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Health Impact and Cost-effectiveness Assessment for the Introduction of Universal Varicella Vaccination in Switzerland

Heininger, Ulrich MD*; Pillsbury, Matthew PhD; Samant, Salome MBBS, MPH; Lienert, Florian PhD; Guggisberg, Patrik MA; Gani, Ray PhD§; O’Brien, Elliott MS; Pawaskar, Manjiri PhD

Author Information
The Pediatric Infectious Disease Journal: June 2021 - Volume 40 - Issue 6 - p e217-e221
doi: 10.1097/INF.0000000000003136

Abstract

Varicella, commonly known as chickenpox, is a highly contagious and common infectious disease caused by the varicella-zoster virus (VZV). The highest incidence in Europe is in children below the age of 5 years.1,2 The disease is typically mild, consisting of a vesicular rash, itching, fatigue and fever; however, complications can occur and may result in more severe systemic manifestations leading to hospitalization and, rarely, death.3–5 Treatment for the disease is typically symptom-directed and can include acetaminophen, topical treatments, fluids; antivirals are recommended for immunocompromised patients and may also be used in otherwise healthy older children and adults.6,7 While usually a mild disease, it has been estimated that in the absence of universal varicella vaccination (UVV), 3–3.9 million patients would consult a primary care physician and 18,200–23,500 patients would be hospitalized, with increased societal burdens due to both work absenteeism for adult patients and caregivers and school time lost for children.2,8

Live-attenuated varicella vaccines were developed in the 1970s and have been available for administration to children since the 1980s, with the first national varicella vaccination program being implemented in 1995 in the United States.9 Vaccination has proven to be highly effective in reducing morbidity, mortality and disease transmission since then.10,11 Varicella vaccines are available in standalone formulations and in combination with measles, mumps and rubella vaccines (MMRVs).9 The World Health Organization (WHO) recognizes the significant burden of the disease for affected individuals and societies and recommends inclusion of varicella vaccination in National Immunization Programs (NIPs) where it is possible to maintain vaccination coverage above 80%.11 Previous models have shown the health impact and cost-effectiveness of national varicella vaccination programs can be impacted by the number of doses, age at first dose and interval between doses.12–14 Immunization program decision-makers should consider these factors when determining the optimal vaccination schedule for a country to meet its public health goal.

The Swiss NIP currently recommends a 2-dose catch-up varicella vaccination schedule for those 11–15 years of age (and up to 40 years) who have no reliable history of varicella or are VZV-IgG seronegative.15,16 There is currently no publicly funded UVV program in the country, although based on private market use, estimated vaccine uptake in children is approximately 10% based on Intercontinental Medical Statistics (IQVIA) MMRV vaccines market data for Switzerland, 2018.

The objective of this study was to assess the long-term clinical and economic impacts and the cost-effectiveness of UVV for children in Switzerland compared with current practice and NIP recommendations.

METHODS

A previously published age-structured, deterministic, dynamic transmission model17,18 implemented in Mathematica 12.0 (Wolfram Research Inc., Urbana, IL) was adapted to Switzerland to assess the potential impact of UVV in Switzerland. It models VZV-related disease transmission and progression and herpes zoster reactivation and is based on a series of disease states (Maternal/Passive Immunity–Susceptible–Exposed–Infectious–Recovered–Susceptible). The model has been used previously to assess the health and economic impact of varicella vaccination in other settings and is able to estimate the costs and outcomes associated with 2 dose vaccination schedules provided at different time intervals as well as catch-up programs.17,18 Two vaccines were considered in this cost-effectiveness analysis: ProQuad (denoted MMRV-Merck Sharp & Dohme Corp [MSD], Kenilworth, NJ), a quadrivalent MMRV combination vaccine and Varivax (denoted V-MSD, Kenilworth, NJ), a standalone varicella vaccine, both manufactured by Merck & Co., Inc. (Kenilworth, NJ).

The vaccination schedules considered in this analysis correspond to current vaccination visits as per NIP schedule for the MMR vaccination (at 9 months and 12 months) primarily recommended during the first 2 visits.2 This and 2 further UVV schedules, each with 2 doses of varicella-containing vaccines, were compared with 2 base case (BC) scenarios reflecting current NIP (denoted BC1—with no private market use) and status quo (denoted BC2—assuming 10% private market use). Each of the 3 UVV strategies assumed the same coverage (95% for the first dose and 90% for the second dose, based on current MMR vaccination coverage in Switzerland) but featured different administration schedules and vaccine combinations. All strategies included catch-up vaccination with 2 doses at age 13 years, 1 month apart. The details are presented in Table 1.

TABLE 1. - Two-dose Varicella Vaccination Strategies Evaluated in This Analysis
Strategies* Age (1st Dose) Coverage (1st Dose) Vaccine (1st Dose) Age (2nd Dose) Coverage (2nd Dose) Vaccine (2nd Dose)
Scenarios without UVV
 No infant vaccination (BC1) NA NA NA NA NA NA
 10% private market use (BC2) 9 mo 10% MMRV-MSD 12 mo 10% MMRV-MSD
Scenarios with UVV
 UVV with a 3-mo interval between first and second dose (UVV-1) 9 mo 95% MMRV-MSD 12 mo 90% MMRV-MSD
 UVV with a 7-mo interval between first and second dose (UVV-2) 12 mo 95% MMRV-MSD 19 mo 90% MMRV-MSD
 UVV with a 12-mo interval between first and second dose (UVV-3) 12 mo 95% MMRV-MSD 24 mo 90% V-MSD
*Catch-up vaccination was included in all schedules, consisting of 2 doses of V-MSD. The first dose was at age 13 with 68% coverage, and the second 1 month later with 35% coverage.
Federal Office of Public Health. Cantonal vaccination monitoring Switzerland. 2020. Available at: https://www.bag.admin.ch/bag/de/home/gesund-leben/gesundheitsfoerderung-und-praevention/impfungen-prophylaxe/informationen-fachleute-gesundheitspersonal/durchimpfung.html. Accessed November 20, 2020.
Federal Office of Public Health.16
MMRV-MSD indicates Proquad; NA, not applicable; V-MSD, Varivax.

The model considered both the payer perspective (considering only direct medical costs [ie, costs directly associated with treatment payable by the healthcare providers]) and a societal perspective (considering productivity losses from caregivers and absenteeism as well as direct medical costs). Input costs from 2011 onwards were assumed current as Tarmed Codes have not changed over the years and inflation rates in Switzerland are close to 0%. A 50-year time horizon was applied for the analysis, with costs and outcomes discounted at 3% per year. Additionally, 25- and 100-year time horizons were considered, and the results presented in the Supplementary Digital Content-4 (http://links.lww.com/INF/E362). Inputs used for the model are summarized in Supplementary Digital Content-1 (http://links.lww.com/INF/E362). Local data for Switzerland included varicella disease costs (inpatient and outpatient visits, treatments, diagnostics and hospitalizations), disease severity, productivity losses (workdays lost) and vaccination costs.19–22 Incidence of herpes zoster was also included as an input for all scenarios as it affects force of infection for varicella. The economic impact of the vaccination programs is presented both with and without Herpes Zoster (HZ) outcomes.

The price of V-MSD, based on the listed public price (as of July 2, 2020), was Swiss Franc (CHF) 67.65 plus CHF 23.70 for administration, delivery and cold-chain requirement costs. The price of the varicella component of MMRV-MSD was based on the assumed public price for MMRV-MSD of CHF 108.00 minus the price for an MMR vaccine (CHF 37.85 = MMRVaxPro) resulting in a price of CHF 70.15 (as of July 2, 2020). Unlike V-MSD, no additional administration, delivery and cold-chain costs were added for MMRV-MSD, as it was assumed to be given instead of the existing MMR vaccine at no additional administration cost.23 The additional cost generated by febrile seizures due to using MMRV instead of separate MMR and varicella doses was considered in the model.17 This is a very conservative assumption as studies have shown that the risk for febrile seizures after MMRV is not increased when compared with MMR + V if the observation period is beyond 2 weeks after immunization.24 A smoothing function was applied to the Swiss annual population data to calibrate the model. The resulting smoothed population data and fertility data were used as inputs for calculating the force of mortality.25,26 Details on the calibration are presented in the Supplementary Digital Content-2 (http://links.lww.com/INF/E362).

The model was used to calculate the number of varicella cases, hospitalizations and deaths for each schedule as well as the direct medical costs, indirect costs (which includes direct medical costs and productivity losses) and quality-adjusted life-years (QALYs) to assess the economic impact of various vaccination schedules. Incremental cost-effectiveness ratios (ICERs) were also calculated. One-way sensitivity analyses were conducted by varying workdays lost, mean costs per lost workday, cases requiring hospitalization, dose 1 and dose 2 vaccination coverage, catch-up vaccination coverage and MMRV-MSD price (Fig. 1). Parameters related to costs and healthcare system burden were adjusted by ±20% from their base-case values, while parameters related to vaccine coverage were adjusted by ±5% to reflect assumed variability in these values. These results aim to demonstrate the costs and benefits of different schedules to healthcare professionals, public health policymakers and payers and are presented as tornado graphs below. To test the robustness of the model and the model inputs, probabilistic sensitivity analysis (PSA) was performed (Supplementary Digital Content-3, http://links.lww.com/INF/E362).

FIGURE 1.
FIGURE 1.:
One-way sensitivity analysis. The labels “Low” and “High” respectively refer to that parameter being greater than or lower than the base case. The change in ICER from the base case indicates how much the ICER varies in response to the inputs perturbance. MMRV-MSD indicates Proquad.

RESULTS

The estimated burden of disease (BOD) for the different vaccination schedules is shown in Table 2. UVV reduces the number of varicella cases by 88%–90% compared with BC1 and BC2, with hospitalizations reduced by 62%–69% and deaths by 75%–77%. Differences in BOD between the various UVV schedules are relatively small.

Costs and outcomes associated with the 3 UVV strategies are also similar, with UVV-2 the least expensive and UVV-3 the most expensive, from both direct medical cost and societal cost perspectives. Costs in the BC scenarios are lower than UVV, with BC1 being the lowest due to no vaccine use. The societal costs for the disease are greater than the direct medical costs for all schedules as is expected since they also include the productivity losses due to absenteeism among caregivers and older patients. The QALYs lost per person are far smaller for the UVV schedules than for the BC strategies (see Table 2), reflecting vaccination effectiveness leading to lower overall BOD.

TABLE 2. - Total Varicella Cases, Hospitalizations and Deaths, Over a 50-year Time Horizon
Strategy Varicella Cases Hospitalizations Varicella Deaths Without HZ Impact With HZ Impact
QALYs Lost Due to VZV* Direct Medical Cost (CHF)* Societal Cost (CHF)* QALYs Lost Due to VZV* Direct Medical Cost (CHF)* Societal Cost (CHF)*
BC1 6,037,706 10,212 94 –0.00180 13.43 29.70 –0.00633 52.10 77.62
BC2 5,452,344 9322 88 –0.00164 18.04 33.15 –0.00617 56.55 80.90
UVV-1 676,208 3575 22 –0.00041 57.59 65.74 –0.00494 95.74 113.07
UVV-2 645,381 3421 22 –0.00040 56.91 64.89 –0.00494 95.16 112.33
UVV-3 616,621 3118 21 –0.00040 61.95 69.81 –0.00495 100.62 117.67
*Per case.
Costs and outcomes were discounted.

The ICERs from the direct medical cost perspective for UVV compared with BC1 vary from CHF 31,194 to CHF 34,793 per QALY and from CHF 31,357 to CHF 35,403 per QALY compared with BC. From a societal perspective, the ICERs range from CHF 25,245 to CHF 30,124 (Table 3). Overall, UVV-2 has the lowest ICERs compared with the other UVV schedules, indicating that UVV-2 is the most cost-effective intervention of those tested. The ICERs only change slightly when including the HZ costs in outcomes with the difference in ICER ranging from –2.18% to 1.54% compared with respective ICERs without HZ costs.

TABLE 3. - ICERs for UVV vs. BC Strategies Over a 50-year Time Horizon
Strategy Without HZ Impact With HZ Impact
vs. BC1 (DMC, CHF) vs. BC1 (Societal, CHF) vs. BC2 (DMC, CHF) vs. BC2 (Societal, CHF) vs. BC1 (DMC, CHF) BC1 (Societal, CHF) vs. BC2 (DMC, CHF) vs. BC2 (Societal, CHF)
UVV-1 31,867 26,006 32,115 26,457 31,524 25,607 31,969 26,239
UVV-2 31,194 25,245 31,357 25,599 31,008 24,990 31,386 25,541
UVV-3 34,793 28,762 35,403 29,552 35,188 29,043 36,111 30,124
DMC indicates direct medical cost.
Costs and outcomes were discounted.

As seen in Figure 1, the ICERs are driven mainly by the price of MMRV-MSD followed by workdays lost and the costs of workdays lost. ICER scatter plots and cost-effectiveness acceptability curves from the PSA are presented in the Supplementary Digital Content-3 (http://links.lww.com/INF/E362).

DISCUSSION

To our knowledge, this is the first study assessing the long-term clinical and economic impact of implementing UVV in Switzerland and provides valuable insight for Swiss policymakers as well as other European nations who may be considering UVV. This study demonstrates significant reductions in the burden of varicella disease for all 3 UVV schedules in terms of varicella cases, hospitalizations and deaths compared with current practice or 10% private market use. Significant reduction in the societal (parent and caregiver) burden of varicella after implementing UVV program in terms of reduction in work loss/absenteeism was also found.

While there are no formal cost-effectiveness thresholds defined in Switzerland, other thresholds have been previously considered,19 such as the WHO threshold of 1 per capita Gross Domestic Product per QALY (equivalent to CHF 79,219 per QALY)27 and the UK National Institute for Health and Care Excellence threshold of £30,000 per QALY (equivalent to CHF 38,100 per QALY based on 2019 exchange rates). The ICERs for all the UVV schedules compared with BC1 and BC2 are below these thresholds indicating that UVV is likely to be cost-effective in Switzerland from both payer and societal perspectives.

The results of this study align with other European modeling studies in Germany, France, Italy and Turkey, which found 2-dose UVV to be either cost-saving or cost-effective from both direct medical cost and societal perspectives.17,18,28,29 Most of the studies showed that UVV implementation significantly reduces caregiver burden in terms of lost productivity and absenteeism. Our study confirms these findings. Other studies have indicated that timing of dose administration is an important factor that will impact effectiveness and needs to be considered by policymakers.30

Sensitivity analyses indicate that key factors driving cost-effectiveness are MMRV-MSD price, vaccination coverage and productivity losses, all of which are directly related to the number of cases. Coverage has a nonlinear influence on case numbers due to the indirect benefits of herd protection, which is seen in the results from the PSA. This provides further justification behind achieving and maintaining high rates of coverage, of at least 80%, as recommended by the WHO.11

A limitation to the study is that some of the inputs were not available from sources such as public health authorities or peer-reviewed publications but were reliant upon expert opinion or assumptions, which may add uncertainty to the analysis. Possible additional benefits associated with the MMRV vaccine compared with separate MMR and varicella vaccine such as parental preferences for fewer injections, less pain and improved timeliness of vaccination associated with combination vaccines were not captured in the analysis.31 Further studies are needed to better understand benefits of using quadrivalent MMRV taking into account reducing injection doses, better completion rate, convenience, etc. The efficacy of MMRV-MSD and the risk of febrile seizures when MMRV-MSD is used at the age of 9 months are unknown, which could impact the ICERs. Also, the model used a static population size and age distribution, which could overestimate transmission in older age groups. However, calibration analysis shows the model fits the prevaccination data well providing support that the model is robust and has been able to replicate disease incidence in many settings.17,18

CONCLUSIONS

This analysis quantifies the reduction in the burden of varicella resulting from UVV and demonstrates UVV is a cost-effective vaccination option compared with NIP recommendations and current clinical practice in Switzerland. Therefore, as recommended by WHO, UVV should be considered as a vaccination policy option by public health providers in Switzerland to improve overall health in the society.

ACKNOWLEDGMENTS

The authors would like to acknowledge the help of Lara Wolfson with the study, Colleen Burgess and Jeff Kyle with the model and Des Dillon-Murphy with the article.

REFERENCES

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Keywords:

varicella; vaccination; Switzerland; cost-effectiveness

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