Timo Vesikari

Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes.

65 episodes of rotavirus diarrhoea, detected during a longitudinal follow-up of 336 infants from birth to 24-32 months of age, were analyzed for clinical symptoms. Rotavirus gastroenteritis was characterized by watery diarrhoea, vomiting (particularly in older children), fever and dehydration. A 0-20 point numerical score was devised according to the distribution of clinical features in the patients. Using this system, the mean severity score for the 65 episodes of rotavirus diarrhoea was 11.0 +/- 3.7 as compared to 5.6 +/- 3.2 for the 183 episodes of non-rotavirus diarrhoea in the same population (p less than 0.0001, t-test). The 20 point score is proposed for analysis of efficacy studies of candidate rotavirus vaccines.

Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis

We compared different lactic acid bacteria for their effect on the immune response to rotavirus in children with acute rotavirus gastroenteritis. After initial oral rehydration, 49 children aged 6 to 35 months with rotavirus gastroenteritis randomly received cither Lactobacillus casei subsp. casei strain GG (LGG), L. casei subsp. rhamnosus (Lactophilus), or a combination of Streptococcus thermophilus and L. delbriickii subsp. bulgaricus (Yalacta) twice daily for 5 days. Serum antibodies to rotavirus, total number of immunoglobulin-secrcting cells (ISC), and specific antibody-secreting cells (sASC) to rotavirus were measured at the acute stage and at convalescence. The mean (SD) duration of diarrhea was 1.8 (0.8) days in children who received LGG, 2.8 (1.2) days in those receiving Lactophilus, and 2.6 (1.4) days in those receiving Yalacta (F = 3.3, p = 0.04). The ISC response was comparable in the three study groups, but the rotavirus-specific immune responses were different. LGG therapy was associated with an enhancement of IgA sASC to rotavirus and serum IgA antibody level at convalescent stage. We conclude that certain strains of lactic acid bacteria, particularly LGG, promote serum and intestinal immune responses to rotavirus, and thus may be important in establishing immunity against rotavirus reinfections

Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study

BACKGROUND We aimed to assess the efficacy of the oral live attenuated human rotavirus vaccine Rotarix (RIX4414) for prevention of rotavirus gastroenteritis in European infants during their first 2 years of life. METHODS 3994 study participants were enrolled from six countries and were randomly assigned two oral doses of either RIX4414 (n=2646) or placebo (n=1348), which were coadministered with the first two doses of specific childhood vaccinations. Follow-up for gastroenteritis episodes was undertaken from 2 weeks post-dose two through the two consecutive rotavirus seasons following vaccinations (combined efficacy follow-up period; mean duration 17 months [SD 1.6]). Our primary endpoint was vaccine efficacy against rotavirus gastroenteritis of any severity during the first efficacy follow-up period (2 weeks post-dose two to the end of the first rotavirus season). Stool specimens obtained during gastroenteritis episodes were tested for rotavirus by ELISA and typed by RT-PCR. Episodes scoring 11 or greater on the 20-point Vesikari scale were classified as severe. Analysis was according to protocol. This study is registered with ClinicalTrials.gov, number NCT00140686 (eTrack102247). FINDINGS 120 infants were excluded from the according-to-protocol analysis. During the first efficacy follow-up period (mean duration 5.7 months [SD 1.2]), 24 of 2572 infants allocated RIX4414 versus 94 of 1302 given placebo had rotavirus gastroenteritis episodes of any severity, resulting in a vaccine efficacy of 87.1% (95% CI 79.6-92.1; p<0.0001). For the combined efficacy follow-up period, vaccine efficacy against severe rotavirus gastroenteritis was 90.4% (85.1-94.1; p<0.0001), for admission owing to rotavirus gastroenteritis 96.0% (83.8-99.5; p<0.0001), and for rotavirus-related medical attention 83.8% (76.8-88.9; p<0.0001), and significant protection against severe rotavirus gastroenteritis by circulating G1, G2, G3, G4, and G9 rotavirus types was shown. INTERPRETATION In a European setting, two doses of RIX4414 coadministered with childhood vaccines provided high protection against any and severe rotavirus gastroenteritis, with an overall reduction of admissions for gastroenteritis over two consecutive rotavirus epidemic seasons.

Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children.

BACKGROUND Certain strains of lactobacilli may promote recovery from acute diarrhea. Lactobacillus reuteri is of human origin and is a natural colonizer of gastrointestinal tract. In this trial, exogenously administered L. reuteri was studied as a therapeutic agent in acute diarrhea. METHODS Forty patients between 6 and 36 months of age hospitalized with acute diarrhea (75% rotavirus) were studied. After parental consent, the patients were randomized to one of two treatment groups to receive either 10(10) to 10(11) colony-forming units of L. reuteri or a matching placebo daily for the length of hospitalization or up to 5 days. The clinical outcome of diarrhea and colonization of L. reuteri were evaluated. RESULTS The mean (SD) duration of watery diarrhea after treatment was 1.7 (1.6) days in the L. reuteri group and 2.9 (2.3) days in the placebo group (p = 0.07). On the second day of treatment only 26% of patients receiving L. reuteri had watery diarrhea, compared with 81% of those receiving placebo (p = 0.0005). Cultures of lactobacilli from stool samples demonstrated that administration of L. reuteri resulted in colonization of the gastrointestinal tract. Lactobacillus reuteri accounted for > 75% of the total lactobacilli found in children fed with this product. CONCLUSIONS Lactobacillus reuteri is effective as a therapeutic agent in acute rotavirus diarrhea in children. Further studies are warranted to confirm the present finding and to explore the full therapeutic potential of L. reuteri in acute viral diarrhea.

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

BACKGROUND In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response. METHODS We conducted a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults. RESULTS A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups. CONCLUSIONS The HZ/su vaccine significantly reduced the risk of herpes zoster in adults who were 50 years of age or older. Vaccine efficacy in adults who were 70 years of age or older was similar to that in the other two age groups. (Funded by GlaxoSmithKline Biologicals; ZOE-50 ClinicalTrials.gov number, NCT01165177.).

Improved immunogenicity of oral D x RRV reassortant rotavirus vaccine by Lactobacillus casei GG

In a search for new strategies to improve oral vaccination, the effect of orally administered Lactobacillus casei strain GG (LGG) in conjunction with D x RRV rhesus-human reassortant live oral rotavirus vaccine was tested in 2-5-month-old infants. Infants who received LGG showed an increased response with regard to rotavirus-specific IgM secreting cells, measured using an ELISPOT technique, on day 8 after vaccination. In infants receiving LGG or placebo, respectively, a rotavirus IgM seroconversion was detected in 26/27 (96%), versus 23/27 (85%) cases (p = 0.15) and rotavirus IgA seroconversion was detected in 26/28 (93%) versus 20/27 (74%) cases (p = 0.05). These findings suggest that LGG has an immunostimulating effect on oral rotavirus vaccination. The clinical significance of LGG-enhanced immune responses to oral vaccines should be further evaluated.

Burden of rotavirus disease in European Union countries.

Two new rotavirus vaccines are expected to be introduced in the European Union (EU) in coming years. A human rotavirus vaccine has already been licensed in several countries worldwide, and a pentavalent bovine vaccine has been submitted for licensure in the United States and the EU. Few data exist on the burden of rotavirus disease and its associated costs within the EU. To estimate the burden of rotavirus disease in the EU, we adapted a model based on the approach developed by the Centers for Disease Control and Prevention to the European situation and applied it to recent population and mortality data from European countries. Country-specific estimates were added to obtain a global estimate of rotavirus episodes treated at home, clinic visits, hospitalization and death. We estimate that 3.6 million episodes of rotavirus disease occur annually among the 23.6 million children younger than 5 years of age in the EU. Every year, rotavirus accounts for 231 deaths, >87,000 hospitalizations and almost 700,000 outpatient visits. Rotavirus disease constitutes a large public health burden in the EU. Except for deaths, the burden of disease is not dissimilar to that in the developing world. Country-specific studies are required to more accurately understand the burden of disease caused by rotavirus. With the introduction of new rotavirus vaccines in sight, rotavirus gastroenteritis may be regarded as the single most frequent vaccine-preventable disease among children in the EU.

Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis

BACKGROUND Rotavirus is the most common cause of acute childhood gastroenteritis. Vaccination with live oral heterologous rotavirus vaccines may prevent rotavirus gastroenteritis. We assessed the efficacy of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) against severe rotavirus gastroenteritis in Finnish children in a randomised placebo-controlled double-blind trial. METHODS Placebo or RRV-TV (titre 4x10(5) plaque-forming units) was given to infants at ages 2, 3, and 5 months. The children were followed up for one or two rotavirus epidemic seasons. The main outcome measure was protection against severe rotavirus gastroenteritis (score > or =11 on a 20-point severity scale). 2398 children were enrolled and received at least one dose of RRV-TV (n=1191) or placebo (n=1207). The primary efficacy analysis was based on children who received three doses of RRV-TV (n=1128) or placebo (n=1145). FINDINGS 256 episodes of rotavirus gastroenteritis occurred at any time during the study; 65 were among 1191 RRV-TV recipients, and 191 among 1207 placebo recipients (vaccine efficacy 66% [95% CI 55-74]; intention-to-treat analysis). 226 episodes were included in the primary efficacy analysis of fully vaccinated children (54 among 1128 RRV-TV recipients, 172 among 1145 placebo recipients; vaccine efficacy 68% [57-76]). 100 episodes were severe, eight in RRV-TV recipients and 92 in placebo recipients (vaccine efficacy 91% [82-96]). INTERPRETATION RRV-TV vaccine was highly effective against severe rotavirus gastroenteritis in young children. Incorporation of this vaccine into routine immunisation schedules of infants could reduce severe rotavirus gastroenteritis by 90% and severe gastroenteritis of all causes in young children by 60%.

Bacteriotherapy with Lactobacillus reuteri in rotavirus gastroenteritis

BACKGROUND Certain lactic acid bacteria may accelerate recovery from acute diarrhea. Lactobacillus reuteri is a commonly occurring Lactobacillus species with therapeutic potential in diarrhea. DESIGN Prospective, randomized, placebo-controlled trial in two hospitals. METHODS Children between 6 and 36 months of age admitted for rotavirus-associated diarrhea were randomized into three groups to receive either 10(10) or 10(7) colony-forming units (cfu) of L. reuteri or a matching placebo once a day for up to 5 days. RESULTS The main effect of L. reuteri was on the duration of watery diarrhea. The mean (+/-SD) duration of watery diarrhea after initiation of treatment was 2.5 (1.5) days in the placebo group (n = 25) vs. 1.9 (0.9) days in the small dosage (n = 20) and 1.5 (1.1) days in the large dosage (n = 21) L. reuteri recipients (P = 0.01). By the second day of treatment watery diarrhea persisted in 80% of the placebo, 70% of the small dosage and 48% of the large dosage L. reuteri recipients (P = 0.04, large dosage vs. placebo). Stool cultures for lactobacilli confirmed that administration of L. reuteri resulted in good colonization of the GI tract. The mean (+/-SD) of total Lactobacillus count 2 days after treatment initiation was 2.8 (1.6) log 10 cfu/g in the placebo group, 4.5 (2.0) log 10 cfu/g in the small dosage L. reuteri group and 6.1 (1.2) log 10 cfu/g in the large dosage L. reuteri group (P = 0.0004). CONCLUSIONS L. reuteri effectively colonized the gastrointestinal tract after administration and significantly shortened the duration of watery diarrhea associated with rotavirus. There was a correlation between the dosage of L. reuteri and the clinical effect.

Viable versus inactivated lactobacillus strain GG in acute rotavirus diarrhoea.

The effect of viable or heat inactivated human Lactobacillus casei strain GG on rotavirus immune responses in patients with rotavirus diarrhoea was assessed. Rotavirus serum IgA enzyme immunoassay antibody responses were higher in infants treated with viable L casei strain GG than in those treated with inactivated L casei strain GG. There was a significant difference at convalescence with rotavirus specific IgA secreting cells found in 10/12 infants receiving viable but only 2/13 infants receiving inactivated L casei strain GG. The results indicate that viable L casei strain GG stimulate rotavirus specific IgA antibody responses, theoretically significant in the prevention of reinfections.