Rotavirus: Prevention and Vaccination Strategies to Address Burden of Disease

Introduction The Epidemiology of Rotavirus Infection Is Changing Gary S. Marshall, MD Epidemiology and Disease Burden of Rotavirus Mary Allen Staat, MD, MPH Immune Response to Rotavirus David O. Matson, MD, PhD Rotavirus Vaccines: Safety, Efficacy, and Recommendations Penelope Dennehy, MD ICAAC Updates from the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy

Introduction

Rotavirus is one of the most common causes of acute gastroenteritis in young children, particularly in their first year of life, and it is more severe than other forms of viral gastroenteritis. Rotavirus gastroenteritis is also a common cause of pediatric outpatient visits and infant hospitalizations, rivaled only by respiratory syncytial virus (RSV).

Vindico Medical Education convened a panel of pediatric infectious disease experts to discuss the epidemiology of rotavirus disease; national and global disease burdens; the immune response to rotavirus infection; and the safety and efficacy of available rotavirus vaccines and recommendations for their use in infants.

I would like to thank the panel for their contributions to the discussion and to the development of this monograph, which provides a succinct overview of the salient aspects of rotavirus infection, disease, and prevention.

Gary S. Marshall, MD
Course Chair

Gary S. Marshall, MD Professor of Pediatrics Chief, Division of Pediatric Infectious Diseases Director, Pediatric Clinical Trials Unit University of Louisville School of Medicine Louisville, KY Mary Allen Staat, MD, MPH Director, International Adoption Center Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center Professor of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH David O. Matson, MD, PhD Professor of Health Professions and Pediatrics Director, Graduate Program in Public Health Eastern Virginia Medical School and Old Dominion University Norfolk, VA Penelope Dennehy, MD Director, Pediatric Infectious Diseases, Hasbro Children’s Hospital Professor of Pediatrics, The Warren Alpert Medical School of Brown University Providence, RI

The Epidemiology of Rotavirus Infection Is Changing

Gary S. Marshall, MD

Rotavirus was first described as a cause of infantile diarrhea in the early 1970s, when it was found by electron microscopy in intestinal biopsy specimens. The virus particle looks like a wheel with spokes (“rota” means wheel in Latin). Rotavirus is categorized along with caliciviruses and shigella as enteric pathogens with a very high propensity for human-to-human transmission. One factor that facilitates spread is the high rotavirus concentration in diarrheal stool, up to 100 billion particles per milliliter of stool. Since the infectious dose is 10,000 particles, it stands that one ten-millionth of a milliliter of stool is enough to transmit infection!^1-4

Rotavirus infection is most common in the first year of life, but it can be seen even into the second and third years of life. Disease is most severe in infants younger than one year of age. The first thing that occurs after rotavirus infection is fecal shedding (Figure 1). This also helps to explain the high level of contagion—the virus can be spread among family members and fellow day care attendees even before symptoms are apparent (infants with diarrhea are efficient stool-sharers). Fever and vomiting are usually the first symptoms, followed quickly by diarrhea. Oftentimes the vomiting is a rate-limiting factor in attempts to provide oral rehydration. When hospitalization for dehydration does occur, it is usually 2 to 6 days into the illness, and intravenous fluid therapy is necessary. Rarely, the dehydration is so severe it leads to acidosis and shock.

Figure 1. Timeline of Rotavirus Pathogenesis Before symptoms of rotavirus infection appear, fecal shedding occurs. Fever and vomiting precede diarrhea, and hospitalization for dehydration usually occurs between days 2 and 6 after infection.

The virus causes diarrhea by three principle mechanisms: (1) infection of villus epithelial cells causes cell destruction, decreased absorption of salt and water, and decreased disaccharidase activity, increasing the osmotic load in the gut lumen; (2) stimulation of the enteric nervous system, leading to increased fluid secretion; and (3) direct enterotoxin effects of nonstructural protein 4 (NSP4), the first viral enterotoxin to be described. The osmotic load in the gut and increased fluid secretion lead to diarrhea and, if unchecked and without fluid replacement, can ultimately lead to dehydration and acidosis.

Rotavirus Vaccination Program

Rotavirus gastroenteritis is now vaccine preventable, and ecological data from the National Respiratory and Enteric Virus Surveillance System suggest that the 2-year-old rotavirus immunization program is already having an impact on the epidemiology of the disease. On average, for the 15 years between 1991 an 2006, the United States rotavirus season peaked around Week 8 (end of February) through 13 (end of March), and during peak season, about 40% of stool specimens have tested positive for rotavirus (Figure 2). After the start of the rotavirus vaccination program, three changes were noted in the 2007–2008 season: onset of the season was delayed, peak activity was much less intense (fewer stool tests positive for rotavirus), and the season was broader and splayed out over time.⁵

Figure 2. Effect of Vaccination Program on Epidemiology Compared to the 15 years before vaccine implementation, the 2007-2008 season was delayed and peak rotavirus activity was less intense. Source: CDC. MMWR. 2008; 57:697-700.

References

1. Musher DM, Musher BL. N Engl J Med. 2004;351:2417-2427.
2. Lloyd-Evans N, Springthorpe VS, Sattar SA. J Hyg. 1986;97:163-173.
3. Ward RL, Bernstein DI, Knowlton DR, et al. J Clin Microbiol. 1991;29:1991-1996.
4. Pickering PK, Bartlett AV, Reves RR, Morrow A. J Pediatr. 1988;112:361-365.
5. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2008;57: 697-700.

Epidemiology and Disease Burden of Rotavirus

Mary Allen Staat, MD, MPH

Human rotavirus is one of a large set of viruses that causes diarrhea, not only in humans but also in animals and birds. In 1973, rotavirus was first detected in humans in duodenal biopsies from children in Australia with acute diarrhea. Since then, rotavirus has been found to be the major cause of acute gastroenteritis in young children. Estimates in the United States show that while deaths due to rotavirus are rare, there is significant disease burden wth 55,000 to 70,000 hospitalizations, 200,000 to 300,000 emergency department (ED) visits, 410,000 outpatient visits, and approximately 2.7 million episodes of acute gastroenteritis episodes in children younger than five years of age.¹

Nearly every child has had at least one rotavirus infection by 5 years of age. Rotavirus is transmitted via the fecal-oral route and the peak incidence of severe infection is between 3 and 24 months of age.² Rotavirus also has a distinct seasonality with peaks in the winter months in temperate climates. Less seasonality occurs closer to the equator. In the United States, rotavirus season peaks in November in the Southwest and from April to May in the Northeast.

Symptoms of Rotavirus Infection

Clinically, children typically present with diarrhea, vomiting, and fever. In a study by Staat and colleagues, symptoms of children hospitalized with rotavirus were examined. A total of 63% of patients reported all three symptoms of diarrhea, vomiting, and fever, however, some children presented only with fever, vomiting, or diarrhea.³ In a study examining risk factors for hospitalization, researchers found that the highest risk for hospitalization was in children who were low birth weight, children who were not breast-fed, children in childcare, or children with a younger child in the household. Targeting only these specific high-risk groups for immunization would not be feasible, thus necessitating a universal rotavirus vaccine recommendation for all infants.⁴

Diagnosis of Rotavirus Infection

The diagnosis of rotavirus infection is often based on clinical and epidemiologic data such as clinical symptoms (vomiting and diarrhea), young age of the child, and the local epidemiology of rotavirus in the community. Testing is generally not needed, since testing does not change management. Often, testing is performed clinically if the child is immunocompromised or if they are older than the typical patient. There are rapid diagnostic tests for rotavirus that are widely available, such as the enzyme immunoassays and a latex agglutination test. Other tests such as electron microscopy, culture, and reverse transcription polymerase chain reaction (RT-PCR) are more expensive and not readiliy available. Rotavirus is not easily cultured, while RT-PCR, which is likely to identify children with asymptomatic infection, is becoming more available.⁵

Burden of Rotavirus

A recent study by Widdowson and colleagues examined the mean medical (Table 1) and non-medical (Table 2) costs of a vaccination program in a hypothetical cohort of 4 million children younger than 59 months old.¹ The highest medical expense was for a 2-day hospitalization, which was estimated to cost $3,496 per person. ED visits and outpatient visits were estimated to cost $500 and $400 per person, respectively. With a rotavirus vaccination program, there was an estimated 51% overall reduction of medical costs. Cost reductions for outpatient visits, ED visits, and hospitalizations were =60%, and there was a 44% reduction in medical costs related to preventing deaths.

Table 1. Medical Costs With and Without a Rotavirus Vaccination Program Source: Widdowson, MA et al. Pediatrics. 2007;119:684-697.

Table 2. Non-Medical Costs With and Without a Rotavirus Vaccination Program Source: Widdowson, MA et al. Pediatrics. 2007;119:684-697.

Non-medical costs were predominantly associated with lost earnings by parents or caregivers and were estimated to be $118 per day. A rotavirus vaccination program was associated with a reduction in non-medical costs of more than 50%.

Serotype Prevalence

Knowing the prevalence of rotavirus serotypes is important for vaccine development. The majority of rotavirus serotypes in the United States from 1979 through 1999 have been G1 through G4; G1 has been the most prevalent (Figure 3). However, the predominant G serotype may vary by year and by region in the United States. Thus, it is possible that the changing serotypes can affect not only small areas and groups, but also large regions and populations.^6,7

Figure 3. Serotype Prevalence in the United States The G serotype prevalence varies by year. However, between 1979 and 1999 the predominant G serotype has been G1. Source: Matson, DO et al. J. Infect Dis. 1990; 162:605-614.

References

1. Widdowson MA, Meltzer MI, Zhang X, et al. Pediatrics. 2007;119:684-697.
2. Charles MD, Holman RC, Curns AT, et al. Pediatr Infect Dis J. 2006; 25:489-493.
3. Staat MA, Azimi PH, Berke T, et al. Pediatr Infect Dis J. 2002;21:221-227.
4. Dennehy PH, Cortese MM, Begue RE, et al. Pediatr Infect Dis J. 2006; 25:1123-1131.
5. Stockman LJ, Staat MA, Holloway M, et al. J Clin Microbiol. 2008; 1842-1843.
6. Matson DO, Estes MK, Burns JW, et al. J Infect Dis. 1990;162:605-614.
7. Griffin DD, Kirkwood CD, Parashar UD, et al. J Clin Microbiol. 2000;38:2784-2787.

Immune Response to Rotavirus

David O. Matson, MD, PhD

Two licensed rotavirus vaccines with different compositions are currently available: one is a pentavalent, live human bovine rotavirus reassortant, and the other is a single native virion from a human isolate attenuated by serial passages in cell culture.

Rotavirus Serotypes

Rotavirus is one of only three viral pathogens in humans that has a segmented genome. The other two are influenza and Colorado tick fever. VP4 and VP7 are expressed on the surface of the virus (Figure 4). Multiple types of VP4 and of VP7 exist; they are classified as neutralization antigens, meaning antibody to either can block infectivity. VP4 is called a P serotype protein because it is protease-sentitive, and VP7 is a G serotype protein because it is a glycoprotein. VP4 is a hemagglutinin that extends above the surface and is thought to have a crucial influence on host susceptability. VP7 contains holes important for rotavirus replication (Figure 4). Two rotaviruses with different protein complement can infect the same cell and create new combinations of the surface proteins.

Figure 4. Rotavirus Structure VP4 and VP7 are the two neutralization antigens expressed on the surface of rotavirus. VP4 is a protease-sensitive protein and determines P serotype; VP7 is a glycoprotein and determines G serotype. Source: Estes, MK. J Infect Dis.1996;174:S37-S46.

Wyatt and colleagues described the existence of the G serotype; G1 has been the most prevalent in the United States.¹ However, the prevalence of the G serotypes varies dramatically by region. For example, in 2006, 99% of the hospitalizations in northern Portugal from rotavirus infections were due to the G9 serotype. In Texas, at a single hospital over many years, the number of hospitalizations for gastroenteritis correlated with rotavirus infection (Figure 5). The most common serotype was G1; however, G3 was the most prevelant in 1981, 1982, and 1987, and G4 was most prevalent in 1985. The total number of hospitalizations from G4 was never as high as the number of hospitalizations from G1 and G3, which led many to believe that G4 was less virulent. Assays for serotype have shown fewer differences among P serotypes than among G serotypes. This, in addition to the presence of epitopes on VP7 and VP4 shared across the serotypes, has led to a blurring of the distinction between serotypes. Thus, a monovalent vaccine can be an effective strategy, even when multiple serotypes are in the community.²

Figure 5. Hospitalizations per Week in Houston, 1979-1989 The number of hospitalizations for gastroenteritis correlates with rotavirus infection, and the predominant serotype differs by year. Source: Matson, DO et al. J Infect Dis 1990;162-605.

Figure 6. Probability of Rotavirus Infection by Age In a cohort of Mexican children, nearly every child had a rotavirus infection by the age of 2 years. Rotavirus vaccination mimics the protection rates of one natural infection. Source: Velazquez, FR, Matson, DO et al. N Engl J Med. 1996;335:1022-1028.

By the age of 2 years, nearly every child in a cohort of children in Mexico had experienced at least one rotavirus infection (Figure 6). These children had greater protection against severe diarrhea with subsequent infections. Two natural infections were required for 100% protection against moderate-to-severe diarrhea. The first exposure to rotavirus also protected 87% (95% CI, 54%, 96%) of children from having severe disease from the second infection (Figure 6, inset). The protection rates observed with one natural infection are similar to those observed with vaccine-induced protection. Vaccination protects 84% to 98% of children againt severe outcomes of a second rotavirus infection. Thus, the vaccines are mimicking the protection rates of one natural infection.³

Protection against first rotavirus gastroenteritis seemed to be serotype-specific and related to levels of antibody against homotypic virus. A serum titre of >800 immunoglobulin A (IgA) was the best titre for predicting protection against infection; the IgA titre continued to rise with subsequent infections. Seroconversions or concomitant antibody responses to type 1 or type 4 rotavirus in most children with type 3 rotavirus infection suggest that immunity to heterotypic virus can be induced by a rotavirus vaccine, which is important because the available vaccines are of different composition.⁴

References

1. Wyatt RG, Kapikian AZ, Mebus CA. J Clin Microbiol. 1983;18:505-508.
2. Wyatt RG, James HD, Jr., Pittman AL, et al. J Clin Microbiol. 1983;18:310-317.
3. Velázquez FR, Matson DO, Calva JJ, et al. N Engl J Med. 1996;335:1022-1028.
4. Chiba S, Yokoyama T, Nakata S, et al. Lancet. 1986;2:417-421.

Rotavirus Vaccines: Safety, Efficacy, and Recommendations

Penelope Dennehy, MD

The primary goal for rotavirus vaccine was not to prevent the disease in a paradigm similar to measles or polio, but to prevent the health outcomes that cause children the most difficulties—the moderate-to-severe disease, doctor visits, ED visits, and hospitalizations. A secondary goal was to develop a vaccine that could be used in the developing world, where mortality with rotavirus is high.

Vaccine Development

Two processes were utilized for rotavirus vaccine development. The traditional approach was to use an attenuated human strain, which is the approach that had been used for polio and other vaccines. The novel approach was to use the segmented genome of rotavirus and explore the multivalent human-animal reassortant approach. With this approach the goal was to express the most important human genes in an animal rotavirus, and produce large-scale vaccine candidates in cell culture.

The first vaccine using this novel approach was approved in 1998 and was a simian-human reassortant vaccine known as RotaShield. However, the vaccine was withdrawn from the market in 1999 after several reports of intussusception that occurred in the 14 days after the first dose of the vaccine.¹

Licensed Rotavirus Vaccines

Currently two vaccines are licensed in the United eStates. One is a pentavalent reassortant vaccine (RV5) that was approved by the FDA in 2006, and the other is a monovalent vaccine (RV1) that was approved in 2008.

RV5 is administered as three oral doses at 2, 4, and 6 months of age. The minimum age for administration is 6 weeks and the maximum age for completing the series is 32 weeks.

The RV1 vaccine is given as two oral doses; the first dose should be given between 6 and 14 weeks of age, and the second dose between 14 and 24 weeks of age. The interval between the two doses should not be less than 4 weeks, and the course should be completed before 24 weeks, as safety has not been assessed in older children.

The tight administration window for rotavirus vaccination is based on clinical trial data that evaluated the incidence of intussusception before the age at which the risk of idiopathic intussusception rises sharply. This has led to difficulty in determining safety and efficacy in administering the first dose to older children.

RV5

The RV5 vaccine contains five reassortant viruses developed from human and bovine parent rotavirus strains and shares neutralizing identity with G1, G2, G3, G4, and P[8], the same P serotype as many of the G9 strains observed in the US. Phase 3 trials included more than 70,000 infants in 11 countries.² The vaccine demonstrated 74% overall efficacy and 98% efficacy for severe rotavirus disease. In a cohort of infants for which data from clinic and ED visits were collected, there was an 86% reduction in the need for a physician visit for diarrhea and a 96% reduction in hospitalization.² RV5 was effective against all the G serotypes tested (Table 3).

Table 3. Serotype-specific Efficacy of RV5 Against Rotavirus Disease of Any Severity Source: Vesikari T, Matson DO, Dennehy P, et al. N Engl J Med. 2006;354:23–33.

Viral shedding of the RV5 vaccine was examined by enzyme immunoassay (EIA) and confirmed by RT-PCR in a randomized placebo-controlled study of 439 healthy infants.³ Approximately 4% of the infants were found to shed virus in the feces 3 to 5 days after the first dose, and about 7% had viral shedding at any time after the first dose. Intussusception associated with RV5 vaccine also was reviewed. Six cases occurred in the vaccine arm and five in the placebo arm, without clustering after the first dose (Figure 7).⁴

Figure 7. Intussusception Cases with RV5 RV5 was not associated with an increased risk of intussusception. Source: Vesikari, T, Matson, DO, Dennehy, P et al. N Engl J Med. 2006;354:23-33.

Approximately 14.3 million doses of RV5 vaccine were distributed between February 1, 2006 and March 31, 2008. According to the Vaccine Adverse Event Reporting System (VAERS), 267 confirmed intussusception cases have been reported during that period. Ninety-one cases occurred within 21 days of vaccination, and 48 of these were within 7 days of vaccination. This rate was not greater than expected. In addition to the VAERS, two other systems examined intussusception postlicensure. The Vaccine Safety Datalink (VSD) Cohort contains data from a number of HMOs that represent about one-fifth of the US population, and can actively look for intussusception vs the passive reporting found in VAERS. The VSD reviewed the data from more than 300,000 vaccinations that were administered between February 1, 2006 and September 25, 2007; no cases of intussusception occurred within 7 days of vaccination, 3 cases occurred within 30 days of RV5 vaccination (n=111,521) compared with 6 cases after non-RV5 cases (n=186,722). These data indicate that RV5 is not associated intussusception.⁵

RV1

RV1, the live-attenuated human rotavirus vaccine, was approved by the FDA in 2008 and contains one strain of live-attenuated human rotavirus, a G1 P[8] strain. RV1 shares neutralizing identity with G1, G3, G4, and G9 through the P[8] VP4 protein. RV1 does not share neutralizing identity with G2 P[4] strains, and a major concern with the RV1 strain is efficacy against G2 P[4] strains.

Phase 3 trials in more than 67,000 infants in Latin America and Finland investigated the efficacy and safety of RV1.^6,7 The trial in Finland, which also examined severe rotavirus disease, demonstrated 90% efficacy against rotavirus-related hospitalizations and 90% efficacy against any rotavirus disease after one dose of vaccine.

Ruiz-Palacios and colleagues reported that the R1 vaccine was 92% effective against disease caused by the G1 strain. Efficacy was 41% against disease caused by G2, but with a wide confidence interval and relatively few cases. Efficacy against G3, G4, or G9 combined was 87%.⁶

The European study of RV1 primarily from Finland reported 90% efficacy against infections caused by the G1 strain and 58% to 85% against the G2, G3, G4, and G9 strains (Table 4).⁷

Table 4. Serotype-specific Efficacy of RV1 Against Rotavirus Disease of Any Severity Source: Vesikari, T Lancet. 2007 Nov 24;370(9601):1757-1763.

An examination of intussusception cases with RV1 demonstrated only one case within the first 10 days after the second dose, suggesting that intussusception was not associated with RV1 (Figure 8). Adverse events included more cases of pneumonia in the vaccine group compared with the placebo group. Intussusception and pneumonia are being monitored in postlicensure surveillance.

The costs of a full series of the two current rotavirus vaccines are similar. The Advisory Committee on Immunization Practices (ACIP) working group has not expressed a preference for either RV5 or RV1 vaccine. The ACIP recommends that when a vaccination series is intiated, efforts should be made to complete the series with the same vaccine. However, substitution of the vaccine is indicated if the same vaccine is not available for subsequent doses. If RV5 is part of the series three doses of vaccine should be given. These recommendations were made to provide a rational approach that would allow practitioners to complete the vaccination course. Contraindications include avoiding the RV1 vaccine if the patient has a known latex allergy; the oral applicator on the RV1 oral vaccine contains latex, whereas the RV5 applicator is latex-free.

Figure 8. Intussusception Cases with RV1 Intussusception was not associated with RV1. Source: Vesikari, T, Matson, DO, Dennehy, P et al. N Engl J Med. 2006;354:23-33.

References

1. Murphy TV, Gargiullo PM, Massoudi MS, et al. N Engl J Med. 2001;344:564-572.
2. Vesikari T, Clark HF, Offit PA, et al. Vaccine. 2006;24:4821-4829.
3. Clark HF, Bernstein DI, Dennehy PH, et al. J Pediatr. 2004;144:184-190.
4. Vesikari T, Matson DO, Dennehy PH, et al. N Engl J Med. 2006;354:23-33.
5. Haber P, Patel M, Izurieta HS, et al. Pediatrics. 2008;121:1206-1212.
6. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. N Engl J Med. 2006;354:11-22.
7. Vesikari T, Karvonen A, Prymula R, et al. Lancet. 2007;370:1757-1763.

ICAAC 2008: Updates from the 48^th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy

Postlicensure Surveillance of Rotavirus Vaccine Uptake

Postlicensure data on the uptake of RV5, which was approved in February 2006, was examined at this meeting. Dr. Umesh Parashar presented an analysis of data from 6 sentinel immunization information systems (IIS) to examine vaccine uptake. It was observed that by late 2007, more than 10 million doses of rotavirus vaccine were distributed in the United States; 50% to 67% of infants 3 months of age had received at least 1 vaccine dose; 27% to 45% of infants 7 months of age received the full vaccine series; and as many as one-third (18% to 32%) of 13-month-old infants received the full 3-dose vaccine series.¹

Postlicensure Surveillance of Rotavirus Vaccine Impact

The impact of RV5 is being monitored using data on diarrhea and rotavirus hospitalizations and emergency department (ED) visits from national and state databases, as well as reports of rotavirus from a national network of sentinel laboratories. By March 2008, onset of rotavirus activity had been delayed by 2 to 3 months across the country. Sentinel laboratories reported a 60% to 70% decline in rotavirus compared with data from the same months in the 7 to 8 years prior to implementation of the vaccine program.¹

Dr. Julie Boom presented data on an analysis of immunization records of children admitted to the Texas Children’s Hospital Emergency Room for acute gastroenteritis, from which it was found that the age-adjusted vaccine effectiveness for a complete 3-dose RV5 series was 85% to 89%.² The vaccine effectiveness for partial immunization was lower but still significant.² In another study that analyzed data from the Quest Diagnostics Informatics Data Warehouse, Dr. Jay Lieberman and colleagues found that of 21,330 tests for rotavirus in the 3 years before vaccine licensure, 29.5% were positive, whereas in the most recent peak season, 7% of 15,754 tests were positive, suggesting that the vaccination program is effective.³

Dr. T. Christopher Mast and colleagues examined a large US health insurance claims database that revealed that RV5 vaccination was effective in preventing claims-based rotavirus-specific gastroenteritis and all-cause gastroenteritis resulting in fewer physician visits, ED visits, and hospitalizations compared to non-immunized children.⁴

Dr. Janak Patel presented data from a retrospective analysis of a small trial on the community-based impact of RV5 vaccination on severe rotavirus infection. Results demonstrated a significant reduction in laboratory-confirmed cases of severe rotavirus gastroenteritis, presenting to the ED or clinical care setting, and an even greater reduction in wider scale infection.⁵ A decline in hospitalizations for rotavirus gastroenteritis was also observed at the Children’s Hospital of Philadelphia and Children’s Mercy Hospital in Kansas City, MO, as reported by Drs. H. Fred Clark and Christopher Harrison, respectively.^6,7

In an analysis of rotavirus hospitalizations at St. Christopher’s hospital in Philadelphia, Dr. Irini Daskalaki and colleagues found that after 1 year of implementation of RV5, there was a substantial decrease in rotavirus hospitalizations across all age groups. Moreover, before implementation of RV5 the rotavirus outbreak occurred from February through May in 2005 and 2006. However, the outbreak in 2007 occurred only in March, and only in May in 2008. These results suggest that immunization with RV5 causes a blunting of seasonality of rotavirus.⁸

Postlicensure Safety Monitoring

The postlicensure safety monitoring of RV5 was also examined at this meeting. RotaShield, the first rotavirus vaccine approved in 1998, was withdrawn from the market in 1999 due to several cases of intussusception that were reported to occur in the 14 days after the first dose of the vaccine.⁹ It is therefore necessary to monitor RV1 and RV5 for cases of intussusception as well as other adverse events. Importantly, Dr. Margaret Cortese presented data demonstrating the importance of improving background estimates of intussusception rates in order to properly monitor safety of the rotavirus vaccines. Background estimates previously have been based on cases only in inpatient discharge databases, and it was observed that this method of estimation, which did not include short-stay or ED visits, underestimated the true incidence of intussusceptions by about 50%.¹⁰

Dr. Stephanie Irving and colleagues analyzed RV5 vaccine safety in the Vaccine Safety Datalink population. Adverse events following RV5 receipt were identified based on ICD-9 diagnosis codes occurring in inpatient, outpatient, and ED files. The investigators found no evidence that RV5 is associated with an increased risk of intussusception or other pre-specified adverse events.¹¹

Rotavirus in Immunocomprimised Patients

Rotavirus antigenemia in immunocompromised patients had not been reported to date at the ICAAC/IDSA meeting. Dr. Niraj Patel presented a case of a patient with X-linked severe combined immunodeficiency in which 2 oral doses of RV5 were not effective. Subsequent hematopoietic stem cell transplantation (HSCT) resulted in clearance of the infection.¹² These observations suggest that HSCT may be an effective treatment strategy for severely immunocompromised patients who are nonresponsive to rotavirus vaccination.

Dr. Ken Sugata presented findings on rotavirus antigenemia in hematopoietic stem cells of 68 HSCT patients. He showed that rotavirus antigen was fdetected in 10 patients, 9 of whom had persistent antigenemia. Some patients with persistent antigenemia manifested clinical symptoms.¹³ These observations led to the conclusion that the period of rotavirus antigenemia for HSCT recipients is longer than that of immunocompetent people.

Conclusion

Overall, at the annual ICAAC/IDSA meeting, much of the rotavirus data focused on postlicensure surveillance and the impact of the two rotavirus vaccines, most notably RV5, as it has been available longer than RV1, which was approved for use in 2008. Data from several resources suggest that RV5 results in fewer hospitalizations and a lower incidence of gastroenteritis in infant populations. Moreover, no serious adverse events, including intussusception, have been significantly associated with RV5. Results from clinical trials suggest that RV1 is also effective and not associated with a risk of intussusception.^14,15 The rotavirus vaccination program may have caused a delay in the onset and severity of the 2007 and 2008 rotavirus seasons. Thus, implementation of the rotavirus vaccination program shows great potential for reducing the health and financial burden caused by rotavirus infection. Further postlicensure monitoring of RV1 and RV5 is required in order to fully assess the effectiveness and safety of these vaccines.

References

1. Parashar U, Panozzo C, Bartlett D, et al. ICAAC/IDSA 2008; Abstract G2-3748.
2. Boom J, Tate J, Sahni L, et al. ICAAC/IDSA 2008; Abstract G2-3748a.
3. Lieberman JM, Huang X, Koski E, et al. ICAAC/IDSA 2008; Abstract G1-437.
4. Mast T, Wang F, Goli V, et al. ICAAC/IDSA 2008; Abstract G1-433.
5. Patel JA, Loeffelholz M. ICAAC/IDSA 2008; Abstract G1-434.
6. Clark HF, Lawley D, Mallette L, et al. ICAAC/IDSA 2008; Abstract G1-438.
7. Harrison CJ, Jackson M, Olson-Burgess C, et al. ICAAC/IDSA 2008; Abstract G1-435.
8. Daskalaki I, Wood SJ, Inumerable YM, et al. ICAAC/IDSA 2008; Abstract G1-432.
9. Murphy TV, Gargiullo PM, Massoudi MS, et al. N Engl J Med. 2001; 344:564-572.
10. Cortese M, Staat M, Weinberg G, et al. ICAAC/IDSA 2008; Abstract G2-3746.
11. Irving SA, Shui M, Kulldorff M, et al. ICAAC/IDSA 2008; Abstract G1-439.
12. Patel NC, Hertel PM, Hanson IC, et al. ICAAC/IDSA 2008; Abstract G1-442.
13. Sugata K, Asano Y, Yoshikawa K, et al. ICAAC/IDSA 2008; Abstract V-3776.
14. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. N Engl J Med. 2006;354:11-22.
15. Vesikari T, Karvonen A, Prymula R, et al. Lancet. 2007;370:1757-1763.