Elsevier

The Lancet Infectious Diseases

Volume 19, Issue 9, September 2019, Pages 988-1000
The Lancet Infectious Diseases

Articles
Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis

https://doi.org/10.1016/S1473-3099(19)30163-XGet rights and content

Summary

Background

The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments.

Methods

In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1–2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18.

Findings

Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1–86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0–4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8–32 153·9) in the vaccine group and 777·6 mIU/mL (702·8–860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09–41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups.

Interpretation

The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population.

Funding

GlaxoSmithKline Biologicals SA.

Introduction

After primary infection, varicella zoster virus establishes latency in sensory nerve ganglia.1 Reactivation of the virus can lead to herpes zoster, a typically unilateral, vesicular, dermatomal rash, usually accompanied by pain.2 The most common complication of herpes zoster, postherpetic neuralgia, can last for months or years.1, 3

Research in context

Evidence before this study

Adjuvanted recombinant zoster vaccine was highly immunogenic and more than 90% efficacious against herpes zoster in individuals aged 50 years and older. The adjuvanted recombinant zoster vaccine has also been reported to be immunogenic and well-tolerated in several immunocompromised populations, as well as efficacious against herpes zoster in autologous haemopoietic stem cell transplant recipients.

Added value of this study

This study assessed the adjuvanted recombinant zoster vaccine in patients with haematological malignancies who were receiving immunosuppressive treatments. The vaccine induced robust and persistent humoral and cell-mediated immune responses in our population of adults aged 18 years and older with various haematological malignancies. Cell-mediated immunity, considered to play a key part in protection against herpes zoster, was similar to that observed in otherwise generally healthy adults aged 50 years and older.

Implications of all the available evidence

Taken together with results of previous clinical trials, the results of our study show that the adjuvanted recombinant zoster vaccine is immunogenic in populations that are at an increased risk of herpes zoster infection, either due to older age or because of underlying conditions and their associated immunosuppressive treatments. This immunocompromised adult population is likely to benefit from vaccination with the adjuvanted recombinant zoster vaccine, which is licensed in Australia, Canada, Japan, USA, China, and the EU for adults aged 50 years and older.

The risk of herpes zoster increases with age, particularly after age 50 years, because of waning cell-mediated immunity.1 Immunocompromised people, particularly those with impaired cell-mediated immunity due to either underlying disease or immunosuppressive therapies,4, 5, 6, 7, 8, 9 are also at an increased risk of herpes zoster. The incidence of herpes zoster in individuals with haematological malignancies receiving immunosuppressive cancer treatments is up to ten times higher than in the overall population (31 per 1000 person-years vs 3·2 per 1000 person-years).3, 10 Herpes zoster occurs in up to a quarter of patients with multiple myeloma,11, 12, 13, 14 Hodgkin lymphoma,4, 15, 16 and chronic lymphocytic leukaemia,6, 7, 16 and in more than 6% of patients with non-Hodgkin lymphoma receiving immunosuppressive cancer treatments.15

Vaccination is an effective approach in the prevention of infectious diseases. Two vaccines are approved for prevention of herpes zoster in adults aged 50 years and older—the live-attenuated varicella zoster virus vaccine (Zostavax; Merck Sharp & Dohme Corp) and the adjuvanted recombinant zoster vaccine (Shingrix; GlaxoSmithKline Biologicals SA).

Zostavax is a live virus vaccine and is contraindicated in people with immunodeficiency due to malignancy or immunosuppressive therapy because of potential virulence in those with substantially impaired immunity.17, 18, 19, 20

Although usually not as immunogenic as live vaccines, inactivated vaccines can be used in immunocompromised populations.17, 18 An investigational inactivated varicella zoster vaccine administered on a four-dose schedule has been shown to be generally safe, immunogenic, and efficacious in autologous haematopoietic stem cell transplant recipients and patients with solid tumour malignancies receiving chemotherapy.21, 22, 23 However, this vaccine was not found to be efficacious in patients with haematological malignancies and evaluation of efficacy in this group was terminated early because of evidence of futility.23

Shingrix is an adjuvanted non-live subunit vaccine, consisting of the truncated form of varicella zoster virus glycoprotein E and the AS01B adjuvant system. This vaccine was highly immunogenic and more than 90% efficacious against herpes zoster in individuals older than 50 years.24, 25, 26 Shingrix was also immunogenic in immunocompromised populations aged 18 years and older, including in autologous haemopoietic stem cell transplant recipients, renal transplant recipients, patients with solid tumours, and people with HIV.27, 28, 29, 30, 31, 32 Two doses of Shingrix showed 68% efficacy in preventing herpes zoster in patients who had undergone autologous haemopoietic stem cell transplantation.32 In this population, 873 (94·7%) of 922 Shingrix recipients completed the two-dose vaccination schedule.32

This study aimed to evaluate the immunogenicity and safety of two doses of the adjuvanted recombinant zoster vaccine (Shingrix) in adults aged 18 years and older with haematological malignancies who were undergoing or had just finished immunosuppressive cancer treatments.

Section snippets

Study design and participants

This was a phase 3, randomised, observer-blind, placebo-controlled study done at 77 centres in Australia, Belgium, Canada, the Czech Republic, Finland, France, Hong Kong, Italy, South Korea, New Zealand, Pakistan, Panama, Poland, Russia, Singapore, Spain, Sweden, Taiwan, Turkey, the UK, and the USA.

Patients with haematological malignancies aged 18 years and older were eligible for the study if, at vaccination, they had a life expectancy of 12 months or longer and were receiving or had just

Results

Between March 1, 2013, and Sept 10, 2015, we enrolled 606 participants in the study. 286 were randomly assigned to the adjuvanted recombinant zoster vaccine, 283 were randomly assigned to placebo, and 37 were not randomised. 562 (98·8%) of 569 randomised patients were vaccinated (total vaccinated cohort; 283 in the vaccine group and 279 in the placebo group). We included 174 (31·0%; 90 in the vaccine group and 84 in the placebo group) of 562 vaccinated participants in the cell-mediated immunity

Discussion

The adjuvanted recombinant zoster vaccine is approved in several countries worldwide for the prevention of herpes zoster in adults aged 50 years and older and is not contraindicated for immunocompromised people. In this study, we showed that two doses of vaccine was immunogenic in adult patients with haematological malignancies aged 18 years and older who had been receiving immunosuppressive cancer treatments. All predefined success criteria for immunogenicity of the adjuvanted recombinant

Data sharing

Anonymised individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com (study ID 116428).

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