Detection of vaccine-derived rotavirus strains in nonimmunocompromised children up to 3-6 months after RotaTeq® vaccination.

We conducted a survey on the presence of RotaTeq vaccine viruses in infants hospitalized with respiratory infection, and detected shedding in 17% of children (<2 years of age) who had ever received the vaccine. The latest detection was at the age of 8 months. We conclude that asymptomatic long-time shedding of RotaTeq viruses is not uncommon, and is particularly associated with genotype G1.

Hospital bed occupancy for rotavirus and all cause acute gastroenteritis in two Finnish hospitals before and after the implementation of the national rotavirus vaccination program with RotaTeq®.

BACKGROUND: Vaccination-impact studies of the live-attenuated pentavalent oral vaccine Rotateq® have demonstrated that the burden of rotavirus gastroenteritis has been reduced significantly after the introduction of RotaTeq® vaccination, but less is known about the benefit of this vaccination on hospital overcrowding. METHODS: As part of an observational surveillance conducted during the RV seasons 2000/2001 to 2011/2012, we analysed hospital discharge data collected retrospectively from two Finnish hospitals (Oulu and Tampere), concerning ICD 10 codes A00-09 (acute gastroenteritis, AGE) and A08.0 (rotaviral acute gastroenteritis RV AGE). We estimated the reduction in the number of beds occupied and analysed the bed occupancy rate, for RV AGE and all cause AGE, among 0-16 year-old children, before and after the implementation of the RV immunisation program. RESULTS: The rate of bed days occupied for RV AGE was reduced by 86% (95% CI 66%-94%) in Tampere and 79% (95% CI 47%-92%) in Oulu after RV vaccination implementation. For all cause AGE, reduction was 50% (95% CI 29% to 65%) in Tampere and 70% (95% CI 58% to 79%) in Oulu. Results were similar among 0-2 year-old children. This effect was also observed on overcrowding in both hospitals, with a bed occupancy rate for all cause AGE >25% in only 1% of the time in Tampere and 9% in Oulu after the implementation of the immunisation program, compared to 13% and 48% in the pre-vaccination period respectively. After extrapolation to the whole country, the annual number of prevented hospitalizations for all cause AGE in the post-vaccination period in Finland was estimated at 1,646 and 2,303 admissions for 0-2 and 0-16 year-old children respectively. CONCLUSIONS: This study demonstrated that universal RV vaccination is associated with a clear decrease in the number of bed days and occupancy rates for RV AGE and all cause AGE. Positive consequences include increase in quality of care and a better healthcare management during winter epidemics.

Genetic analyses of norovirus GII.4 variants in Finnish children from 1998 to 2013.

Noroviruses (NoVs) are the major causative agents of acute gastroenteritis (AGE) in outbreaks and in sporadic AGE in young children. Since the mid-1990s, NoV genotype GII.4 has been predominant worldwide. New GII.4 variants appear every two to three years, and antigenic variation is focused on the highly variable protruding domain (P2) of the NoV capsid protein which contains the receptor-binding regions. We studied NoV GII.4 variants in cases of endemic AGE in Finnish children from 1998 to 2013. Fecal specimens were collected from cases of AGE followed prospectively in rotavirus vaccine trials from 1998 to 2007, and from children seen at Tampere University Hospital because of AGE from 2006 to 2013. Partial capsid sequences were identified with RT-PCR and sequenced allowing P2 domain alignment and phylogenetic comparison of different GII.4 strains, with virus-like particles (VLPs) developed as candidate vaccines. Of 1495 NoV positive specimens 829 (55%) were of the GII.4 genotype, and altogether twelve GII.4 variants were identified. Identical GII.4 variants were detected in outbreaks of NoVs worldwide. A phylogenetic tree of the amino acid changes in the P2 region showed nine variants that arose over time. Our data indicates that GII.4 continues to be the predominant NoV genotype circulating in the Finnish community, and the changes in the P2 domain over time result in the development of new variants that cause AGE in children. Future NoV vaccines should either induce type specific immunity for each variant or, alternatively, induce broadly reactive protective immunity covering multiple variants.

Detection of rotateq vaccine-derived, double-reassortant rotavirus in a 7-year-old child with acute gastroenteritis.

We describe a case of acute gastroenteritis in a schoolgirl associated with a detection of vaccine-derived, human-bovine double reassortant G1P[8] rotavirus, without any known contact with recently vaccinated infants. We propose that human-bovine double reassortant G1P[8] may be formed in RotaTeq-vaccinated infants and can occasionally cause gastroenteritis symptoms in vaccine recipients who may rarely transmit the virus to close contacts. The present case suggests that such viruses can remain stable in environment longer than 1 transmission cycle.

Rotavirus antigenemia in children is associated with more severe clinical manifestations of acute gastroenteritis.

BACKGROUND: Rotavirus (RV) antigenemia and RNAemia are common findings in rotavirus-infected children. Sporadic associations between RV antigenemia and extraintestinal manifestations of RV infection have been observed. We examined the clinical severity of RV gastroenteritis in patients with and without RV antigenemia or RNAemia. METHODS: Stool, serum and whole blood samples were collected from children seen with acute gastroenteritis in Tampere University Hospital and studied for RV using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Only exclusively RV-positive specimens were included into this study. The patients were divided into groups according to RV findings from stool, serum and blood specimens. Clinical manifestations were graded according to 20-point Vesikari scoring system. RESULTS: Of 374 children, 155 (41%) had RV in their stools. Of these 155 children, 105 (67%) were found to have RV RNA in the serum; of those, 94 (90%) had also RV enzyme-linked immunosorbent assay antigen. Thus antigenemia occurred in 61% (94 cases) of RV-infected children all of whom had concomitant RNAemia. Neither antigenemia nor RNAemia were detected in 85 patients with non-RV gastroenteritis. Patients who had RV RNA and RV antigen in both serum and stools were more likely to have a higher level of fever and more severe vomiting than patients who had RV only in stools. G1 genogroup RV was more often associated with RNAemia and antigenemia than other genogroups combined. CONCLUSION: Rotavirus antigenemia and viremia are commonly detected in children hospitalized for RV gastroenteritis and may be associated with increased severity of fever and vomiting.

Impact and effectiveness of RotaTeq® vaccine based on 3 years of surveillance following introduction of a rotavirus immunization program in Finland.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Severe RVGE requiring hospitalization was virtually eliminated in vaccine-eligible children in the 3 years following implementation of universal RotaTeq vaccination in Finland.

Genetic diversity of G1P[8] rotavirus VP7 and VP8* antigens in Finland over a 20-year period: No evidence for selection pressure by universal mass vaccination with RotaTeq® vaccine.

Two live-attenuated oral vaccines (Rotarix™ and Rotateq®) against rotavirus gastroenteritis were licensed in 2006 and have been introduced into National Immunization Programs (NIPs) of several countries. Large scale use of rotavirus vaccines might cause antigenic pressure on circulating rotavirus types or lead to selection of new rotaviruses thus decreasing vaccine efficacy. We examined the nucleotide and amino acid sequences of the surface proteins VP7 and VP4 (cleaved to VP8(*) and VP5(*)) of a total of 108 G1P[8] rotavirus strains collected over a 20-year period from 1992, including the years 2006-2009 when rotavirus vaccine (mainly Rotarix™) was available, and the years 2009-2012 after implementation of RotaTeq® vaccine into the NIP of Finland. In G1 VP7 no changes at amino acid level were observed. In VP8(*) periodical fluctuation of the sublineage over the study period was found with multiple changes both at nucleotide and amino acid levels. Most amino acid changes were in the dominant antigenic epitopes of VP8(*). A change in VP8(*) sublineage occurred between 2008 and 2009, with a temporal correlation to the use of Rotarix™ up to 30% coverage in the period. In contrast, no antigenic changes in the VP8(*) protein appeared to be correlated to the exclusive use of RotaTeq® vaccine after 2009. Nevertheless, long-term surveillance of antigenic changes in VP4 and also VP7 proteins in wild-type rotavirus strains is warranted in countries with large scale use of the currently licensed live oral rotavirus vaccines.

Major reduction of rotavirus, but not norovirus, gastroenteritis in children seen in hospital after the introduction of RotaTeq vaccine into the National Immunization Programme in Finland.

UNLABELLED: Universal rotavirus (RV) vaccination is expected to reduce hospitalizations for acute gastroenteritis (GE) of children by eliminating most of severe RVGE, but it does not have any effect on norovirus (NV), the second most common causative agent of GE in children. After the introduction of the RV vaccine into the National Immunization Programme (NIP) of Finland in 2009, we conducted a prospective 2-year survey of GE in children seen in Tampere University Hospital either as outpatients or inpatients and compared the results with a similar 2-year survey conducted prior to NIP in the years 2006-2008. Compared with the pre-NIP 2-year period, in 2009-2011, hospitalizations for RVGE were reduced by 76 % and outpatient clinic visits were reduced by 81 %. NVGE showed a slight decreasing trend and accounted for 34 % of all cases of GE seen in hospital in pursuance of RVGE having decreased to 26 % (down from 52 %). In cases admitted to the hospital ward, RV accounted for 28 % and NV accounted for 37 %.The impact of RV vaccination was reflected as a 57 % decrease in all hospital admissions and 62 % decrease in all outpatient clinic visits for GE of any cause. CONCLUSION: RV vaccination in NIP has led to a major reduction of hospital admissions and clinic visits due to RVGE, but has had no effect on NVGE. After 2 years of NIP, NV has become the leading cause of acute GE in children seen in hospital.

Vaccine-derived human-bovine double reassortant rotavirus in infants with acute gastroenteritis.

We describe 3 cases of acute gastroenteritis in healthy infants after vaccination with RotaTeq, shedding a G1P[8] human-bovine double reassortant rotavirus in stools. Such a double reassortant virus appears stable in vitro and may explain diarrheal symptoms in a small percentage of RotaTeq recipients, and might also be transmitted to contacts in the environment.