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Impact of the Rotavirus Vaccination Program in Norway After Four Years With High Coverage

Bruun, Tone MD*; Salamanca, Beatriz Valcarcel MSc, PhD; Bekkevold, Terese MPhil; Døllner, Henrik MD, PhD‡,§; Gibory, Moustafa MSc; Gilje, Ann Marit MD; Haarr, Elisebet MD**; Kran, Anne-Marte Bakken MD, PhD††; Leegaard, Truls M. MD, PhD‡‡,§§; Nakstad, Britt MD, PhD§§; Nordbø, Svein Arne MD§,¶¶; Rojahn, Astrid MD‖‖; Størdal, Ketil MD, PhD***; Flem, Elmira MD, PhD; for the Norwegian Enhanced Pediatric Immunisation Surveillance Network

Author Information
The Pediatric Infectious Disease Journal: April 2021 - Volume 40 - Issue 4 - p 368-374
doi: 10.1097/INF.0000000000003020

Abstract

Rotavirus is the leading cause of severe acute gastroenteritis (AGE) among children <5 years of age globally.1,2 In 2006, 2 rotavirus vaccines were licensed internationally, following large trials on efficacy and safety3,4: the monovalent (RV1) vaccine Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) and the pentavalent (RV5) vaccine Rotateq (Merck & Co., Inc., Kenilworth, NJ). In 2009, the World Health Organization recommended that all countries introduce rotavirus vaccination into their national immunization programs.5 As of October 2018, universal rotavirus vaccination was in place in 98 countries. Two thirds of European countries had not yet implemented universal vaccination.6

Rotavirus gastroenteritis (RVGE) used to be the primary cause of severe AGE in Norwegian children.7 In October 2014, Norway introduced rotavirus vaccination in the national immunization program using RV1 with first dose offered at 6 weeks of age and the second dose at 12 weeks of age.8 To minimize the intussusception risk, Norway adopted strict age limits for vaccine administration: the first dose is recommended to be given by maximum 12 weeks of age and the second dose before 16 weeks of age.9 High national coverage was achieved during the first year: 89% for the first dose and 82% for the second dose.10 Nearly 95% of vaccinated children receive their first vaccine dose before 8 weeks of age. Vaccine coverage increased gradually and measured 95% for 1 dose and 93% for 2 doses at the age of 2 years in 2018, being among the highest across countries in Europe and globally.11–14

Although several studies provide real-world evidence about the effectiveness of rotavirus immunization programs, the coverage and vaccine impact vary across countries, also within the high-income European settings.11,14,15 The exclusive use of RV1 and a high vaccination coverage from the start, together with the use of Norwegian population-based registries, provided a valuable opportunity to evaluate the impact of rotavirus vaccination in a low-mortality setting. We aimed to assess the effectiveness and impact of the rotavirus immunization program during a 4-year follow-up period after vaccine introduction.

METHODS

We performed a case-control study to estimate vaccine effectiveness (VE) against hospital admission, and a time-series analysis to estimate the impact of the vaccination program.

Case-control Study of VE

The study was based on a previously established7 rotavirus sentinel surveillance network of the Norwegian Institute of Public Health and 5 hospitals: Oslo University Hospital Ullevål, Stavanger University Hospital, St. Olavs University Hospital in Trondheim, Østfold Hospital and (from December 2015) Akershus University Hospital, covering approximately 40% of all Norwegian children. Surveillance was implemented from February 1, 2014 until May 31, 2018. Children <5 years of age admitted to hospital with AGE within 10 days of illness onset were enrolled if their parents provided written informed consent. AGE was defined as diarrhea (at least 3 loose stools in 24 hours) or vomiting (at least 1 episode in 24 hours). Children were not enrolled if they were hospitalized within 48 hours before illness onset, to exclude nosocomially transmitted infections. Health data and stool samples were collected within 48 hours of admission. Samples were screened for rotavirus at the hospital laboratory and then transferred to the national rotavirus reference laboratory at the Norwegian Institute of Public Health for further testing. We applied the Vesikari severity scale16 to classify cases as severe (score of ≥11), moderate(7–10) or mild (<7).

Cases

We included as cases consecutive children from the sentinel surveillance who fulfilled the following criteria: (1) birth after September 1, 2014; (2) age ≥56 days when admitted to hospital (to ensure eligibility to have received at least 1 vaccine dose from age 6 weeks (42 days) at least 14 days before admission); and (3) a fecal specimen obtained within 48 hours after admission tested positive for rotavirus by both enzyme immunoassay (EIA) (RIDASCREEN Rotavirus, R-Biopharm, Darmstadt, Germany) and RT-polymerase chain reaction (PCR) (RIDAGENE, R-Biopharm, Darmstadt, Germany; Seegene, Seoul, South Korea). Testing positive both by EIA and RT-PCR was required to avoid false positive results. We used Jaccard similarity index to test for similarity between EIA and RT-PCR results, and found the correlation between the tests to be 0.84. Positive samples were genotyped by a multiplex seminested RT-PCR,17,18 and samples with genotype G1P,8 were tested by Rotarix qRT-PCR for the presence of vaccine virus strain, using previously described protocols with adjustments.19 Those who tested positive for the vaccine strain were excluded from the study.

Controls

Two control groups were included: test-negative controls and community controls. Test-negative controls were children enrolled in the sentinel surveillance that fulfilled the same criteria as cases, except testing negative for rotavirus by EIA and RT-PCR. Community controls were children born after September 1, 2014 who were registered in the National Immunization Registry20 on August 25, 2018 when immunization data were extracted from the registry, lived in the catchment area of the study hospitals and were ≥56 days of age at the extraction date. Use of population-based immunization registries for selection of community controls has been shown to produce valid results in other VE studies.21,22

Immunization Data

Rotavirus vaccination status (the number and dates of doses received) of cases and controls was ascertained through linkage with the National Immunization Registry. Registration is mandatory for all vaccines included in the childhood immunization program.20

A vaccine dose was considered valid if given at least 14 days before admission for cases and test-negative controls. Matched community controls were considered vaccinated if they were immunized at least 14 days before the admission of the corresponding case.

Analysis of VE

Characteristics of cases and controls were compared by the two-sided Wilcoxon rank-sum test for continuous variables and χ2 test for categorical variables.

We estimated the VE against hospital admission for RVGE after 2 doses using the following formula: VE = (1 − Odds Ratio [OR]) × 100%.

Using test-negative controls, we calculated ORs (odds of being vaccinated among cases versus the odds of being vaccinated among controls) and 95% confidence intervals (CIs) by using unconditional logistic regression, adjusting for date of birth and date of hospital admission. In addition, we conducted conditional logistic regression, matching each case to 1 or 2 (if possible) test-negative controls by date of birth (±60 days) and date of hospital admission (±60 days), also adjusting for date of birth and admission date. Using community controls, we calculated OR and 95% CI for vaccination by using unconditional logistic regression, adjusting for date of birth and using conditional logistic regression, matching each case to 5 community controls by date of birth (±60 days), also adjusting for date of birth. The matched controls were resampled with replacement from the original dataset (by bootstrapping). The VE was calculated for each set of cases and controls with the mean value being reported.23

Time-series Analysis of Impact of the Vaccination Program

We used national population-based registry data for healthcare encounters associated with AGE during the years 2009–2018. Two or more encounters registered within 10 days in 1 patient were considered the same AGE episode.

Hospital Admissions

We used data from the Norwegian Patient Registry,24 which holds information about hospital treatment in all public and private hospitals in Norway. We selected all contacts (outpatients and inpatients) <5 years of age with International Classification of Diseases (ICD-10) codes corresponding to AGE as the main discharge diagnosis: A080 (rotavirus), A081 (norovirus), A082 (adenovirus), A083-A084 (other or unspecified viral infection), A000-A059 (bacterial), A060-A079 (parasitic) and A085; A090; A099 (other, specified or unspecified infection). We also selected contacts with the dehydration code E86 as the main discharge diagnosis in combination with one of the AGE codes as secondary discharge diagnosis.

Primary Care Consultations

We used data from the National Health Economics Administration Database (KUHR),25 which contains reimbursement claims from all general practitioners and emergency primary care providers. We selected all consultations in children <5 years of age during the years 2009–2018 with the International Classification of Primary Care (ICPC-2) codes corresponding to AGE on the main diagnosis: D10 (vomiting), D11 (diarrhea), D70 (bowel infection) and D73 (gastroenteritis, presumed infectious).

Population Data

Population data by year and age group provided by Statistics Norway were used to calculate AGE rates.26

Analysis

We analyzed the data by rotavirus epidemiologic year, defined as July through June. As vaccination was introduced in mid-October 2014, we defined a prevaccine period from July 2009 through June 2015 (when vaccine coverage was low and the impact of the program was negligible), and a postvaccine period from July 2015 through June 2018. Using a similar approach as Thomas et al,27 we estimated the vaccine impact using age-stratified time-series analysis of monthly counts of AGE cases using negative binomial regression, accounting for age-specific population size per month. We controlled for long-term trends by adding epidemiologic year as a linear term, and for seasonal patterns by using month as an indicator variable. An indicator variable that distinguished prevaccine and postvaccine periods was included in the model to obtain adjusted incidence rate ratios (IRRa). To control for autocorrelation, we included an autoregressive term up to 1 month in the model. The model was built in a stepwise fashion by first constructing the long-term trend, seasonality model and then the pre/postvaccine indicator variable. The results of the final model were expressed as IRRa compared with the prevaccine period. We evaluated plots of model residuals, predicted and observed time-series plots and partial autocorrelation function of the residuals to ensure the adequate fit of the data.

Statistical Analyses and Ethics

Analyses were performed using Stata version 13 (StataCorp., College Station, TX) and R version 3.2 (R Foundation for Statistical Computing, Vienna, Austria). The Regional Committee for Medical and Health Research Ethics approved this study (Application number 2013/2038).

RESULTS

Rotavirus VE

Characteristics of Cases and Controls

Overall, we enrolled 39 rotavirus-positive cases and 266 rotavirus-negative AGE controls (see Figure, Supplemental Digital Content 1, http://links.lww.com/INF/E261; Table 1). Rotavirus cases were older than test-negative controls (median age of 17.6 vs. 7.6 months, Table 1) and had more severe disease, with 96% being classified as severe compared with 53% among rotavirus-negative controls (Table 1). The majority (69%) of rotavirus cases were admitted to hospital during a typical season between December and May, which was not significantly different from controls (Table 1). Breakthrough infections occurred in 29 fully vaccinated children (age range 4–37 months).

TABLE 1. - Characteristics of Rotavirus-positive Cases, Test-negative Controls and Community Controls, Norway 2014–2018
Characteristics Cases (n = 39) Test-negative controls (n = 266) P Community controls (n = 113,429) P
Age in months, median (IQR) 17.6 (12.1–22.8) 7.6 (4.5–12.9) <0.001
Age groups (mo) <6 3 (8%) 101 (38%) <0.001
6–12 7 (18%) 90 (34%)
12–18 10 (26%) 46 (17%)
18–24 10 (26%) 16 (6%)
>24 9 (23%) 13 (5%)
Sex Female 15 (38%) 125 (47%) 0.320 54928 (48%) 0.210
Male 24 (62%) 141 (53%) 58501 (52%)
Vaccination* Fully vaccinated 29 (74%) 196 (74%) 0.007 99769 (88%) <0.001
Partially vaccinated 1 (3%) 44 (17%) 7755 (7%)
Nonvaccinated 9 (23%) 26 (10%) 5905 (5%)
Type of hospital contact Inpatient 33 (87%) 165 (62%) 0.003
Outpatient 5 (13%) 100 (38%)
Vesikari score Severe 24 (96%) 109 (53%) <0.001
Mild 0 (0%) 22 (11%)
Moderate 1 (4%) 76 (37%)
Admission during rotavirus season No 12 (31%) 101 (38%) 0.380
Yes 27 (69%) 165 (62%)
*Fully vaccinated means 2 doses and partially vaccinated means 1 dose.
†Information on severity was incomplete for 14 cases and 59 test-negative controls.
‡December–May.

VE Assessment

Using test-negative controls, we estimated the VE of full immunization with 2 doses against hospital admission for RVGE to be 76% (95% CI: 34%–91%). Restricting the analysis to those admitted during the rotavirus seasons from December until May resulted in VE of 79% (95% CI: 29%–94%) (Table 2). The VE in children <18 months of age was 83% (95% CI: 35%–96%). Similar VE estimates were demonstrated in the matched analysis, with an overall 2-dose VE of 78% (95% CI: 20%–94%). Using community controls, the overall VE of 2 doses was 75% (95% CI: 44%–88%), with similar results in the matched analysis.

TABLE 2. - Rotavirus Vaccine Effectiveness* for 2 Doses Against Hospital Admission for Rotavirus Gastroenteritis Among Vaccine-eligible Children, Norway 2014–2018
No. Rotavirus-positive Cases No. Test-negative Controls VE (%) 95% CI
Overall 38 222 76 34%–91%
<18 mo of age at admission 19 193 83 35%–96%
Inpatients 32 135 85 51%–95%
Admitted during rotavirus season 26 142 79 29%–94%
*OR calculated by unconditional logistic regression using test-negative controls, adjusting for age and date of hospital admission.

Impact of Rotavirus Vaccination on Acute Gastroenteritis

In the prevaccine period from July 2009 to June 2015, 20,786 AGE episodes during 1,852,177 person-years in children <5 years of age were treated in hospital (average 3464 episodes per epidemiologic year [range: 2825–3841]). Of these, 52% were inpatients and 48% were outpatients. In the postvaccine period from July 2015 to June 2018, 5007 AGE episodes were seen in the hospital during 912,977 person-years of follow-up (average 1669 episodes per epidemiologic year [range: 1608–1739]); 49% inpatients and 51% outpatients. The median age of AGE cases admitted to hospital before vaccine introduction were 17 (IQR: 10–27) months, similar to the median age of those admitted postvaccination (16 [IQR: 9–30] months).

A total of 222,035 AGE episodes were registered in primary care during the 6-year prevaccine period (average 37,006 episodes per epidemiologic year [range: 32,528–39,847]) and 90,002 cases during the 3 postvaccine years (average 30,001 episodes [range: 29,049–30,608]). The median age for AGE cases treated during pre and postvaccine periods was 19 months (IQR: 12–32) and 20 (IQR: 11–34), respectively. We observed a marked winter seasonality in both hospital and primary care during the study period (Fig. 1). Fourteen percent of the hospital cases had a rotavirus-specific code on the main discharge diagnosis before vaccine introduction, compared with 8% postintroduction (see Figure, Supplemental Digital Content 2, http://links.lww.com/INF/E262).

FIGURE 1.
FIGURE 1.:
AGE incidence among Norwegian children <5 years of age 2009–2018. Incidence of AGE cases in (A) hospital and (B) primary care per 1000 person-years, Norway July 2009–June 2018.

The time-series analysis demonstrated a 45% decrease in the rates of AGE-associated hospital episodes among children <5 years of age in the postvaccine period compared with the prevaccine years (IRRa 0.55; 95% CI: 0.49–0.61) overall (Table 3). The reduction among children <1 year of age was 40%, and among children 1–3 years of age 40%–52%. There was also a 37% decrease among children between 4 and 5 years of age who were not eligible for vaccination (IRRa 0.63; 95% CI: 0.52–0.78). We found modest reductions in the rates of AGE episodes in primary care (Table 3). The overall reduction in the postvaccine period compared with the prevaccine period was 10% (IRRa 0.90; 95% CI: 0.85–0.96), whereas rates decreased by 13% during the first postvaccine epidemiologic year 2015–2016 (IRRa 0.87; 95% CI: 0.82–0.93), with significant reductions across all age groups.

TABLE 3. - Change in AGE Incidence (Incidence Rate Ratios) Among NORWEGIAN Children <5 Years of Age, Seen in Hospital and Primary Care in the Postvaccine Era 2015–2018 Compared With the Prevaccine Era 2009–2015*
Incidence Rate Ratio (95% CI)
Hospital Care
Age (y) 2015–2016 P 2016–2017 P 2017–2018 P 2015–2018 P
0 0.63 (0.54–0.73) <0.05 0.59 (0.50–0.69) <0.05 0.55 (0.46–0.66) <0.05 0.60 (0.53–0.69) <0.05
1 0.55 (0.47–0.64) <0.05 0.47 (0.40–0.55) <0.05 0.49 (0.41–0.59) <0.05 0.52 (0.45–0.59) <0.05
2 0.47 (0.40–0.56) <0.05 0.51 (0.42–0.61) <0.05 0.43 (0.35–0.52) <0.05 0.48 (0.41–0.57) <0.05
3 0.53 (0.43–0.67) <0.05 0.70 (0.56–0.87) <0.05 0.53 (0.41–0.69) <0.05 0.60 (0.49–0.73) <0.05
4 0.61 (0.48–0.78) <0.05 0.65 (0.50–0.83) <0.05 0.70 (0.53–0.92) <0.05 0.63 (0.52–0.78) <0.05
Total 0.56 (0.49–0.63) <0.05 0.55 (0.48–0.63) <0.05 0.52 (0.45–0.61) <0.05 0.55 (0.49–0.61) <0.05
Primary Care
0 0.94 (0.88–1.00) <0.05 0.98 (0.91–1.00) 0.5 1.00 (0.92–1.10) 0.94 0.95 (0.90–1.00) 0.13
1 0.81 (0.75–0.88) <0.05 0.85 (0.78–0.93) <0.05 0.88 (0.80–0.97) <0.05 0.83 (0.77–0.90) <0.05
2 0.81 (0.75–0.89) <0.05 0.89 (0.81–0.98) <0.05 0.86 (0.77–0.95) <0.05 0.84 (0.78–0.91) <0.05
3 0.89 (0.82–0.96) <0.05 0.99 (0.91–1.10) 0.77 1.10 (0.96–1.20) 0.24 0.94 (0.87–1.00) 0.1
4 0.89 (0.81–0.98) <0.05 0.98 (0.89–1.10) 0.77 1.00 (0.89–1.10) 0.96 0.93 (0.86–1.00) 0.12
Total 0.87 (0.82–0.93) <0.05 0.93 (0.87–1.00) 0.07 0.96 (0.89–1.00) 0.34 0.90 (0.85–0.96) 0.12
*Compared with the prevaccination period, adjusted for month and rotavirus epidemiologic year (July–June).
†Estimates in bold are results for vaccine-ineligible age groups.

There was a marked seasonality with higher AGE rates observed during the winter months also after vaccine introduction (Fig. 1).

DISCUSSION

Four years after the introduction of RV1 in the Norwegian childhood immunization program, AGE-associated hospitalizations have declined substantially, attributable to a high effectiveness of the vaccine against rotavirus hospitalizations, as established in this study.

The impact of vaccination has been significant worldwide,2,6,28 manifesting as early as during the first year after introduction.29,30 The benefits of rotavirus vaccination were estimated to largely exceed the increased risk of vaccine-associated intussusception also in Norway, as estimated in a recent modeling study.9 Our VE estimates are comparable with results from studies in other high-income settings. In high-income European countries, VE against rotavirus hospital admissions were estimated to be between 80% and 98%,14,15,31–34 while in middle-income European countries, the estimates are lower.35,36 In a review from the United States, the pooled VE of full series RV5 and RV1 against rotavirus-associated hospitalizations and emergency department visits were 84%.37 Both with test-negative and community controls, we found a VE against hospital admission for RVGE among vaccine-eligible children after 2 vaccine doses to be around 75%, with wide CIs. Other studies show that VE decreases with age, suggesting waning vaccine-induced protection,32,38 but significant VE was documented up to the fifth year of life in a German study32 and the seventh year in a US study.38 High VE is demonstrated through the first 2 years of life,21,31 which is of importance because the risk of rotavirus hospitalizations is high during this period.39,40 The current study was not powered to demonstrate significant differences in VE by age, but future studies in Norway are planned to provide more evidence on the durability of vaccine protection.

We found a 40%–52% decline in AGE hospitalizations overall in the postvaccine years compared with pre-vaccine years in vaccine-eligible cohorts, and even significant reductions in vaccine-ineligible cohorts, indicating a herd effect. Finland reported a 69% reduction in AGE inpatient hospitalizations among children <5 years of age in the postvaccination period (2010–2014) compared with the prevaccination period (1999–2005)41 and in Belgium, the mean incidence of all-cause AGE hospitalizations was found to decrease by 27% between the pre and postvaccination period.42 A review of 10 US studies with impact data from 2006 to 2017 found that the median reduction of AGE hospitalization rates was 38.5% (IQR: 33.3–46.5).37 Protection of unvaccinated age groups was suggested in several studies.14,37,43–45

Few studies have assessed the impact of vaccination on utilization of primary care. The program-impact in the primary care was lower in Norway, likely because the VE is presumably lower against mild rotavirus disease.45 The smaller observed reductions in the incidence of AGE in primary care can be also related to the inclusion of gastroenteritis episodes caused by a wide range of microbiologic agents, many giving milder disease that do not require hospital care. A lower impact of rotavirus vaccination in pediatric outpatient care was also reported in Sweden,46 Finland29,41 and England.47 Interestingly, there was a declining trend in rotavirus consultations in the years immediately before vaccine introduction in our primary care data, which may be related to secular trends. Similar observations were reported in the Netherlands and Belgium but a decrease in rotavirus cases in those countries was observed only during the 2013/2014 season without any obvious explanation.42,48

Strengths of our study are the use of comprehensive national registries complemented with prospective hospital surveillance, which allowed data linkage with the national immunization registry to obtain reliable information about vaccination status, including accurate dates for vaccine administration. The use of test-negative controls can reduce confounding from healthcare-seeking behavior, and has been shown to be an efficient approach to estimate VE against rotavirus, influenza and other diseases.49,50 Also, the use of immunization registries as source of controls is believed to produce valid results in rotavirus VE studies.21,22 The National Immunization Registry in Norway is a suitable source for selection of controls because it captures 98% of the Norwegian pediatric population.51 In addition, we could distinguish wild-type infection from excreted vaccine virus and exclude cases with the vaccine strain. A further strength is the use of long observation period of over 6 epidemiologic years before vaccine introduction, which allowed to control for underlying trends in the AGE incidence. A minimal uptake of rotavirus vaccines in Norway before the introduction of routine vaccination in 2014, and the high coverage provided an ideal setting for studying the impact of vaccination.

Our estimates of VE should be interpreted in light of several limitations. First, the exact recruitment rate is not known and this may affect the representativeness of the study participants. Also, the 150 samples were not available for supplemental EIA testing due to loss or low sample volume, and thereby were excluded from the study. However, we do not believe that inclusion differed between cases and controls and affected the results. Second, high vaccine coverage was achieved rapidly after the program start in Norway, resulting in a small study sample and a limited power. Case-control studies are more efficient to assess VE in settings with vaccine coverage under 80%, and there is a stronger potential for confounding if the coverage is very high or low.52 Thus, our study was underpowered to estimate VE by genotypes, age groups or number of doses. Finally, misclassification of test-negative AGE controls could occur, although we reduced this risk by requiring 2 different assays to be negative. The impact studies have the limitations of being descriptive and ecologic, and therefore, the measured effects could be due to other factors than vaccination only. Testing and diagnostic practices could have changed during the study period, diagnostic coding is often inaccurate and unspecific, and coding practices can also evolve over time. Some of the observed reductions can be due to secular trends in the virus circulation.

In conclusion, 4 years after the introduction of rotavirus vaccination in the Norwegian childhood immunization program, the vaccine program has been shown to be effective against RVGE treated in the hospital thereby reducing the burden of AGE among children <5 years of age in Norway, and also to some degree among children not eligible for vaccination. High vaccine coverage will contribute to a continuous protection of the youngest and most vulnerable children. Further monitoring is vital to measure the durability of protection and identify possible indirect effects in nonvaccinated individuals.

ACKNOWLEDGMENTS

We would like to acknowledge staff at the study hospitals for their assistance during the study, particularly: Olaug Aarseth, Ine Bjørndal, Eli Dahl, Sara Debes, Magnhild Owesen Eidem, Hanne Holm-Gabler, Anja Dyresen Guleng, Kirsti Jakobsen, Anita Kanestrøm, Anette Lunde, Barbro Marie Medås, Siv Anita Myhre, Dianne Carlyn Ditlevsen Nordstoga, Ann Cathrin Pettersen, Ida Helen Simonstad and Heidi Christin Sivertsen. We thank Liliana Vazquez Fernandez at the Norwegian Institute of Public Health for assistance with the models and statistical analysis, and all enrolled children and their families for valuable contribution to this study.

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Keywords:

rotavirus; gastroenteritis; vaccine effectiveness; epidemiology

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