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Title: The potential economic impact of the updated COVID-19 mRNA fall 2023 vaccines in
Japan
Authors:
Fust K1, Joshi, K2, Beck E2, Maschio M1, Kohli M1, Lee A1, Hagiwara Y3, van de Velde N2,
Igarashi A4,5
1Quadrant Health Economics Inc; 92 Cottonwood Crescent, Cambridge, Ontario, Canada
2Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA
3Moderna, Inc., 4-1-1 Toranomon, Kamiyacho, Minato ward, Tokyo, 105-6923, Japan
4Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo City,
Tokyo, 113-0033, Japan
5Graduate School of Data Sciences, Yokohama City University School of Medicine, 22-2 Seto,
Kanazawa Ward, Yokohama, Kanagawa Prefecture, 236-0027, Japan
Correspondence: Michele Kohli, Quadrant Health Economics Inc.; 92 Cottonwood Crescent,
Cambridge, Ontario, Canada; michele.kohli@quadrantHE.com
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Abstract:
This analysis estimates the economic and clinical impact of a Moderna updated COVID-19
mRNA Fall 2023 vaccine for adults ≥18 years in Japan. A previously developed Susceptible-
Exposed-Infected-Recovered (SEIR) model with a 1-year analytic time horizon (September
2023-August 2024) and consequences decision tree were used to estimate symptomatic
infections, COVID-19–related hospitalizations, deaths, quality-adjusted life-years (QALYs),
costs, and incremental cost-effectiveness ratio (ICER) for a Moderna updated Fall 2023 vaccine
versus no additional vaccination, and versus a Pfizer-BioNTech updated mRNA Fall 2023
vaccine. The Moderna vaccine is predicted to prevent 7.2 million symptomatic infections,
272,100 hospitalizations and 25,600 COVID-19 related deaths versus no vaccine. In the base
case (healthcare perspective), the ICER was ¥1,300,000/QALY gained ($9,400 USD/QALY
gained). Sensitivity analyses suggest results are most affected by COVID-19 incidence, initial
vaccine effectiveness (VE), and VE waning against infection. Assuming the relative VE
between both bivalent vaccines apply to updated Fall 2023 vaccines, the base case suggests
the Moderna version will prevent an additional 1,100,000 symptomatic infections, 27,100
hospitalizations, and 2,600 deaths compared to the Pfizer-BioNTech vaccine. The updated
Moderna vaccine is expected to be highly cost-effective at a ¥5 million willingness-to-pay
threshold across a wide range of scenarios.
Declaration of Funding: This study was supported by Moderna, Inc.
Declaration of financial/other interests:
MK is a shareholder in Quadrant Health Economics Inc, which was contracted by Moderna, Inc.
to conduct this study. KF, AL and MM are consultants at Quadrant Health Economics Inc. EB,
YH, KJ, and NV are employed by Moderna, Inc. and hold stock/stock options in the company. AI
has received honorarium or research consultation fees from Moderna Inc., Pfizer Inc., Takeda
Pharmaceuticals Inc., Shionogi Co, Ltd, and AstraZeneca Japan Inc.
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Introduction
The first confirmed case of COVID-19 infection in Japan occurred on January 15, 2020.1 Since
then, there have been over 33.8 million cases and almost 75,000 COVID-19 related deaths
reported.2 COVID-19 vaccinations in Japan started on February 17, 2021, with priority to health
care workers, before expanding to the broader population. On May 8, 2023, following the World
Health Organization (WHO) announcement that the world pandemic was over,3 Japan changed
the immunization category of COVID-19 from Category 2, which includes diseases such as
tuberculosis, to Category 5, which is in the same classification as seasonal influenza.4,5 This
meant that government funding for COVID-19 screening and treatment changed such that
Spring 2023 COVID-19 vaccinations were only publicly funded for specific high-risk populations,
whereas the Fall 2023 COVID-19 campaign covered the general population aged 6 months and
above. The COVID-19 vaccine will continue to be funded and procured directly through the
Japanese government until March 2024, but it is expected that the Japanese government will
transition COVID-19 vaccines to the traditional National Immunization Program (NIP) in 2024
with regular NIP funding mechanisms from April 2024 onwards.6
First booster vaccinations in Japan became available in December 2021, where individuals
were boosted primarily with one of the two available mRNA COVID-19 vaccines.7,8 Japanese
studies have shown that vaccine effectiveness (VE) varies depending on the variant, as well as
the version of vaccines being administered.8-14 Adapting to the changing variants, Moderna and
Pfizer-BioNTech both updated their vaccines to a bivalent version against BA.4/BA.5 for Fall
2022. For Fall 2023, monovalent versions of the vaccine against the XBB.1.5 versions are
available for administration. While the Moderna and Pfizer-BioNTech vaccines have the same
mechanism of action, their formulations differ, for instance, in terms of lipid nanoparticles
(delivery system) and dosage. Studies on previous versions of the mRNA vaccines have found
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higher VE values for different versions of the Moderna mRNA-1273 vaccine compared to the
Pfizer-BioNTech BNT162b2 versions, including high-risk populations.15-21
Given the new Fall 2023 vaccine campaign, with updated Fall 2023 vaccines from both
Moderna and Pfizer-BioNTech it is important to determine the economic and clinical
consequences of vaccination during the Fall 2023, and understand the impact of newly
emerging variants, to assist in the decision-making process and inform currently ongoing NIP
discussions. Additionally, as the Japanese government has previously recommended and
funded a Spring season vaccination campaign for select high-risk populations, the economic
and clinical consequences of continuing to fund this population needs to be explored, as it likely
will be a discussion subject for the NIP in 2024.
Therefore, the objective of this analysis is to estimate the economic and clinical impact of a NIP
vaccination campaign from April 2024 onwards using the Fall 2023 updated mRNA COVID-19
Moderna vaccine compared to the Fall 2023 updated mRNA COVID-19 Pfizer-BioNTech
vaccine for adults 18 years of age and older, using a previously developed Susceptible-
Exposed-Infected-Recovered (SEIR) model.22 The impact of a Spring 2024 vaccination
campaign in select, high-risk individuals (60-64 high-risk and 65+ general population; 65+
general population only) is also explored.
Methods
Overview
Two sets of comparisons were performed using a 1-year analytic time horizon
(September 2023 to August 2024). First, vaccination of individuals aged ≥18 years with the
updated Moderna COVID-19 mRNA Fall 2023 vaccine (Moderna Fall Campaign) was compared
to no additional COVID-19 vaccination in Fall 2023 (No Fall Vaccine). Second, the Moderna Fall
Campaign was compared to vaccination of individuals aged ≥18years with the updated Pfizer-
BioNTech COVID-19 mRNA Fall 2023 vaccine (Pfizer-BioNTech Fall Campaign). A previously
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published23 SEIR model was used to estimate the total number of infections, and a decision tree
was used to calculate infection-related consequences including numbers of symptomatic
infections, COVID-19 related hospitalizations and deaths, treatment-related costs, and quality-
adjusted life-years (QALYs) for the Moderna Fall Campaign, No Vaccine, and Pfizer-BioNTech
Fall Campaign. The incremental cost effectiveness ratio (ICER), in terms of incremental cost
per QALY gained, comparing the Moderna Fall Campaign and No Fall Vaccine was estimated.
the economically justifiable price (EJP) differences between the Moderna and Pfizer-BioNTech
vaccine was estimated at different willingness-to-pay thresholds (WTP) (¥5 million, ¥6 million,
¥10 million).24,25 The base-case was conducted from the healthcare cost perspective, while a
scenario analysis was conducted using the societal cost perspective. Results are presented in
both Japanese yen and United States dollars, using a conversion rate of ¥1 = 0.006996 USD.26
SEIR Model
A previously developed SEIR model was used to calculate the number of infections
(symptomatic and asymptomatic) as well as the VE against hospitalization for this analysis.22,27
This model has been adapted to Japan and has been used to project incidencefor the analytical
time horizon of September 2023 to August 2024. The base case incidence projections and all of
the incidence scenario analyses have been previously described.28 In the current analysis, we
use all of the same inputs from the previous Japanese analysis except for VE as described
below. As described in the previous analysis, we assume uptake of the Fall 2023 vaccine by
age is similar to the first COVID-19 booster in Japan. 28 The VE against infection reduces the
incidence of asymptomatic or symptomatic infection on each day of the simulation. The average
incremental protection against hospitalization due to COVID-19 infection is also calculated on a
monthly basis within the simulation and used within the infection consequences model. The
number of infections predicted by the SEIR model is summarized by month for use in the
infection consequences model. The proportion of infections with symptoms, assumed to be
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67.6% based on a meta-analysis for Omicron variants,29 is applied as only symptomatic
infections have economic consequences.
Fall 2023 Vaccine Effectiveness Inputs
Japanese Vaccine Effectiveness Real-Time Surveillance for SARS-CoV-2 (VERSUS) is an
ongoing test-negative case-control study examining the VE of the COVID-19 vaccines in
individuals aged 16 years and over.30 Results are reported by different time frames
corresponding to periods of different variant dominance, and with different versions of the
mRNA vaccines (e.g. monovalent primary series, monovalent boosters, bivalent boosters).8-
14Neutralizing antibody titre data have shown a strong immune response from the Moderna Fall
2023 vaccine to XBB.1.5.31, however, data on clinical outcomes will not be available until 2024.
For our previous Japanese analysis,28 we developed a base case and ranges that reflect the
values reported across the different VERSUS reports.
For the base case of the current analysis, we assumed that the Moderna and Pfizer-BioNTech
Fall 2023 vaccines are well-matched to the dominant circulating variant at the time. The VE
values of the Moderna Fall 2023 vaccine are therefore predicted based on existing VE values of
the bivalent vaccines against the BA.4/BA.5 variants from the VERSUS study.32 Although titre
data may indicated a stronger response with the higher dose updated monovalent XXB.1.5
vaccine, data from the bivalent was deemed most appropriate because it is the most recently
administered vaccine with real-world evidence data.33 The VE against infection and of those
between 16-64 years old and those aged ≥65 years was 54.7% and 75.2% respectively. The
model does not accommodate different VE inputs by age groups, so 54.7% was applied in the
base case to all ages as the initial VE against infection, with the 95% confidence interval (40.3%
- 65.6%) being used in sensitivity analyses. Due to sample size, the VE for hospitalizations was
not disaggregated by age groups in this phase of the VERSUS study and was found to be
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84.9% overall. This estimate was used for base case with the 95% confidence intervals (65.7% -
93.3%) applied in sensitivity analyses.
In order to approximate the VE against infection and hospitalization for the Pfizer-
BioNTech Fall 2023 vaccine, the relative Ves (rVEs) between the Moderna and Pfizer-BioNTech
bivalent vaccines for infections and hospitalizations were assumed to be maintained for the Fall
2023 vaccine. The rVE values for aged ≥ 18 years were obtained from a retrospective cohort
study from the US, which estimated the adjusted rVE for hospitalizations and outpatient visits of
the Moderna bivalent booster compared to the Pfizer-BioNTech bivalent booster using cox
regression models. The rVE was defined as 100*(1 – adjusted hazard ratio from the analysis)
and was estimated to be 5.1% (95% confidence interval: 3.2%-6.9%) for outpatient and 9.8%
(95% confidence interval 2.6% - 16.4%) for hospitalization.21 As the rVE values for infection
were not reported, the rVEs for outpatient visits were used as a proxy for infection. Final VE
inputs are displayed in Table 1.
The monthly waning rates of both vaccines were based on data from a meta-analysis on
the duration of protection from monovalent boosters against infection and hospitalization during
the Omicron period.34 These values were 4.8% for infection, and 1.4% for hospitalization. In
sensitivity analyses, the 95% confidence intervals were used: 3.1%-6.8% for infection and 0.6%-
2.4% for hospitalization.
Consequences Model Structure and Inputs
Monthly outputs from the SEIR model, including total number of symptomatic infections
and incremental reduction in risk of hospitalization for vaccinated versus unvaccinated cohorts
are used in a decision tree (Figure 1) to calculate the clinical and economic consequences of
infections. Although not depicted in the decision tree figure, the model includes an infection-
related myocarditis toll. The risk of infection-related myocarditis 35 is assumed to vary by age,
and cost and QALY losses are applied to those patients experiencing infection-related
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myocarditis. Independent of the myocarditis risk, a proportion of COVID-19 infections are
assumed to be treated in hospital, either in a general ward or more severe intensive care unit
(ICU) setting. The age-dependent probabilities of hospitalization in the unvaccinated were
derived previously.28 The percent of cases treated in the ICU care were calculated based on an
insurance claims analysis of the DeSC database.36 Hospitalization probabilities are reduced
according to VE for those who are vaccinated; VE is assumed to vary by vaccination strata and
is calculated within the SEIR model. Death associated with COVID-19 is assumed to occur in
hospitalized patients only (Table 2).37,38. Inputs are displayed in Table 2.
For the healthcare cost perspective, the average cost of outpatient care was calculated
from an insurance claims analysis of the DeSC database, which derives information from one
insurance system for retired persons and one designed for persons aged 75 years and above in
Japan.36 Costs in the claims analysis were estimated by establishing a baseline period of 1 to 3
months prior to the onset of COVID-19 infection and comparing the incremental medical costs
for the 6 months following COVID-19 infection to baseline for the following age groups: 0-19
years, 20-39 years, 40-59 years, 60-64 years, 65-74 years, 75-84 years, and ≥85 years.36
Accordingly, outpatient costs utilized in the base-case analyses reflect a weighted average
(calculated using the Japanese population distribution across age groups) of the 6-month
COVID-19 attributable cost. The cost of outpatient care was weighted by the probability of
seeking outpatient care for treatment to account for the percentage of patients with non-severe
COVID-19 who do not seek medical attention. A similar approach was employed for
hospitalization costs, which were also estimated using insurance claims from the DeSC
database and represent the 6-month COVID-19 attributable cost.36 As both the outpatient and
hospitalization costs reflect the 6-month period following infection, explicit post-infection and
long COVID costs are not included as they are assumed to be reflected in the base-case cost
inputs. The infection-related myocarditis cost was estimated to be ¥20,262 based on the DeSC
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data. Given the 1-year time horizon for the analytic period, none of the costs were discounted.
Base case cost inputs are displayed in Table 2.
The expected number of life years lost due to early deaths from COVID-19 was
calculated using expected survival by age as reported by e-Stat (Official Statistics of Japan).39
Age-specific utility values for individuals without infection, obtained from Shiroiwa (2021), were
attached to each year lost due to early death from COVID-19.40 All future QALYs lost were
discounted by 2% annually to present value.41 QALY losses associated with COVID-19
infection were estimated based on EQ-5D survey data measured up to 90 days following
infection onset from a Japanese clinic for patients treated whether in-hospital or on an
outpatient basis using an area under the curve approach.42 QALY losses for hospitalized
patients also include 3 days of outpatient impact to account for the period of time prior to
hospitalization with infection symptoms. As base-case QALY losses reflect the 3-month period
following infection, post-infection and long COVID QALY loss impacts are assumed to be
reflected in the base-case inputs and are not explicitly included. Baseline utility estimates and
QALY losses associated with infection-related outcomes are presented in Tables 3 below.
Vaccine-Related Costs and QALYs Lost
Vaccine costs included an administration cost of ¥3,40043 and the unit cost of the
vaccine itself. As the commercial price of the vaccines in Japan has not yet been determined, a
unit cost of both vaccines was assumed to be ¥12,040 in the base case based on the German
list price.44 All individuals receiving vaccines also received an average cost and QALY loss
associated with adverse events (AE), weighted by the probability of experiencing the AE. AEs
include local and systemic grade 3 reactions, anaphylaxis, and vaccine-induced myocarditis
(relevant for those ages 18-39 years only); risks were estimated based on Moderna clinical trial
data and published sources.45-47 The unit cost of myocarditis following COVID-19 infection was
assumed to apply to the vaccine-induced myocarditis AE.48 All other AE costs were derived
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from Teng (2022), with the assumptions that 20% of grade 3 systemic AEs would require an
outpatient visit, and that 60% of anaphylaxis cases would require hospitalization (and the
remaining 40% would require emergency room care).49 AE QALY losses were obtained from
Teng (2022), and the QALY loss associated with infection-induced myocarditis was estimated
based on data from Prosser (2019).49,50 Inputs for vaccine-related AEs are presented in Table 4
below.
Analysis of Uncertainty
A number of scenario analyses and deterministic sensitivity analyses were conducted to
determine the impact of uncertainty on the predicted ICER of the Moderna Fall Campaign
compared to No Fall Vaccine. The discount rate applied to the calculation of lifetime QALYs was
varied from 0% to 4% as per the Japanese guidelines.41 The societal cost perspective was also
considered using the inputs displayed in Table 5. Days lost from work associated with
vaccination and vaccine-related AEs, as well as infection-related consequences, were applied
but weighted by age based on the proportion of individuals in the workforce.51 Days of lost
productivity were valued assuming an average daily wage of ¥18,700.52
Alternative vaccination target populations for the Fall 2023 Campaign were tested as
Japan has varied the population eligible for booster doses over time. A subgroup analysis was
conducted where vaccines were offered only to those aged 65 and older. A second analysis
included those aged 65 years and older plus those aged 60 to 64 years at high risk of severe
outcomes. We estimated the number of high-risk individuals ages 60-64 to be 4.48 million, or
60%, through an analysis of the DeSC data.36
One scenario was created to estimate the impact of an annual strategy with two doses.
As in the base case, the first dose was provided as Fall 2023 vaccination to those 18 and older
starting in September. A second dose was then assumed to be provided to those 18 – 64 at
high risk of severe outcomes and those 65 years of age and older starting 6 months later in
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March 2024. The coverage rate for this second vaccine was assumed to mirror the observed
bivalent dose which had similar eligibility criteria. The technical appendix of Kohli et al.
estimating the corresponding clinical impact provides the uptake over time.28
The inputs to the SEIR model were varied in several scenarios. The cost-effectiveness
of vaccination was tested using the six different incidence strategies that were developed in
Kohli et al.28 These scenarios were created by changing the calibration process (Adjusted
Tokyo data 2.5X or 1.5X; Adjusted Tokyo data 2.0x with Revised Waning), a scenario assuming
change in contact patterns during the year (Seasonality: phi=0.2), and two further scenarios
assuming that a new variant that reduced vaccine VE and natural immunity evolved (immune
escape assumed to happen either April 2024 or June 2024). Please see the previous clinical
manuscript for further details.28 Vaccine coverage was also reduced in scenarios to 50% and
75% of base case values. The initial VE of the Moderna vaccine and the monthly waning rates
were varied as described in the vaccine section above.
Deterministic sensitivity analyses were conducted by varying inputs in the infection
consequences decision tree. Percent with symptoms, mortality rates, and percent in the ICU
were varied using the lower and upper bounds of the 95% confidence interval associated with
the base case input. Hospitalization costs, outpatient costs, and QALY losses were varied by +/-
25%. Finally, alternative prices for the Moderna vaccine were assumed to be ¥10,072 and
¥18,525, corresponding to the list price of $129.50 per dose in the United States, were tested.53
In comparing the Moderna and Pfizer-BioNTech Fall Campaign, the initial VE against
both infection and hospitalization of the Pfizer-BioNTech Campaign was varied in sensitivity
analyses using the values displayed in Table 1.
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Results
Base Case Comparison: Updated Moderna Fall Campaign versus No Fall Vaccine
For the 18 year old plus base-case scenario, the model predicted 35,241,000
symptomatic infections without a fall vaccine, this decreased by 20% to 28,055,300 with the
Moderna Fall Campaign (Table 6). The model predicted 690,000 COVID-19 related
hospitalizations without a fall vaccine, compared to 417,800 with the Moderna Fall Campaign, a
reduction of 39%. Model predicted deaths were also decreased from 62,000 to 36,100 by
implementing the Moderna Fall Campaign (41% reduction). Base-case clinical results, which
align with the previously published clinical manuscript, are presented in Table 6.28
Given the clinical impact of the updated Moderna COVID-19 mRNA Fall 2023 vaccine, it
is expected to result in a gain of 207,000 QALYs relative to No Fall Vaccine by preventing
COVID-19 related deaths and 266,800 QALYs gained due to prevented morbidity for a total of
473,900 QALYs gained. Vaccination and adverse events cost ¥1,123,500 million ($7,860
million USD) compared with savings in COVID-19 treatment costs of ¥485,900 million ($9,400
million USD) due to vaccination. The incremental cost per QALY gained of the updated
Moderna COVID-19 mRNA Fall 2023 vaccine compared to no additional COVID-19 vaccination
in Fall 2023 is therefore ¥1,300,000 ($9,400 USD) (Table 7; See Technical Appendix Table 1 –
2 for details).
Scenario Analysis: Societal Perspective and Target Population
Analyses performed from the societal cost perspective yield an ICER of ¥800,000/QALY
gained ($5,600 USD/QALY gained), representing a decrease from the base-case ICER of 40%.
Limiting the population vaccinated to high-risk individuals aged 60-64 years and those aged ≥65
years decreases the ICER compared to no Fall vaccine by 32% to ¥910,000 ($6,400 USD)
compared to the base case (healthcare payer cost perspective). Limiting the population
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vaccinated to only those aged ≥65 years yields a similar ICER of ¥940,000/QALY gained
($6,600 USD/QALY gained).
Scenario Analysis: Two Annual Boosters
In the scenario analysis examining a two-booster strategy, the total number of COVID-19
infections prevented by the Moderna Fall Vaccine Campaign compared to the no Fall Vaccine
strategy increases by 28%, from the base-case value of 7,185,614 to 9,691,565. Incremental
QALYs gained also increased from the base-case from 473,870 to 605,737. With the increased
number of vaccinations and associated costs of providing a larger number of doses, total costs
of the Moderna Vaccine Campaign also increase in the 2-booster scenario to ¥2,740,270 million
($19,171 million USD). As a result, the ICER increases from the base-case of ¥1,300,000
($9,400 USD) to ¥1,600,000 ($11,200 USD) per QALY gained relative to no vaccine.
Additional Sensitivity Analyses
Varying the updated Moderna COVID-19 mRNA Fall 2023 vaccine price yields ICERs of
¥1,000,000 ($7,300 USD) per QALY gained and ¥2,300,000 ($16,400) per QALY gained
relative to no fall vaccine, representing a decrease of 22% and increase of 74% respectively.
Results of the remaining sensitivity analyses are displayed in Figure 2, with economic details in
Technical Appendix Table 3 and clinical details in Technical Appendix Table 4. COVID-19
incidence, vaccine waning against infection, and initial VE against infection have the greatest
impact on model results due to their effect on the number of infections prevented by vaccination.
For example, with incidence scenario, “Adjusted Tokyo Data (2.5X)”, the timing of the incidence
of cases has changes so that a larger proportion of infections occur before the vaccine is
administered. With this scenario, the ICER increases by 318% to ¥5,600,000 per QALY
($39,000 USD), as the Fall 2023 vaccine is predicted to prevent 80% fewer infections relative to
the base-case (1,465,400 compared to 7,185,600). Varying vaccine waning rates against
infection has the next largest impact, yielding ICERs ranging from ¥600,000 ($4,200 USD) to
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¥4,300,000 ($30,000 USD) per QALY. This is also due to the large impact on COVID-19
infections prevented (1,464,382 [80%] for the infection waning rate lower bound and 12,077,866
[168%] for the upper bound). Similarly, initial VE against infection has the third strongest impact
on the ICER, which ranges from ¥540,000 ($3,800 USD) to ¥3,800,000 ($26,900) per QALY
gained relative to no vaccine using the upper and lower bounds, respectively. Using the lower
bound infection waning rate yields 1,756,555 infections prevented, while varying to the upper
bound yields 12,648,644 infections prevented, representing a 76% decrease and 176%
increase from the base case, respectively. The pattern is similar for the other incidence
scenarios (adjusted Tokyo data [2.0x] revised waning, adjusted Tokyo data [1.5x], immune
escape June 2024, and immune escape April 2024), as well as the percentage of infection with
symptoms, which appear toward the top of the tornado diagram (Figure 2) due to their impact on
infections prevented by vaccination.
Initial VE against hospitalization also has a substantial impact on the ICER, with
variation from the upper and lower bounds yielding ICERs of ¥1,100,00 ($7,600 USD) and
¥2,200,00 ($15,000 USD) per QALY gained relative to no vaccine. These results are driven by
the total number of hospitalizations prevented which range from 338,397 to 120,673
respectively compared to the base case estimate of 272,133. QALY losses due to infection
(both hospitalized and non-hospitalized varied simultaneously) yield ICERs ranging from
¥1,200,000 to ¥1,600,000 per QALY gained relative to no vaccine. Hospitalization rates in the
unvaccinated, vaccine waning against hospitalization, and hospitalization costs appear together
in the tornado diagram, due to their similar impact on number of hospitalizations prevented by
vaccination and importance of hospitalization costs in driving cost-effectiveness results. All other
parameters varied in deterministic sensitivity analyses yield changes from the base case ICER
of less than 10%.
Comparison: Moderna Fall Campaign versus Pfizer Fall Campaign
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The predicted initial VE of the updated Moderna Fall 2023 vaccine was based on input
data assumed to be greater than the initial VE of the updated Pfizer-BioNTech version, leading
to a reduction in the total number of symptomatic infections of 1,091,100 (4%). The Moderna
Fall Campaign is also predicted to reduce the total number of hospitalizations by 6%, and
COVID-19 related deaths by 7%. These reductions in clinical outcomes translate to economic
benefits, with the Moderna Fall Campaign leading to a gain of 60,800 QALYs (4% increase) and
COVID-19 treatment cost savings of ¥60,400 million ($422 million USD; 5% reduction compared
to the Pfizer-BioNTech Fall ampaign). If the Moderna and Pfizer-BioNTech Fall vaccines are
priced equivalently, the updated Moderna COVID-19 mRNA Fall 2023 vaccine would be
considered the dominant choice.
In analyses comparing the Moderna Fall Campaign to the Pfizer-BioNTech Fall
Campaign, the EJP difference for the updated Moderna COVID-19 mRNA Fall 2023 vaccine is
presented in Technical Appendix Table 5. Given the assumption of superior effectiveness of the
updated Moderna COVID-19 mRNA Fall 2023 vaccine, a higher price for the Moderna vaccine
relative to the Pfizer-BioNTech vaccine could be justified economically. Assuming a base-case
price per dose of ¥12,040 ($84 USD), the price difference at a ¥5 million WTP threshold is
¥5,022 ($35 USD), while the price differences at the ¥6 and ¥10 million WTP thresholds are
¥5,860 ($41 USD) and ¥9,212 ($64 USD), respectively. As differences between the Moderna
and Pfizer-BioNTech VE increase or decrease, the price difference that could be justified at any
WTP threshold also increases or decreases. For example, scenario analyses varying the
relative VE to the upper and lower bounds suggest that the EJP difference could range from
¥2,829 ($20 USD) using the lower bound at a WTP threshold of ¥5 million up to ¥13,709 ($96
USD) using the upper bound at a WTP threshold of ¥10 million (Technical Appendix Table 5).
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Discussion
Using a previously published SEIR model28, this analysis examined the potential cost-
effectiveness of an updated Moderna COVID-19 mRNA Fall 2023 vaccine administered to
adults in Japan aged ≥18 years relative to no vaccine. An updated Moderna COVID-19 mRNA
Fall 2023 vaccine is predicted to prevent 7.2 million symptomatic infections, 272,100
hospitalizations and 25,600 COVID-19 related deaths in Japan between September 2023 and
August 2024 compared to no vaccination. In the base case analysis, the incremental cost per
QALY gained was predicted to be ¥1,300,000 ($9,400 USD) using the healthcare payer cost
perspective. Considering a WTP threshold of ¥5 million, the vaccine would be highly cost-
effective if priced at ¥12,040. Considering a societal cost perspective yields an ICER of
¥800,000 per QALY gained. Changing the target population to vaccination of high-risk
individuals aged 60-64 years combined with the general population aged 65+ or only the
general population aged 65+ yields ICERs of ¥910,000 and ¥940,000 per QALY, respectively.
Overall, sensitivity analyses suggest that results are robust to parameter uncertainty and
demonstrate that the cost-effectiveness model results are most affected by COVID-19 infection
incidence, initial VE against infection, and VE waning against infection. These key drivers were
also important to the clinical impact of vaccination in Japan in the clinical analysis by Kohli et al.
that focused on the SEIR model adaptation process.28 Infection incidence and VE have a large
impact on the number of infections prevented by vaccination, which in turn impacts the
economic results. These results are also consistent with a previously published analysis
performed examining the cost-effectiveness of vaccination in the United States (US), although 23
differences between results for the two jurisdictions exist. For example, varying the
hospitalization rates in the unvaccinated appears to have a greater impact on the ICER in the
US when compared to Japan. The range used in the US sensitivity analysis was wider than the
range used for Japan. It incorporated uncertainty around the US hospitalization rates based on
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data from the Delta period and around the relative risk used to adjust those rates for Omicron. A
limitation of the current analysis is that while hospitalization rates in Japan reflect data from April
2022 to March 2023, the vaccination status of hospitalized patients was not tracked.
Hospitalization rates in the unvaccinated population were therefore estimated using by varying
the assumptions about the level of residual VE due to prior vaccinations in the population.28
QALY losses associated with COVID-19 infection also appear to have a greater impact
on model results in Japan compared to the US. This is likely due to differences in how QALY
losses were estimated between the two countries. In Japan, estimates were based on EQ-5D
survey data measured up to 90 days following infection onset from the VERSUS clinic for
patients treated whether in-hospital or on an outpatient basis and represent a 3-month time
period following infection onset36, while in the US23, separate QALY loss estimates were used for
the acute and post-infection periods. Hospitalization costs appear to have a similar impact in
both settings; however, outpatient costs appear to have a greater impact on model results in
Japan compared to the US. In Japan, hospitalization and outpatient costs reflect the 6-month
period following infection, while in the United States, separate cost estimates were used to
reflect the acute and the 6 month post-infection periods.23 Furthermore, the QALY and cost
impacts of the post-infection consequences of COVID-19 infections are likely under-estimated in
this analyses as data is now showing the effects of “long COVID” are likely to last longer than 6
months.
The Centers for Disease Control and Prevention (CDC) in the United States has
presented evidence that COVID-19 may impact quality-of-life for up to 2 years post-acute
infection.54-56 In the United States, a database analysis was conducted on individuals that tested
positive for COVID-19 between March – December 2020 and matched controls.57 Individuals
were followed for 2 years to estimate the risk of pre-specified COVID-19 post-acute sequalae.
The analysis found that at 2 years, 65% of individuals that were hospitalized for COVID-19 and
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31% of those that were not hospitalized still had post-sequalae risks. These risks contributed to
disability-adjusted life-year decrements (DALYs) in this population, with 25% and 21% of DALYs
lost during the second year in non-hospitalized and hospitalized individuals, respectively. Based
on data from Japan, our model includes 3 months of QALY decrements. Given the evidence
that QALY loss extends beyond the 3-month period, and given fewer COVID-19 infections and
cases of long COVID are estimated with the use of the Moderna Fall 2023 vaccine compared to
the Pfizer-BioNTech Fall 2023 vaccine, our estimates of QALYs gained with the Moderna
vaccine are likely underestimated.
A recently published analysis conducted in the United Kingdom (UK) using electronic
health records from January 2020-January 2023 compared resource utilization in individuals
with and without long COVID post-infection to controls.58 The resource use of the long COVID
group was also compared to pre-2020 resource use. The study found that per year, individuals
with long COVID had more general practitioner consultations and outpatient visits than all other
control groups but fewer inpatient, critical care, and emergency department visits than those
with COVID-19 without a long COVID diagnosis. Annual healthcare utilization cost for the long
COVID group was estimated at £3,335 per year; the cost for those with COVID but not long
COVID was £5,961 while the control groups had costs ranging from £1,210 to £1,283. Although
healthcare utilization patterns and costs differ between the UK and Japan, this study
demonstrates that long COVID costs extends beyond the 6 months included in our analysis.
Additionally, even if not diagnosed with long COVID, healthcare utilization is increased in
COVID patients compared to those that did not become infected. Similar to QALYs gained, our
estimates of cost-savings with the Moderna Fall 2023 vaccine is likely underestimated.
This analysis also demonstrated the potential economic impact of a difference in vaccine
effectiveness between the two Fall 2023 COVID-19 mRNA vaccines. Assuming that the rVE
observed with the bivalent vaccine will also apply to the updated fall 2023 version, the base
case comparison of the two mRNA vaccines indicates that the Moderna version will prevent
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1,100,000 more symptomatic infections, 27,100 more hospitalizations, and 2,600 more deaths
relative to the Pfizer-BioNTech vaccine. Therefore, the unit cost of the Moderna vaccine could
be higher than the Pfizer-BioNTech vaccine. Under base-case assumptions, a price difference
of ¥5,022 ($35 USD) would be economically justifiable considering a ¥5 million WTP threshold.
Scenario analyses varying the VE suggest the EJP difference may range from ¥2,800 ($20
USD) to ¥7,500 ($52 USD) at the ¥5 million WTP threshold. While both of the mRNA COVID-19
vaccines have the same mechanisms of action, differences in VE may exist because their
delivery systems and dosage differ. A meta-analysis in immunocompromised populations
concluded that the Moderna version of the COVID-19 vaccine is more effective than the Pfizer-
BioNTech version59 In the general population, several studies of the original monovalent
versions make the same conclusion.15-18 For this analysis, we use evidence from a study that
compares the bivalent versions60 in the general population.
Although scenario analyses have been included in the current analysis to explore the
impact of incidence and VE on cost-effectiveness results, as noted in previous publications, the
future incidence of infection, expected pattern of infection, and VE against infection and
hospitalization remain highly uncertain and may impact the value of vaccination in the
future.23,28,61 In addition to long-COVID inputs which may underestimate the cost savings and
QALYs gained with the use of the Moderna Fall 2023 vaccine, due to lack of data, other
parameters, which may increase the value of vaccination, were not included. Estimates of
mortality included in the current analysis represent in-hospital mortality only, and therefore any
COVID-19 related deaths occurring post-discharge are not captured. For the societal cost
perspective, we considered short-term lost productivity but did not have data on long-term
losses or other informal health care resource used, such as caregiver time, 62 or other impact of
family spillover.63 The impact of COVID-19 using the societal cost perspective is therefore
under-estimated.
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Despite the limitations, our model consistently predicted that the Moderna updated
COVID-19 mRNA Fall 2023 vaccine is highly cost-effective at a ¥5 million WTP threshold across
a wide range of parameter values and scenario analyses. The VE of the new vaccines will not
be known until after the vaccine is delivered and real world, such as VERSUS study, have
completed their assessment. However, if VE is similar to past versions of the vaccine, then the
updated Moderna mRNA Fall 2023 vaccine is expected to prevent a significant number of
COVID-19 symptomatic infections, hospitalizations, deaths and associated health care costs
both in comparison against no vaccination and in comparison against the Pfizer-BioNTech
vaccine. Finally, a higher price for a more effective vaccine is economically justifiable. If the
Moderna version of the Fall 2023 vaccine is more effective that the Pfizer-BioNTech vaccine,
our model predicted that a higher unit cost is justifiable given the additional cases of
symptomatic infections, hospitalizations and deaths.
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Tables:
Table 1. Base case initial vaccine effectiveness values
Infection
Hospitalization
Moderna updated Fall 2023 vaccine
Base case*
54.7%
84.9%
Scenario analysis compared to
no vaccine: 95% confidence
intervals
40.3% - 65.6% 65.7% - 93.3%
Pfizer-BioNTech updated Fall 2023 vaccine
Base case
52.3%
83.3%
Scenario analysis (Moderna
vs. Pfizer-BioNTech): based on
rVE 95% confidence interval
(Moderna updated Fall 2023
vaccine initial VE held
constant).
51.3%-53.2% 81.9% - 84.5%
* These values were also used for the following scenarios: 1) Target population of 65 years and
above; 2) Target population of 60 – 64 years (high risk) plus 65 years and above.
Table 2. Base case probabilities for the economic consequences model
Age
Group
(years)
Hospitalization in
the
unvaccinated28
Proportion
hospitalized who
receive ICU
care
36
In-hospital
mortality37,38
COVID-19
infection–related
myocarditis, by
age (%)
35
0-11
0.46%
17.35%
0.14%
0.12%
12-17
0.18%
17.35%
0.14%
0.12%
18-29
0.30%
33.21%
0.15%
0.08%
30-39
0.47%
36.39%
0.15%
0.07%
40-49
0.51%
51.39%
1.10%
0.09%
50-59
1.04%
51.39%
1.10%
0.14%
60-64
2.93%
56.38%
4.98%
0.14%
65-74
8.62%
52.56%
7.07%
0.16%
75+
13.76%
55.85%
12.91%
0.21%
ICU: Intensive care unit
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Table 3. Base case cost and quality of life inputs for the economic consequences model
Model Parameter
Value
Discount rate41
2.0%
Costs
Booster cost (per dose)
¥12,040
Booster administration cost43
¥3,400
COVID-19 infection–related myocarditis (per
event)
48
¥20,262
Outpatient care (per patient seeking care)*36
¥65,361
Hospitalization (no ICU)* 36
¥508,683
Hospitalization (ICU)* 36
¥1,366,787
Quality of Life
Baseline utility data40
0-11 years
0.973
12-17 years
0.973
18-29 years
0.955
30-39 years
0.949
40-49 years
0.946
50-59 years
0.928
60-64 years
0.928
65-74 years
0.929
75+ years
0.832
QALYs lost, not hospitalized42
0.0367
QALYs lost, hospitalized† 42
0.05
QALYs lost, SARS-CoV-2 infection–related
myocarditis (per event)
50
0.0019
* Reflects the excess COVID-attributable cost for the 6-month period following infection
(including acute treatment)
†Includes an additional 3 days of disutility to account for the symptomatic time prior to
hospitalization
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Table 4. Adverse event inputs
Model Parameter
Value
Key Assumptions
Adverse Event Rates
Grade 3 local45
4.20%
Rates from AEs for
monovalent boosters and
assumed to apply to future
vaccine versions. Grade 4
AEs were not included (no
grade 4 AEs reported in the
clinical trial). Rates assumed
to be the same between
Moderna and Pfizer-
BioNTech Fall 2023
vaccines.
Grade 3 systemic45
5.90%
Anaphylaxis46
0.0005%
Vaccine-specific rates had
overlapping 95% CI.
Therefore, rates assumed to
be the same between
Moderna and Pfizer-
BioNTech Fall 2023
vaccines.
Myocarditis47
0.0018%
Vaccine-specific rates had
overlapping 95% CI.
Therefore, reported pooled
data for Moderna and Pfizer-
BioNTech used sex-specific
pooled rates weighted by
proportion of male and
female US population aged
18-39 years. Risk applies to
those ages 18-39 years only.
Adverse Event Costs
Grade 3 local49
¥0
Grade 3 systemic49
¥788
Assumes 20% would require
an outpatient visit (consistent
with global approach)
Anaphylaxis49
¥128,733
Assumes 40% of cases
require treatment in the
emergency room and 60%
require hospitalization
Myocarditis48
¥20,262
Assumes same cost as
infection-related myocarditis
Adverse Event QALY Loss49
Grade 3 local
0.0001
Grade 3 systemic
0.0001
Anaphylaxis
0.0050
Assumes 40% of cases
require treatment in the
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emergency room and 60%
require hospitalization
Myocarditis
0.0082
Assumes 100% of cases
require hospitalization
AE: Adverse event; CI: Confidence Interval
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Table 5. Lost productivity for analysis from the societal perspective
Model Parameter
Value
Key Assumptions
Percentage in labor force51
0-11 years
0.0%
12-17 years
23.3%
18-29 years
63.2%
30-39 years
86.4%
40-49 years
86.4%
50-59 years
82.3%
60-64 years
78.1%
65-74 years
25.2%
75+ years
25.2%
Daily wage rate52
¥18,700
Days lost for:
Vaccination
0.6
Assumption
Infection, not hospitalized64
5
Infection, hospitalized*
15
Includes time loss for the
hospitalization length of stay (10
days) and an additional 5 days
to reflect time with symptoms
prior to hospitalization
SARS-CoV-2 infection–related myocarditis
3
Assumption based on US data
Grade 3 Local AE
0.50
Assumption
Grade 3 Systemic AE
0.50
Assumption
Myocarditis65
2.25
Assumption based on US data
(inpatient length of stay of 2.25
days and 8 hours missed per
day)
Anaphylaxis65
2.00
Assumption based on US data
(inpatient length of stay of 2
days and 8 hours missed per
day)
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Table 6. Base-case (18+ general population): Number of cases, hospitalizations, and
deaths
Total
Prevented by Moderna
Vaccine (% Decrease)
No Vaccine
Pfizer-
BioNTech
Vaccine
Moderna
Vaccine
Vs. No
Vaccine
Vs. Pfizer-
BioNTech
Vaccine
Symptomatic
infections
35,240,923 29,146,363 28,055,308
7,185,614
(20%)
1,091,054
(4%)
Hospitalizations
689,973 444,948 417,839
272,133
(39%)
27,108
(6%)
Deaths
61,738 38,736 36,128
25,610
(41%)
2,607
(7%)
Table 7. Base-case (18+ general population): Cost-Effectiveness Results
Vaccination
Strategy
Total Costs
(millions)
Total QALYs
Lost
Incremental
Costs
Incremental
QALYs
Gained
ICER
(Incremental
Cost per
QALY
Gained)
No Fall 2023
Vaccine
¥1,771,342 1,800,209 -- -- Reference
Moderna Fall
2023 Vaccine
¥2,408,883 1,326,339 ¥637,540 473,870 ¥1,345,392*
*In USD: $9,412 based on exchange rate of ¥1 = 0.006996 USD26
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Figures:
Figure 1. Consequences diagram
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Figure 2. Impact of scenario analyses on the projected incremental cost-effectiveness
results with a COVID-19 vaccine updated for Fall 2023
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