one month after the second dose.⁴⁹ The US Centres for Disease Control and Prevention recommends that, if possible, patients receive RZV at 3–12 months after HSCT or before transplantation (or chemotherapy). If this is difficult, then RZV should be administered when immunosuppression is reduced.⁵³

The next patient cohort to be targeted for RZV trials are moderately immunocompromised patients on immunosuppressive medication for autoimmune diseases. These include chemical and biological agents, some of which are antirheumatic drugs or DMARDS. JAK inhibitors are the most potent of these agents in predisposing to HZ¹⁰ so several trials to examine RZV efficacy in such people are in progress. In the interim, recent studies of vaccine immunogenicity are reassuring, showing that RZV stimulated increased anti-gE antibody in 80 to 100% of people on JAK inhibitors. However, T cell responses were not reported.^54,55

RZV reactogenicity and safety in immunocompromised people

RZV is safe for immunocompromised patients, including those accidentally immunized, because it is not a live vaccine.^24,56

Local or injection site reactogenicity in all five of the above trials (75–85%) was quite similar compared to immunocompetent people in the ZOE50/70 trials (84% for those 50 years and over and 79% in those 70 years and over.^27,28 However, systemic reactogenicity was markedly increased in all five immunocompromised groups (67–83%) and, as shown by the similar rate of reactogenicity in the placebo recipients (46–79%), was mostly due to the underlying disease. Severe or ‘grade 3’ local or systemic reactions in immunocompromised groups were mildly elevated (10–20%) compared to immunocompetent people.^48,56

In these trials no severe adverse effects related to immunization were reported.^48–52

Comparison of RZV with the live attenuated vaccine (ZVL; Zostavax).

RZV shows distinct advantages over ZVL in efficacy for:

1. Immunocompetent people: In those 50 years or over vaccine efficacy in the pivotal trials was 97% for RZV vs 51% for ZVL. In those 70 years and over efficacy was 91% for RZV vs 41% for ZVL. The efficacy against PHN was >90% for RZV and 66.5% for ZVL where there was also less variation with advancing age. The durability of RZV efficacy was 82% vs 21% for ZVL both at 11 years^{27,28,31,57,58}

2. Immune-compromised patients: In severe immunocompromise ZVL is contraindicated. For mild and moderate immunocompromise ZVL can be used but is not recommended in many countries as RZV is more efficacious⁵⁹

Reactogenicity is much higher for RZV with grade 3 local and systemic reactions in 9–11% of recipients vs <1% for ZVL.^27,28,57

Future research

• In immunocompetent people

  1. – follow-up studies on the durability of efficacy of RZV up to 15 years are continuing.
  2. – studies on the safety of RZV coadministration with other adjuvanted vaccines are urgently needed.
  3. – future development of RZV-like vaccines that have reduced reactogenicity but retain immunogenicity and efficacy may be facilitated by research on the mechanism of action of RZV, as the correlation between reactogenicity and efficacy is weak.³⁹
• In immunocompromised patients, further research is required on:

  1. – the completion of phase 3 trials in patients receiving SOTs and those with solid tumors receiving chemotherapy.
  2. – the durability of immunogenicity and vaccine efficacy beyond 12 to 18 months needs to be defined for all the five groups with severe immunosuppression.
  3. – the safety and efficacy of RZV in patients with autoimmune diseases who are being treated with biological and synthetic DMARDs, especially agents with an immunosuppressive effect on T cell responses (phase 3 trials of RZV in patients on the most important DMARDS, JAK inhibitors, are in progress).

• In severely immunocompromised children: studies on the use of RZV to prevent varicella/chickenpox should be conducted as live attenuated vaccines are contraindicated. One study showed efficacy in adults in this setting and a recent report also showed RZV can induce naïve T cell responses to VZV gE.^60–62

• There are other vaccines under development including protein-adjuvant vaccines, similar to RZV, and RNA vaccines but phase III clinical trial results are not yet available for comparison with RZV.

• The recent report of the association of RZV with a 17% reduction in diagnosis of dementia over six years after immunization compared to the live attenuated zoster vaccine and even more compared to influenza and diphtheria-tetanus-pertussis vaccines in a retrospective electronic health records study needs to be confirmed in prospective trials and a potential mechanism of action examined.⁶³

Indications for the recombinant zoster vaccine

In most countries where RZV is licensed, it is recommended for immunocompetent people over the age of 50 years and in patients aged 18 years and older who are moderately to severely immunocompromised. Household contacts are also recommended to be immunized.

Conclusions

(see Box 1) RZV is highly efficacious against herpes zoster and all complications including PHN and ocular HZ. Its efficacy is unaffected by age (even people aged 80 years or more), frailty and comorbidities. Protection remains stable for more than 11 years after immunization. Longer-term trials are in progress. Optimal vaccine efficacy requires two doses, two to six months apart. RZV induces a high level of local (injection site) and systemic reactogenicity. However, the incidence of severe reactogenicity impairing every day activity occurs in only 9–11% of vaccinees and lasts one to two days, and only one-third experience such severity after the second dose. The vaccine is very safe, with an extremely low incidence of Guillain Barré syndrome. It is also safe and immunogenic after natural herpes zoster and attenuated live zoster vaccine.

Box 1: Recent advances in understanding the immunogenicity, efficacy, durability and reactogenicity of the recombinant zoster vaccine (RZV).

• Frailty or multiple comorbidities in aging people do not affect the excellent vaccine efficacy of RZV (in contrast to influenza and pneumococcal vaccines).

• The efficacy of RZV over 11 years is 87% with only a mild decline to 82% in the 11th year.

• Where breakthrough herpes zoster occurs after RZV, the vaccine still reduces pain and analgesic use in the acute stages of the disease. • Retrospective community effectiveness studies show a single dose is about 13% less effective than the standard double dose, which is therefore recommended.

• The excellent RZV immunogenicity does not require marked reactogenicity because there is only a weak association between the two.

Furthermore, it is safe in moderately to severely immunocompromised patients with very good, albeit lower, efficacy against HZ in patients with transplants and hematologic malignancy. RZV also has very good immunogenicity in people with other cancers and HIV infection and immunosuppression. Local reactogenicity is similar in immune-compromised and immune-competent people but systemic reactogenicity is increased owing to the underlying disease.

Biographies

Professor Anthony (Tony) Cunningham, AO, FAHMS, MD, FRACP, FRCPA is a viral immunologist, infectious diseases physician and vaccinologist, who has longstanding research interests in the immunology of herpesviruses and HIV and in vaccine development and trialing. He has contributed to the development and played a major role in trialing of a partially effective Herpes simplex vaccine candidate and the highly efficacious Recombinant Zoster Vaccine. He is one of the three top cited herpes vaccinologists internationally over the past 10 years (Expertscape 2024) and was recently made an honorary life member of the Australasian Society for Immunology. He is Director, Centre for Virus Research, The Westmead Institute for Medical Research, Professor and vaccine theme leader, Sydney Infectious Diseases Institute, University of Sydney, an NHMRC Senior Leadership Fellow and Director of the Australian Centre for HIV and Hepatitis Virology Research (ACH4). He was the founding director of The Westmead Institute for Medical Research and a past president of the Australian Association of Medical Research Institutes. He consults for four global vaccine companies.

Dr Kerrie Jane Sandgren received her PhD from the University New South Wales in 2008 and completed a post-doctoral fellowship at the Karolinska Institute, Sweden and partly at the Vaccine Research Centre, NIH, USA. Her research has focused on the role of dendritic cells in viral immunity and vaccination, and she developed an interest in the potential of vaccine adjuvants. She is now a senior research scientist, co-leading the Vaccines and Adjuvants research group at WIMR. The group utilises an in situ human lymph node model that she developed to study how vaccines and adjuvants work at their actual site of action in the human body. She also uses this model to study the influence of ageing on vaccine responses. The group also focuses on COVID-19 immunology following infection and vaccination and is involved in several clinical trials. Kerrie is the recipient of a Moderna Global Fellowship in Vaccine research.

Ms. Janette Taylor is a clinical scientist who has conducted clinical antiviral and vaccine trials for over 25 years, including the two pivotal trials of recombinant zoster vaccine and the long term follow up study.

Funding Statement

ALC is supported by the National Health and Medical Research Council, Australia, GNT#1177942.

Disclosure statement

Professor Cunningham has received honoraria for consultancies from GSK, Moderna, Seqirus and AbbVie, paid to his institution. Dr Sandgren has received honoraria for presentations for Moderna.