Drug levels of VEDOLIZUMAB in patients with pediatric-onset inflammatory bowel disease in a real-life setting.

Vedolizumab (VDZ) is used off-label in pediatric inflammatory bowel disease (PIBD). There are less data on drug levels to achieve and maintain remission in children. We aimed to study vedolizumab (VDZ) trough levels in a pediatric population in a real-life setting. We traced 50 patients with PIBD receiving VDZ treatment at our hospital, reviewed their treatment protocol, trough levels, and antidrug antibodies, and compared those to fecal calprotectin (FC) levels and achievement of corticosteroid-free maintenance therapy (CF). VDZ trough level was available from 198 samples during a median follow- up of 12.6 months. Proceeding to maintenance therapy was associated with a decline in FC but not with VDZ trough levels that were comparable between patients with FC < 100 µg/g (remission), 100-1000 µg/g, or > 1000 µg/g at 3 months (mean levels of 36.8, 28.6, and 27 µg/mL, respectively p = 0.188). At 3 months, patients achieving CF (41%) and those on corticosteroids had comparable VDZ trough levels (33 vs. 27.5 µg/mL, respectively). At 6 months, the trough level was similar in groups with FC < 100 µg/g or FC > 1000 µg/g (31.5 and 27.6 µg/mL, p = 0.859). Treatment intensification did not improve the achieved CF at 12 months. None developed drug antibodies nor discontinued the therapy for an adverse event.   Conclusion: VDZ was a well-tolerated and safe biologic treatment. A positive response on gut inflammation after induction predicted proceeding to maintenance therapy whereas trough levels did not. A VDZ trough level associated with clinical remission or continuing with VDZ treatment could not be determined. What is Known: • In pediatric inflammatory bowel disease, vedolizumab is still in off-label use. • The results on the relationship between drug levels of vedolizumab and clinical remission in pediatric patients are contradictory. What is New: • This real-life setting in pediatric-onset inflammatory bowel disease showed no benefit of therapy enhancement during a median follow-up of one year. • Trough levels of vedolizumab were not associated with therapy outcomes.

Long-term surveillance of rotavirus vaccination after implementation of a national immunization program in Finland (2008-2018).

BACKGROUND: Rotavirus (RV) vaccination was included in the Finnish National immunization Program (NIP) in 2009. RotaTeq (RV5) has been used exclusively with a national average vaccination coverage rate (VCR) of > 90%. While previous studies have demonstrated that inpatient rotavirus gastroenteritis (RVGE) admissions declined by as much as 96% in Finnish children ≤ 5 years old following RV vaccination introduction, no study has evaluated long-term protection after vaccination in Finland. In this study, we analyze incidence of hospital outpatient visits and inpatient admissions of gastroenteritis in children up to 7 years of age. METHODS: We first describe the incidence of RVGE, viral gastroenteritis (VGE), and acute gastroenteritis (AGE) for all Finnish children born during 2008-2011. Children were stratified by the year of birth into not-eligible, partially eligible and rotavirus vaccine-eligible (born in 2008, 2009, 2010 and 2011, respectively). Hospital inpatient and outpatient data was collected from the National Care Register for all children from birth until December 31st, 2018. We also studied RVGE incidence during 2014-2017 for children<3 years of age in municipalities with VCRs of 90% and above and municipalities with VCRs below 90%. RESULTS: RVGE incidence decreased significantly soon after implementation of RV vaccination in the NIP. In vaccine-eligible cohorts, no clear peak incidence in the youngest age groups could be observed, and no RVGE cases were observed beyond 6 years after vaccination, in contrast to vaccine ineligible and partially eligible cohorts. Despite an overall high VCR in Finland, regions with high VCR had lower incidence of RVGE than regions with lower VCR. CONCLUSION: Incidence of RVGE has remained low in all age groups during the 10 years following introduction of RV vaccine in the Finnish NIP. Differences in RVGE incidence were observed in regions with high as compared with lower VCR, highlighting the importance of maintaining high vaccination coverage.

Sapovirus, Norovirus and Rotavirus Detections in Stool Samples of Hospitalized Finnish Children With and Without Acute Gastroenteritis.

BACKGROUND: Sapovirus, norovirus and rotavirus are major causes of childhood acute gastroenteritis (AGE) globally. Asymptomatic infections of these viruses have not been extensively studied. AIM: To examine the prevalence and the genetic variations of sapovirus, norovirus and rotavirus in children with and without symptoms of AGE. METHODS: We collected 999 stool samples from children under 16 years old from September 2009 to August 2011 at Tampere University Hospital, Finland. In total 442 children (44%) had symptoms of AGE and 557 patients (56%) had acute respiratory tract infection (ARTI) only. Samples were examined for sapovirus, norovirus and rotavirus using reverse transcription-polymerase chain reaction and the positive amplicons were sequenced. RESULTS: Totally 54% and 14% of the patients in AGE and ARTI groups, respectively, tested positive. All viruses were more frequently detected in AGE patients than in ARTI patients (norovirus, 25% vs. 7.2%, respectively; rotavirus, 24% vs. 6.1%; sapovirus, 5.2% vs. 1.4%). In ARTI patients, the cases were seen most frequently during the first two years of life. Norovirus was the most detected pathogen in both groups with genogroup GII covering ≥97% of norovirus strains. Sapovirus was mostly detected in children under 18 months old without predominating genotype. Rotavirus was often detected after recent rotavirus vaccination and 18% and 88% of the strains were rotavirus vaccine-derived in AGE and ARTI groups, respectively. CONCLUSIONS: We showed that the most common viruses causing gastroenteritis in children may be found in the stools of an asymptomatic carrier which may function as a potential reservoir for AGE.

Lot-to-lot consistency, safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in healthy adults aged ≥50 years: A randomized phase 3 trial (PNEU-TRUE).

BACKGROUND: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years. METHODS: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50-64 years, 65-74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively. RESULTS: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5-2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F). CONCLUSIONS: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots. CLINICAL TRIALS REGISTRATION: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).

A major decrease in viral acute gastroenteritis in hospitalized Finnish children as rotavirus returns as the most detected pathogen.

INTRODUCTION: This study was performed to assess the prevalence and circulating genotypes of rotavirus, norovirus, and sapovirus in children. The results were compared to those of previous surveillance studies covering the years 2006-2008, 2009-2011, and 2012-2014 with similar methodology and setting, encompassing the start of universal vaccination with RotaTeq in 2009. METHODS: Stool samples were collected from children aged <16 years with acute gastroenteritis at Tampere University Hospital, Finland, from January 1, 2017 to December 31, 2018. The samples were analysed using reverse transcription PCR and positive amplicons were sequenced. RESULTS: A total of 178 stool samples were collected from 214 children. Rotavirus was detected in 56 (32%) stool samples, norovirus in 48 (27%), and sapovirus in 11 (6.3%). Rotavirus G9P[8] and G12P[8] were the most detected genotypes in vaccinated and unvaccinated children. GII.4 comprised 96% of the norovirus detections. CONCLUSIONS: The prevalence of all-cause acute gastroenteritis in a hospital setting decreased by 51% compared to 2012-2014, and by 88% compared to 2006-2008 . Rotavirus returned as the most common cause of viral acute gastroenteritis in children, but the prevalence remains at a low level. No considerable changes were seen in the genotyping results of norovirus and sapovirus.

Continuing rotavirus circulation in children and adults despite high coverage rotavirus vaccination in Finland.

OBJECTIVES: To determine occurrence of residual rotavirus (RV) disease in different age groups in Finland after five to nine years of high coverage (≥90%) mass-vaccination with RotaTeqⓇ vaccine, and to examine the vaccine effect on circulating genotypes. METHODS: Since 2013 all clinical laboratories in the country were obliged to send RV positive stool samples for typing. RVs were genotyped by RT-PCR for VP7 and VP4 proteins, sequenced and compared to reference strains. RESULTS: RV continued to circulate throughout the study period at low level with a small increase in 2017-2018. There were three age-related clusters: young children representing primary or secondary vaccine failures, school-age children who may not have been vaccinated, and the elderly. Genotype distribution differed from the pre-vaccination period with a steady decline of G1P[8], emergence of G9P[8] and especially more recently G12P[8]. In the elderly, G2P[4] was predominant but was also replaced by G12P[8] in 2017-18. CONCLUSIONS: RV vaccination with a high coverage keeps RV disease at low level but does not prevent RV circulation. New RV genotypes have emerged replacing largely the previously predominant G1P[8]. Increase of overall RV activity with emergence of G12P[8] in the latest follow-up season 2017-18 might be a potential alarm sign.

Shedding of oral pentavalent bovine-human reassortant rotavirus vaccine indicates high uptake rate of vaccine and prominence of G-type G1.

BACKGROUND: Live oral pentavalent bovine-human reassortant rotavirus (RV) vaccine, RotaTeq®, contains bovine rotaviruses reassorted with human G-types G1, G2, G3 and G4, and P-type P[8]. Shedding of RotaTeq® vaccine, as studied by RT-PCR, has been shown to be more common than initially reported, and may include formation of vaccine-derived double-reassortant G1P[8] RVs. We studied the extent and duration of RotaTeq® vaccine virus shedding, genotypes shed, and clinical symptoms associated with shedding. MATERIAL AND METHODS: We enrolled a total of 301 infants who received RotaTeq® vaccine according to Finnish schedule at 2, 3 and 5 months of age. Stool samples were collected 5-10 days after the first and 0-7 days before the third dose of the vaccine. Additional stool samples 6 and 12 weeks later were collected if the second stool sample was positive. All stools were studied with RT-PCR for RV VP7, VP4 and VP6. Parents filled a symptom diary for a week after each vaccine dose. RESULTS: We found that 93% of the vaccinees shed vaccine related viral particles in one sample taken 5-10 days after the first dose, indicating that stool shedding is very common and may be regarded as a marker of successful vaccination. Genotype G1 was the predominant genotype in shedding, often in association with P[8], and the only genotype found in long-term shedding. Also G4 was commonly detected whereas other vaccine G-types and bovine-type P[5] were not. CONCLUSIONS: Shedding of RotaTeq® vaccine-derived viruses is a sign for successful vaccination. Intense shedding of G1 with or without P[8]reflects effective multiplication and may be an important factor in the induction of protective immunity. Shedding of G1 containing vaccine viruses may be prolonged up to 8 months of age. These results suggest that the pentavalent vaccine functions largely like a monovalent G1 vaccine. Eudra-CT: 2014-004252-60.

Rotavirus Vaccination Does Not Increase Type 1 Diabetes and May Decrease Celiac Disease in Children and Adolescents.

BACKGROUND: Rotavirus (RV) infection has been proposed to trigger type 1 diabetes mellitus (DM1) and celiac disease (CD) by molecular mimicry in genetically susceptible children. If so, a live attenuated oral RV vaccine could also trigger these autoimmune diseases, or else, prevent the effect of wild-type RV infection. METHODS: In Rotavirus Efficacy and Safety Trial, conducted between 2001 and 2003, the participant children received RotaTeq (Kenilworth, NJ) vaccine or placebo in 1:1 ratio. The surveillance was extended as Finnish Extension Study. A questionnaire was sent in 2015 to the parents of 19,133 Finnish Extension Study participants and 5764 (30%) returned the questionnaire. Diagnosis of DM1, biopsy-proven CD and other autoimmune disease over the 11-14 year period were inquired. RESULTS: At the time of questionnaire, the prevalence of DM1 was similar in both groups, 0.97% (25 of 2580 children) in the placebo group and 1.04% (33 of 3184 children) in the vaccine group (P = 0.810). The prevalence of CD was significantly higher in placebo recipients (1.11%; confidence interval: 0.78%-1.6%) than in vaccine recipients (0.60%; confidence interval: 0.38%-0.93%) (P = 0.027). CONCLUSIONS: RV vaccination using RotaTeq did not alter the occurrence of DM1 but decreased the prevalence of CD in childhood and adolescence. We propose that wild-type RV may trigger CD and the triggering effect can be prevented or reduced by RV vaccination.

The role of the sapovirus infection increased in gastroenteritis after national immunisation was introduced.

AIM: This study examined the prevalence and clinical significance of the sapovirus infection in children with acute gastroenteritis before and after the introduction of the rotavirus vaccination in Finland in 2009. METHODS: We collected 1437 stool samples from children under 16 years during three prospective hospital-based surveillance studies of acute gastroenteritis at Tampere University Hospital, Finland. The children were seen in the emergency department (47%) or admitted to the ward (53%). Sapovirus findings from 2006 to 2008 (n = 759), before national immunisation, were compared to 2009-2011 (n = 330) and 2012-2014 (n = 348), after the national programme was launched. RESULTS: The overall incidence of the sapovirus was 3.3%. It was present in 1.4% of acute gastroenteritis cases in 2006-2008 and 5.5% in the post-vaccination years, but the absolute number did not increase. Sapoviruses mainly occurred in the winter and spring, but did not follow the prevalence of the norovirus or rotavirus. Sapovirus GI.1 and GII.1 were the most common genotypes, but the predominant strain was different each season. Many sapovirus lineages appeared during multiple seasons and reappeared later. CONCLUSION: The sapovirus was uncommonly and sporadically detected in children seen in the hospital for acute gastroenteritis, and its relative role increased after national immunisation was introduced.

Rotavirus epidemiology 5-6 years after universal rotavirus vaccination: persistent rotavirus activity in older children and elderly.

BACKGROUND: Rotavirus (RV) vaccination using RotaTeq® vaccine exclusively was introduced into Finnish National Immunization Program (NIP) in 2009, and soon reached high (≥90%) coverage. Since mid-2013, all stool samples from laboratory diagnosed cases of RV gastroenteritis in the entire country have been typed. METHODS: 364 RV positive stool samples collected from clinical laboratories over a 2-year period were G- and P-typed using RT-PCR, and the results were confirmed by sequencing. In addition, the genome segment encoding for VP6 was sequenced to distinguish between wild-type and vaccine origin (bovine) RVs. RESULTS: RV winter epidemic seasons 2013-2014 and 2014-2015 lasted until July each. The age distribution of RV cases showed two unusual clusters: one in children 6-16 years of age, too old to have been vaccinated in NIP, and the other in elderly over 70 years of age. In children, diverse genotypes were observed without any obvious predominance. The most common ones were G1P[8] (30.0%), G2P[4] (22.4%), G9P[8] (15.8%), G3P[8] (12.2%) and G4P[8] (11.2%). The genotype distribution was not different among vaccinated and unvaccinated children. Most cases in the elderly were associated with G2P[4]. CONCLUSIONS: Even at high vaccine coverage and high effectiveness of RV vaccine, RV activity continues to persist, particularly in unvaccinated older children. RV genotypes show greater diversity than before RV vaccinations. We conclude that RV disease can be controlled but not eliminated by vaccinations. Herd-protection in long-term follow-up may be less than at the start of RV vaccinations.

Sustained High Effectiveness of RotaTeq on Hospitalizations Attributable to Rotavirus-Associated Gastroenteritis During 4 Years in Finland.

KEY POINTS: The effectiveness of pentavalent rotavirus vaccine against rotavirus-associated hospitalization was more than 90% 4 years after introduction into the national immunization program in Finland. A major impact on hospitalization for all-cause gastroenteritis was observed also. BACKGROUND: Rotavirus vaccination with exclusive use of RotaTeq was added to the National Immunization Programme (NIP) of Finland in September 2009. The objective of our study was to estimate the effectiveness and impact of RotaTeq after 4 years of follow-up. METHODS: Between 2009 and 2013, we conducted a prospective surveillance study of children aged <16 years with acute gastroenteritis (AGE) and admitted in 2 hospitals in Finland. Rotavirus and other gastroenteritis viruses were detected in stool samples by reverse-transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assays. The effectiveness of RotaTeq was investigated by using a case-control design; wild-type rotavirus-positive children were classified as "cases" and rotavirus-negative children as "controls." Hospital discharge records were used to estimate the impact of RotaTeq on rotavirus-associated AGE (RV-AGE) and all-cause AGE (AC-AGE) hospitalizations of age-eligible children in the NIP by comparing the prevaccination (2001-2006) and post-NIP seasons (2009-2013). RESULTS: The crude estimate of the effectiveness of RotaTeq to prevent RV-AGE hospitalization in NIP age-eligible children was 94.4% (95% confidence interval, 79.8%-98.4%). No change in prevalent wild-type rotavirus genotypes was observed. Vaccine-derived rotaviruses were detected in 8% of the children with RV-AGE, with a probable causal association in 2 children. Hospital discharge records revealed that RV-AGE and AC-AGE hospitalizations in children aged <16 years decreased in the two post-NIP seasons by 79% and 58%, respectively, compared to those in the prevaccination seasons. CONCLUSIONS: Over 4 years of follow-up, high rotavirus vaccine coverage in the NIP (>95%) has led to a major reduction in RV-AGE and AC-AGE hospitalizations without a resurgence of rotavirus activity. However, rotavirus continues to circulate in older unvaccinated children.

Decrease of Rotavirus Gastroenteritis to a Low Level Without Resurgence for Five Years After Universal RotaTeq Vaccination in Finland.

BACKGROUND: Universal rotavirus (RV) vaccination with RotaTeq was introduced into National Immunization Programme (NIP) of Finland in September 2009. We have previously reported the reduction of RV gastroenteritis (GE) cases in the first 2 years after RV vaccination in NIP in Finland. METHODS: In Tampere University Hospital, a 2-year survey of acute GE (AGE) in children was conducted before NIP in the years 2006 to 2008. This was followed by a similar prospective survey in years 2009 to 2011 and now extended to years 2012 to 2014. Stool samples from children examined in the hospital for AGE were analyzed by real-time polymerase chain reaction assays for RV and norovirus, and positive samples were typed by sequencing. RESULTS: The proportion of RVGE of all AGE cases decreased from 52% (421 of 809 cases) in pre-NIP years to 26% (86 of 330 cases) in post-NIP years 2009 to 2011 falling to 12% (40 of 347 cases) in 2012 and 2014. The hospitalizations for RVGE were reduced by 90% and the outpatient clinic visits also by 90% in 2012 to 2014, compared with pre-NIP year; all AGE cases were reduced by 59%. Norovirus was a major causative agent of AGE in the post-NIP period, accounting for 34% of the cases in 2009 to 2011 and 29% in 2012 to 2014. CONCLUSIONS: RV vaccination in NIP has led to a major reduction of RVGE cases seen in hospital with no resurgence in 5 years after NIP. A high coverage of RV vaccination will maintain RV activity at a low level but not eliminate wild-type RV circulation.

Norovirus detection from sera of young children with acute norovirus gastroenteritis.

BACKGROUND: Antigenemia and viremia are common in rotavirus infection but only few studies have shown norovirus (NoV) RNA in the blood circulation. OBJECTIVES: To detect NoV RNA from serum of NoV-infected children and study if NoV RNAemia correlates with clinical severity of acute gastroenteritis. STUDY DESIGN: Serum specimens were collected from 176 Finnish children with acute NoV gastroenteritis. Semi-nested PCR was optimized to detect NoV capsid RNA from sera. NoV positive samples were further analyzed by sequencing. RESULTS: NoV RNA was found in 11/176 (6.3%) of serum specimens. NoV GII.4 was found in 8 cases and GII.3, GII.6 and GII.7 in one case each. The genotypes detected in serum were identical to findings in stools in all cases. Most of the NoV RNA detections in serum were in young children less than 18 months of age. The clinical features of NoV serum-positive cases were not different from NoV serum-negative cases. CONCLUSION: NoV RNA in serum is an uncommon finding limited to young children.