Pentavalent Human-bovine Reassortant Rotavirus Vaccine Research Articles

Risk of Rotavirus Nosocomial Spread After Inpatient Pentavalent Rotavirus Vaccination.

Infants born prematurely or with underlying conditions are at increased risk of severe rotavirus disease and associated complications. Given the theoretical risk of nosocomial transmission of vaccine-type rotavirus, rotavirus vaccination is recommended for infants at or after discharge from neonatal care settings. Because the first dose should be administered by 104 days of age, some infants may be age-ineligible for vaccination if delayed until discharge. This prospective cohort included infants admitted to an urban academic medical center between birth and 104 days who received care in intensive care settings. Pentavalent human-bovine reassortant rotavirus vaccine (RV5) was used, per routine clinical care. Stool specimens were collected weekly (February 2013-April 2014) and analyzed for rotavirus strains using real-time reverse transcription-polymerase chain reaction. Demographic and vaccine data were collected. RV5 safety was not assessed. Of 385 study infants, 127 were age-eligible for routine vaccinations during hospitalization. At discharge, 32.7% were up-to-date for rotavirus vaccination, compared with 82.7% for other vaccinations. Of rotavirus-unvaccinated infants, 42.6% were discharged at age >104 days and thus vaccination-ineligible. Of 1192 stool specimens collected, rotavirus was detected in 13 (1.1%): 1 wild-type strain from an unvaccinated infant; 12 vaccine-type strains from 9 RV5-vaccinated infants. No vaccine-type rotavirus cases were observed among unvaccinated infants (incidence rate: 0.0 [95% confidence interval: 0.0-1.5] cases per 1000 patient days at risk). These data suggest that delaying rotavirus vaccination until discharge from the hospital could lead to missed vaccination opportunities and may be unnecessary in institutions using RV5 with comparable infection control standards.

Impact and Effectiveness of RotaTeq® Vaccine Based on 3 Years of Surveillance Following Introduction of a Rotavirus Immunization Program in Finland

Finland introduced universal rotavirus (RV) vaccination in September 2009, with exclusive use of the pentavalent human-bovine reassortant RV vaccine RotaTeq® and following a vaccination schedule at 2, 3 and 5 months of age. This study monitored the impact of RV vaccination on hospitalizations due to RV acute gastroenteritis (RVGE). The results following the first 3 RV seasons after implementation of universal RV vaccination are presented. Prospective hospital-based surveillance identified children with acute gastroenteritis admitted to 2 University Hospitals (Tampere and Oulu, Finland), from December 2009 to August 2012. The surveillance covered a population of approximately 173,000 children from the 2 hospitals' catchment areas. Stool samples were taken and analyzed centrally for RV by enzyme-linked immunosorbent assay, with genotyping by reverse transcription polymerase chain reaction. International Classification of Diseases discharge codes were collected retrospectively pre- and postvaccination. During the 3-year prospective surveillance, 127 RVGE episodes were identified. Of these, 117 were in unvaccinated children and 6 were in fully vaccinated children (RotaTeq, n = 3; Rotarix, n = 3). The vaccine effectiveness against hospitalized RVGE for fully vaccinated children was 92.1% [95% confidence interval (CI): 50.0-98.7] among children eligible for the National Immunization Program. When analyzing retrospectively the Tampere and Oulu hospital databases for all children aged <16 years, hospitalizations for RVGE had decreased by 78% in the postvaccination period (2009-2012) compared with the prevaccination data (2001-2006). Severe RVGE requiring hospitalization was virtually eliminated in vaccine-eligible children in the 3 years following implementation of universal RotaTeq vaccination in Finland.

Immunogenicity and safety of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine (PRV) in Indian infants

Objective: To evaluate the immunogenicity and safety of a pentavalent rotavirus vaccine (PRV) in Indian infants.Study Design:Open-label, single-arm multicentric study.Setting:Hospital facilities (out patients)Subjects:One hundred and ten (110) healthy Indian infants were enrolled between the ages of 6 weeks and 12 weeks.Intervention:Three doses of oral pentavalent rotavirus vaccine (PRV) were administered with an interval of 4 to 10 weeks (28 to 70 days).Main Outcome Measures:Immunogenicity of PRV was based on the proportion of infants exhibiting a >3-fold rise in serum anti rotavirus IgA antibodies (from pre dose 1 to 14 days post dose 3). Safety was evaluated for 14 days after each dose. Results:Of the 110 infants enrolled, 83% exhibited at least a 3-fold rise (seroconversion) in serum anti rotavirus IgA antibodies. There were no clinically significant adverse events reported.Conclusions:A 3-dose regimen of PRV was found to be immunogenic and well tolerated in healthy Indian infants.Clinical trials registration:ClinicalTrials.gov; NCT00496054

Efficacy of a Pentavalent Human-bovine Reassortant Rotavirus Vaccine Against Rotavirus Gastroenteritis Among American Indian Children

Before the widespread use of rotavirus vaccines, rotavirus was a leading cause of gastroenteritis among children. Navajo and White Mountain Apache children suffer a disproportionate burden of severe rotavirus disease compared with the general U.S. population. We enrolled Navajo and White Mountain Apache infants in a multicenter, double-blind, placebo-controlled trial of pentavalent human-bovine reassortant rotavirus vaccine (PRV). Subjects received 3 doses of vaccine or placebo at 4 to 10 week intervals, with the first dose given between 6 and 12 weeks of age. Gastroenteritis episodes were identified by active surveillance. Disease severity was determined by a standardized scoring system. There were 509 and 494 randomized children who received vaccine and placebo, respectively. Among placebo recipients, the incidence of rotavirus gastroenteritis was 34.2 episodes/100 child-years (95% confidence interval [95% CI]: 25.8-38.9) versus 8.1 episodes/100 child-years (95% CI: 5.4-12.5) in the vaccine group. The percentage of rotavirus episodes caused by serotypes G1, G2, and G3 was 72.3%, 23.4%, and 2.1%, respectively. There were no severe rotavirus episodes among vaccinees and 4 among placebo recipients. PRV was 77.1% (95% CI: 59.7-87.6), 89.5% (95% CI: 65.9-97.9), and 82.9% (95% CI: 61.1-93.6) effective against G1-G4 rotavirus disease, severe and moderate rotavirus disease combined, and outpatient visits for rotavirus disease, respectively. The risk of adverse events was similar for the vaccine and placebo groups. PRV was highly effective in preventing rotavirus disease and related health care utilization in these American Indian infants. Vaccine efficacy and immunogenicity were similar to the overall study population enrolled in the multicenter trial.

Lessons From the US Rotavirus Vaccination Program

EVERY WINTER, CHILDREN, PARENTS, AND CLINICIANS IN the United States have to deal with the annual seasonal outbreak of rotavirus, the most common cause of severe diarrhea in children worldwide. Before the implementation of routine vaccination against rotavirus in 2006, most US children had experienced an episode of rotavirus diarrhea by the age of 5 years, an estimated 400 000, or 1 child in 6, required outpatient treatment and about 55 000 to 70 000 children, or 1 in 50, were hospitalized. The health consequences of this annual event in the United States were unsettling and were estimated to cost more than $1 billion per year. When the first new rotavirus vaccine was licensed in 2006, uncertainty existed about whether parents would agree to have their infants immunized and whether clinicians would actively promote its use. Rotavirus vaccines had been severely stigmatized in 1999 when an earlier vaccine, tetravalent rhesus-human reassortant vaccine (RotaShield, Wyeth Laboratories) was abruptly removed from the market because of its link with intussusception, an uncommon form of intestinal obstruction. To assess whether the next generation of rotavirus vaccines harbored the same complication, the US Food and Drug Administration (FDA) required manufacturers to enroll and follow up more than 60 000 infants in clinical trials. Merck and GlaxoSmithKline set off cautiously to conduct multicenter trials of the pentavalent human-bovine WC3 reassortant rotavirus vaccine (RotaTeq, Merck & Co) and the RIX4144 strain human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals), ultimately recruiting more than 70 000 infants each, some of the largest and most costly licensure trials ever conducted. Neither vaccine was associated with intussusception in these trials. Over the past 4 years, uptake of the new vaccines has been remarkable. In the United States, the vaccines are expensive, about $200 for the series, but this hurdle of cost was addressed in part by Centers for Disease Control and Prevention’s (CDC’s) Vaccines for Children Program, a federally funded program that provides vaccines at no cost to those unable to pay. By 2010, nearly 60% of US children aged 19 to 35 months were immunized against rotavirus. Because rotavirus diarrhea affects children in the first 5 years of life, it may soon be possible to evaluate the full benefit of the vaccine. For the past decade, the CDC has monitored rotavirus activity in the United States from laboratories that document weekly the number of fecal specimens from children seeking care for diarrhea and the percentage of these specimens that test positive for rotavirus. In 2008, the effects of the rotavirus immunization program were first noted from this surveillance program when the number of rotavirus detections decreased by 64%; these declines have been sustained through 2010. Reports assessing discharge data from hospitals around the country noted that hospitalizations for acute gastroenteritis declined by 45% during the 2008 winter rotavirus season, averting approximately 50 000 hospitalizations nationwide. An unanticipated finding was that hospital admissions for diarrhea also declined among unvaccinated individuals aged 5 through 24 years, suggesting that the vaccine was having a herd effect, perhaps by preventing rotavirus transmission from a younger immunized cohort. More recently, a series of independent regional studies have documented excellent performance of the vaccine against rotavirus disease and documented an 85% to 90% reduction in hospital discharges and visits to emergency departments. Previously, diarrheal illnesses were reported on 10% to 12% of all hospital discharge records for children younger than 5 years, and surveillance indicated that rotavirus accounted for about 40% to 50% of these events. Consequently, an 85% to 90% reduction in this disease from vaccination should lead to a 4% to 6% reduction in total hospitalizations for children younger than 5 years with the commensurate savings in hospital and indirect costs. The introduction of rotavirus vaccines has not been without challenges. In 2010, the identification of porcine circovirus (PCV) in Rotarix led to a temporary suspension of this vaccine; PCV genetic material was also later identified in RotaTeq. More recently, both Rotarix and RotaTeq have been associated with a low-level but elevated risk of intussusception—about 5to 10-fold lower than that seen

Cost-effectiveness of a pentavalent human–bovine reassortant rotavirus vaccine for children ≤5 years of age in Taiwan

Objective:A Markov model was used to assess the impact of RV5, a pentavalent (G1, G2, G3, G4, P1A[8]) human bovine (WC3 strain) reassortant rotavirus vaccine, on reducing the healthcare burden and cost associated with rotavirus gastroenteritis (RGE) in Taiwan. Other cost-effectiveness analyses for rotavirus vaccination in industrialized countries have produced varying results depending on the input parameters assumed.Methods:Vaccination with RV5 is compared to no vaccination in a hypothetical cohort of Taiwanese children during their first 5 years of life to determine the per dose prices at which vaccination would be cost neutral or provide good value based on established standards from the healthcare (direct medical care costs only) and societal (all RGE-related costs) perspectives. The effects of vaccination on RGE healthcare utilization and days of parental work loss missed are based on results from the Rotavirus Efficacy and Safety Trial.Results:Without vaccination there would be 122,526 symptomatic episodes of RGE. Universal vaccination would reduce RGE-related deaths, hospitalizations, emergency department, and outpatient visits by 91.7%, 92.1%, 83.7%, and 73.4%, respectively. The price per dose at which vaccination would be cost-neutral is US$ 21.80 (688 NTD) and US$ 26.20 (827 NTD) from the healthcare and societal perspectives, respectively. At $25 per dose, the cost per QALY gained is US$ 2261 (71,335 NTD) from the healthcare perspective and cost saving from the societal perspective.Key limitations:The model only assesses the effect of RV5 on vaccinated children and does not account for herd immunity. However, given that high levels of coverage are anticipated in Taiwan, the effects of herd immunity are likely to be short-term.Conclusion:A pentavalent rotavirus vaccination program is likely to substantially reduce the healthcare burden associated with rotavirus gastroenteritis at a cost per QALY ratio within the range defined as cost-effective.

Spotlight on Pentavalent Rotavirus Vaccine (RotaTeq®) in the Prevention of Rotavirus Gastroenteritis in Europe†

In Europe, rotavirus gastroenteritis is associated with a significant health, economic, and social burden, as it is responsible for large numbers of hospitalizations and other healthcare encounters among infants and children, as well as numerous days of work lost by parents and caregivers. RotaTeq is a three-dose, orally administered, live, pentavalent human-bovine reassortant rotavirus vaccine used for the active immunization of infants for prevention of rotavirus gastroenteritis. The protective efficacy of RotaTeq has been evaluated in terms of its effects on the incidence of rotavirus gastroenteritis and on healthcare resource use. Clinical trial data from REST (a randomized, double-blind, placebo-controlled, multinational study in ≈70 000 healthy infants aged 6-12 weeks) and various subgroup analyses, including a large European cohort, have shown that RotaTeq may be administered at the same time as various other routine vaccines, has high and sustained efficacy covering the main period of risk for rotavirus gastroenteritis, has early protective efficacy after the first and second doses, reduces rotavirus gastroenteritis-associated hospitalization and emergency department and physician visits, and is generally well tolerated. Moreover, RotaTeq has demonstrated efficacy against the five most prevalent serotypes of rotavirus in Europe (G1-G4, G9), in terms of reductions in associated healthcare resource use. There is also evidence that the widespread use of RotaTeq may provide herd immunity, as it appears to have indirect benefits in older, unvaccinated children. Reports on the 'real world' effectiveness of RotaTeq in Europe are just emerging, but data from the US have shown a rapid and marked reduction in rotavirus burden nationwide during the ≈2-year period following the introduction of RotaTeq and the subsequent availability of official recommendations advocating universal use of the vaccine as part of routine childhood immunization. Postmarketing surveillance data from the US have not identified any concerns, such as an association with intussusception or Kawasaki disease, related to the safety of RotaTeq. In conclusion, RotaTeq is a generally well tolerated vaccine that has efficacy against the five most prevalent serotypes of rotavirus in Europe and provides sustained efficacy over the main risk period for rotavirus gastroenteritis in infants and children, reducing hospitalizations and emergency department visits by decreasing the incidence and severity of illness.

Prevention of rotavirus gastroenteritis in infants and children: rotavirus vaccine safety, efficacy, and potential impact of vaccines

Rotavirus infection is the most common cause of severe gastroenteritis globally, with greater than 86% of deaths occurring in low-income and middle-income countries. There are two rotavirus vaccines currently licensed in the United States and prequalified by the World Health Organization. RV1 is a monovalent attenuated human rotavirus strain, given orally in two doses. RV5 is a pentavalent human-bovine reassortant rotavirus vaccine, given orally in three doses. A third rotavirus vaccine, LLV, is a lamb rotavirus strain given orally as a single dose, which is currently available only in China. RV1 and RV5 have been shown to be highly efficacious in developed countries, and initial results from trials in Africa and Asia are promising as well. At least three other vaccines are in development, which are being developed by manufacturers of developing countries. Further studies are needed to clarify issues including administration of oral rotavirus vaccines with breastfeeding and other oral vaccines, and alterations in dosing schedule. Using new data on global diarrheal burden, rotavirus is estimated to cause 390,000 deaths in children younger than 5 years. Should rotavirus vaccines be introduced in the routine immunization programs of all countries, a potential of 170,000 deaths could be prevented annually. The largest impact on mortality would be seen in low-income and middle-income countries, despite poor immunization coverage and lower efficacy. Therefore, international efforts are needed to ensure that rotavirus vaccines reach the populations with highest burden of rotavirus disease.

Pentavalent Rotavirus Vaccine (RotaTeq®)

In Europe, rotavirus gastroenteritis is associated with a significant health, economic and social burden, as it is responsible for large numbers of hospitalizations and other healthcare encounters among infants and children, as well as numerous days of work lost by parents and caregivers. RotaTeq is a three-dose, orally administered, live, pentavalent human-bovine reassortant rotavirus vaccine used for the active immunization of infants for prevention of rotavirus gastroenteritis. The protective efficacy of RotaTeq has been evaluated in terms of its effects on the incidence of rotavirus gastroenteritis and on healthcare resource use. Clinical trial data from REST (a randomized, double-blind, placebo-controlled, multinational study in approximately 70,000 healthy infants aged 6-12 weeks) and various subgroup analyses, including a large European cohort, have shown that RotaTeq may be administered at the same time as various other routine vaccines, has high and sustained efficacy covering the main period of risk for rotavirus gastroenteritis, has early protective efficacy after the first and second doses, reduces rotavirus gastroenteritis-associated hospitalization and emergency department and physician visits, and is generally well tolerated. Moreover, RotaTeq has demonstrated efficacy against the five most prevalent serotypes of rotavirus in Europe (G1-G4, G9), in terms of reductions in associated healthcare resource use. There is also evidence that the widespread use of RotaTeq may provide herd immunity, as it appears to have indirect benefits in older, unvaccinated children. Reports on the 'real world' effectiveness of RotaTeq in Europe are just emerging, but data from the US have shown a rapid and marked reduction in rotavirus burden nationwide during the approximately 2-year period following the introduction of RotaTeq and the subsequent availability of official recommendations advocating universal use of the vaccine as part of routine childhood immunization. Similar benefits have also been demonstrated in Australia after the introduction of a publicly funded rotavirus vaccination programme. Postmarketing surveillance data from the US have not identified any concerns, such as an association with intussusception or Kawasaki disease, related to the safety of RotaTeq. In conclusion, RotaTeq is a generally well tolerated vaccine that has efficacy against the five most prevalent serotypes of rotavirus in Europe and provides sustained efficacy over the main risk period for rotavirus gastroenteritis in infants and children, reducing hospitalizations and emergency department visits by decreasing the incidence and severity of illness.

EFFICACY AND SAFETY OF PENTAVALENT HUMAN-BOVINE REASSORTANT ROTAVIRUS VACCINE WHEN ADMINISTERED WITH GREATER THAN 10 WEEKS BETWEEN DOSES

The pentavalent human-bovine reassortant rotavirus vaccine is indicated as a 3-dose series with first dose administered orally at 6 to 12 weeks with subsequent doses at 4 to 10 week intervals. In pre-licensure phase III trials, the majority followed this schedule, but there were 2956 instances where infants received a dose of pentavalent human-bovine reassortant rotavirus vaccine/placebo >10 weeks after the previous dose. Among this subset, the efficacy against any severity of disease, the reduction in utilization of healthcare resources and the safety profile after vaccination were comparable with overall results.

Vaccine-Acquired Rotavirus in Infants with Severe Combined Immunodeficiency

Live pentavalent human-bovine reassortant rotavirus vaccine is recommended in the United States for routine immunization of infants. We describe three infants, two with failure to thrive, who had dehydration and diarrhea within 1 month after their first or second rotavirus immunization and subsequently received a diagnosis of severe combined immunodeficiency. Rotavirus was detected, by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, in stool specimens obtained from all three infants, and gene-sequence analysis revealed the presence of vaccine rotavirus. These infections raise concerns regarding the safety of rotavirus vaccine in severely immunocompromised patients.

Experience of Pentavalent Human-bovine Reassortant Rotavirus Vaccine Among Healthy Infants in Taiwan

Rotavirus infection is the most common etiology of acute gastroenteritis in young children worldwide. The first rotavirus vaccine was licensed by the United States Food and Drug Administration in 1998 but was suspended soon after in 1999 because of the possibility of induced intussusception. This study evaluated the safety and immunogenicity of a newly developed pentavalent rotavirus vaccine in Taiwanese children. This was a phase III global trial designed to evaluate the safety and immunogenicity of an oral, live pentavalent rotavirus vaccine (RotaTeq). Taiwan was the only site in Asia enrolled in this trial. Normal healthy infants aged 6-12 weeks were enrolled, and each of the subjects received either three oral doses of the vaccine or placebo solution. The safety of the vaccine, particularly the risk of intussusception, and immunogenicity were studied. A total of 189 infants were enrolled. No increased risk of intussusception or other adverse reactions were noted following the vaccination. RotaTeq was immunogenic among subjects enrolled in Taiwan. At least a three-fold rise in serum antirotavirus IgA antibody was found among 93% of the vaccine group. The immunogenicity of RotaTeq in Taiwan was comparable to that in other areas. The pentavalent human-bovine vaccine, RotaTeq, was safe, generally well-tolerated, and immunogenic among Taiwanese infants.

Pentavalent human-bovine (WC3) reassortant rotavirus vaccine in special populations: a review of data from the Rotavirus Efficacy and Safety Trial

Rotavirus gastroenteritis is a disease that causes significant morbidity and mortality worldwide in infants and children. The recent availability of efficacious rotavirus vaccines with favorable safety profiles has prompted medical agencies around the world to register the vaccines and countries and regions to recommend universal vaccination of healthy infants to prevent the serious health and economic consequences of rotavirus illness in children. Premature infants can be especially vulnerable to severe rotavirus infections, which may lead to serious outcomes. The clinical efficacy and safety of the pentavalent human-bovine rotavirus vaccine (PRV, RotaTeq, Merck, Whitehouse Station, NJ, USA) in healthy infants has been evaluated in the large phase III Rotavirus Efficacy and Safety Trial (REST). Preterm (N = 2,070) and exclusively breastfed infants (N = 1,566) were included in this study. The efficacy and safety of PRV in premature infants and in breastfed infants from the REST database are reviewed along with guidelines from national medical organizations for the use of PRV in these populations. Based on these data from the REST study, premature infants receive the same protection from PRV compared with nonpremature infants, without additional safety risk. Similarly, breastfed and nonbreastfed infants are equally protected from severe consequences of rotavirus gastroenteritis.

IMMUNOGENICITY AND SAFETY OF A PENTAVALENT HUMAN-BOVINE (WC3) REASSORTANT ROTAVIRUS VACCINE IN HEALTHY INFANTS IN KOREA

We evaluated the immunogenicity and safety of pentavalent human-bovine reassortant rotavirus vaccine in 178 Korean healthy infants. Seroresponse rate for serum antirotavirus IgA titers was 94.7% among 94 vaccine recipients, as compared with 13.5% among 52 placebo recipients. Seroresponse rates in serum neutralizing antibody to each human rotavirus serotype in the vaccine were significantly higher in the vaccine group than in the placebo group. This vaccine was generally well tolerated and immunogenic.

The Pentavalent Rotavirus Vaccine: Discovery to Licensure and Beyond

Twenty-five years passed between the discovery of the parent strain (WC3) of the pentavalent human-bovine reassortant rotavirus vaccine (PRV) in 1981 and the licensure of PRV in 2006. This orally administered liquid vaccine, which is given as a 3-dose series, is indicated for the prevention of rotavirus gastroenteritis, caused by the G serotypes contained in the vaccine, in infants and children. PRV is recommended by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics for administration to all infants in the United States. These recommendations are supported by the results of the phase III studies, which demonstrated that PRV is well tolerated and efficacious. PRV reduced rotavirus-related hospitalizations by 96% and was not associated with an increased incidence of serious adverse events, including intussusception. This report focuses on the safety and efficacy data from the late-phase studies of PRV and discusses plans for providing this vaccine to the developing world.

Safety and Efficacy of the Pentavalent Human-Bovine (WC3) Reassortant Rotavirus Vaccine in Healthy Premature Infants

Premature infants seem to be at greater risk of hospitalization from rotavirus gastroenteritis than term infants. Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine were assessed in premature infants enrolled in the large-scale, blinded, placebo-controlled rotavirus efficacy and safety trial (REST). Healthy infants 6-12 weeks of chronologic age at study entry were randomized to receive 3 oral doses of pentavalent rotavirus vaccine or placebo at 4- to 10-week intervals. Infants born at < or =36 weeks of gestational age were eligible if thriving at the time of enrollment. Safety and efficacy were retrospectively assessed in these premature infants comparing vaccine with placebo recipients. Cases of rotavirus gastroenteritis were defined as forceful vomiting and/or > or =3 watery or looser-than-normal stools within a 24-hour period, accompanied by detection of rotavirus antigen in the stool. A total of 2070 infants between 25 and 36 gestational weeks received at least 1 dose of vaccine or placebo; 1005 vaccine recipients and 1061 placebo recipients were evaluable for safety. Serious adverse events occurred in 55 vaccine recipients (5.5%) and 62 placebo recipients (5.8%). In a nested substudy of 308 premature infants evaluable for detailed safety (154 in each group), the frequencies of fever, diarrhea, vomiting, and irritability were comparable between vaccine and placebo recipients. Overall, 3 doses of the pentavalent vaccine reduced the rate of hospitalizations and emergency department visits in premature infants due to rotavirus gastroenteritis by 100% (95% CI: 82.2-100) compared with placebo. The vaccine also prevented 73.0% (95% CI: -2.2-95.2) of rotavirus gastroenteritis cases of any severity. In this post hoc analysis of healthy premature infants, the pentavalent rotavirus vaccine was generally well-tolerated and substantially reduced rotavirus-attributable hospitalizations and emergency department visits compared with placebo. Overall, vaccine safety and efficacy seemed to be generally comparable to the results in the REST study population as a whole. These results support vaccinating healthy premature infants on the same schedule as term infants.

Rotavirus live, oral, pentavalent vaccine

Background: On February 3, 2006, the US Food and Drug Administration (FDA) approved a live, oral, pentavalent (G1-G4, P1[8]) human-bovine reassortant rotavirus vaccine for the prevention of rotavirus gastroenteritis (RVGE) in infants in the United States. The Advisory Committee of Immunization Practices of the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics (AAP) recommended routine immunization of infants using 3 doses of the oral pentavalent rotavirus vaccine (PRV) at 8, 12, and 24 months of age, with the first dose administered between 6 and 12 weeks of age and subsequent doses administered at 4- to 10-week intervals. Objective: This article reviews the composition, clinical efficacy, adverse events, and cost-effectiveness associated with its use. Methods: Relevant literature was identified through searches of MEDLINE (1990-June 2007) and International Pharmaceutical Abstracts (1990-July 2007). Search terms included, but were not limited to, RotaTeq, PRV, intussusception, rotavirus infection, and cost-effectiveness. Further publications were selected from the reference lists of identified articles. Guidelines for use were identified from the Web sites of the CDC and the AAP. Results: Two published Phase III clinical trials involving the PRV were identified. The Rotavirus Efficacy and Safety Trial (REST) and the Concomitant Use Study, a subanalysis of REST, found that PRV was efficacious and well tolerated. The vaccine was associated with preventing RVGE of any severity in 74% of patients and severe RVGE in 98%. The combined prevalence of hospitalizations and emergency department (ED) visits was reduced by 94.5% (95% CI, 91.2%-96.6%), including a decrease in hospitalizations of 95.8% (95% CI, 90.5%-98.2%) and a decrease in ED visits 93.7% (95% CI, 88.8%-96.5%), with vaccine administration compared with placebo. There were also reductions in physician's office visits of 86% (95% CI, 73.9%-92.5%) and the number of workdays lost for parents (65 vs 487). There were no confirmed cases of intussusception due to the vaccine. The prevalences of fever, diarrhea, and vomiting were not significantly different between the vaccine and placebo groups. Overall, the vaccine was well tolerated. The second study, a multicenter, randomized, placebo-controlled trial, found that PRV was efficacious, well tolerated, and immunogenic at the end of the vaccine's shelf-life. The vaccine was associated with preventing RVGE of any severity in 72.5% of cases and severe RVGE in 100% of cases. No cases of intussusception were reported. The Concomitant Use Study found that PRV could be administered concomitantly with other routine vaccinations during the first 24 weeks of life. Recently, the FDA's Vaccine Adverse Event Reporting System (VAERS) received 28 reports of cases that occurred after the first, second, and third doses. Approximately 50% of cases occurred 1 to 21 days after vaccination. Sixteen of the infants required hospitalization, while the remaining 12 required contrast or air enema intervention to reduce the intussusception. Conclusions: Based on the results from published studies, PRV appears effective in decreasing the prevalence of RVGE in the United States. Despite evidence from the large trial and no reported cases of intussusception, this event has been reported to VAERS. Con-tinued postmarketing surveillance by the manufacturer, together with the VAERS and the CDC, will confirm whether use of the vaccine increases the risk for intussusception.

Cost-effectiveness and Potential Impact of Rotavirus Vaccination in the United States

In February 2006, a safe, efficacious, orally administered pentavalent human-bovine reassortant rotavirus vaccine was licensed and recommended for routine immunization of all children in the United States. We assessed the health and economic impacts of a national rotavirus immunization program in the United States. Monte Carlo cost-effectiveness analyses, from health care and societal perspectives, of vaccination of a hypothetical US birth cohort of 4,010,000 children monitored from birth to 59 months of age were performed. We compared the disease and economic burden of rotavirus infection in an unvaccinated cohort of children with one vaccinated at 2, 4, and 6 months with pentavalent human-bovine reassortant rotavirus vaccine. A routine rotavirus immunization program would prevent 13 deaths, 44,000 hospitalizations, 137,000 emergency department visits, 256,000 office visits, and 1,100,000 episodes requiring only home care for children <5 years of age in the United States. Assuming costs of administration of $10, the break-even price per dose of vaccine was $42 from the societal perspective and $12 from the health care perspective. From the societal perspective, at the manufacturer's price of $62.50 per dose, vaccination would cost $138 per case averted, $3024 per serious case averted, and $197,190 per life-year saved, at a total cost of $515 million to the health care system and $216 million to society. Key variables influencing the results were parental workdays lost, costs of hospitalization, emergency department visits, and child care. Despite a higher burden of serious rotavirus disease than estimated previously, routine rotavirus vaccination would unlikely be cost-saving in the United States at present. Nonetheless, rotavirus vaccination may still be considered a cost-effective intervention.

Concomitant Use of an Oral Live Pentavalent Human-Bovine Reassortant Rotavirus Vaccine With Licensed Parenteral Pediatric Vaccines in the United States

A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A[8] was evaluated in a blinded, placebo-controlled study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial. From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or -3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards. The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5-99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines. In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.

Efficacy, Immunogenicity, and Safety of a Pentavalent Human-Bovine (WC3) Reassortant Rotavirus Vaccine at the End of Shelf Life

Rotavirus is the leading cause of dehydrating acute gastroenteritis in infants worldwide. Previous studies of a live pentavalent human-bovine reassortant rotavirus vaccine have shown it to be efficacious across a range of potencies. Our goal was to evaluate the efficacy, immunogenicity, and safety of pentavalent rotavirus vaccine at the end of shelf life in healthy infants. During 2002-2004, 1312 healthy infants approximately 6 to 12 weeks old from the United States (47%) and Finland (53%) were randomly assigned to receive 3 oral doses of vaccine (vaccine at approximately 1.1 x 10(7) infectious U per dose) or placebo approximately 4 to 10 weeks apart. Infants were to be followed for acute gastroenteritis through 1 rotavirus season after vaccination and for adverse events postvaccination. Three doses of pentavalent rotavirus vaccine at the end of shelf life demonstrated efficacy against rotavirus gastroenteritis caused by human G-serotypes included in the vaccine (G1-G4). Efficacy against severe rotavirus gastroenteritis was 100%, and efficacy against any rotavirus gastroenteritis regardless of severity was 72.5%. A threefold rise in G1 serum neutralizing was observed in 57% and in anti-rotavirus immunoglobulin A in 96% of pentavalent rotavirus vaccine recipients. No statistically significant increase in vomiting, diarrhea, or irritability was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients within the 7-day period from each dose. A statistically significant increase in fevers (> or = 100.5 degrees F, rectal equivalent) was observed among pentavalent rotavirus vaccine recipients compared with placebo recipients after dose 1. This pentavalent human-bovine rotavirus vaccine was generally well tolerated, efficacious, and immunogenic at the end of shelf life.