Association between the Rotavirus Vaccine and Intussusception in China: Study Protocol for Target Trial Emulation

doi:10.21203/rs.3.rs-5237664/v1

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Study protocol

Association between the Rotavirus Vaccine and Intussusception in China: Study Protocol for Target Trial Emulation

https://doi.org/10.21203/rs.3.rs-5237664/v1

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Background:Rotavirus vaccines represent a cost-effective and efficacious strategy for the prevention and management of severe rotavirus gastroenteritis, but potential associations of vaccines with intussusception often raise concerns, and this relationship has rarely been reported in China.

Methods:This study aims to explicitly emulate a target trial that is consistent with previous randomized controlled trials and subsequently conducts a nested case-control study to evaluate the risk of intussusception within 90 days of rotavirus vaccination. The study will utilize local birth cohorts from 2015 to 2023 across three locations: Ningbo city, Chongqing city, and Jiangsu Province, where the feasibility of accessing electronic healthcare records has been confirmed through a pilot assessment. Cases of suspected intussusception will be identified from various diagnostic settings, including outpatient and inpatient records, imaging, enema records, and surgical reports, adhering to Brighton's criteria for the inclusion of first-occurring cases classified as Brighton certainty level 1. The risk of intussusception will be evaluated via pooled logistic regression methods, adjusting for age, sex, birth season, site, pregnancy exposure, etc. Subgroup analyses will include the postvaccination period, vaccine type, number of doses, and full vaccination. Sensitivity analysis will consider the vaccination day 0, multiple imputation for missing data, propensity score matching, self-controlled analysis, and negative outcome control.

Discussion:This is the first, multicenter, large-scale, proactive surveillance study of the risk of intussusception after rotavirus vaccination in China. With the framework of target trial emulation, the nested case-control design would minimize or control relevant bias and confounding in real-world comparative safety studies. This evidence will support the decision of immunization programs in China and contribute to addressing the vaccine hesitancy worldwide.

Rotavirus vaccine

Intussusception

Target trial emulation

Active surveillance

Real-world

Rotavirus is the most common cause of severe diarrhea in children under five years of age worldwide(1). Nearly every child is infected with RV at least once by the age of five, and in developing countries, three-quarters of children are infected by the age of one year. Globally, the incidence rate of severe rotavirus gastroenteritis (RVGE) is 29.4 per 1000 person-years, resulting in approximately 18.88 million cases. Rotavirus infection is the leading cause of diarrheal death, accounting for 19.11% of deaths from diarrhea(2). In China, rotavirus is associated with 45.05% of diarrhea cases of all ages(3), and is detected in nearly 90% of children with viral gastroenteritis among hospitalized children(4).

The most common rotavirus genotype combinations regularly infecting humans worldwide are G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8]. These genotypes are responsible for almost 90% of RV infections globally(5). The most common RV strains in China from 2011 to 2020 were G9P[8] (20.9%), G3P[8] (19.5%) and G1P[8] (10.6%)(6). Vaccines are an effective intervention for the control of RV(5). In areas where the vaccine has been used for many years, the number of adult hospitalizations for gastroenteritis has decreased(7). To prevent rotavirus infection, the World Health Organization (WHO) recommended the rotavirus vaccine for national immunization programs and advocated for the administration of the rotavirus vaccine to all infants worldwide since 2009, while also emphasizing the importance of monitoring the potential risk of intussusception(8,9).There are 6 RV vaccines on the market worldwide, of which Rotarix, RotaTeq, Rotavac and RotaSiil are WHO prequalified.

Overall, rotavirus vaccines are considered safe, with no significant adverse reactions other than intussusception. Meta-analysis revealed that Rotavac, Rotasiil and Lanzhou lamb rotavirus vaccines (LLRs) demonstrated no risk of serious adverse events(10). Another randomized controlled meta-analysis also indicated that different vaccine brands and types did not significantly influence the incidence of intussusception. However, postmarketing studies have reported variable risks of intussusception across different countries, populations, and vaccine types(11–14). Meta-analyses of cohort studies, case-control studies, and self-controlled case series conducted in 2017 suggested an increased risk of intussusception following rotavirus vaccination(15).

An increasing number of countries and regions are beginning to conduct proactive surveillance studies on vaccine safety using real-world data to provide reliable evidence for decision-making in immunization planning. For example, the US Vaccine Safety Datalink project has supported the development of white papers on childhood immunization strategies, and Canada's Immunization Monitoring Program, ACTive has supported adjustments in acellular pertussis vaccine immunization strategies. However, generating high-quality real-world evidence should be “fit-for-purpose” and use rational study designs should be used to reduce bias(16). Target trial emulation (TTE) is a method of using real-world data to design studies that approximate the high credibility of randomized controlled trials (RCTs) when RCTs are not feasible(17). Typically, TTEs refers to the randomized controlled trial design framework, which includes seven principles that mimic the process of randomization and has received wide acceptance and application in real-world comparative studies(18).

There is an increasing amount of real-world data available in China, particularly regional health information platforms, which integrate key data sources for proactive monitoring of vaccine safety, such as maternal and child health care, vaccinations, resident records, electronic medical records, and death registries(19). Therefore, this study uses the regional health information platforms of Ningbo, Chongqing, and Jiangsu, in order to conduct multicenter active vaccine safety monitoring. With the framework of target trial emulation, the primary design of a nested case-control study with a parallel design of a self-controlled case series study will be conducted to evaluate the risk of intussusception within 90 days after rotavirus vaccination.

Study design

This study aims to evaluate the relationship between rotavirus vaccination and the risk of intussusception via the design of TTE, which incorporates eligibility criteria, treatment strategies, treatment assignment, outcomes, start and end of follow-up, causal contrasts, and a data-analysis plan(20). The detailed TTE design is shown in Supplementary Table 1.

Eligibility criteria: This study selects infants aged 6 to 12 weeks who were born locally in the study area and were vaccinated with BCG and the first dose of hepatitis B vaccine. The exclusion criteria includes a history of previous rotavirus vaccination, intussusception, other serious diseases, such as malignant tumors, immunodeficiency or autoimmune diseases, and medication within 14 days (such as high fever, infection, and the use of immune preparations, etc.).

Treatment strategy: The intervention group of the study is infants vaccinated with rotavirus vaccine. Exposure is defined as at least one dose of rotavirus vaccine (RotaTeq or LLR) in the baseline period. The non-exposed group is infants who have not received any rotavirus vaccine at baseline or during the follow-up period.

Treatment assignment: The groups are divided according to the vaccination status at baseline. Furthermore, the randomization is simulated by adjusting the baseline confounding factors to ensure the comparability between the groups.

Outcome definition: The main outcome event of the study is the first confirmed case of intussusception in children aged 0-3 years, and the diagnosis is based on medical records such as outpatient, emergency, and hospitalization records, as well as intussusception confirmed by imaging (such as X-ray, B-scan ultrasonography, and CT).

Start and end of follow-up: Follow-up starts from the baseline period and ends at the first diagnosis of intussusception, death, loss to follow-up, the expiration of the 90-day follow-up period, or the end of the study, whichever occurs first.

Causal contrasts: This study adopts intention-to-treat analysis and per-protocol analysis. The intention-to-treat analysis is grouped by baseline period. The per-protocol analysis addresses protocol violation cases. Protocol violation cases are defined as incomplete vaccination or rotavirus vaccination in the control group.

Statistical analysis: Pooled logistic regression models will be used to estimate risk ratios and generate survival curves, with follow-up time (months) set as linear or quadratic terms. In addition, subgroup analysis (such as analysis of vaccine type, gender, and number of doses) and sensitivity analysis will be performed.

The study plans to include a birth cohort from 2015 to 2023. Given the 99% coverage rate of the national immunization program vaccines for children of appropriate age by 2020, it is assumed that the immunization planning information system can cover all locally born resident children. "Locally born" is defined as being born in a local hospital or having a household registration address in the region (province/city). "Resident" is defined as having a permanent or residential address in the region (province/city). The rotavirus vaccination schedules are as follows: LLR is recommended for infants aged 2 months to 3 years, with one dose annually. Rotateq is recommended at 2, 4, and 6 months of age, with the first dose given at 6-12 weeks, subsequent doses at 4-10 week intervals, and all three doses completed by 32 weeks of age. Considering the above immunization schedules, a 90-day postvaccination risk period, and potential delays in diagnosis, the study observation period for the rotavirus vaccine is set from birth to 39 months of age, and that for Rotateq is set from birth to 11 months of age. The follow-up will utilize the vaccination schedules for children aged 0-3 years (including both immunization program vaccines and nonimmunization program vaccines), migration, and death data.

The cohort start time is defined as the baseline period (6-12 weeks of age for Rotateq, 8-52 weeks for LLR), with the first dose administration time for the exposed group. The cohort end time is defined as the earliest occurrence of any of the following: 1) first occurrence of intussusception, 2) death, 3) loss to follow-up, 4) 42 days after the last dose, or 5) end of the study. Loss to follow-up is defined as any of the following events during the observation period: death, migration, or failure to receive any vaccine doses (including both immunization program vaccines and nonimmunization program vaccines) at 8-12 months, 12-24 months, or 25-36 months of age (for RotaTeq recipients, loss to follow-up includes failure to receive any vaccine doses at 8-12 months of age).

During the observation period, the birth cohort will be divided into different subgroups on the basis of rotavirus vaccination status. The exposed group includes children who received at least one dose of rotavirus vaccine and were subdivided into rotavirus vaccine and Rotateq groups. The control group includes children who did not receive any rotavirus vaccine during the baseline and follow-up periods.

Data sources

The study will be conducted on regional health information platforms in Ningbo, Chongqing, and Jiangsu, which have been validated for data quality and sample size sufficiency. Ningbo, a subprovincial city in Zhejiang Province located on the southeast coast of China, had a permanent population of 9.618 million at the end of 2022, with an urbanization rate of 78.9%, a birth rate of 5.58‰, and a death rate of 6.83‰. Chongqing, a directly administered municipality and national central city located in Southwest China, had a permanent population of 32.133 million at the end of 2022, with an urbanization rate of 70.96%, a birth rate of 5.98‰, and a death rate of 8.09‰. Jiangsu Province, located on the east coast of China, had a permanent population of 85.15 million at the end of 2022, with an urbanization rate of 75.0%, a birth rate of 5.23‰, and a death rate of 7.04‰. These four regions have stable populations in the millions, which are suitable for establishing dynamic cohorts for the entire lifecycle and conducting active safety monitoring of vaccines for rare clinical outcomes at single or multiple centers. The study uses information from these platforms, including resident records, immunization planning, maternal and child health, electronic medical records, and mortality surveillance, as detailed in the Supplementary Table 2.

Data collection and management

Exposure measurement

The rotavirus vaccination records will be extracted from the immunization planning information, including anonymous vaccination ID, vaccine name or code, vaccination date, dose, manufacturer, and records of other vaccinations administered on the same day and within 14 days before and after each rotavirus vaccination. If the interval between two consecutive doses of rotavirus vaccine is less than the risk period, i.e., the risk period overlaps with the date of the next dose, the 0th day of the next dose is the end of the risk period for the previous dose. Fully vaccinated population is defined as the children with completion of three doses according to the recommended immunization schedule.

Outcome Measurement

The suspected cases of intussusception in children aged 0-3 years will be extracted from electronic medical records, including diagnoses from outpatient, emergency, inpatient, and discharge records with the term "intussusception" or the ICD-10 code K56.1; imaging examinations (X-ray, ultrasound, CT) indicating intussusception; Enema treatments (hydrostatic enema, air enema, ultrasound-guided enema) indicating intussusception; and surgical or autopsy indications of intussusception.

New-onset intussusception is defined as the interval between the current and the most recent episode of intussusception being greater than 72 hours. The onset time is defined as the earliest occurrence of the visit time, or specific clinical symptoms (paroxysmal abdominal pain, bloody stool, or an abdominal mass). Only the first episode of intussusception is included in this study.

In line with the Brighton criteria, the study will establish levels of certainty and criteria for diagnosing intussusception. An adjudication committee, including surgeons, pediatricians, and radiologists related to intussusception, will be formed. Surgeons will serve as adjudicators, with other physicians as auxiliary members. The adjudicators will independently review the data of suspected intussusception cases and assign certainty ratings. If there is a disagreement between two adjudicators, a more senior surgeon will be invited to reach a consensus through a meeting. The data collection and case adjudication process will be blinded to the patients' vaccination history.

Covariate measurement

General demographic information: Anonymous ID (including parents), anonymous vaccination ID, birth date, gender, ethnicity, registration date, migration date, birth hospital, household registration address (city), residential address (city), urban/rural area from the immunization planning information.

Mortality information: Anonymous ID, death date, death diagnosis, and ICD-10 code from mortality registration information.

Previous clinical information: Anonymous ID, diagnosis time, and disease history from 4-12 weeks of age (including high fever, acute respiratory infections, acute gastrointestinal infections, adenovirus infections, and diarrhea); medication history from 4-12 weeks of age (including immunomodulators, antiviral drugs, and antibiotics); malignancies, HIV infection, complement system deficiencies from 0-12 weeks; and any hospitalization records from 0 weeks.

Previous birth information: Anonymous ID, mother's last menstrual period, preterm birth, birth weight, Apgar score from maternal and child health information.

Unmeasured confounding factors: Including breastfeeding, other special health conditions such as congenital birth defects, other serious diseases (including metabolic diseases, neurological diseases, kidney diseases, liver diseases, and hematologic diseases). The negative outcome control is set as hand foot and mouth disease.

Statistical analysis

The statistical analysis will be conducted via SAS 9.4 or R software. Continuous variables will be presented as the means and standard deviations or median and quartiles. Group comparisons will be performed via ANOVA or the Wilcoxon rank-sum test, depending on the distribution of the data. Categorical variables will be presented as frequencies and percentages, and comparisons between groups will be carried out via the chi-square test.

For the primary study, a nested case-control design will be implemented. The analysis will include both an intention-to-treat (ITT) approach and a per-protocol analysis. In the ITT analysis, the incidence rate ratio (IRR) will be estimated via Poisson regression, adjusting for potential confounders such as age, gender, birth year, birth season, and other relevant factors. The per-protocol analysis will account for deviations from the study protocol by applying inverse probability weighting.

Subgroup analyses will further explore the exposure periods postvaccination, considering different time intervals (1-7 days, 8-14 days, 15-28 days, 29-42 days, and 43-90 days). Additionally, sensitivity analyses will be conducted to assess the robustness of the results. These will include day 0 of vaccination analysis, multiple imputations for missing data, self-controlled case series analysis, propensity score matching for comparison groups, and the use of a negative outcome control.

Sample size calculation

The conditional logistic regression module of PASS15 software is used to calculate the sample size required for the case-control study, with case-control ratio = 1:100, exposure rate Pᴇ = 0.3-0.5, and other parameters as above. The logarithm N of the required case-control matching is shown in the following table.

Table 1. Sample size for the nested case-control study

P_E	OR
P_E	1.1	1.3	1.5	2.0
0.3	6182	816	342	117
0.4	5409	714	299	103
0.5	5193	686	287	99

Quality Control and Management

Before the study implementation, senior epidemiology, statistics, and clinical experts will be invited to guide the improvement of the study methodology. On the basis the final protocol, data management, case validation, and statistical analysis plans will be formulated.

During the study implementation, prejob training will be provided to all relevant personnel, including data managers, case adjudicators, and statistical analysts, who will participate in this study upon passing the tests. The study will be conducted in strict accordance with the relevant protocols, with parallel quality control and documentation conducted by the researchers.

At the conclusion of the study, senior epidemiology, statistics, and clinical experts will be invited to review the study report and related materials, evaluate the study's processes, and thoroughly review the study's conclusions to reach a consensus.

Study strengths

This study is the first large-scale, multicenter proactive surveillance of rotavirus vaccines in China and will provide crucial safety data to help identify and prevent potential problems. The use of a high-quality regional health information platform and innovative methods such as target trial emulation are expected to improve the quality of vaccine safety studies.

Comparison with Other Studies

The WHO recommends that intussusception monitoring should be strengthened during large-scale RV vaccination, but the conclusions on the association between rotation vaccination and intussusception are not completely consistent across different countries and regions. A meta-analysis of RCTs did not find an association between the two(21), but the study and results has been controversial and questioned(22). It is obvious and difficult in an RCT to detect the rare events of intussusception, so the zero events or sparse data may cause serious estimation bias. Moreover, a meta-analysis from post-marketing study in 2017 suggested increased risks of intussusception after 7 days of rotavirus vaccination, and no such study has been conducted since then.

The latest meta-analysis collected data ended in 2018, with no more newly published studies that have analyzed data since then(21). Real world data after 2017 mostly reveaked that rotavirus vaccination was not associated with increased risk of intussusception(23–26), while some research has indicated varied results among different areas(27). In China, conclusions from retrospective birth cohorts using electronic health records from Ningbo city are consistent with those from Taiwan(13,28), however, these regional studies cannot represent the whole population in China, and neither of these study included the risk of intussusception after LLR.

Our study is the first in China to utilize a large-scale, multicenter approach for active rotavirus vaccine safety monitoring, with a focus on assessing the risk of intussusception following vaccination via a nested case-control study within a TTE framework. The study will be conducted with millions of birth cohorts in three economically developed and demographically stable regions (Ningbo, Jiangsu and Chongqing,), respectively from the east, central and west of China, enhancing the generalizability and applicability of the findings across different settings.

Moreover, another distinctive feature of our study is the utilization of the TTE framework, which can simulate randomized controlled trials using real-world data, and is vital for averting selection and immortal time biases that always arise from mishandling the start of follow-up (time zero) in the real-world(20), as well as the confounding.

Intriguingly, no comparative studies on rotavirus vaccine safety have utilized this approach, which may be a potential reason for the inconsistent results among them. Therefore, this is the first and significant attempt in our study to adopt this framework and provide reliable and reproducible evidence about the relationship between RV vaccines and intussusception.

Study Limitations

Despite its strengths, this study has several limitations. Although the study includes a large sample from Ningbo, Chongqing, and Jiangsu, which have high economic levels and urbanization rates, the results may not fully apply to regions with lower economic levels, scarce medical resources, or higher population mobility.

Moreover, it is impossible to completely rule out all potential confounders in real-world, as well as in our study. Furthermore, we will utilize the hand, foot and mouth disease group as the negative control, to reduce the influence of residual confounding, and ensure the robustness of the results.

RVGE: Rotavirus gastroenteritis; WHO: World Health Organization; LLR: Lanzhou lamb rotavirus vaccine; TTE: Target trial emulation; RCTs: Randomized controlled trials; ITT: Intention-to-treat; IRR: Incidence rate ratio.

Ethics approval and consent to participate

Prior to the implementation of this study, ethical approval and continuous review approval were obtained from the Peking University Health Science Center Ethics Committee and the ethics committees of participating institutions (if required). The ethical review number is IRB00001052-24039. The study will be conducted in strict accordance with the Declaration of Helsinki, ethical review regulations, the Personal Information Protection Law, the Cybersecurity Law, and other relevant laws and regulations.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Competing interests

None of the authors has any relevant conflicts of interests.

Funding

This study was supported by National Natural Science Foundation of China (Grant No. 82204175; 72361127500; 82330107), and Bill and Melinda Gates Foundation (Grant No. INV-035024). The funder had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit the article for publication.

Authors' contributions

Yulin Wang and Zhike Liu designed the study. Yulin Wang and Zhike Liu drafted the manuscript. Zhike Liu and Siyan Zhan revised the manuscript. Xin Gao, Junting Yang and Mengdi Zhang provided supportive scientific advice on the designing of this study. All the authors approved the final version of this manuscript.

Acknowledgements

None.

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No competing interests reported.

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Association between the Rotavirus Vaccine and Intussusception in China: Study Protocol for Target Trial Emulation

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Version 1

Abstract

Background

Methods

Study design

Data sources

Data collection and management

Statistical analysis

Sample size calculation

Quality Control and Management

Discussion

Study strengths

Comparison with Other Studies

Study Limitations

Abbreviations

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors' contributions

Acknowledgements

References

Additional Declarations

Supplementary Files

Status:

Version 1