Intussusception and rotavirus vaccines

doi:10.1016/j.vaccine.2005.07.031

Vaccine

Volume 24, Issue 18, 1 May 2006, Pages 3772-3776

https://doi.org/10.1016/j.vaccine.2005.07.031 Get rights and content

Abstract

The association between the first oral rotavirus vaccine to be licensed in the U.S. (Rotashield^®) and intussusception has presented a major challenge to the effort to reduce the global burden related to rotavirus infection. Although the risk of developing intussusception following immunization with Rotashield^® is low, debate continues about the estimation of intussusception risk and the events surrounding the withdrawal of the vaccine. The experience with Rotashield^® has highlighted the wisdom of parallel clinical trials in developing and developed countries and the value of post-licensure surveillance for the detection of uncommon adverse events. This review retraces the steps leading up to the withdrawal of the Rotashield^® vaccine and reflects on how this experience has influenced the development of other rotavirus vaccines.

Introduction

The association between an oral rotavirus vaccine (Rotashield^®, RRV-TV: Wyeth Lederle Vaccines and Pediatrics, Marietta, PA, U.S.A.) and intussusception has presented a major challenge to the effort to reduce the global burden related to rotavirus infection [1], [2]. Although the risk of developing intussusception following receipt of this vaccine is low, it has made a significant impact on the development of other rotavirus vaccine candidates [1], [2], [3]. This experience has also highlighted the paucity of knowledge of the global epidemiology and aetiology of intussusception–the most common cause of intestinal obstruction in infants. The aim of this review is to present the events leading up to the withdrawal of Rotashield^®, the debate that still surrounds the estimate of risk of intussusception associated with this vaccine and the implications this experience has had on the development of other rotavirus vaccines.

Section snippets

Experiences with Rotashield^®

The first oral rotavirus vaccine licensed in the U.S. was the rhesus-human reassortant tetra-valent vaccine (Rotashield^®). This is a live-attenuated, oral vaccine consisting of three reassortant strains, each containing one of the major VP7 outer capsid protein types of human rotavirus (G1, G2, G4) and the parent rhesus rotavirus strain (G3). It was given orally as a three-dose regime and was highly efficacious for the prevention of severe diarrhoea and hospitalisation due to rotavirus

Is the association of a rotavirus vaccine and intussusception specific to Rotashield^®?

The answer to this question is critical to the development of other rotavirus vaccine candidates. Pre-licensure trials of Rotashield^® suggested that the vaccine was reactogenic with low grade fever (38 °C/100.4 °F) reported more commonly in vaccine recipients than among infants receiving placebo [5], [20]. Decreased appetite, irritability and decreased activity were also reported in one of the pre-licensure studies [20]. During the period of Rotashield^® availability, the VAERS reports suggest

What has the Rotashield^® experience taught us about intussusception?

Intussusception is not a newly recognised disease. Intussusception occurs when one part of the bowel telescopes into a more distal segment and is the most common cause of intestinal obstruction in infants [26]. The symptoms and signs in children presenting with intussusception reflect the underlying pathophysiology. Intestinal obstruction results in vomiting, abdominal distension and abnormal or absent bowel sounds. The intussusception and associated oedema may be identified as a mass on

Implications for future development of rotavirus vaccines

Although the Rotashield^® experience has presented a major challenge for the development of further rotavirus vaccines, important lessons have been learnt from this experience [2]. Subsequent vaccine developers have been required by the U.S. FDA to increase the sample size of Phase III trials to enable detection of ‘vaccine-associated’ intussusception, with at least 50,000 subjects. The practicalities of conducting a clinical trial sufficiently powered to identify the risk of an adverse event of

Summary

The association between Rotashield^® and intussusception has presented a major challenge to development of rotavirus vaccines. The events surrounding the withdrawal of the vaccine and estimation of intussusception risk remain the subject of debate. Despite this setback in efforts to reduce the global burden of rotavirus disease, two rotavirus vaccines are currently in advanced stages of development (Rotarix^®, GSK and RotaTeq^®, Merck & Co.) and to date, no association with intussusception has

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A few months later, the U.S. Advisory Committee on Immunization Practices and the CDC withdrew their recommendation for RotaShield. Although it was not understood how RotaShield could have caused intussusception, the manufacturer voluntarily withdrew it from the market (Bines, 2006). A second example shows a process by which certain symptoms became successfully attached to a vaccine despite conflicting scientific evidence.
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The current manifestations of global resistance to vaccination, which lead to low acceptance of vaccines despite their availability, have been conceptualized as vaccine hesitancy by the World Health Organization [12]. Present-day vaccine hesitancy has been shaped by a recent history of vaccine scares that raised the issue of trust in vaccination on the public agenda, including the UK pertussis controversy, the mercury poisoning controversy, and the alleged measles, mumps, rubella (MMR)–autism vaccination link [13,14]. Country-specific threats to trust shape vaccine hesitancy and lead to decreasing vaccination coverage.
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Public trust in vaccines was significantly eroded by the pertussis vaccine controversy in the mid-1970s, and more recently by a publication in the Lancet proposing a causal relationship between the measles–mumps–rubella (MMR) vaccine and autism[39]. Other events that eroded public trust in vaccines include reporting of the H1N1 influenza vaccine increasing the risk of narcolepsy[33], the RotaShield rotavirus vaccine causing intussusception in healthy infants[2]and the HPV vaccine safety recall in 2013[36]. In addition to the forgone benefit of disease prevention in individuals, vaccine hesitancy also limits positive externalities offered by vaccine programs[11,38,8].
In absence of a COVID-19 vaccine, testing, contact tracing and social restrictions are among the most powerful strategies adopted around the world to slow down the spread of the pandemic. Citizens of most countries are suffering major physical, psychological and economic distress. At this stage, a safe and effective COVID-19 vaccine is the most sustainable option to manage the current pandemic. However, vaccine hesitancy by even a small subset of the population can undermine the success of this strategy.
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The human immune response is regulated by a wide array of genes located across the genome. Lymphocytes use germline rearrangement of T and B cell receptor genes to create the fine specificity associated with adaptive immune response. While this fine specificity is the hallmark of adaptive immunity, research has shown that the response requires a coordinated interaction between lymphocytes and many other cell types. As such, genes that can affect the immune response continue to be identified and our understanding of the role of individual genes and gene networks is improving. Understanding immune responses has long been viewed as one of the keys to vaccine design. As genomic approaches mature, so too will our ability to characterize the diversity of vaccine responses and design better vaccines. This chapter outlines the relevant concepts and includes a discussion of hurdles we still face in implementing genomic and/or personalized approaches to vaccine design and administration.
Clinical research design and causality: Does oral rotavirus vaccine cause intussusception?
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Los diseños de investigación clínica, cuyo propósito es responder preguntas sobre causalidad, se pueden clasificar en relación con cuatro ejes: el número de grupos de estudio, la aplicación de una maniobra experimental, la direccionalidad causa-efecto y la fuente de la que se recaban los datos. Los diseños básicos más utilizados en epidemiología son el ensayo clínico, el estudio de cohortes, el estudio de casos y controles y la encuesta transversal. Este texto pretende facilitar la identificación y comprensión de cada uno de estos diseños mediante ejemplos relacionados con la asociación entre la vacunación con rotavirus y la invaginación intestinal.
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Retrospective surveillance for intussusception in children aged less than five years at two tertiary care centers in India
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However, surgery may be required in some cases, and approximately 10% of patients with intussusception undergo an intestinal resection due to a vascular injury to the intestine. Intussusception primarily affects children, with the peak incidence reported between 4 and 10 months of age [1]. The background incidence and case fatality vary widely by region, and deaths from intussusception are more common in developing than in industrialized countries [2].
A rotavirus vaccine could soon become part of India's national immunization program. However the occurrence of intussusception due to rotavirus vaccine is a potential safety concern. This surveillance aimed at the collection of baseline data on childhood intussusception which would facilitate the monitoring of intussusception cases after the introduction of rotavirus vaccines.
We retrospectively reviewed medical records of confirmed intussusception cases in children under the age of five, treated during 2007–2012 at two tertiary care hospitals attached to medical schools in India. Demographic, clinical, diagnostic and treatment practices data were obtained from hospital records.
Over a five to six year observation period, we identified 187 confirmed cases of intussusception, of which 75% were males. The median age of intussusception was 8 months, and we observed a possible trend in the distribution of cases with the highest number of cases being reported in the month of April and lowest in the month of October. The most common diagnostic methods used were ultrasonography and abdominal radiography with most cases being treated surgically (71%). The median length of hospital stay was 8 days (range 1–40) and mean was 10.2 days. Records of any fatality due to intussusception were not found during the review of the records.
This analysis provides an estimate of the baseline data of childhood intussusception prior to the introduction of the rotavirus vaccination as a part of routine immunization in India. A prospective surveillance system using a standardized case definition is needed in order to better examine the incidence of intussusception in developing countries.

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Intussusception and rotavirus vaccines

Abstract

Introduction

Section snippets

Experiences with Rotashield®

Is the association of a rotavirus vaccine and intussusception specific to Rotashield®?

What has the Rotashield® experience taught us about intussusception?

Implications for future development of rotavirus vaccines

Summary

Lancet

Vaccine

Lancet

Lancet

Vaccine

Intussusception among infants given an oral rotavirus vaccine

NEJM

Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions

JID

Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela

N Engl J Med

The first oral rotavirus vaccine 1998–1999 estimates of uptake from the National Immunization Survery

Public Health Rep

Intussusception among recipients of rotavirus vaccine—United States

Morb Mortal Wkly Rep

Withdrawal of rotavirus vaccine recommendation

Morb Mortal Wkly Rep

Acute intussusception in infants and children: a global perspective. Vaccines and biologicals

Experiences with Rotashield^®

Is the association of a rotavirus vaccine and intussusception specific to Rotashield^®?

What has the Rotashield^® experience taught us about intussusception?