
==== Front
Hum Vaccin Immunother
Hum Vaccin Immunother
Human Vaccines & Immunotherapeutics
2164-5515
2164-554X
Taylor & Francis

39269780
10.1080/21645515.2024.2386750
2386750
Version of Record
Research Article
Rotavirus
Health impact of rotavirus vaccination in China
S. OLUWASEUN ET AL.
HUMAN VACCINES & IMMUNOTHERAPEUTICS
Oluwaseun Sharomi a
Yang Chelsey b
Si Tu Su Jian c
Yin Jia d e
Song Yan f
https://orcid.org/0000-0003-3056-2322
Sun Qiang d e
Kanibir Nabi g
Hartwig Susanne h
Carias Cristina i
a BARDS-HEDS, Merck & Co. Inc ., Rahway, NJ, USA
b HEOR, Analysis Group , Beijing, China
c HEOR, MSD China Holding Co. Ltd ., China
d Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University , Jinan, China
e NHC Key Lab of Health Economics and Policy Research, Shandong University , Jinan, China
f HEOR, Epidemiology & Market Access, Analysis Group , Boston, MA, USA
g Global Medical and Scientific Affairs, MSD International GmBH , Luzern, Switzerland
h BARDS Epidemiology, MSD France , Lyon, France
i Value and Implementation, Merck & Co. Inc ., Rahway, NJ, USA
CONTACT Qiang Sun qiangs@sdu.edu.cn.
Jia Yin yinjia@sdu.edu.cn Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
13 9 2024
2024
13 9 2024
20 1 2386750Integra31 8 2024
Integra31 8 2024
24 1 2024
16 7 2024
29 7 2024
© 2024 Merck & Co., Inc., Rahway, NJ, USA and its affiliates. Published with license by Taylor & Francis Group, LLC.
2024
Merck & Co., Inc., Rahway, NJ, USA and its affiliates
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

Rotavirus (RV) vaccines have demonstrated substantial effectiveness in reducing the healthcare burden caused by gastroenteritis (RVGE) worldwide. This study aims to understand the differential impact of RV vaccination in reducing RVGE burden in children under 7 years old in China. A Markov Model was used to investigate the health impact of introducing two different RV vaccines into the Chinese population. The analysis was conducted for RV5, a live pentavalent human-bovine reassortant vaccine, and Lanzhou Lamb RV (LLR), a live-attenuated monovalent RV vaccine, separately, by comparing the strategy of each vaccine to no vaccination within a Chinese birth cohort, including 100,000 children modeled until 7 years of age. The vaccination scenario assumed a vaccination coverage of 2.5%, 2.5%, 90% and 5% for doses one, two, three and no vaccine, respectively, for both vaccines. Strategies with RV5, LLR, and no vaccination were associated with 9,895, 49,069, and 64,746 symptomatic RV infections, respectively. RV5 and LLR were associated with an 85% and 24% reduction in the total symptomatic RV infections, respectively, suggesting that the health benefits of RV5 are at least three-fold greater than those associated with the LLR. Further, strategies with RV5 and LLR resulted in an estimated 206 and 59-year increase in quality-adjusted life years (QALYs), respectively. Sensitivity and scenario analyses supported the robustness of the base-case findings. Use of RV vaccine is expected to improve RV-associated health outcomes and its adoption will help alleviate the burden of RVGE in China. RV5 use will result in significantly better health outcomes.

KEYWORDS

Rotavirus
rotavirus vaccination
Markov model
gastroenteritis
health impact analysis
vaccine effectiveness
Lanzhou lamb
RV
RV5
Merck Sharp & Dohme LLC Merck & Co., Inc. The work was supported by the Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. 
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pmcIntroduction

Rotavirus (RV) is a highly contagious virus with several circulating strains.1,2 In the absence of vaccination, almost all children will experience RV gastroenteritis (RVGE) before the age of 5 years.1 In 2016, 128,530 children under 5 years old were estimated to have died from RV globally, with 474 of these deaths occurring in China.3 Due to the high disease burden associated with RV, the World Health Organization (WHO) recommends that all countries vaccinate children between the ages of 6 weeks and 2 years against RV.4 Implementation of RV vaccination has been shown to reduce RVGE burden on patients and healthcare systems worldwide.5,6

In China, the annual societal costs for RVGE were reported at 365 million USD between 2006 and 2007 (440 million 2020 USD).7 RV vaccines are not included in the national immunization program vaccines and are provided through the private market.8 Two RV vaccines were available in China before 2023: Lanzhou Lamb RV (LLR), a live attenuated monovalent RV vaccine (approved in 2001),9 and RV5, a live pentavalent human-bovine reassortant vaccine (approved in 2018).8 In 2023, LLR3, a live trivalent human-lamb reassortant vaccine, was approved in China.10

Observational studies and randomized controlled trials have demonstrated the differential effectiveness of RV vaccines in reducing the burden of RVGE in children.9,11–14 With a vaccination coverage of at least 8.36%, LLR was reported to reduce the incidence rate of RVGE by 32.4% in children aged up to 4 years old in Guangzhou, China (0.68; 95% CI: 0.66–0.69, p < .001).12 A casecontrol study, comparing single-dose LLR to no vaccine in children aged less than 5 years in Beijing, China, demonstrated a vaccine effectiveness of 34.9% (95% CI: 5.30–55.30); the same study showed limited long-term effectiveness of the LLR vaccine.9 Meanwhile, the vaccine effectiveness of RV5 against RVGE of any severity and serotype in China was reported as 69.3% (95% CI: 54.50–79.40) in a doubleblinded randomized controlled trial.11 Similarly, a case-control study reported an 85% (95% CI: 50.00–95.00) vaccine effectiveness of RV5 against mild-to-moderate RVGE, among Chinese infants aged 14 weeks to 4 years.15 Further, a United States (US) multi-center, active surveillance study of children aged less than 8 years who were hospitalized or visited the emergency department with RVGE, demonstrated long duration of protection of RV5 up to 7 years of age.16 Observational studies have also demonstrated that mass RV vaccination results in herd immunity, subsequently reducing the number of RVGE-associated hospital visits among children.17,18

The aim of this study was to understand the differential impact of RV vaccination with RV5 or LLR in reducing RVGE burden in children aged 0–7 years in China, considering vaccines with available evidence on both effectiveness and durability. One publication has previously compared the health impact and cost-effectiveness of three RV vaccines (Rotarix®, RV5 and LLR) at 91.05% vaccine coverage in China, compared to the status quo (0% and 27.54% for RV5 and LLR, respectively),8 but to our knowledge, this is the first study to compare the effectiveness of RV5 and LLR versus no vaccination in China using a revised Markov model allowing for fitting observed to modeled data and a 7-year time horizon. Despite the approval of LLR3 in China in 2023, there are limited data for the effectiveness and durability of protection for this vaccine. LLR3 was thus not included in the current analysis. A Markov model was developed to investigate the health impact of receiving an RV vaccine (RV5 or LLR) versus no vaccination in China. The results of the current study may inform public health decision-makers of future national RV immunization strategies.

Materials and methods

We estimated the health impact (number of RV infections, life years [LYs], and quality-adjusted life years [QALYs]) of RV vaccination (RV5 or LLR) versus no vaccination using a Markov model to follow the progression of RVGE in 100,000 children. This model followed best practice guidelines for cost-effectiveness analyses, by ensuring the time horizon captured all relevant outcomes.19 Arakaki et al. 2021 demonstrated that up to 8% of the older children presenting with diarrhea have RV, and there is evidence that RV5 protects against RVGE and decreases disease in children up to 7 years of age.16,20,21 Therefore, a 7-year time horizon was deemed suitable for this analysis.

Markov models are static models that follow individuals as they progress through different disease states and where the likelihood of progression through different states is regulated, cycle by cycle, by epidemiological parameters. They are especially suited to model RVGE since children can have multiple RV infections in their first years of life.22 The model was designed to allow for a comparison between no vaccination and a vaccine strategy, with analyses conducted for RV5 and LLR separately.

Markov models

Children entered the model as susceptible (following the waning of maternal immunity after 3 months) and could have up to 5 RV infections (episodes), up to 7 years of age. They progressed through four primary health states: susceptible (no RV infection); RV infected, including asymptomatic or symptomatic (home care, outpatient treatment, or inpatient treatment); partially immune (no RV infection); and dead (Figure 1). Figure 1. State transition diagram of the health states and transitions in the Markov model.

Schematic diagram of the Markov model. The base-case model includes all-cause mortality. All-cause mortality occurs in every health state, which is not presented in the figure. Within each cycle, children could remain in a susceptible or partially immune state. The boxes with dashed outlines indicate no transitions to certain states. Specifically, the model assumes that RV infection does not lead to inpatient treatment or RV-related deaths after the second episode. The base-case model includes maternal immunity, which protects children ages up to 3 months against RV infection.

To accommodate both the vaccine dosing schedules and the minimal interval required between two consecutive episodes, a monthly cycle length was used.23 Within each cycle, children could remain in a susceptible state, partially immune state, or experience one RV infection. In the case of symptomatic infection, treatment was provided immediately, and treatment decisions were based on the severity of RV: home care (mild infections), outpatient treatment (moderate infections), or inpatient treatment (severe infections). At the end of each cycle, children who were alive and who had a previous infection became partially immune to subsequent RV infections. Every partially immune state was distinguishable by its different susceptibility to RV infection, which was fitted using the age-related incidence of RV infection (Table 1). Deaths included RV-related deaths and all-cause mortality. In the vaccine arm, children received either RV5 or LLR at the beginning of each cycle, and immunity was obtained upon vaccination. Partial protection was assumed after one or two dose(s) of the vaccine and full protection after three doses (Table 1).Table 1. Summary of the input parameters used in the Markov model.

Parameter	Value	Range for sensitivity analysis	Source	
Epidemiological parameters	
Total number of symptomatic RV infections among children aged 0–5 years (per 100,000 persons)	11,996	NA	Hai et al 202124	
Incidence of RV infections by age group (per patient-year)	 	 	 	
0 years	0.0548	±20% of the basecase value	Hai et al 2021, Parashar et al. 2003, Luo et al. 2020, and China Statistics Bureau 202124–27
Ages 5 and 6 assumed the same as age 4	
1 years	0.0475	
2 years	0.0107	
3 years	0.0043	
4–6 years	0.0029	
HCRU	
Proportion of RV cases cared for in the outpatient and inpatient setting (%)	19.6	NA	Parashar et al. 200326	
Outpatient to inpatient care multiplier	11.7	±20% of the basecase value	
Homecare to inpatient care multiplier	52.0	±20% of the basecase value	
Duration of RV episode by age group (homecare, outpatient, and inpatient cases)	 	 	 	
0–5 years	7.0	NA	Hoffman et al. 2011 and Marlow et al. 201528,29	
6 years	3.0	Wikswo et al. 202030	
Vaccine characteristics	
RV5 dosing schedule (month)	 	 	 	
First dose	2	NA	Package insert31	
Second dose	4	
Third dose	6	
RV5 effectiveness after 3 doses (%)*	97.00	±20% of the basecase value (within the bounds of 0 and 1)	Dennehy et al. 2011, Payne et al. 2015 and Ma et al. 202315,16,32	
RV5 duration of effectiveness after 3 doses (years)**	7.0	NA	 	
LLR dosing schedule (month)	 	 	 	
First dose	9	NA	Liu et al. 201233	
Second dose	21	
Third dose	33	
LLR effectiveness after 3 doses (%)†	 	 	 	
Asymptomatic, home care, and outpatient cases	41.06	±20% of the basecase value	Li, et al, 2019 and Huang et al. 20209,34	
Inpatient cases	45.88	
LLR duration of effectiveness for each dose (years)‡	3.0	NA	Li, et al, 2019 and Huang et al. 20209,34	
QALY weights	
Utility inputs of healthy children (susceptible or partial immune)	0.96	NA	Marlow et al. 201529	
Age-related duration of infection per episode (decrement in utility)§	 	 	 	
0–5 years	7.00	NA	Hoffman et al. 2011 and Marlow et al. 201528,29	
6 years	3.00	Wikswo et al. 202030	
Age-related decrement in utility associated with RV infection among infected children	
Asymptomatic cases	0.00	±20% of the basecase value	NA	
Home care and outpatient cases – ages 0–5 years	0.204	Martin et al. 2008, Marlow et al. 2015, and Gold et al. 199829,35,36	
Home care and outpatient cases – age 6 years	0.122	Bartsch et al. 202137	
Inpatient cases – ages 0–5 years	0.367	Martin et al. 2008, Marlow et al. 2015, and Gold et al. 199829,35,36	
Inpatient cases – age 6 years	0.271	Bartsch et al. 202137	
Decrement in utility associated with RV infection among caregivers	
Asymptomatic cases	0.00	±20% of the basecase value	NA	
Home care and outpatient cases	0.18	Marlow et al. 201529	
Inpatient cases	0.35	Rochanathimoke et al. 202123	
HCRU: Healthcare resource utilization; LLR: Lanzhou Lamb RV; NA: Not applicable; RV: Rotavirus; RV5: Rotateq®; QALY: Quality-adjusted life years.

*The model assumed that the effectiveness ratio between two doses and one dose, and that between three doses and two doses were constant across countries. The vaccine effectiveness of one dose and two doses for Chinese children were extrapolated from the three doses effectiveness in Ma et al. 2023 as the reference, and the relative effectiveness between two consecutive doses was extrapolated from Payne et al. 2015 as ratios.15,16

**Waning rates were calculated using the same method as vaccine effectiveness: the year specific vaccine effectiveness was calculated using the effectiveness of three doses in the inpatient cohort from Ma et al. 2023 as reference in the first year, assuming constant ratios across doses.15 The dose-specific waning vaccine effectiveness rate per year for RV5 for first, second, and third dose were 0.08, 0.0619, and 0.0457, respectively.15,16 Due to the lack of data, LLR vaccine effectiveness at different years was assumed the same as that of Rotarix®, another monovalent vaccine, and the waning rate after all three doses were administered was 0.1016 per year for all doses.34 The protection periods were assumed to be 1.5, 5, and 7 years for 1, 2, and three doses, respectively.16 The dose-specific linear reductions in vaccine effectiveness were subsequently estimated within the dose-specific duration of protection by assuming constant waning rates.

†Payne et al. 2015 was utilized to estimate the ratios between two consecutive doses.16 The vaccine effectiveness of children who received 1 dose were obtained from Li et al. 2019.9

‡A 3-year duration of protection for each dose (i.e., children who took all three doses will be protected till age 6) was taken from Li et al. 2019 and used in this model.9 Due to lack of data, LLR vaccine effectiveness at different years was assumed the same as that of Rotarix®.34 A constant waning rate in vaccine effectiveness was estimated.40

§No decrement in utility or duration of infection were considered for asymptomatic children.

In each cycle of the no vaccine arm, the age-specific annual incidence rate of RV infection (converted to monthly incidence) was used to calculate the transition probability to an RV infection state or to remain in the susceptible or partially immune state. In the vaccine arm, the incidence of RV infection was reduced, considering dose-specific vaccine effectiveness, waning rate, and duration of protection for children who received 1–3 doses. For each RV episode, the ratio of asymptomatic to symptomatic infections and the relative susceptibility before each episode (total of 5) were fitted so that the expected symptomatic RV incidence per year of age without vaccination matched the modeled incidence. That is, the sum of squared errors between the observed (derived from the literature) and modeled incidence per year of age was minimized, subject to the constrains that all ratios of asymptomatic to symptomatic infections should be no less than one and all the relative susceptibilities should be no less than 0.2.38

The expected number of RV infections, LYs, and QALYs for the vaccine and no vaccine strategies were calculated and the LYs and QALYs gained for the vaccine arm versus no vaccine arm were then estimated. Of note, for the vaccine strategies, projected outcomes were equal to the weighted average of the cohorts who received 0–3 doses, using vaccine coverage as weights. Results are tabulated and reported as a total, by disaggregated health states and by age.

Deterministic univariate and multivariate sensitivity analyses on the number of symptomatic RV infections averted, and the number of RV-related hospitalizations averted were conducted to test the robustness of the model. Separate deterministic sensitivity analyses were conducted for RV5 versus no vaccine and LLR versus no vaccine (Table 1). Scenario analyses were conducted to assess the uncertainty related to key model assumptions and specifications on the same projected outcomes as the deterministic sensitivity analyses (number of symptomatic RV infections averted and number of RV-related hospitalizations averted; see Table S1 in the supplementary appendix).

The Markov model was implemented in Microsoft Excel® (Microsoft Office 365). The minimization routine used Solver (GRG Nonlinear solving method).

Model parameters

Incidence and burden of RV infections

Age-specific annual incidence rate (per 100,000 persons) for RV infection was derived from the overall RV incidence and RV case distribution per year of age. The overall incidence rate of symptomatic RV infection in children aged 0–5 years (home care, outpatient treatment, and inpatient treatment) was 11,996 per 100,000 persons, based on disease burden data from an economic evaluation of RV vaccines in China (Table 1).24 The incidence per age group was calculated using the age distribution of RV incidence in children aged 0–5 years from Luo et al. 2020, an analysis of epidemiological characteristics of RV-related diarrhea in children under 5 years old from 2005 to 2018.25 Age-specific population size was derived from the China Statistics Bureau 2021 (Table 1).39 RV incidence in the 6th and 7th year of life was assumed to be equal to RV incidence in the 5th year of life. In the base-case, LYs and QALYs were discounted at 3% annually, following the WHO recommendations.4

To calculate inpatient and outpatient RV incidence per year of age, the proportion of RV infections requiring inpatient or outpatient treatment was considered to be 19.6% of the total RV infections.26 This was estimated according to a global disease burden model, which was based on a review of studies published from 1986 to 2000, and estimated the global illness and deaths caused by RV.26 The ratios of RV infections across symptomatic health states were derived from the same model, which reported the ratios of home care (52.0) and outpatient (11.7) cases, considering the inpatient state as reference.26

Age-related all-cause mortality rates were obtained from the Chinese Population and Employment Statistics Yearbook 2019, which were the most recent mortality data for China at the time of this study.39 The model assumed that all RV-related deaths occurred in the inpatient setting, with the estimated incidence of RV-related deaths in the inpatient setting based on published literature (0.004 per patient-year, which could only occur after the first and second RV hospitalizations since subsequent RV infections are less severe than previous infections).3,23,26,35

Utility inputs

Utility inputs for children and caregivers were derived from quality of life studies (Table 1).28–30,35,36,41 No decrement in utility was considered for children with asymptomatic infection. The age-related decrements in utility associated with RV infection per episode was 0.000 for asymptomatic (0–6 years), 0.204 (0–5 years) and 0.122 (6 years) for symptomatic home care and outpatient treatment, and 0.367 (0–5 years) and 0.271 (6 years) for symptomatic inpatient treatment.29,35–37 The decrements in utility associated with RV infections among caregivers was 0.000 for asymptomatic, 0.180 for symptomatic home care and outpatient, and 0.350 for symptomatic inpatient.23,29 These estimates were obtained from Marlow et al. 2015, a quality of life study which elicited utility values among families with children less than 6 years old in the United Kingdom (UK), and Rochanathimoke et al. 2021, an economic evaluation of a 2020 birth cohort which compared RV vaccination versus no vaccination over 5 years in Thailand.23,29 Further information on utility inputs can be found in Table 1.

Vaccine characteristics

RV5 vaccine effectiveness was estimated based on Dennehy et al. 2011 (using efficacy data between doses from the REST trial), Payne et al. 2015 (US-specific data on vaccine effectiveness associated with one, two, and three doses), and Ma et al. 2023 (Chinese-specific data on vaccine effectiveness in children who received three doses).15,16,32 Based on the literature, the 3-dose vaccine effectiveness for RV5 used in this analysis was 97.00% for symptomatic inpatient, outpatient, home care and asymptomatic cases (Table 1).15,16 For LLR, the vaccine effectiveness was obtained from studies in Asian infants, reported by severity (45.88% for inpatient cases [severe] and 41.06% for outpatient, home care, and asymptomatic cases [any severity]) (Table 1).9,34 To estimate the dose-specific vaccine effectiveness for RV5 and LLR, we used the ratios between effectiveness after the first, second, and third doses, as estimated by a longterm study of RV5 in US infants (Payne et al. 2015).16

To determine the duration of protection for RV5, we anchored the initial vaccine effectiveness to the value obtained by Ma et al. 2023 (97.00% among all children aged 14 weeks to ≤2 years with any severity of RVGE) and decremented the subsequent results proportionally to the results obtained in the US longterm study of vaccine duration (Payne et al. 2015).15,16 RV5 vaccine protection was assumed to last for 7 years for individuals receiving all 3 doses, based on the study by Payne et al. 2015.16 We decremented vaccine effectiveness with yearly waning. The waning rate was estimated via ordinary least squares (OLS) regression on vaccine effectiveness per year. Vaccine effectiveness in the first year corresponded to the one obtained by Ma et al. 2023, and yearly decrements were assumed to be proportional to the ones obtained by Payne et al. 2015 until 7 years of age.15,16

For LLR, the waning rate was also calculated via OLS regression, with both waning and duration of protection derived from studies by Huang et al. 2020 and Li et al. 2019.9,34 Due to the lack of data, the LLR vaccine effectiveness at different years was assumed the same as that of Rotarix®. Vaccine protection lasted up to 3.0 years of age according to a study of Chinese infants by Li et al. 2019 (Table 1).9

We assumed that vaccination was administered within the recommended time-windows for each dose.9,31,33,42,43 RV5 vaccination occurred at 2, 4, and 6 months of age, while the LLR vaccinations occurred at 9, 21, and 33 months of age. Vaccine coverage was assumed to be the same for both vaccines: 2.5% received one dose, 2.5% received two doses, 90% received three doses, and 5% received no vaccine (Table 1). While the national RV vaccine coverage in China is not currently at 90%, the impact of a 90% coverage rate was investigated to reflect a hypothetical universal vaccination scenario and vaccination goal in China among children aged up to 12 months.44 To supplement this scenario, the health impact considering a 50% vaccine coverage was studied to reflect lower vaccination uptake in a non-universal vaccination uptake scenario.45

Results

Base-case results

For the non-vaccine arm, over a 7-year time horizon and a cohort of 100,000 infants, the number of symptomatic RV infections was estimated to be 64,746, including 52,138 in the home care setting 11,708 in the outpatient setting, and 899 in the inpatient setting (Table 2; Table S2).Table 2. Disaggregated base-case results – RV5 and LLR versus no vaccine (90% vaccine coverage).

Outcomes	RV5	LLR	No vaccine	Difference: RV5 versus no vaccine	Difference: LLR versus no vaccine	
Health outcomes – children	
Number of RV infections – undiscounted	21,245	103,890	137,034	−115,789	−33,145	
Number of symptomatic RV infections – undiscounted	9,895	49,069	64,746	−54,851	−15,677	
Symptomatic – home care	7,960	39,510	52,138	−44,178	−12,628	
Symptomatic – outpatient	1,788	8,872	11,708	−9,921	−2,836	
Symptomatic – inpatient	147	687	899	−752	−212	
LYs	627,286	627,286	627,285	1	0	
QALYs	601,442	601,296	601,236	206	59	
Health outcomes – caregivers	
Disutility associated with RV infection among caregivers	−32	−161	−213	182	52	
LLR: Lanzhou Lamb rotavirus; LY: Life year; QALY: Quality-adjusted life year; RV: Rotavirus; RV5: RotaTeq®.

For RV5, with a vaccine coverage of 90%, the number of symptomatic RV infections were estimated to be 9,895, including 7,960 in the home care setting, 1,788 in the outpatient setting, and 147 in the inpatient setting. Compared with no vaccine, RV5 was associated with an 85% reduction in total symptomatic RV infections. Further, vaccination with RV5 resulted in a reduction of 85% in home care cases, 85% in RV-related outpatient visits, and 84% in RV-related hospitalizations. Furthermore, an increase of 206 QALYs was observed in the RV5 arm compared with the no vaccine arm. This means that the use of RV5, for the single cohort, resulted in the gain of 206 years among children, lived in good health. A reduction in the disutility associated with RV infection among caregivers was observed with RV5 compared with the no vaccine arm (difference: 182) (Table 2). Health impact considering a lower vaccination coverage, depicting the impact of implementing a universal vaccination campaign (at 50% VCR), is presented in the supplementary appendix (Table S3).

For LLR, with a vaccine coverage of 90% and for a cohort of 100,000 infants followed up to 7 years, the number of symptomatic RV infections was estimated to be 49,069, including 39,510 in the homecare setting, 8,872 in the outpatient setting, and 687 in the inpatient setting. Compared with the no vaccine arm, LLR was associated with a 24% reduction each in all symptomatic RV infections, RV-related home care cases, outpatient visits, and hospitalizations. An increase in QALYs (difference: 59) and a reduction in the disutility associated with RV infection among caregivers (difference: 52) was observed in the LLR arm compared with the no vaccine arm, respectively.

Deterministic sensitivity analysis and scenario analysis

The deterministic sensitivity analysis results showed that the model was generally robust to changes in model inputs by varying one parameter (univariate) or one set of parameters (multivariate) at a time while holding the other inputs at the base-case values (Figure 2). Figure 2. Deterministic sensitivity analysis of the number of symptomatic RV infections and RV-related hospitalizations averted with RV5 and LLR.

Tornado diagram for the deterministic sensitivity analysis of the number of symptomatic RV infections and RV-related hospitalizations averted with RV5 and LLR. Larger ranges indicate that the analysis was more sensitive to these parameters and smaller ranges indicate that the analysis was robust to changes in these parameters.
LLR: Lanzhou Lamb RV; RV: Rotavirus; RV5: RotaTeq®.

In deterministic sensitivity analyses considering RV5, the number of averted symptomatic RV infections ranged from 43,197 to 65,421, and the number of averted RV-related hospitalizations ranged from 574 to 874, compared with no vaccination. The model was most sensitive to the following for the number of RV-related hospitalizations averted: vaccine effectiveness by dose, incidence of overall symptomatic RV infection rate by age, and the ratio of home care infections to inpatient symptomatic infections (Figure 2). In the scenario analysis for RV5, the number of symptomatic RV infections averted ranged from 19,756 to 47,351 (basecase: 44,178). Compared to the base-case number of RV-related hospitalizations averted (752), the scenario analysis outputs ranged from 375 to 850 (Table 3).Table 3. Scenario analysis results for RV5 versus no vaccine.

Parameters	Number of symptomatic RV infections averted	Number of RV-related hospitalizations averted	
RV5 versus no vaccine	
Assume 80% of relative susceptibility*	47,351	699	
Time horizon: 1 year	19,756	375	
Time horizon: 3 years	40,314	706	
Cost and effectiveness (undiscounted)	44,178	752	
Not consider half-cycle correction	44,178	752	
Not consider natural mortality	44,465	756	
Not consider maternal immunity	42,313	714	
Assume that RV will lead to hospitalization and death in all episodes	44,179	850	
LLR versus no vaccine	
Assume 80% of relative susceptibility*	12,366	197	
Time horizon: 1 year	4,164	69	
Time horizon: 3 years	14,558	208	
Cost and effectiveness (undiscounted)	15,677	213	
Not consider half-cycle correction	15,677	213	
Not consider natural mortality	15,794	214	
Not consider maternal immunity	14,686	197	
Assume that RV will lead to hospitalization and death in all episodes	15,738	273	
LLR: Lanzhou Lamb RV; RV: Rotavirus; RV5: RotaTeq®.

*The 80% scenario analysis inputs for relative susceptibility by infections were based on assumptions.

Compared to the no vaccine arm, the deterministic sensitivity analyses results for LLR demonstrated that the number of symptomatic RV infections averted ranged from 12,379 to 18,980 and the number of RV-related hospitalizations averted ranged from 165 to 261. The model was most sensitive to the following variables for both the number of symptomatic RV infections averted, and the number of RV-related hospitalizations averted: vaccine effectiveness by dose, incidence of overall symptomatic RV infection rate by age, and the ratio of home care infections to inpatient symptomatic infections (Figure 2). For LLR compared to the no vaccine arm, the scenario analysis outputs for the number of symptomatic RV infections averted ranged from 4,164 to 15,794 (base-case: 15,677), and the number of RV-related hospitalizations averted ranged from 69 to 273, compared to 213 in the base-case (Table 3).

Discussion

We used a novel Markov model that allowed for fitting to observed data, and locally sourced parameters, when available, to estimate the impact of RV5 and LLR in RV outcomes in China. We estimated that universal use of RV vaccine at the recommended 90% coverage level, particularly RV5, would substantially reduce RV healthcare burden. RV5 was associated with an 85% reduction in total symptomatic RV infections and RV-related home care cases and outpatient visits, and an 84% reduction in RV-related hospitalizations, compared with no vaccination. Comparatively, LLR use would result in a 24% reduction in total symptomatic RV infections, RV-related home care cases, outpatient visits, and hospitalizations. Results from the deterministic sensitivity and scenario analyses were conducted to determine the robustness of these findings and to assess the uncertainty related to key model assumptions and specifications. The greatest degree of sensitivity was observed when varying the vaccine effectiveness by dose, incidence of overall symptomatic RV infection rate by age, and the ratio of home care infections to inpatient symptomatic infections.

The findings of this study align with other health impact analyses in China, which concluded that RV5 was associated with a greater health benefit than LLR.8,46 Cui et al. 2016 used a Markov model to compare the health impact associated with RV vaccination programs in China, and found that RV5 was associated with the largest health benefit in terms of decreased incidence of RV infection, versus Rotarix® and LLR.46 The cumulative infection rate up to 5 years was 6.32%, 12.05%, and 64.25% for of RV5, Rotarix® and LLR, respectively.46 Similarly, in a separate Markov model developed by Wang et al. 2022 to assess the health impact of RV vaccination in the 2019 Chinese birth cohort, RV5 was projected to result in the largest reduction in RVGE cases (62.6%), compared to Rotarix® (48.7%) and LLR (20.3%).8 In a deterministic sensitivity analysis, the most sensitive parameters for RV5 were vaccine efficacy against hospitalization and vaccine price, whereas the most sensitive parameters for LLR were vaccine efficacy against outpatient or home care cases and protection of natural infection against hospitalization.8

The differential vaccination impact reported in this study is in line with the differential effectiveness of the vaccines, as observed in previous studies, which indicate a higher vaccine effectiveness for RV5 compared to LLR.9,47,48 A systematic literature review of 48 articles published between 2006 and 2016 from 24 countries demonstrated a median vaccine effectiveness of 90% and 45% for RV5 in countries with low and high child mortality, respectively.49 A separate systematic literature review and meta-analysis of 60 studies from 32 countries reported that the RV5 vaccine effectiveness in children younger than 12 months was 86% and 66% in countries with low- and high-mortality in children less than 5 years, respectively.47 A comparatively lower vaccine effectiveness has been previously reported for LLR.9 The vaccine effectiveness of one dose of the LLR vaccine in children less than 5 years was 34.9% (95% CI: 5.3–55.3), compared with unvaccinated children (n = 1,766), based on 598 cases of LLR vaccination from a hospital surveillance system in a case-control study in Beijing between 2015 and 2017.9 Similar results have been demonstrated for the vaccine effectiveness of LLR in rural areas of China.48 A population-based surveillance study of children under 5 years conducted between October 2011 and March 2012 in rural Zhengding County estimated LLR protection against RVGE to be 12.5% (95% CI: −20.4–36.5%, p = .41).48

The Markov model is a well-established modeling approach that has been commonly used to model RV infections.8,23,46 Compared to other published studies, the model comprehensively described the RV disease course.8,23,46,50 The time horizon described in the current model was 7 years, which is longer than the commonly used 5-year horizon but in line with the finding that children ≥5 years old still experience RV.20 Additionally, the inclusion of an asymptomatic and partially immune health states provided a way to fit the model so that the modeled incidence approximated the observed incidence.

There are some limitations of the current study. First, the current Markov model design is static and conservative and does not account for herd immunity.51 However, observational studies have demonstrated that universal mass RV vaccination results in herd immunity.17,18 Mast et al. 2015 reported that the incidence of RVGE among children under 12 months old in the US was lower following the widespread availability of the RV5 vaccine (110 per 100,000 infants), compared to before the availability of RV5 (151 per 100,000), and concluded that the results provided evidence of herd immunity.17 Similarly, PaulkeKorinek et al. 2011 reported a decreased incidence of RVGE and evidence of herd immunity in Austria in 2009, following universal RV vaccination; a 30% reduction in hospitalizations was reported compared to 2008 as well as a 79% reduction in hospitalizations compared to the pre-vaccination period of 2001–2005, in children aged under 12 months.18 Dynamic transmission models are recommended to account for herd protection in order to capture the full value of RV vaccination.4,51 Therefore, the health impact estimate reported in this study is likely conservative. Second, we estimated outcomes by using globally derived multipliers.26 Globally derived multipliers may under or overestimate healthcare resource utilization in China. Further research is needed to establish healthcare resource use in China.

At the time of the study, there was no wide-scale surveillance study available in China. Therefore, multiple-published studies were used to calculate the transition probabilities in the first episode (i.e., incidence rate among children aged 0–5 years, the distribution of RV infection by age, and ratios of infections in the home care to inpatient setting), and therefore local estimates may vary, which may limit the generalizability of the results. There was also a lack of direct evidence on the dose-specific vaccine effectiveness and waning among Chinese children. The current effectiveness inputs were extrapolated, using data from children who received three vaccine doses in China as a reference and the relative effectiveness across doses in the RV5 global trial as ratios.11,16 Waning rates were further extrapolated following the same method, by assuming a constant rate within the protection periods.11,16 These extrapolated data may not represent a real-world scenario in China. However, the sensitivity analyses showed results were robust to variation in inputs. Of note, we used conservative parameters for the duration of protection of RV5, as protection may last beyond year 7 given gradual, and not abrupt, waning of immunity.16 There were also limited data available at the time of the study on diarrhea and RVGE prevalence. However, we used the most up-to-date data available, derived from China specific publications when available, and the prevalence of RVGE would stay constant without vaccination.

This study demonstrated RV5’s health impact was three-fold greater than the impact associated with LLR. Further, sensitivity and scenario analyses supported the robustness of the base case findings. Overall, this study highlights the importance of the implementation of RV vaccination with RV5, to strongly reduce RV-associated morbidity (homecare, outpatient, and inpatient cases), and should be considered by policy makers in China discussing RV immunization strategies.

Supplementary Material

Table S3.docx

Table S1.docx

Table S2.docx

Acknowledgments

The authors thank Adelphi Values PROVE for their support in the development of this manuscript.

Sharomi Oluwaseun is a Principal Scientist and Health Economist at Merck, where he has led modeling activities for RotaTeq and is currently leading and supporting modeling activities for Epstein-Barr Virus and Pneumococcal Disease. Prior to joining Merck, Dr. Sharomi served as an Associate Director of Modeling at CHEORS and as an Assistant Professor in the Department of Mathematics at Khalifa University in the United Arab Emirates. Dr. Sharomi’s work focuses on using mathematical modeling approaches and analyses to understand the transmission dynamics and control of emerging and re-emerging diseases of public health interest. He has designed, analyzed, and simulated novel mathematical models for the spread of various diseases, including respiratory diseases (H1N1, Mycobacterium tuberculosis), sexually transmitted infections (Chlamydia, HIV, HPV, syphilis), and their coinfections (e.g., HIV-TB coinfection). Dr. Sharomi has used these models to provide realistic assessments of various intervention strategies, such as vaccines (e.g., for H1N1 and HPV) and drug treatments (e.g., for HIV). His statistical skills include proficiency in parameter estimation, uncertainty and sensitivity analysis of model parameters, optimal control analysis, and fitting models to data. Dr. Sharomi’s expertise also encompasses the design and analysis of mathematical models of infectious diseases, simulation of electrical activity in myocardial tissue, parallel computing, problem-solving environments, and numerical algorithms and software for exascale computer architectures.

Chelsey Yang specializes in health economics and outcomes research (HEOR) and real-world evidence (RWE) studies. She has led the design and implementation of complex economic modeling and RWE solutions to support pharmaceutical clients in regulatory submissions, health technology assessments (HTAs), and clinical and economic evidence generation. Her research covers a variety of study types, including cost-effectiveness analyses, budget impact analyses, treatment pattern and outcome analyses, burden-of-illness analyses, systematic literature reviews, and indirect treatment comparisons. In her work, Ms. Yang uses data from large retrospective databases, medical chart reviews, disease registries, clinical trials, surveys, and qualitative interviews. She has experience with a broad range of therapeutic areas, including hematology, oncology, cardiovascular disease, rheumatology, dermatology, gastroenterology, rare diseases, and vaccines. Ms. Yang’s work has been presented at clinical and economic research conferences and published in various peer-reviewed journals.

Su Jian Si Tu specializes in vaccine health economics and outcomes research. Ms. Situ’s work spans across public and private sectors, and has worked on health economics, disease prevention and control, public health, and international cooperation in the health sector.

Prof. Jia Yin is an associate professor at Centre for Health Management and Policy, Shandong University. Prof. Yin obtained her PhD in Health Systems and Policy Research (HSPR) in the Chinese University of Hong Kong. Her primary areas of research interest are in the health economics and health policy evaluation. Specifically, in health technology assessment, drug policy and healthcare security. Prof. Yin has published more than 20 papers (first and corresponding author) in peer-reviewed academic journals.

Yan Song is an epidemiologist with expertise in biostatistics and clinical medicine, which he uses to address a wide array of analytical questions in health care. He has broad experience designing and implementing advanced and innovative real-world data analytic and economic modeling solutions for pharmaceutical clients. Dr. Song conducts research to evaluate and compare the clinical, economic, and humanistic impacts of diseases and treatments across a variety of therapeutic areas. He is experienced in disease areas including oncology, hematology, infectious disease and vaccines, dermatology, rheumatology, and endocrinology. Dr. Song has provided cross-indication consulting for multiple blockbuster pharmaceutical products as well as novel pipeline agents. In his work, Dr. Song uses data from clinical trials, administrative claims, medical chart reviews, surveys, qualitative interviews, and medical literature. His research has covered many different study types, including disease epidemiology, burden of illness, disease treatment and management patterns, comparative effectiveness research, individualized medicine, systematic literature reviews, indirect treatment comparisons, economic modeling such as cost-effectiveness analyses and budget impact analyses, analyses of patient-reported outcomes, and preference research such as discrete-choice experiments. Dr. Song’s work has been published in peer-reviewed journals and presented at international conferences on medical and health care research.

Qiang Sun was trained in the field of social medicine and health management for over 20 years. His research areas focused on health economics and policy research, pharmaceutical policy and hospital management. During the past decades, Prof. Sun has published over 60 articles (first and corresponding author) in international peer review journals including Lancet Global Health, Plos Medicine, Bulletin of WHO, Health Affairs and BMC journals and others. He has rich experience in social medicine and health policy survey. In the past decades, Prof. Sun has led and participated in many household-based studies, in particular a study on antibiotic knowledge, attitude and practice of rural residents funded by National Science Nature Foundation of China, China Medical Board and Medical Research Council. Meanwhile he cultured and trained over 60 masters and PhD students including a PhD student at Karolinska Institute as a mentor in the field of pharmaceutical policy.

Dr. Nabi Kanibir is a Turkish-trained physician who began his career with a research associate position at Columbia University Mailman School of Public Health, where he collaborated on studies related to HPV and preventive healthcare. He later served as a clinical research coordinator at Columbia University Presbyterian Hospital, focusing on pituitary gland tumors. During this time, he received advanced training in epidemiology and research methodologies. In 2008, Dr. Kanibir joined MSD Turkey as Vaccines Medical Affairs Manager, overseeing the introduction of HPV and Rotavirus vaccines. In 2011, he became the Vaccines Regional Medical Affairs Director (RDMA) for Eastern Europe, Middle East, and Africa, based in Luzern, Switzerland. Following a restructuring in 2017, he was appointed RDMA for the EU-Canada region, helping to establish vaccines teams across Europe while based in Lyon, France. In April 2020, Dr. Kanibir was appointed Global Medical Director at MSD, responsible for the pediatric and hepatitis vaccines portfolio, based in Luzern, Switzerland.

Susanne Hartwig is a pharmacist by training with additional specialization in Epidemiology and Biostatistics. She currently works as an epidemiologist and has more than 15 years of experience in the pharmaceutical vaccine industry.

Cristina Carias is a Technological Physics Engineer with a PhD in Strategy, Entrepreneurship, and Technological Change, and advanced training in Econometrics. She has experience in both the public and private sectors, and has worked on health economics, outcomes research, emergency preparedness, and public health modeling.

Disclosure statement

SO, SJST, NK, CC and SH were employees of Merck Sharp & Dohme (MSD, Rahway, NJ, USA), the manufacturer of RotaTeqTM. CY and YS were employees of Analyses Group, whose work on this analysis was funded by Merck Sharp & Dohme (MSD, Rahway, NJ, USA). JY and QS were academic staff members of Shandong University and received funding support from MSD China Holding Co. Ltd., for research on health economics of rotavirus vaccine and antimicrobial resistance control.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2386750
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