Pediatric News. Rotavirus in the Modern Age. Prevention as a Strategy for Reducing Morbidity, Mortality, and Economic Burden of the Disease

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1 A SUPPLEMENT TO Pediatric News Rotavirus in the Modern Age Prevention as a Strategy for Reducing Morbidity, Mortality, and Economic Burden of the Disease TOPIC HIGHLIGHTS: BURDEN OF DISEASE UNDERSTANDING ROTAVIRUS ROTAVIRUS VACCINES VACCINE SAFETY VACCINE EFFICACY FACULTY Penelope H. Dennehy, MD Director Pediatric Infectious Diseases Hasbro Children's Hospital Professor of Pediatrics Brown Medical School Rhode Island Hospital Providence, R.I. Release Date: October 2006 Expiration Date: October 31, 2007 Estimated Time to Complete Activity: 1.25 hrs Sponsored by

2 Pediatric News President, Elsevier/IMNG Alan J. Imhoff Vice President, Medical Education Sylvia H. Reitman, MBA Program Manager, Medical Education Jenny R. McMahon National Account Manager Rory Flanagan Graphic Designer Lehner & Whyte Production Specialist Anthony Draper Sponsored by This supplement is based on a clinical dialogue with the faculty member. It is supported by an educational grant from Program content supplied by ROTAVIRUS IN THE MODERN AGE Prevention as a Strategy for Reducing Morbidity, Mortality, and Economic Burden of the Disease INTRODUCTION 4 BURDEN OF DISEASE 4 UNDERSTANDING ROTAVIRUS 5 ROTAVIRUS VACCINES 6 VACCINE SAFETY 8 VACCINE EFFICACY 9 CONCLUSIONS 10 REFERENCES 11 CME POST-TEST AND EVALUATION 12 This supplement was produced by the medical education department of International Medical News Group. Neither the editor of Pediatric News, the Editorial Advisory Board, nor the reporting staff contributed to its content. The opinions expressed in this supplement are those of the faculty and do not necessarily reflect the views of the supporter or of the Publisher. Copyright 2006 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. Elsevier Inc. will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. TARGET AUDIENCE This activity has been designed to meet the educational needs of pediatricians and allied health care professionals involved in the treatment of children. STATEMENT OF NEED/PROGRAM OVERVIEW Rotavirus is a common childhood disease that affects most children at least once prior to their fifth birthday. It is a leading cause of acute gastroenteritis. In developed countries, rotavirus affects approximately 7 million children less than 5 years of age annually. Although common, the disease can have serious consequences. In the United States, rotavirus is responsible for approximately 600,000 physician office, clinic, and emergency room visits; 47,000 to 60,000 hospitalizations; and 20 to 60 deaths each year. It is estimated that rotavirus is responsible for 4% to 5% of all childhood hospitalizations. In addition, the economic burden of rotavirus is significant. The average nonmedical cost of rotavirus per child is approximately $450, including approximately $360 for missed work, $57 for transportation, $12 for oral rehydration, $10 for diapers, $7 for child care changes, $4 for dietary changes, and $1 for formula changes. In the developing world, rotavirus is a significant cause of mortality, accounting for approximately 611,000 deaths per year, largely due to limited health care resources. Because of the tremendous morbidity, mortality, and economic burden of rotavirus and the structure and pathogenesis of the virus itself, the future of rotavirus management may largely be prevention through vaccination.

3 Rotavirus in the Modern Age: Prevention as a Strategy for Reducing Morbidity, Mortality, and Economic Burden of the Disease will provide an overview of the pathology and burden of disease. This program will focus on prevention of rotavirus as a means to reducing morbidity, mortality, and costs associated with the disease. Specifically, it will examine the history of vaccine development and provide a detailed discussion of the two new rotavirus vaccines, including mechanisms of action, efficacy and safety, and appropriate use. The goal of the program is to provide physicians with a clear understanding of rotavirus and strategies for disease prevention. LEARNING OBJECTIVES After completing this activity, the participant should be better able to: Identify the major health concern for children infected with rotavirus. Outline the standard treatment for rotavirus in the developed world. Name three ways the rotavirus disease burden negatively affects the economy. Identify the ages at which children should receive the new rotavirus vaccines, specific for each vaccine. FACULTY ADVISOR Penelope H. Dennehy, MD Director Pediatric Infectious Diseases Hasbro Children s Hospital Professor of Pediatrics Brown Medical School Rhode Island Hospital Providence, R.I. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Med Learning Group. PIM is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST Postgraduate Institute for Medicine (PIM) assesses conflicts of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in health care and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Penelope H. Dennehy, MD Grant/Research support: GlaxoSmithKline, Merck & Co., Inc., Wyeth The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Jan Hixon, RN, BSN, MSN, Postgraduate Institute for Medicine No financial relationship with any commercial entity. Tara Hun-Dorris, Med Learning Group No financial relationship with any commercial entity. METHOD OF PARTICIPATION There are no fees for participating and receiving CME credit for this activity. During the period of October 2006 through October 31, 2007, participants must (1) read the learning objectives and faculty disclosures; (2) study the educational activity; (3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; (4) complete the evaluation form; and (5) fax the evaluation form with the answer key to Postgraduate Institute for Medicine at A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better. Your statement of credit will be mailed to you within 3 weeks. MEDIUM Monograph DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Elsevier Inc., Postgraduate Institute for Medicine (PIM), Med Learning Group, and Merck & Co., Inc., do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Elsevier, PIM, Med Learning Group, or Merck & Co., Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. For additional free CME programs, please visit and

4 Rotavirus is the most common cause of severe diarrhea in infants and young children in the United States and worldwide. 1 In the United States, rotavirus infections tend to peak each year during the winter months, beginning in November in the Southwest and traveling across the United States from west to east, concluding in April in the Northeast. 2 Rotavirus, which is highly transmissible, is so common that nearly every child has at least one rotavirus infection by 5 years of age. The most severe manifestations of rotavirus generally occur in children 4 to 36 months of age 3 ; subsequent infections tend to be less severe than first infections. 4 Rotavirus spreads directly from person to person, primarily via the oral-fecal route. On average, children shed virus for 7 days after the onset of symptoms. The duration of each rotavirus infection tends to be brief 1 to 2 days of incubation followed by up to a week of symptoms. The primary symptom of rotavirus is diarrhea. 5 Other common symptoms include vomiting, fever, and abdominal pain. A recent analysis of active disease surveillance of 862 children 15 days through 4 years of age who were admitted to three children s hospitals for rotavirus-like INTRODUCTION symptoms from November 1997 through June 1998 found that patients who have rotavirus infection are more likely to have two or three of the common symptoms rather than a single symptom such as diarrhea. 5 Rotavirus infection was most likely when diarrhea, vomiting, and fever occurred together (56%); was less likely when two symptoms occurred together, specifically diarrhea with vomiting (38%), diarrhea with fever (19%), or fever with vomiting (13%); and was least likely when one symptom occurred alone, eg, diarrhea (3%), vomiting (11%), or fever (6%). The main threat from rotavirus is dehydration, as children infected with rotavirus may experience 10 to 20 bowel movements per day and 24 hours or more of vomiting. Young children are particularly at risk of dehydration because of their higher surface-to-volume ratio, higher metabolic rates, smaller fluid reserves, and dependency on others for fluid intake. 4 In the United States and other developed countries, rotavirus treatment typically consists of managing dehydration either at home through oral rehydration therapy or in the hospital, with either oral rehydration therapy or intravenous administration of fluids, depending on disease severity. 6,7 BURDEN OF DISEASE Even though rotavirus is a common, treatable disease in the developed world, the disease burden is high in terms of morbidity and economic costs. Each year in the United States, there are approximately 3.2 million episodes of rotavirus infection resulting in about 600,000 physician, clinic, and emergency room visits 8 ; 46,800 to 60,100 hospitalizations 9 ; and 20 to 60 deaths (Figure 1). 10 Hospitalizations due to rotavirus present a tremendous burden in the United States. Dr Malek and colleagues recently used the Kids Inpatient Database (KID) to estimate the number and rate of diarrheaand rotavirus-associated hospitalizations among children less than 5 years of age in 1997 and Diarrhea was coded in 13% of hospitalizations, indicating that one hospitalization due to diarrhea occurs for every 23 to 27 children by 5 years of age. Although the etiology of diarrhea was not recorded in 62% of hospitalizations, 35% were recorded as viral and just under 20% were recorded as rotaviral in both years studied. Further, diarrhea-related hospitalizations captured as not specified or viral peaked during the winter months of the year 2000, suggesting that many rotavirus hospitalizations were not adequately captured. The researchers concluded that rotavirus is associated with 4% to 5% of all childhood hospitalizations in the United States. In the developing world, rotavirus is a significant cause of mortality, accounting for approximately 611,000 deaths per year, with greater than 80% of these occurring in South Asia and Sub-Saharan Africa, where health care resources are limited. 13 Worldwide, rotavirus accounts for about 5% of all deaths among children less than 5 years of age. 11 Figure 1. Estimated Prevalence of Rotavirus Illness in the United States Sources: Fischer et al 8, ; Malek et al 9 ; Parashar and Glass. 10 Deaths Inpatient visits Outpatient visits Home care Events per year ,000 60, , million 4 ROTAVIRUS IN THE MODERN AGE

5 Because of the tremendous morbidity and mortality and economic burden of rotavirus worldwide, and because of the structure of the virus and the lack of effective antiviral therapy, the future of rotavirus management is thought to be prevention through vaccination. Figure 3. Rotavirus Pathogenesis Malabsorption UNDERSTANDING ROTAVIRUS Human rotaviruses are part of a large family of viruses that cause diarrhea in a variety of mammals and birds. Rotavirus was first detected in Australia in 1973 in duodenal biopsies from children who had acute diarrhea. These biopsies showed wheel-shaped viruses in the epithelial cells lining the intestine; the name rotavirus is derived from the Latin word rota, meaning wheel. Figure 2 shows the structure of rotavirus, which has a double-shelled capsid. 12 Rotavirus has structural proteins called VPs or viral proteins. 13 Each VP type is denoted by a number. The outer shell or capsid contains VP7 antigens studded with VP4 spikes. VP4 and VP7 elicit a host s disease-fighting immune responses and induce the production of neutralizing antibody directed against rotavirus. Thus, VP4 and VP7 are important components of vaccine development. The inner capsid contains VP6, the major rotavirus group antigen. VP6 is the antigen detected by the rotavirus tests available to clinical laboratories and is present in all group A rotaviruses. Rotaviruses are segmented double-stranded RNA viruses. The 11 RNA segments code for VPs and for nonstructural proteins, including the nonstructural protein (NSP)4 enterotoxin, which is thought to cause diarrhea. Figure 2. Structure of Rotavirus VP4 Neutralization antigen (P serotype) VP6 Group and subgroup antigen VP7 Neutralization antigen (G serotype) VP=viral protein. Source: Estes. 12 Virus invasion Source: Desselberger and Gray. 24 Cell death Villous atrophy Crypt hyperplasia Classification Rotaviruses are classified into serogroups and serotypes. 14,15 There are at least seven distinct serogroups (A through G); A, B, and C are human pathogens; A is the major cause of illness in humans. 14,15 Serotypes have been described for group A only and are based on the VP4 and VP7 antigens The VP7 antigen determines the G serotype; 10 G serotypes have been identified in humans, with four causing most illness in the United States. 14,15 The VP4 antigen determines the P serotype; 11 have been identified in humans. 17 The predominant G serotype varies by region and year. 16 G1 tends to be the predominant pathogenic serotype in the United States. 18,19 Dr Matson and colleagues conducted a longitudinal study of group A rotaviruses in the United States. 18 Part of their analysis looked at stool samples taken from children at Texas Children s Hospital, Houston, from 1979 to They found that although the predominant G type was generally G1, in some years it was G3 and one year it was G4. Worldwide the predominant serotype is also G1, although to a lesser extent, occurring about 53% of the time. 20 Other predominant serotypes worldwide have included G2 (11%), G3 (14%), G4 (5%), and other genotypes (17%). 20 Pathophysiology Rotaviruses directly infect the small intestine following oral ingestion. When rotavirus particles are ingested, three mechanisms facilitate development of Enteroblast replacement Secretion Recovery diarrhea: infection of the absorptive intestinal villus cells; stimulation of the enteric nervous system; and activation of NSP Based on animal models, NSP4 or one of its peptides is thought to induce diarrhea in the absence of histologic changes by causing an increase in intracellular calcium ion concentration, which disturbs cellular electrolyte homeostasis. 24 Once rotavirus enters the small intestine, it attaches to glycolipids on the surface of the mature villous tip cells that line the small intestine. 21 The virus invades the villous tip cells, causing villous atrophy, loss of digestive enzymes, and a reduction of absorption. 24 Once the villi become blunted, the resulting malabsorption of carbohydrates results in diarrhea which persists until the villi are regenerated (Figure 3). 24 Shedding of rotavirus in the stool occurs during the recovery process, facilitating the spread of disease. 24 Immunity Rotavirus infection confers some natural immunity to subsequent infections. Specifically, infection causes serum and intestinal antibody responses that protect against severe diarrhea upon reinfection with rotavirus. 23 Dr Velázquez and colleagues evaluated the protection conferred by each rotavirus infection by monitoring 200 Mexican infants from birth through 2 years of age. 4 The researchers found that children who had one, two, or three previous rotavirus infections had progressively lower risks of additional rotavirus infections (adjust- ROTAVIRUS IN THE MODERN AGE 5

6 ed relative risk, 0.62, 0.40, and 0.34, respectively) and diarrhea (adjusted relative risk, 0.23, 0.17, and 0.08, respectively). Further, subsequent infections were significantly less severe than initial infections (P=0.024) and more likely to be caused by rotavirus of a different G type (P=0.054). The researchers concluded that protection against future infections increased with each rotavirus infection, although natural infection best protects against more severe disease and is less protective against less severe or asymptomatic disease (Figure 4). ROTAVIRUS VACCINES Goals Rotavirus illness is difficult to prevent because it is so easily transmitted (eg, between family members in the home, between children in preschools or daycare settings) and children can be infected more than one time. The nature of rotavirus is that first infections tend to be the most severe and protective immunity, which is strongest against moderateto-severe disease, tends to develop after the first infection. Therefore, implementing a vaccine program, where very young infants receive the vaccine to become protected against more severe subsequent infections, represents the ideal means of preventing moderate-to-severe rotavirus infections. The goals for rotavirus vaccine programs are to: 6 ROTAVIRUS IN THE MODERN AGE Duplicate the degree of protection that follows natural infection. Prevent moderate-to-severe disease but not mild disease from rotavirus. Reduce disease burden in the developed world (eg, office visits, emergency room visits, hospitalizations, lost productivity through caregivers missing work). Provide vaccine in developing countries where rotavirus mortality is high. Estimated Vaccine Cost Savings Diarrheal illness is common, and it has a tremendous economic burden. One US study of children less than 3 years of age during the rotavirus season found the following costs associated with each episode of diarrhea: missed work (50% of associated costs), office visits (20%), clinical laboratory tests (8%), medication (7%), change of diet and oral rehydration solution (6%), travel (5%), extra diapers (2%), and change of child care (2%). 25 An analysis of the cost-effectiveness of a rotavirus vaccine program conducted in 1998 for a birth cohort of 3.9 million children through 5 years of age found that a vaccine program would be associated with a 55% cost savings in office visits, 59% savings in emergency room visits, 75% savings in hospitalizations, and 67% savings in costs associated with deaths, for a total medical cost savings of Figure 4. Protection Conferred by Natural Rotavirus Infection (N=200) Adjusted Efficacy After Each Infection (%)* Asymptomatic infection Mild diarrhea * Efficacy was calculated as the percent reduction in the risk of an outcome compared with the risk for children who were not yet infected. Sources: Fischer et al 8 ; Malek et al 9 ; Parashar and Glass Moderate-to severe diarrhea First infection Second infection Third infection 40%. 26 The same study also looked at nonmedical costs associated with a rotavirus vaccine program and found that a rotavirus vaccine would reduce lost earnings by 55%, would reduce other direct nonmedical costs by 45%, and would increase lifetime productivity by 67% (in children whose lives were saved by the vaccine), for a total nonmedical cost savings of 55%. Lessons Learned From the Rhesus Rotavirus Tetravalent Vaccine The rhesus rotavirus tetravalent vaccine (RotaShield ; RRV-TV), a live, oral, tetravalent, simian-based rotavirus vaccine, was briefly licensed in the United States in The US Food and Drug Administration (FDA) approved RRV-TV based on safety studies that included administration of the vaccine to 4,000 to 5,000 children, the standard for phase III vaccine trials at that time. The vaccine was licensed in August 1998 and universally recommended for infants by the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP). Once approved, RRV-TV was subject to continued safety monitoring through the Vaccine Adverse Event Reporting System (VAERS), a cooperative postmarketing safety surveillance program for vaccine safety of the CDC and the FDA. Intussusception, or an infold of one part of the intestine into the other, was listed as a possible risk factor of RRV-TV because it had been seen in clinical trials, although it was seen only after the second dose of vaccine had been administered, and it had not been reported more frequently in children receiving vaccine than in children receiving placebo. 27 From December 18, 1998, through June 2, 1999, 10 cases of intussusception were reported to VAERS, compared with a total of four cases reported during the previous 10 years. 26 In response, the CDC conducted a large study of intussusception and RRV-TV. 27 The study analyzed data from 429 infants with intussusception and 1,763 matched healthy infants in a case-controlled analysis. Seventy-four (17.2%) infants with intussusception and 226 (12.8%) case controls had received RRV-TV

7 (P=0.02). Researchers also found an increased risk of intussusception in the 3 to 14 days following the first dose of vaccine (adjusted odds ratio, 21.7; 95% confidence interval [95% CI], 9.6, 48.9). The researchers concluded there was a strong association between vaccination with RRV-TV and intussusception among healthy infants. They estimated that one case of intussusception would occur for every 4,670 to 9,474 infants vaccinated with RRV-TV, an unacceptable risk in the United States, where rotavirus is largely a treatable, non lifethreatening disease. Consequently, RRV- TV was withdrawn from the US market. Because it was withdrawn from the US market, it was not deemed acceptable for approval elsewhere in the world, including countries where rotavirus is a major cause of infant and toddler death and the risk of intussusception associated with RRV-TV may have been more justified. The global consensus has been that the need exists for a safer rotavirus vaccine to prevent the spread of rotavirus infection in the developed and developing world. 29 Vaccine Development Approaches Researchers have attempted rotavirus vaccine development by three approaches: monovalent animal rotavirus vaccines, multivalent human-animal reassortant vaccines, and vaccines from attenuated human strains of rotavirus. The monovalent animal rotavirus vaccine development attempts used a Jennerian approach. The theory was that in the same way Edward Jenner discovered that cowpox could be given to humans to prevent smallpox, some animal rotaviruses that are not normal pathogens for humans may cause immunity to human rotavirus without causing illness. Vaccine attempts using this approach included a rhesus monkey strain and a bovine strain; however, these initial vaccines did not provide reproducible protection against rotavirus, and this approach was abandoned in favor of two new approaches. 30 The multivalent human-animal reassortant vaccines represent a modified Jennerian approach to vaccine development. For these vaccines, an animal rotavirus strain, either bovine or simian, is used as a gene donor and human VP7 or VP4 encoding genes are reassorted into the animal rotavirus genome. 31,32 The attenuated human strain approach to vaccine development involves multiple passages of virulent human rotavirus strains through cell culture to obtain weakened strains to use as vaccines. 31 Two new rotavirus vaccines have received approval in various parts of the world: one is a multivalent humananimal reassortant vaccine and is licensed in numerous countries, including the United States; the other is an attenuated human strain and is licensed in numerous countries excluding the United States but including the European Union. Pentavalent Rotavirus Vaccine Overview Pentavalent rotavirus vaccine (RotaTeq ; PRV) is a live, oral, pentavalent rotavirus vaccine developed using the multivalent human-animal reassortant technique. It is based on a bovine strain, WC3, and contains five human-bovine reassortants: G1, G2, G3, G4, and the P1A component, which cross-reacts with G9, a rotavirus type found in the United States. 33 The WC3 strain is naturally attenuated for humans. However, it is not broadly cross-protective, so each reassortant virus has a single human rotavirus gene that encodes a major outer capsid protein from each of the most common serotypes of human rotavirus. The vaccine does not grow as well as natural rotavirus in the intestine, so a larger amount of virus is required to immunize each child. However, the vaccine strains do not replicate well in the gastrointestinal tract and are generally rarely shed in the stool. PRV is licensed in several countries worldwide and was licensed in the United States on February 3, On February 21, 2006, the CDC s ACIP recommended universal vaccination of US infants against rotavirus, and an AAP recommendation for universal rotavirus vaccination is anticipated in According to ACIP, PRV should be administered as follows: Three oral doses, given at 2, 4, and 6 months of age The first dose must be given between 6 and 12 weeks of age Dosing must be complete by 32 weeks of age there is no catch-up period for older infants who have not received the vaccine The minimum interval between doses is 4 weeks The vaccine should not be readministered if it is regurgitated. ACIP s full recommendation, Prevention of Rotavirus Gastroenteritis Among Infants and Children, is available online at preview/mmwrhtml/rr5512a1.htm. PRV is safe to give to breastfeeding infants and infants with transient, mild illness. It can be given in conjunction with the diphtheria/tetanus/acellular pertussis, Haemophilus influenzae type B, inactivated poliovirus, hepatitis B, and pneumococcal conjugate vaccines. PRV can be given to premature infants (less than 37 weeks gestation) who are at least 6 weeks old, are clinically stable, and have been discharged or are at discharge from the hospital nursery. Infants in households with immunocompromised people (eg, people with human immunodeficiency virus [HIV]) can be vaccinated with PRV. PRV is contraindicated in infants who have a serious allergy to any of the vaccine components. Precautions should be taken in infants with altered immunocompetence (eg, infants born to HIV-infected mothers whose HIV status is unknown), moderate-to-severe gastroenteritis, moderateto-severe febrile illness, preexisting chronic gastrointestinal disease, or a history of intussusception. Human Rotavirus Vaccine Overview Human rotavirus vaccine (Rotarix TM ; HRV) is a monovalent attenuated human strain vaccine. It was derived from the most common strain of human rotavirus in the United States, G1P[8]. It shares neutralizing epitopes with G1, G3, G4, and G9 rotavirus serotypes but not G2. It has been attenuated through serial passage. HRV is administered in two oral doses, 1 to 2 months apart. The vaccine strain replicates in the intestine and, similar to natural rotavirus infection strains, is shed by more than 50% of recipients after the first dose. HRV provides cross-protection against other rotavirus serotypes. HRV is currently not licensed in the United States, and no timeline for licen- ROTAVIRUS IN THE MODERN AGE 7

8 sure had been established at the time of publication. However, it is licensed in more than 30 countries, including the European Union, and is part of the national immunization programs in Brazil and Panama. VACCINE SAFETY Because of the RRV-TV experience, the PRV and HRV phase III safety trials enrolled an unprecedented number of patients (more than 60,000 patients in each clinical trial compared to less than 10,000 patients enrolled in previous vaccine safety trials) and used active surveillance to monitor for adverse events. 34,35 Safety results for PRV and HRV are described below. PRV In the large, double-blind Rotavirus Efficacy and Safety Trial (REST), Dr Vesikari and colleagues used active surveillance to study healthy infants 6 to 12 weeks old from 11 countries, including the United States, who were randomly assigned to receive three oral doses of PRV or placebo at 4- to 10- week intervals. 34 The safety cohort included all patients 34,035 assigned to PRV and 34,003 assigned to placebo and monitored all serious adverse experiences, including intussusception and hospitalization and emergency visits for acute gastroenteritis caused by rotavirus. A smaller safety substudy of 9,605 patients, 4,806 vaccine recipients, and 4,799 placebo recipients, looked at all adverse experiences, regardless of seriousness. All patients were monitored for serious adverse events for at least 42 days after vaccine administration. Caregivers were contacted by study personnel on days 7, 14, and 42 after each vaccination dose and every 6 weeks thereafter for 1 year. The primary concern was the risk of intussusception. The primary safety hypothesis was that compared with placebo, administration of vaccine would not increase the risk of intussusception within 42 days after administration of vaccine. To satisfy this hypothesis, there could not be a significantly increased risk of intussusception from vaccine compared with placebo between 7 and 42 days after any dose, and at the end of the study, the upper bound of the 95% CI had to be less than ROTAVIRUS IN THE MODERN AGE Intussusception occurred within 1 year after vaccination in 27 patients, 12 PRV recipients, and 15 placebo recipients. Within 42 days after any dose, intussusception occurred in six vaccine recipients and five placebo recipients. Intussusception did not occur in any vaccine recipients within 42 days after the first dose. The relative risk (odds ratio) was 1.6 (95% CI, 0.4, 6.4 well within the upper bound defined by the safety hypothesis [Figure 5]). Only one case of intussusception occurred by day 10 after vaccination; it occurred so shortly after vaccination that investigators determined it was unlikely to be related to PRV administration. 34 In the safety substudy of 9,605 patients, caregivers filled out report cards in detail and reported all adverse events that occurred after administration of vaccine. The rates of fever, vomiting, diarrhea, and other gastrointestinal adverse events within 42 days after administration of any dose were similar among vaccine and placebo recipients (fever: vaccine, 40.9%, placebo, 43%; vomiting: vaccine, 12.8%, placebo, 13.4%; diarrhea: vaccine, 19.7%, placebo, 19.1%; abdominal pain: vaccine and placebo, 0.5%; upper abdominal pain: vaccine, 1.1%, placebo, 0.8%; hematochezia: vaccine and placebo, 0.6%). 34 Dose 1 Dose 2 Dose 3 HRV In the large, double-blind Human Rotavirus Vaccine Study Group trial, Dr Ruiz-Palacios and colleagues used active surveillance to study 31,673 healthy infants who received two doses of HRV and 31,552 infants who received two doses of placebo at approximately 2 and 4 months of age in 11 Latin American countries and Finland. 35 (The safety and immunogenicity of HRV were previously studied in a smaller US-Canadian trial. 36,37 ) After administration of the second dose of vaccine or placebo, the overall cohort was followed for a median of 100 days after the first dose for assessment of adverse events, including intussusception; a smaller safety and efficacy cohort of 20,169 patients was followed until they reached 1 year of age. As in the REST study, the primary safety concern was the risk of intussusception. The primary and secondary safety objectives were to assess the risk of definite intussusception within 31 days of each vaccine dose and to assess the occurrence of serious adverse events, including intussusception, throughout the study period. Overall, 25 cases of definite intussusception occurred during hospital surveillance and active follow-up. Within 31 days of vaccine administration, six vac- Figure 5. REST Confirmed Intussusception Cases 42-Day Period After Any Dose Vaccine 6; Placebo 5; Relative risk 1.6; 95% CI 0.4, 6.4 X X X O X X PRV Days After Any Dose CI=confidence interval; PRV=pentavalent rotavirus vaccine; REST= Rotavirus Efficacy and Safety Trial. Copyright 2006 Massachusetts Medical Society. All rights reserved. Reprinted with permission Source: Vesikari et al. 34 O O OXX O One Case O Placebo

9 Figure 6. Intussusception Cases (IS) with HRV vs Placebo or RRV-TV Dose 1 IS cases Dose 2 IS cases V V P RRV-TV HRV=human rotavirus vaccine; RRV-TV=rhesus rotavirus tetravalent vaccine. Sources: Murphy et al 28 ; Ruiz-Palacios et al. 35 cine recipients and seven placebo recipients experienced intussusception (difference in risk per 10,000 infants; 95% CI, -2.91, 2.18; P=0.78). As shown in Figure 6, no temporal cluster of intussusception was noted after either dose, in contrast to intussusception that occurred following administration of RRV-TV in the 1990s. 28,35 In the safety cohort, fewer serious adverse events were reported by vaccine recipients (293.0 per 10,000 infants) compared with placebo recipients (331.8 per 10,000 infants [P=0.005]). 35 Although the Ruiz-Palacios study did not report details about nonserious adverse events, in an earlier study of 529 infants administered one of two doses of HRV or placebo, the incidence of solicited symptoms of fever, vomiting, or diarrhea was not significantly different between the HRV treatment groups and the placebo group. 36 VACCINE EFFICACY In the two large, double-blind clinical trials, PRV and HRV both proved highly efficacious against severe rotavirus gastroenteritis. 34,35 Specific results for the two vaccines are described below. HRV/placebo V=HRV P=Placebo V V P P V P P P P P P V V P V P P P P P P Days After Administration PRV The REST study included an efficacy substudy of 5,686 patients. 34 The primary efficacy hypothesis was that PRV would have efficacy in preventing wildtype G1, G2, G3, and G4 rotavirus gastroenteritis from day 14 onward after the third dose of vaccine was administered, through the first complete rotavirus season after vaccine administration. End points included efficacy against all cases of rotavirus gastroenteritis and office visits, emergency room visits, and hospitalizations for rotavirus gastroenteritis. Among the 4,512 patients (2,207 vaccine recipients and 2,305 placebo recipients) in the per-protocol efficacy population, 82 cases of rotavirus occurred in vaccine recipients and 315 cases occurred in placebo recipients 14 or more days after the last dose of vaccine during the first full rotavirus season. The clinical efficacy of the vaccine against rotavirus gastroenteritis of any severity was 74% (95% CI, 66.8, 79.9); however, against severe rotavirus gastroenteritis, the vaccine demonstrated efficacy of 98% (95% CI, 88.3, 100.0). 34 The vaccine also proved strongly efficacious against the predominant G1 serotype (74.9% efficacy [95% CI, 67.3, 80.9]) and the G2 serotype (63.4% efficacy [95% CI, 2.6, 88.2]). There was a trend toward efficacy for the remaining serotypes, but patient numbers were too small to show statistical significance: G3, 82.7% efficacy (95% CI, <0.0, 99.6), G4, 48.1% efficacy (95% CI, <0.0, 91.6), and G9, 65.4% efficacy (95% CI, <0.0, 99.3). 34 The large-scale study analyzed rotavirus gastroenteritis related hospitalizations and emergency room visits among 28,646 vaccine recipients and V ,488 placebo recipients. Six patients who received the vaccine were hospitalized for rotavirus gastroenteritis, compared with 138 patients who received the placebo. The hospitalization reduction rate associated with PRV was 95.8% (95% CI, 90.5, 98.2). Similarly, 13 vaccine recipients had rotavirus gastroenteritis related emergency room visits, compared with 191 placebo patients. The reduction in the rate of gastroenteritis related emergency room use associated with PRV was 93.7% (95% CI, 88.8, 96.5). A small efficacy sub-study (n=5,673) found that PRV vaccine use was also associated with a large reduction in office visits due to rotavirus gastroenteritis. Thirteen of 2,834 vaccine recipients had office visits for rotavirus gastroenteritis, compared with 99 of 2,839 placebo recipients. PRV was associated with an 86% (95% CI, 73.9, 92.5) reduction in physician office visits due to rotavirus. 34 HRV The primary efficacy end point of the Ruiz-Palacios study was prevention of severe rotavirus, according to case definition, from 2 weeks after the second dose was administered until 1 year of age. 35 The secondary end points were efficacy against severe rotavirus gastroenteritis defined according to the Vesikari scale, efficacy against gastroenteritis associated with specific circulating rotavirus types, and efficacy against severe rotavirus gastroenteritis after the first dose of vaccine. Other efficacy end points included the prevention of hospitalization due to rotavirus gastroenteritis, hospitalization for any reason, and severe gastroenteritis from any cause. Within the efficacy subset of the HRV study, 12 of 9,009 vaccine recipients experienced severe gastroenteritis compared with 77 of 8,858 placebo recipients. The HRV vaccine demonstrated efficacy of 84.7% (95% CI, 71.7, 92.4; P<0.001) against severe rotavirus gastroenteritis. 35 The HRV vaccine was strongly efficacious against the predominant G1 serotype (91% efficacy; 95% CI, 74.1, 98.4), and it demonstrated efficacy against the G3, G4, and G9 serotypes (87.3% efficacy; 95% CI, 64.1, 96.7 for all serotypes combined). However, HRV does not share neutralizing ROTAVIRUS IN THE MODERN AGE 9

10 epitopes with the G2 rotavirus serotype and did not prove efficacious against this strain of rotavirus (41.0% efficacy; 95% CI, <0.0, 82.4). 35 Nine of 9,009 patients who received the rotavirus vaccine required hospitalization due to gastroenteritis, compared with 59 of 8,858 patients who received placebo. The HRV vaccine was 85% (95% CI, 69.6, 93.5; P<0.001) effective at preventing hospitalizations due to rotavirus. 35 Comparison of Rotavirus Vaccines Unlike RRV-TV, neither PRV nor HRV were associated with an increased occurrence of intussusception. 34,35 A recent study of RRV-TV could not establish a definitive pathogenic mechanism for the association between RRV-TV and intussusception in the first 2 weeks after vaccine administration. 38 However, another recent case control analysis of vaccine-related events within the CDC database for RRV-TV found that the incidence of intussusception associated with the first dose of vaccine increased with the patient s age. 39 Although the first dose of RRV-TV was to be given at 2 months of age, many older infants received the vaccine as catch-up. Dr Simonsen and colleagues found that infants at least 90 days old accounted for 80% of cases of intussusception associated with the first dose of RRV-TV, even though they received only 38% of first doses. The relative risk of RRV-TV associated intussusception within 21 days after first dose was: patients aged 1 to 2 months, 5.7 (95% CI, 1.2, 28.3); aged 3 to 4 months, 10.5 (95% CI, 4.0, 27.4); aged 5 to 11 months, 15.9 (95% CI, 4.6, 54.2). 39 Although RRV-TV and PRV are both human-animal attenuated strains, they are very different vaccines. RRV-TV was a simian-based tetravalent vaccine, whereas PRV is a bovine-based pentavalent vaccine. Furthermore, RRV-TV and PRV behave differently within the human host. The simian-based rotavirus strain used to create RRV-TV was reactogenic and caused low-grade fever in a substantial number of vaccine recipients. 31 PRV has been associated with little to no reactogenicity. 31 Most infants vaccinated with RRV-TV shed live vaccine in their feces, 10 ROTAVIRUS IN THE MODERN AGE but less than 10% of vaccinated infants shed PRV in their feces; when shedding does occur with PRV, it is in much lower quantities than with RRV-TV. 40 Another theory is that viral replication of RRV-TV may have been related to intussusception, which occurred within 3 to 7 days after vaccination with RRV-TV and corresponded with a peak in viral replication. 40 However, another difference between RRV-TV and PRV is their ability to grow within the body. 40 RRV-TV proved mildly contagious and replicates better in the human intestine, causing more severe side effects, whereas PRV is not contagious and does not replicate well in the human intestine. 40,41 HRV is a human attenuated strain and differs from RRV-TV and PRV in that it is not animal based. HRV and PRV are both produced in Vero cells and administered to infants at 2 and 4 months of age (with a third dose of PRV given at 6 months). 31 Both vaccines are also immunogenic, but their immunogenicity has not been directly compared. 31 HRV recently underwent a large safety trial as described above. Both the PRV and HRV phase III studies monitored patients for extended periods, the PRV study for 1 year from vaccination (through the first rotavirus season) and the HRV study from the first vaccination through 1 year of age. In these PRV and HRV studies, the incidence of intussusception was extremely low, not statistically different from the incidence in placebo recipients, and not clustered in the initial 1 to 2 weeks after administration, when vaccine-related intussusception was seen with RRV-TV. Researchers in both the PRV and HRV studies concluded that intussusception was not associated with these newer vaccines. 34,35 Overall, both PRV and HRV were very efficacious. PRV demonstrated 98% efficacy against severe rotavirus gastroenteritis and 74% efficacy against rotavirus gastroenteritis of all severities (mild, moderate, severe); HRV demonstrated slightly less efficacy, 84.7%, against severe gastroenteritis but was also deemed very efficacious. 34,35 Both vaccines significantly reduced hospitalizations associated with rotavirus gastroenteritis, and PRV also significantly reduced physician office visits and emergency room visits associated with rotavirus gastroenteritis (data on these end points for HRV were not provided). 34,35 Both PRV and HRV demonstrated strong efficacy against the predominant G1 rotavirus serotype. 34,35 PRV also demonstrated strong efficacy against the G2 rotavirus serotype, which is the globally predominant serotype 11% of the time. 20,34 Because HRV does not share neutralizing epitopes with the G2 rotavirus serotypes, it was not efficacious against this strain of rotavirus. 35 PRV also trended toward efficacy against the G3, G4, and G9 serotypes, but efficacy could not be confirmed because of low patient numbers; HRV demonstrated efficacy against these serotypes. 34,35 In large, phase III clinical trials both PRV and HRV proved safe and effective at reducing the occurrence of severe rotavirus gastroenteritis. PRV is licensed in numerous countries including the United States, whereas HRV is licensed in numerous countries excluding the United States but including the European Union. CONCLUSIONS Rotavirus infects almost every child at least one time during the first 5 years of life. In the United States and developed world, rotavirus poses a tremendous economic burden in terms of physician visits, emergency room visits, and hospitalizations as well as lost earnings by caregivers and other financial burdens. 9,26 In the developing world, rotavirus is responsible for 611,000 deaths per year. 11 Because rotavirus infection is difficult to prevent but does confer some natural immunity after the first infection, prevention of severe rotavirus gastroenteritis represents a solution to the global burden of rotavirus illness. Two vaccines, PRV and HRV, have both demonstrated efficacy in preventing severe rotavirus gastroenteritis while demonstrating safety in terms of the occurrence of serious adverse events, particularly intussusception. 34,35 In addition, the CDC s ACIP has universally recommended that rotavirus be added to the routine vaccination schedule for US children. Administration of rotavirus vaccine to infants of appropriate age may greatly reduce the morbidity, mortality, and economic burden associated with rotavirus.

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