Projected Public Health Impact of a Universal Rotavirus Vaccination Program in France

Abstract

Objective:

In June 2022, French health authorities issued a universal recommendation for routine administration and reimbursement of rotavirus vaccines in infants. Given this recent recommendation by French health authorities, we sought to understand the public health impact of a universal rotavirus vaccination strategy compared with no vaccination.

Materials and Methods:

A deterministic, age-structured, nonlinear dynamic transmission model, accounting for herd immunity, was developed. We considered 3 vaccination coverage scenarios: high (95%), medium (75%) and low (55%). Model parameter values were based on published modeling and epidemiological literature. Model outcomes included rotavirus gastroenteritis (RVGE) cases and healthcare resource utilization due to RVGE (hospitalizations, general practitioner or emergency department visits), as well as the number needed to vaccinate to prevent 1 RVGE case (mild or severe) and 1 RVGE-related hospitalization. Model calibration and analyses were conducted using Mathematica 11.3.

Results:

Over 5 years following implementation, RVGE cases for children under 5 years are estimated to be reduced by 84% under a high vaccination coverage scenario, by 72% under a medium vaccination coverage scenario and by 47% under a low vaccination coverage scenario. Across all scenarios, the number needed to vaccinate to avert 1 RVGE case and hospitalization varied between 1.86–2.04 and 24.15–27.44, respectively.

Conclusions:

Rotavirus vaccination with high vaccination coverage in France is expected to substantially reduce the number of RVGE cases and associated healthcare resource utilization.

INTRODUCTION

Rotavirus gastroenteritis (RVGE) is the primary cause of acute gastroenteritis in children worldwide¹ and one of the leading causes of hospitalization and death in children under 5 years.^1,2 Rotavirus is highly contagious; infection typically manifests with vomiting, fever, abdominal pain, watery diarrhea and dehydration.³ In France, rotavirus infection causes 430,000 acute RVGE cases, including 14,000 hospitalizations and 181,000 ambulatory visits annually among children under 5.⁴ Besides its clinical burden, rotavirus infection causes substantial costs for healthcare payers, families of patients and employers.⁵ In France, in 2002, the annual direct cost of rotavirus infection care was estimated at €28 million 2002€⁴ (€26.7 million 2020€⁶), and in 2007, the societal costs for children hospitalized with RVGE amounted to €1525 (2007€, €1670, 2020€) per episode.⁵

In 2009, the World Health Organization recommended the inclusion of rotavirus vaccines in the National Immunization Program (NIP) of all countries.⁷ As of January 2022, 114 countries had included rotavirus vaccines in their pediatric immunization programs, including several countries in the European Union.⁸ The introduction of rotavirus vaccination has led to a substantial decrease in the rotavirus burden in Europe⁹ and worldwide.^10–13 In Finland, universal rotavirus vaccination with RotaTeq (RV5) has led to a reduction of RVGE cases in the 5 years following vaccine introduction, as reported in a prospective study.¹⁴ The proportion of RVGE in all acute GE cases decreased from 52% in the pre-NIP period to 12% in the post-NIP period; RVGE-related hospitalizations and outpatient clinic visits each declined by 90%.¹⁴ In addition, rotavirus vaccination was determined to be cost-saving, leading to €33 (in 2015€) per vaccinated child in averted medical costs.¹⁵

In France, two rotavirus vaccines are licensed and available for use: Rotarix (a 2-dose monovalent vaccine manufactured by GlaxoSmithKline or RV1) and RV5 (a 3-dose pentavalent vaccine manufactured by Merck & Co., Inc, Rahway, NJ, or RV5). Both vaccines have been shown to be highly efficacious and safe in large clinical trials and postlicensure real-world studies.^16–18

The SARS-CoV-2 pandemic prompted the European Society for Paediatric Infectious Diseases, the European Society for Paediatric Gastroenterology Hepatology and Nutrition and the National Academy of Medicine¹⁹ in France to recommend rotavirus vaccination to decrease rotavirus emergency admissions, hospitalizations and bed occupancy rates.^11,20 In 2022, rotavirus vaccination was recommended and reimbursed to the general population²¹ by the Transparency Commission. The Transparency Commission is a commission of Haute Autorité de Santé, which is the French health authority in charge of assessing the benefit of the drug for the price and reimbursement.

In response to this approval, we sought to assess the public health impact of rotavirus vaccination in France with RV5 compared with no vaccination. The results of the current study can inform public health decision-makers of future national rotavirus immunization planning.

METHODS

We used a deterministic, cohort, age-structured, susceptive-exposed-infectious-recovered nonlinear dynamic transmission model to quantify the potential public health impact of rotavirus vaccination with RV5 administered to infants at the ages of 2, 4 and 6 months. Model outcomes included RVGE cases and healthcare resource utilization [hospitalizations, general practitioner (GP) or emergency department (ED) visits], as well as the number needed to vaccinate (NNV) to prevent 1 RVGE (mild or severe) case and 1 RVGE-related hospitalization. Before 2023 in France, rotavirus vaccines were not reimbursed, resulting in a low vaccination coverage rate of approximately 5%.²¹ To better understand the effects of introducing rotavirus vaccination in the French population, 3 hypothetical scenarios have been created based on varying vaccination coverage rates.

We modeled 3 vaccination coverage scenarios: high coverage, which corresponds to the approximate vaccination coverage of mandatory vaccines²¹ (95% of infants take the full series, 96.5% of all eligible infants take the first dose, 99% of infants taking the first dose would take the second dose and 99% of infants taking the second dose would take the third dose); medium coverage, which corresponds to observed vaccination coverage of nonmandatory vaccines (75% of infants take the full series; with 76.5% of eligible infants taking the first dose, 99% of infants taking the first dose would take the second dose and 99% of infants taking the second dose would take the third dose); and low coverage, which corresponds to observed vaccination coverage in a low compliance setting (55% vaccination coverage assumed for 3 doses based on Spain, a neighboring European country where vaccination coverage was low,⁹ 56% for the first dose and 99% for the second and third doses).

Model

We used an age-stratified susceptive-exposed-infectious-recovered dynamic transmission model to simulate population-wide transmission dynamics of rotavirus in France over the 5 years following rotavirus vaccine introduction (Figure, Supplemental Digital Content 1, http://links.lww.com/INF/F625). Dynamic transmission models divide the population into compartments related to disease progression; individuals’ progression through the compartments is then regulated by parameters related to disease transmissibility and length of the latent and infectious period, among others.

In the model, individuals are born with maternal immunity that wanes after 3 months.²² Susceptible individuals can be exposed to rotavirus, become infectious and recover from the infection. Infectious individuals may have an asymptomatic, mild, or severe case and may, thus, require no care, care at home or visit to a clinic or hospital. Epidemiological inputs were mainly derived from a cohort study of Mexican infants followed for 2 years.²³ Healthcare resource utilization parameters were derived from a previous cost-effectiveness study for France.²⁴ Given the natural history of the disease, individuals could experience several reinfections events after the first infection, with the fourth or more infections having the same reinfection properties.

RVGE health outcomes such as hospitalization, GP visits and ED visits were calculated with and without vaccination. All analyses were conducted using Mathematica 11.3 (Wolfram Research, Champaign, IL).

Model Calibration

Model calibration was performed by finding parameter values that minimized the error between the projected RVGE incidence data and the observed incidence data in a scenario without any rotavirus vaccination. Using historical incidence data, the method of least square was used to find the optimal parameter values by minimizing the sum of square errors (the sum of squared differences between observed and projected incidence) over 5 years (Table 1). The parameters estimated via calibration included relative rates of infectiousness and seasonality parameters (see Table 1, Supplemental Digital Content 2, http://links.lww.com/INF/F626 for details on the calibration parameters and their calibrated values). A plot of projected versus observed incidence for each age group over the 5 years was further inspected to confirm that the calibration process yielded a good fit (see Supplemental Digital Content 2, http://links.lww.com/INF/F626 for more details).

TABLE 1.

Epidemiologic Parameters of the Model

Parameter	Value	Source
Initial population size	66,992,699	INSEE, 01/01/2019(6)
Probability that newborns have maternal antibodies (min = 0; max = 1)	1	25
Duration of maternal immunity in rotavirus-infected infants	90/365 yr	26
Incubation period −1ζ	2/365 yr	27
Duration of infectious period, yr
Duration of infectious period for the first infection −1γs1	7/365	28
Duration of infectious period for the second infection −1γs2	3.5/365
Duration of infectious period for the third infection −1γs3	3.5/365
Duration of infectious period for the fourth infection −1γs4	3.5/365
Proportion of rotavirus-infected people who recover with natural immunity −1-αsh (min = 0; max = 1, h = 1, 2, 3, 4)	1	23
Degree of natural protection (min = 0; max = 1)
Extent of natural protection for first infection −ψj1	0	23
Extent of natural protection for second infection −ψj2	0.38
Extent of natural protection for the third infection −ψj3	0.6
Extent of natural protection for the fourth infection −ψj4	0.66
First infection (severity distribution in first infection cases)
Proportion of first infection cases that are severe −ρS1	0.13	Calculated from23
Proportion of first infection cases that are mild −ρM1	0.34
Proportion of first infection cases that are asymptomatic −ρA1	0.53
Second infection (severity distribution in second infection cases)
Proportion of second infection cases that are severe −ρS2	0.03	Calculated from23
Proportion of second infection cases that are mild −ρM2	0.22
Proportion of second infection cases that are asymptomatic −ρA2	0.75
Third infection (severity distribution in third infection cases)
Proportion of third infection cases that are severe −ρS3	0	Calculated from23
Proportion of third infection cases that are mild −ρM3	0.32
Proportion of third infection cases that are asymptomatic −ρA3	0.68
Fourth infection (severity distribution in later infection cases)
Proportion of fourth infection cases that are severe −ρS4	0	Calculated from23
Proportion of fourth infection cases that are mild −ρM4	0.25
Proportion of fourth infection cases that are asymptomatic −ρA4	0.75
Relative infectivity (compared to the first infection)
Relative rate of infectiousness for first infection −κs1	1	28
Relative rate of infectiousness for second infection −κs2	0.5
Relative rate of infectiousness for third infection −κs3	0.2
Relative rate of infectious for the fourth infection −κs4	0.2
Duration of natural immunity, yr (min = 0; max = 115)
Duration of natural immunity after one infection cycle −1τ1	1.5	22
Duration of natural immunity after two infection cycles −1τ2	2
Duration of natural immunity after 3 infection cycles −1τ3	2
Duration of natural immunity after 4 infection cycles −1τ4	115	Assumed

The symbols denote the associated variables in the equations featured in Supplemental Digital Content 1.

INSEE indicates National Institute of Statistics and Economic Studies.

Calibration Data

The model calibration required population-wide age-structured incidence data, which is not available. Therefore, we instead estimated the synthetic age-dependent RVGE incidence in France. The annual number of RVGE cases in France for children 5 years or younger was obtained by multiplying the total population under 5 years, obtained from the national database (National Institute of Statistics and Economic Studies⁶) by 12 times the previously published average monthly probability of RVGE.²⁴ We estimated the age distribution of RVGE cases for the age groups 0–5, 5–25, 25–45, 45–65 and 65+ years using hospitalization data for the United States.²⁹ The estimated age distribution for RVGE cases was then used to estimate the RVGE cases for older age groups 5–25, 25–45, 45–65 and 65+ years relative to the 0–5 years age group (with known RVGE cases). This corresponds to a conservative assumption for cases in young and working-age adults, who are less likely to be affected by dehydration and, thus, be hospitalized due to RVGE (we also did sensitivity analyses to this distribution, Supplemental Digital Content 3, http://links.lww.com/INF/F627).

The annual RVGE cases for age groups below 5 years were stratified into 3 subgroups, 0–1, 1–2 and 2–5 years using values previously observed for France³⁰ (extracted via WebPlotDigitizer, version 4.6; Table 2, Supplemental Digital Content 2, http://links.lww.com/INF/F626).

TABLE 2.

Vaccine-Related and Country-Specific Resource Utilization Input Parameters

Parameter	Value	Source
Vaccine efficacy
Severe RVGE (3 doses)* −ηS,3	0.983	17,31
Mild RVGE (3 doses) −ηM,3	0.68
Asymptomatic RVGE (3 doses) −ηA,3	0.68	Assumed equal to mild RVGE
Duration of vaccination immunity, yr
Duration of protection after the first dose −1/σ1	1.5	Assumed equal to immunity duration from the first infection
Duration of protection after the second dose −1/σ2	5	Assumed
Duration of protection after the third dose −1/σ3	7	32
Resource utilization
Percentage of mild cases of RVGE resulting in hospitalization, %	0	Calculated from 24
Percentage of severe cases of RVGE resulting in hospitalization, %	29
Percentage mild cases of RVGE resulting in ED visits, %	2
Percentage of severe cases of RVGE resulting in ED visits, %	31
Percentage of mild cases of RVGE resulting in GP visits, %	24
Percentage of severe cases of RVGE resulting in GP visits, %	65

^*The efficacy of RV5 against severe RVGE was 98% after 3 doses, 84% after two doses and 82% after one dose^17,31 based on published clinical trial results.^17,31 The efficacy of RV5 against mild RVGE was 68%, as estimated in clinical trials.¹⁸ The relationship between efficacy against mild RVGE after 1 or 2 doses was assumed to be the same as that between efficacy against severe RVGE after 1 or 2 doses.^17,31

ED indicates emergency department; GP, general practitioner; RV5, RotaTeq; and RVGE, rotavirus gastroenteritis.

To depict the seasonality of RVGE, the average number of RVGE cases was extracted over 3 years (2015–2017) using values obtained from rotavirus strain surveillance in France.³³ The monthly average proportions were multiplied by the estimated annual RVGE cases per age group to obtain monthly RVGE cases across all age groups in 2018 (Table 3, Supplemental Digital Content 2, http://links.lww.com/INF/F626). For model calibration, the monthly number of RVGE cases was repeated for 5 years (5 years chosen for speed and computational efficiency during calibration). The time series of cases constructed, thus, reflects an average rotavirus season repeated over 5 years.

TABLE 3.

Projected Average Annual Cases (and Averted Cases), Hospitalizations, ED Visits and DP Visits Due to Rotavirus Gastroenteritis in Children Below 5 Years of Age

	No vaccination scenario	Low vaccination coverage 55%		Medium vaccination coverage 75%		High vaccination coverage 95%
	Cases	Cases	Averted cases	Cases	Averted cases	Cases	Averted cases
All	340,165	179,459	160,706	95,973	244,192	52,859	287,306
Hospitalization	25,342	11,609	13,733	6,078	19,264	3,794	21,548
ED visit	32,146	15,198	16,948	7,997	24,149	4,852	27,294
GP visit	117,468	59,483	57,985	31,626	85,842	18,051	99,417

ED indicates emergency department; and GP, general practitioner.

Model Parameters

The efficacy of RV5 against severe RVGE was 98% after 3 doses, 84% after two doses and 82% after 1 dose based on published clinical trial results.^17,31 The efficacy of RV5 against mild RVGE was 68%.¹⁸ The relationship between efficacy against mild RVGE after 1 or 2 doses was assumed to be the same as that between efficacy for severe RVGE after 1 or 2 doses.^17,31 The efficacy of RV5 against asymptomatic RVGE was assumed to be the same as that for mild RVGE (Table 2). Resource utilization parameter values for GP visits, ED visits and hospitalizations due to mild and severe RVGE cases were obtained from the published literature for France²⁴ (Table 2).

Number of People Needed to Vaccinate to Prevent a Single Rotavirus-Related Event

The number of children needed to be vaccinated³⁴ with all 3 doses to prevent 1 rotavirus-related event at the population level over a 5-year time horizon was calculated through two sets of analyses: the first to prevent 1 (mild or severe) RVGE case and the second to prevent 1 RVGE-related hospitalization. The respective NNV was calculated as N divided by P, where N represents the number of children who received 3 doses of the vaccine over the 5-year time horizon and P represents the averted number of rotavirus-related events within the same duration.

Sensitivity Analysis

A 1-way sensitivity analysis was performed on the vaccine-related parameters of the model (for the different vaccination coverage scenarios), over the 5 years’ time horizon. Model results were generated by varying each parameter one at a time using lower (−20%) and upper (+20%) values. With low and medium vaccination coverage, the number of cases averted, obtained from comparing the scenarios where vaccination is implemented versus the scenario with no vaccine, was most sensitive to the third dose vaccine efficacies against mild, severe and asymptomatic infections, while, at high vaccination coverage, the number of cases averted was most sensitive to first dose vaccine efficacies against mild and asymptomatic infections, as well as the third dose efficacy against asymptomatic infection.

RESULTS

Universal rotavirus vaccination is projected to substantially reduce RVGE cases over a 5-year time horizon (Table 3, Figures 1–3; Supplemental Digital Contents 2, 3, and 4, http://links.lww.com/INF/F626; http://links.lww.com/INF/F627; http://links.lww.com/INF/F628). Cumulative RVGE cases for children under 5 years are estimated to be reduced by 47% under a low vaccination coverage scenario, 72% under a medium vaccination coverage scenario and 84% under a high vaccination coverage scenario over the 5-year time horizon. Vaccination is projected to avert over 210,000 severe RVGE cases in children younger than 2 years of age in a low vaccination scenario, increasing to over 284,000 and 312,000 cases for medium and high vaccination coverage scenarios, respectively (Supplemental Digital Content 4, http://links.lww.com/INF/F628). On average, vaccination is estimated to avert 54% (85%) hospitalizations, 53% (85%) ED visits and 49% (85%) GP visits per year for low(high) vaccine coverage scenarios, respectively (Supplemental Digital Content 3, http://links.lww.com/INF/F627). Results are qualitatively unchanged by assuming different distributions for cases above 5 years of age (Supplemental Digital Content 2, http://links.lww.com/INF/F626). Low and medium vaccination coverage scenarios would further lead to oscillatory seasonal patterns, with some seasons having more cases than others (Figures 2 and 3). Over a 5-year time horizon, a low vaccination coverage rate is projected to avert 803,530 RVGE cases that translate to averting 68,665 hospitalizations, 84,740 ED visits and 289,925 GP visits in children aged under 5 years. A high vaccine coverage rate is projected to avert 1,436,530 RVGE cases leading to 107,740 hospitalizations, 136,470 ED visits and 497,085 GP visits averted in children aged under 5 years (Supplemental Digital Content 4, http://links.lww.com/INF/F628: Table 2).

FIGURE 1.

Projected number of rotavirus gastroenteritis cases with and without the RotaTeq vaccination program (high vaccination coverage: 95% for the full series). The time series plot shows the projected number of rotavirus cases with (yellow line) and without (blue line) vaccination programs. The projected time series without vaccination is a composite time series abstracted from different data elements as described in the Methods, given the lack of longitudinal population–based rotavirus surveillance in France. The yellow line describes the effect of the vaccination program when implemented with a 3-dose vaccination coverage of 95% based on a deterministic infectious disease model. Because the times series without vaccination is repeated average season over 5 years, results should be interpreted as averages over 5 years as well.

FIGURE 3.

Projected number of rotavirus gastroenteritis cases with and without the RotaTeq vaccination program (low vaccination coverage: 55% for the full series). The time series plot shows the projected number of rotavirus cases with (yellow line) and without (blue line) vaccination programs. The projected time series without vaccination is a composite time series abstracted from different data elements as described in the Methods, given the lack of longitudinal population–based rotavirus surveillance in France. The yellow line describes the effect of the vaccination program when implemented with a 3-dose vaccination coverage of 55% based on a deterministic infectious disease model. Because the times series without vaccination is repeated average season over 5 years, results should be interpreted as averages over 5 years as well.

FIGURE 2.

Projected number of rotavirus gastroenteritis cases with and without RotaTeq vaccination program (medium vaccination coverage: 75% for the full series). The time series plot shows the projected number of rotavirus cases with (yellow line) and without (blue line) vaccination programs. The projected time series without vaccination is a composite time series abstracted from different data elements as described in the Methods, given the lack of longitudinal population–based rotavirus surveillance in France. The yellow line describes the effect of the vaccination program when implemented with a 3-dose vaccination coverage of 75% based on a deterministic infectious disease model. Because the times series without vaccination is repeated average season over 5 years, results should be interpreted as averages over 5 years as well.

The NNV ranged from 1.86 to 2.04 to prevent 1 RVGE case and from 24.15 to 27.4 to prevent 1 hospitalization (Supplemental Digital Content 4, http://links.lww.com/INF/F628: Table 3), depending on the vaccine coverage rate assumed.

DISCUSSION

Using a deterministic transmission model, we assessed the potential public health impact of a universal rotavirus vaccination program with RV5 in France over a 5-year time horizon. The model showed that a vaccination program would substantially reduce RVGE cases and healthcare resource utilization over the 5-year period. Specifically, in children aged under 5 years, the vaccination program would avert over 1 million cases and consequent resource utilization over 5 years duration, under a high vaccination coverage scenario of 95%. The model also estimated that an average of 2 children would need to be vaccinated to prevent 1 RVGE case. Lower vaccination coverage leads to smaller reductions demonstrating the need for high vaccination coverage. Sensitivity analysis of the vaccine-related parameters revealed that the number of cases averted is most sensitive to the third dose efficacies for low and medium vaccination coverages and most sensitive to the first dose efficacies for high vaccination coverages (Supplemental Digital Content 5, http://links.lww.com/INF/F629). The effect of herd immunity can be seen in Supplemental Digital Content 6, http://links.lww.com/INF/F630, showing the cumulative number of cases, hospitalization, GP and ED visits by age groups.

Our results predicting a significant reduction in disease burden with rotavirus vaccination are consistent with large postlicensure real-world studies that demonstrate substantial reductions in cases, outpatient visits and hospitalizations following rotavirus vaccination in Europe and worldwide.^9,11,12 In Europe, a systematic review of the published literature conducted by Bencina et al³⁵ demonstrated the significant public health benefit of routine rotavirus vaccination, with vaccination decreasing healthcare utilization related to RVGE across all age groups. In a meta-analysis by Burnett et al,¹¹ the impact of rotavirus vaccination increased with vaccination coverage; the median reduction in rotavirus hospitalization among children aged <1 year old was 85% when coverage was 85% or higher in low mortality countries, whereas the median reduction was 43% with coverage <65%. The model, thus, reinforces the need for high vaccination coverage for consistently low levels of RVGE.

Several models have estimated the health and economic impact of a rotavirus vaccination program in France. Huet et al³⁶ projected that the vaccination program would avoid 249,000 RVGE cases, 26,000 hospitalizations, 6000 nosocomial infections, 81,000 emergency visits, 40,000 GP or pediatrician consultations, 11 deaths and 207,000 parental workdays lost per year in a birth cohort followed up to 5 years of age. Using a Markov decision tree model, Melliez et al²⁴ estimated that routine universal rotavirus immunization would avoid 89,000 diarrhea cases, 11,000 hospitalizations and 8 deaths in children up to 3 years of age. In 2016, Yamin et al²² predicted that after 5 years, rotavirus vaccination would decrease RVGE incidence by 72% and associated clinical outcomes by 72% to 74% in vaccinated and unvaccinated individuals using a dynamic transmission model. While these results are in line with the estimates observed in the current study, our model estimated more averted outcomes. These differences can potentially be explained by differences in model structure. Melliez et al²⁴ and Huet et al³⁶ did not account for herd immunity effects, thus underestimating the impact of vaccination. Herd immunity effects due to rotavirus vaccination have been demonstrated in Finland^14,15,37 and the United States,¹³ among others.^9,38 Yamin et al²² did not explicitly account for the incubation period and only tracked infection up to 3 infection cycles. Thus, the current model complements existing models by allowing for herd immunity and a more detailed disease description, as demonstrated by real-world evidence. Our model also adds to existing dynamic transmission models for France by accurately accounting for individuals with a history of rotavirus infection, as it includes, on average, 4 rotavirus infections, as shown in cohort studies of rotavirus.²³

The predicted NNV in our study, which depends on vaccine coverage, ranges from 1.86 to 2.04 for 1 averted case and 24.15 to 27.4 for 1 averted hospitalization. A previous analysis in France by Huet et al³⁶ also predicted a similar NNV with RV5. They estimated an NNV of 27 to avoid 1 RVGE hospitalization and an NNV of 5 to avoid 1 case seeking medical care (hospitalization, ER visit, GP/pediatrician visit). Notably, the driver of the higher NNV in (mild or severe cases) versus hospitalized cases is due to a higher number of cases averted in (mild and severe cases) compared with the number of hospitalized cases averted.

Strengths and Limitations

Strengths of the current model include accounting for detailed epidemiological features of rotavirus infection and incorporation of herd immunity effects when evaluating the public health impact of universal rotavirus vaccination. The model also considers the risk of multiple infections (up to 4) over a person’s lifetime and how the history of past infections can affect rotavirus transmission dynamics.

The analysis is limited by the lack of explicit age-specific incidence data for France used in the calibration process. In the absence of surveillance data, we constructed a time series that repeats the average rotavirus season over 5 years. This time series does not incorporate observed yearly variations in the incidence of rotavirus. As a result, while our results for low and medium coverages show oscillatory patterns, our results should be interpreted as averages across multiple seasons. While the reduction in rotavirus incidence when averaged across multiple seasons is in line with observations,⁹ the magnitude of individual seasons may vary, especially in nonhigh vaccine coverage scenarios. Modeling work on this topic has explained postvaccine observed biannual seasonal patterns because of the accumulation of susceptibility.²⁸ In particular, the rate of asymptomatic infection among adults is not well understood, with a recent household study from the Netherlands, showing that 22% of household members of a rotavirus case acquired asymptomatic rotavirus infection.³⁸ Our results of high seasonal variation in a low vaccination coverage scenario are, thus, potentially impacted by overestimating the susceptible population, especially under low and medium vaccination coverage scenarios, as, even under lower vaccination coverage, rotavirus vaccination has been shown to be highly impactful across multiple seasons.⁹ It is, therefore, likely that underestimation of asymptomatic infection may lead to a faster buildup of susceptible individuals and consequent higher differences between seasons than what would otherwise be observed. As a result, our model results on the number of symptomatic infections should be interpreted as yearly averages only. Results on the precise magnitude of individual seasons should be interpreted as suggestive of possible seasonal disruptions or alterations. The extent of seasonal alterations and the relative magnitude of individual seasons can only be predicted with more accurate incidence data.

Like models published earlier, we did not account for adverse effects from vaccination [intussusception (IS)]. We expect that their inclusion will not influence the results, given the significant benefits of vaccination and the rare occurrence of IS,³⁹ as recent analyses have shown that IS rates remain the same for the first year of life with and without vaccination.^40,41 Additionally, in France, acute gastroenteritis has been shown to be a risk factor for IS.³⁹ We also did not include mortality due to rotavirus infection, as this is infrequent. Of note, in France, Lamrani et al⁴² estimated an average of 16 deaths per year due to rotavirus. Given the expected reduction of rotavirus deaths due to vaccination, the potential inclusion of deaths would further emphasize the benefits of the vaccine.

CONCLUSIONS

Based on our rotavirus dynamic transmission model, a universal vaccination program with RV5 in France is projected to avoid 84% of cases of rotavirus infection over 5 years period after vaccine introduction, with a consequent reduction in health care resource utilization. The NNV was 2 to prevent 1 rotavirus-related case. A national rotavirus vaccination program has significant public health benefits. A rotavirus vaccination program should, thus, be considered as a possible public health intervention to decrease RVGE burden and associated health care resource utilization and costs.

Acknowledgments

The authors thank Nadine Saleh for the medical writing services provided for this manuscript. The authors are also grateful to the two anonymous reviewers and the Handling Editor for their very constructive comments, which have significantly enhanced the manuscript.