Unlocking the value of Shingrix: how vaccination empowers older adults

The world’s population is aging, with those aged ≥60 years old expected to double by 2050 and those ≥80 years of age are predicted to triple.¹ Healthy elderly people make enormous contributions to the economy, for example, through caring for grandchildren, voluntary work, international travel and spending their pensions and superannuation. However, the elderly are more prone to severe outcomes and death from infections, and sick elderly people are a major drain on resources. Healthy aging is, therefore, a major public health priority.²

Shingles, caused by reactivation of the herpes zoster virus (HZV) in the dorsal root or cranial nerve ganglia in a person who has previously had chickenpox, causes a painful rash with vesicles, papules and pustules, generally in a dermatomal distribution. Post-herpetic neuralgia (PHN) is characterised by persistent pain ≥90 days after the rash resolution but can last for years and be extremely debilitating.³ Shingles incidence and severity increase with advancing age, in part due to declining innate and adaptive immunity associated with aging, so called ‘immunosenescence’.⁴ Inflammaging also occurs with advancing age, characterised by enhanced immune activation and cellular decline, and potentially associated with frailty and early death.⁵ Since one in three people experience shingles during their lifetime, it presents a considerable economic and clinical burden.

The live–attenuated HZV Oka strain shingles vaccine Zostavax (Merck) is given as a single intramuscular dose. Its use is contraindicated in pregnancy and the immunocompromised in whom deaths have been reported from disseminated Oka virus infection, including three in Australia.⁶ Zostavax was registered for use in USA and Europe in 2006 and in Australia in 2007 for people ≥50 years. It was added to the Australian National Immunisation Program (NIP) in November 2016 for immunocompetent people aged 70 years old, with catchup between the ages of 71 and 79 years old. Several pivotal trials demonstrate the moderate efficacy of Zostavax, namely the Shingles Prevention Study (SPS) in those aged ≥60 years old⁷ and Zoster Vaccine Efficacy and Safety Trial (ZEST) in 50–59 years of age.⁸ In the former, Zostavax provided 51.3% efficacy against HZV and 66.5% against PHN over a median of 3.1 years. Efficacy declined with advancing age from 69.8% in 50–59 years of age⁸ to 37.6% in those aged ≥70 years old.⁷ Significant efficacy could not be demonstrated at ≥80 years of age. An 11-year follow-up on the SPS showed that Zostavax efficacy waned over time to zero protection against HZV by 8 years post-vaccination.⁹

It has been difficult to assess the likely impact of shingles vaccination in Australia due to challenges in ascertaining all cases and the lack of a systematic evaluation plan. However, there have been modest reductions in shingles incidence and complications since the Zostavax program was introduced. The program was challenged by suboptimal uptake (only 16.2% for 70 year olds in year 1 and ~32% since), particularly among those living in remote areas and with socioeconomic disadvantage,¹⁰ and safety concerns regarding the inadvertent use in immunocompromised persons.⁶

The recombinant subunit zoster vaccine Shingrix (Glaxo-SmithKline) containing HZV glycoprotein E adjuvanted with liposome-based ASO1_B was licensed and recommended in USA in 2017 for people ≥50 years old, and authorised in Europe and Australia for the same age group the following year. In 2020, the marketing authorisation in Europe was extended to immunocompromised people ≥18 years old and USA and Australia followed suit in 2021 by similarly extending their indications. Shingrix has been on the Australian market since June 2021 and was added to the NIP in November 2023. It is administered in two doses 2–6 months apart, or 1–2 months apart if immunocompromised. A randomised placebo-controlled phase 3 trial of two intramuscular doses of Shingrix 2 months apart conducted in 18 countries in 15,411 participants showed impressive efficacy against shingles of 97.2% (95% CI 93.7–99.0, P < 0.001) compared to placebo.¹¹ A second trial performed concurrently at the same sites in 13,900 participants ≥70 years old reported an overall efficacy was 89.8% (95% CI 84.2–93.7) against HZV and 88.8% (95% CI 68.7–97.1) against PHN.¹² This high-level efficacy was maintained in the oldest individuals, being 90% in 70–79 years of age and 89.1% in those aged ≥80 years old.

Determining the economic value of a vaccine program is complex. Most published studies use a Markov model, which describes a sequence of possible events changing over in time for which the probability of each event depends only on the health state attained in the previous event.¹³ Multiple factors need to be taken into account including the epidemiology of the targeted disease, vaccine efficacy and duration of protection, target age group, co-morbidities, and health sector and productivity costs (Table 1).¹⁴ Quality-adjusted life years (QALYs) that combine quantity gains (reduced mortality) and quality gains (reduced morbidity) are used in economic modelling.¹⁴

Several studies have conducted cost-effectiveness analyses of Shingrix, notably using varying parameters in their models, particularly predicted vaccine uptake and targeted age groups. Despite this, in a literature review of 18 studies comparing recombinant zoster vaccine (RZV) against Zostavax live–attenuated vaccine (ZVL) or no vaccine 15 of the studies reported that RZV is cost effective.¹⁵ A Canadian study compared RZV to no vaccination or the ZVL in those aged ≥60 years old.¹⁶ A multi-cohort Markov model (single dose static state transition model) was applied to the Canadian population using recent demographic and epidemiologic data. Simulations consisted of varying age cohorts from 50 years old annually transitioning between health states. Health outcomes and costs were discounted at 1.5% per year. A coverage of 80% for the first RZV and ZVL dose and a compliance of 75% for the second RZV dose were assumed. RZV was estimated to be cost effective compared with no vaccination. The model calculated an incremental cost-effectiveness ratio (ICER) of C$28,360 per QALY in persons aged ≥60 years old, avoiding 554,504 HZV and 166,196 PHN cases. Compared with ZVL, RZV accrued more QALYs through the remaining lifetime. These figures are well below the Canadian willingness to pay (WTP) standard threshold of C$50,000 per QALY used in Canadian cost-effectiveness studies. The analysis found that the HZV incidence rate and persistence of vaccine efficacy had the largest impact on cost effectiveness.

A German cost-effectiveness analysis compared Shingrix with no vaccination also using a static multi-cohort Markov model in those ≥60 years old.¹⁷ Health outcomes and costs were discounted at 3% per year. They estimated coverage of 40% for the first RZV dose and 70% compliance for dose 2 in incremental age cohorts from 60 years old. They calculated that vaccinating those aged ≥60 years old would result in 45,000 HZV cases avoided and 1713 QALYs gained at a cost of ~€63 million. This compared to 38,000 cases avoided, 1545 QALYs gained at a cost of ~€68 million in the population ≥70 years of age. This equated to respective ICERs of ~€37,000 and €44,000 per QALY for the age cohort ≥60 and ≥70 years old. The number needed to vaccinate (NNV) was similar across age cohorts (range 7–9), but the NNV for PHN was higher. Scenario analyses demonstrated that vaccinating at 60 or 65 years of age would have a greater public health impact and result in the lowest ICER compared to vaccinating at 70 years of age. They concluded that starting vaccination with RZV in the German population ≥60 years old would demonstrate the best value from a public health and economic standpoint.

It is notable that the cost-effectiveness studies cited above are industry funded, a factor shown to report more favourable outcomes in varicella zoster vaccination evaluations compared to non-industry funded (NIF) analyses, and should therefore be interpreted with caution.¹⁸ For example, a Belgian NIF analysis of vaccinating 50–85 year olds failed to demonstrate cost effectiveness for either Zostavax or Shingrix using a Markov decision tree without a substantial price drop.¹⁹ Indeed, assumed vaccine price is a key factor in these evaluations, as are the discount rates applied.

A cost-effectiveness analysis of Shingrix in the USA conducted by the Centers for Disease Control and Prevention compared RZV, ZVL or no vaccine.²⁰ The modelling approach and discounted rates were not reported, but the analysis estimated a QALY of US$31,000 for RZV compared to no vaccine in those ≥50 years of age and most assumptions concluded that RZV was more cost effective than ZVL. The baseline model assumed an unrealistic 100% compliance to the second dose, although lower values were used in sensitivity analyses. In October 2017, the US Advisory Committee on Immunisation Practices recommended RZV for immunocompetent adults aged ≥50 years old. They also recommended RZV for immunocompetent adults who previously received ZVL and stated a preference for RZV over ZVL for the prevention of herpes zoster and related complications. Zostavax was subsequently discontinued in the USA in November 2020.

Shingrix was made available for free in Australia under the NIP since November 2023 for those considered at greatest risk of complications of shingles (Table 2), and Zostavax was discontinued at that time. If someone has previously received a free Zostavax vaccine under the NIP, they are not eligible for a free Shingrix vaccine for at least 5 years. However, if they purchased it privately, they can receive Shingrix for free if eligible but should wait at least 12 months.

To conclude, the economic and public health burden of HZV and PHN is considerable, particularly with advancing age. The recombinant zoster vaccine Shingrix is highly effective and provides long-lasting immunity and protection. Cost-effective analyses are complex but many published studies support the use of Shingrix over the live Zostavax vaccine or no vaccine. Australia introduced the vaccine onto the NIP in 2023 for certain high-risk groups and uptake to date has been good.