Authors' objectives: This Health Technology Assessment aims at evaluating the efficacy, safety, cost-effectiveness and budget impact of a non-live adjuvanted recombinant subunit vaccine (Shingrix, GSK) against herpes zoster (HZ). Shingrix is administered intramuscularly 2 months apart. Shingrix received a market authorisation granted by the European Medicine Agency (EMA) in March 2018. Shingrix is indicated in adults 50 years of age or older and in adults 18 years of age or older at increased risk of HZ

Authors' results and conclusions: There is high quality evidence that Shingrix is very effective in preventing HZ in immunocompetent individuals ≥50 years over a period of approximately 4 years. Vaccine efficacy appears similar in all age ranges.There are good indications that this protection is still high nearly 8 years after vaccination. Data collection is on-going to assess if vaccine efficacy is maintained on a longer period. There is also good quality evidence that the risk of PHN, which is considered the main complication of HZ, is drastically reduced by the vaccine. However, the absolute risk reduction is much smaller than for HZ (10 per 10 000 person-years in individuals ≥ 50 years), resulting in a NNV higher than 330 over the first 4 years after vaccination. Moreover, there is currently no data on protection over a longer period. There is no solid data from clinical studies on protection of other complications, including hospitalisation. Good vaccine efficacy against HZ and PHN was confirmed in post-marketing in-population studies, although lower than in the pivotal trials. There is moderate quality evidence from post- marketing in-population studies that Shingrix can reduce significantly the risk of ophthalmic zoster. Here again, the absolute risk reduction is small (5 fewer cases per 10 000 person-years). Such information does not exist for hospitalisation. There is good quality data that the vaccine is effective in reducing the risk of HZ also in immunocompromised adults ≥18 years with haematopoietic stem cell transplantation or haematological malignancies. Although the relative reduction is smaller than in immunocompetent persons, the number of cases prevented for a given number of vaccinations is much higher because of the higher baseline risk (618 cases avoided per 10 000 person-years). Vaccine efficacy in the presence of other immunosuppressive conditions is not well known as only immunogenicity studies are available, and the threshold of cell-mediated immunity ensuring protection is unknown. However, 2 post- marketing in-population studies in immunocompromised individuals (various conditions) reported a similar vaccine efficacy (around 65%). There are indications of a similar vaccine efficacy also for patients with auto-immune diseases. All studies carried out in immunocompromised individuals were of short duration (maximum 2 years) and protection on a longer period is unknown. Vaccine efficacy derived from RCTs applied to Belgium would result in around 64 (95%CI: 63-66) cases of zona avoided per 10 000 person-years vaccinated ≥ 50 years, between 8 and 10 cases of PHN and less than 2 hospitalisations. The corresponding numbers for individuals ≥60 years would be 77 cases of zona avoided per 10 000 person-years vaccinated, between 10 and 12 cases of PHN, and between 2 and 3 hospitalisations. Based on post-marketing studies and surveillance, the vaccine safety appears high. An association with Guillain-Barré syndrome was reported in 2 studies but the attributable risk was very low. KCE shared a preliminary version of the present clinical review with the Superior Health Council of Belgium in early 2022. The latter very recently recommended RZV in immunocompetent adults ≥60 years, a following the example of a number of other European countries. The cut-off of 60 years was deemed to yield the best clinical return in an immunocompetent population. The Council also recommended vaccination in immunocompromised patients ≥16 years. Of note the vaccine is off-label between 16 and 18 years. As regards the economic evaluation of Shingrix vaccination, a Belgian study was published in 2021. It estimated that, compared to Zostavax, Shingrix was more clinically effective (in terms of QALYs gained and avoided clinical outcomes) in all age groups. Further, administering Shingrix at a younger age (50 years) was more cost-effective assuming a long duration of protection of the vaccine (providing on average 40-50 years of protection), while vaccination at a later age (80 years) was more cost-effective assuming a short duration of protection of the vaccine (providing around 7 to 10 years of protection) However, with incremental cost-effectiveness ratios (ICER) above € 87 000 per QALY gained, RZV vaccination was not found to be cost-effective at any of the explored vaccination ages (at 50, 60, 70, 80 or 85 years) or at any of the assumed duration of protection (long or short) when the US private sector price of RZV was used (€ 140.26 per dose). Meantime the Belgian list price of RZV was set up at € 170.26 per dose. Hence strong decreases in the price of RZV vaccine were advocated for a better balance between the health gains and the costs. For example, assuming a long duration of vaccine protection, the price for 1 dose of Shingrix should drop to € 37.49 per dose such that vaccination at 50 years would cost € 30 000 per QALY gained. As a comparison, the ICER for influenza vaccination in ≥65-year- olds, a strategy recommended and funded in Belgium, was previously estimated at € 19 125 per QALY at most. The assumed duration of protection of Shingrix had a strong impact on the cost-effectiveness results. This duration of protection was estimated based on the 4-year data from the two pivotal ZOE trials. Our extrapolations based on the 8-year data of the ZOE-LTFU trial showed that the assumption of a short duration of vaccine protection can clearly be discarded. They also showed that the assumption of a long duration of vaccine protection is plausible though too optimistic. The lowest ICER in Pieters et al. is thus likely underestimated. The incidence of HZ cases also had a strong impact on the cost-effectiveness results. This incidence was derived from the medically attended cases and was limited to the immunocompetent population, providing a lower estimate of the number of individuals who can benefit from vaccination. Consideration of the whole population (including the immunocompromised) would likely improve the ICERs The results of recent economic evaluations performed in settings similar to Belgium (Europe and North America) were explored. The bulk of those evaluations (both sponsored and non-sponsored) reported more favourable results about the cost-effectiveness of RZV vaccination in the overall or immunocompetent population, with ICERs not exceeding € 47 000 per QALY (see section 6.4 for a full description of those results). Only two studies reported less favourable results. A Dutch economic evaluation estimated that RZV prices should decrease to be cost-effective at the € 20 000 per QALY gained, while, in a Swedish study, RZV was not found to be cost-effective as it costed € 170 000 per QALY. The cost-effectiveness of RZV vaccination in specific populations such as the immunocompromised still needs to be explored, as only one GSK-sponsored conference abstract on this topic was published so far. 1. The budget required to fund RZV vaccination would be substantial, with annual budgets of € 27.14 or € 10.56 million to vaccinate 46.2% (coverage observed for other vaccines in Belgium) of the adults at 50- or 80-year-old, respectively, at the list price of the vaccine (€ 170.26 per dose). Vaccinating 90% of the severely immunocompromised adults aged ≥18 years was estimated to cost € 26.26 million.

Authors' recommendations: Based on the results of the clinical evaluation and economic analysis carried out in this study - and summarised in the conclusion above - we recommend : RIZIV : - Not to reimburse the vaccine at the current official price of €170.26 per dose, whether or not the vaccinated person belongs to one of the target populations (immunocompetent ≥ 60 years and immunocompromised ≥ 16 years); - To consider reimbursement of the vaccine only if the price of the vaccine is significantly reduced. As an indication, a maximum price around €30 per dose as established from the Belgian economic evaluation can be used as a reference; - If a price reduction is obtained but the impact of reimbursement on the budget envelope is deemed too high by the RIZIV, it will be up to the RIZIV to consider reimbursement of the vaccine only in immunocompromised patients and to assess whether the budgetary impact of this more restricted approach is acceptable. To health care providers: - In the event of reimbursement, to offer vaccination as a priority to those at higher risk of herpes zoster, namely: immunocompromised persons from 18 years of age (in accordance with the vaccine insert) ; people ≥ 60 years of age combining one or more additional risk factors; - To promote shared decision-making by presenting the advantages and disadvantages of vaccination to the patient; - To contribute to active pharmacovigilance by reporting to the FAMHP any side effect potentially related to the vaccine. To the scientific community: - Continue to evaluate the efficacy, safety and long-term cost-effectiveness of vaccination, particularly with regard to the prevention of post-herpetic neuralgia and other complications: in the general population ; in people with various immunosuppression profiles. To Sciensano: - To continue the collection and analysis of data from the medical officers regarding herpes zoster and more specifically on post-herpetic neuralgia.

Project Status: Completed

Year Published: 2022

URL for published report: https://doi.org/10.57598/R360C

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Belgium

DOI: 10.57598/R360C

Organisation Name: Belgian Health Care Knowledge Centre

Contact Address: Administrative Centre Botanique, Doorbuilding (10th floor), Boulevard du Jardin Botanique 55, B-1000 Brussels, Belgium tel: +32 2 287 33 88 fax: +32 2 287 33 85

Contact Name: info@kce.fgov.be

Contact Email: info@kce.fgov.be

Copyright: Belgian Health Care Knowledge Centre (KCE)