The Adjuvanted Recombinant Zoster Vaccine Confers Long-Term Protection Against Herpes Zoster: Interim Results of an Extension Study of the Pivotal Phase 3 Clinical Trials ZOE-50 and ZOE-70.

BACKGROUND: This ongoing follow-up study evaluated the persistence of efficacy and immune responses for 6 additional years in adults vaccinated with the glycoprotein E (gE)-based adjuvanted recombinant zoster vaccine (RZV) at age ≥50 years in 2 pivotal efficacy trials (ZOE-50 and ZOE-70). The present interim analysis was performed after ≥2 additional years of follow-up (between 5.1 and 7.1 years [mean] post-vaccination) and includes partial data for year (Y) 8 post-vaccination. METHODS: Annual assessments were performed for efficacy against herpes zoster (HZ) from Y6 post-vaccination and for anti-gE antibody concentrations and gE-specific CD4[2+] T-cell (expressing ≥2 of 4 assessed activation markers) frequencies from Y5 post-vaccination. RESULTS: Of 7413 participants enrolled for the long-term efficacy assessment, 7277 (mean age at vaccination, 67.2 years), 813, and 108 were included in the cohorts evaluating efficacy, humoral immune responses, and cell-mediated immune responses, respectively. Efficacy of RZV against HZ through this interim analysis was 84.0% (95% confidence interval [CI], 75.9-89.8) from the start of this follow-up study and 90.9% (95% CI, 88.2-93.2) from vaccination in ZOE-50/70. Annual vaccine efficacy estimates were >84% for each year since vaccination and remained stable through this interim analysis. Anti-gE antibody geometric mean concentrations and median frequencies of gE-specific CD4[2+] T cells reached a plateau at approximately 6-fold above pre-vaccination levels. CONCLUSIONS: Efficacy against HZ and immune responses to RZV remained high, suggesting that the clinical benefit of RZV in older adults is sustained for at least 7 years post-vaccination. Clinical Trials Registration. NCT02723773.

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.

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.

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.

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.

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.

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.

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.