Safety monitoring of ROTAVAC vaccine and etiological investigation of intussusception in India: study protocol

Abstract

BackgroundROTAVAC, an indigenous rotavirus vaccine, was introduced in the universal immunization program of India in four states in 2016 and expanded to five more states in 2017. The clinical trial on efficacy of ROTAVAC did not detect an increased risk of intussusception, but the trial was not large enough to detect a small risk. This protocol paper describes the establishment and implementation of a surveillance system to monitor the safety of rotavirus vaccine and investigate the potential infectious etiologies of intussusception.MethodsThis is a multi-centric hospital-based active surveillance being conducted at 28 hospitals in nine states of India. Data gathered from surveillance will be used to assess the risk of intussusception after ROTAVAC administration and to determine the infectious etiologies of intussusception. For safety assessment of ROTAVAC vaccine, children aged less than two years with intussusception admitted at the sentinel hospitals are enrolled into surveillance, a case report form completed, and a copy of the vaccination card obtained. The risk of intussusception following rotavirus vaccination will be assessed using a self-controlled case-series design. The investigation for potential infectious etiologies of intussusception is through a matched case-control design. Children enrolled for the safety assessment serve as cases and for each case, an age, gender and location matched control is enrolled within 30 days of case enrollment. Stool specimens are obtained from cases and controls. All forms and specimens are sent to the referral laboratory for data entry, analysis, multiplexed molecular testing, and storage.DiscussionAnticipated public health benefits of this surveillance include the generation of information useful to national government on safety of vaccine and to make future decisions on vaccine use through risk-benefit analysis. Investigating infectious agents may help to determine the potential infectious etiologies of intussusception.Electronic supplementary materialThe online version of this article (10.1186/s12889-018-5809-7) contains supplementary material, which is available to authorized users.

Intussusception after Rotavirus Vaccine Introduction in India

“…Surveillance started in four states in April 2016 and was expanded concurrently with vaccine introduction. The protocol, previously published, 23 has detailed methods and is also posted at NEJM.org . All children less than two years of age and meeting level 1 diagnostic certainty for intussusception per Brighton collaboration criteria were eligible for recruitment.…”

“…The self-controlled case-series (SCCS) method was used to assess the intussusception risk after vaccine administration. The relative incidences (RIs) were calculated using conditional Poisson regression analysis by comparing the incidence in the risk period i.e 1-7 days, 8-21 days, 1-21 days after each dose of vaccine with the incidence in all other observational periods (non–risk periods) for each case as required for SCCS analysis 23 , 26 , 27 . The pseudo-likelihood method 27 was used to allow the contraindication of vaccination after an episode of intussusception and event ascertainment was independent of vaccination status.…”

“…Two studies have reported a general incidence of intussusception of 18/100,000 infants and 20/100,000 infants 20 , 21 . The Indian National Technical Advisory Group on Immunization and the WHO recommended monitoring of vaccine safety after introduction into the immunization program 22 , in response to which we established the Indian Intussusception Surveillance Network 23 . Since the vaccine on which we now report is WHO pre-qualified, safety data are important for India, for the Gavi Alliance and for countries considering the introduction of rotavirus vaccines.…”

Current and new rotavirus vaccines

“…Given the importance of this research question, the wide variability in intussusception epidemiology by geography, and the possibility that associations could vary by vaccine product, ongoing investigation is necessary. In this vein, surveillance is ongoing in two multicountry networks: postintroduction intussusception surveillance is currently underway in several African countries using RotaTeq [45], whereas baseline (preintroduction) and postintroduction intussusception surveillance is ongoing in several Asian countries, including in India (for the newly prequalified vaccines) [46,47]. Results from these evaluations will be helpful in further understanding the risk–benefit profile of rotavirus vaccines globally.…”

Rotavirus vaccine impact assessment surveillance in India: protocol and methods

“…With the introduction of an indigenous vaccine into India’s UIP, issues including vaccine impact on disease burden under conditions of routine use, effectiveness against currently circulating strains of rotavirus, safety of the vaccine with respect to intussusception and cost effectiveness of the vaccination programme need to be examined. Studies to examine rotavirus vaccine impact and safety using proven study designs can help answer these questions and provide support for broader introduction of rotavirus vaccine in India 28. The paper describes the protocol and implementation of an ongoing multisite surveillance to monitor the impact and effectiveness of rotavirus vaccine following its introduction into the routine childhood immunisation programme.…”