Four-year safety follow-up of the tetravalent dengue vaccine efficacy randomized controlled trials in Asia and Latin America.

OBJECTIVE: Our objective was to describe the risk of hospital admission for virologically confirmed dengue (VCD) and the risk of clinically severe hospitalized VCD occurring up to 4 years after the first dose (years 1 to 4) in three randomized clinical trials comparing tetravalent dengue vaccine with placebo. METHODS: The relative risks (RR) for hospitalized VCD from first dose to year 4 were estimated by year and age-group in individual and combined studies. RESULTS: Overall, from Year 1 to Year 4, 233 and 228 participants had at least one episode of hospitalized VCD in the vaccinated (n = 22 603) and placebo (n = 11 301) groups, respectively (RR = 0.511, 95% CI 0.42-0.62). Among these, 48 and 47 cases, respectively, were classified as clinically severe. In children aged ≥9 years, 88 and 136 participants had at least one episode of hospitalized VCD in the vaccinated (n = 17 629) and placebo (n = 8821) groups, respectively (RR = 0.324; 95% CI 0.24-0.43). In vaccinated participants aged <9 years, particularly in those aged 2-5 years, there were more hospitalized VCD cases compared with the control participants in Year 3 but not in Year 4. The overall RR in those aged <9 years for Year 1 to Year 4 was 0.786 (95% CI 0.60-1.03), with a higher protective effect in the 6-8 year olds than in the 2-5 year olds. CONCLUSIONS: The overall benefit-risk remained positive in those aged ≥9 years up to year 4, although the protective effect was lower in years 3 and 4 than in years 1 and 2.

Three Decades of Dengue Surveillance in Five Highly Endemic South East Asian Countries.

We described and quantified epidemiologic trends in dengue disease burden in 5 Asian countries (Indonesia, Thailand, Malaysia, Philippines, and Vietnam) and identified and estimated outbreaks impact over the last 3 decades. Dengue surveillance data from 1980 to 2010 were retrieved from DengueNet and from World Health Organization sources. Trends in incidence, mortality, and case fatality rate (CFR) were systematically analyzed using annual average percent change (AAPC), and the contribution of epidemic years identified over the observation period was quantified. Over the 30-year period, incidence increased in all countries (AAPC 1980-2010: 6.7% in Thailand, 10.4% in Vietnam, 12.0% in Indonesia, 18.1% in Malaysia, 24.4% in Philippines). Mortality also increased in Indonesia, Malaysia, and Philippines (AAPC: 6.8%, 7.0%, and 29.2%, respectively), but slightly decreased in Thailand and Vietnam (AAPC: -1.3% and -2.5%), and CFR decreased in all countries (AAPC: -4.2% to -8.3%). Epidemic years, despite representing less than a third of the observation period, contributed from 1 to 3 times more cases versus nonepidemic years. Implementation of more sensitive surveillance methods over the study period may have contributed to a reporting or ascertainment bias in some countries. Nonetheless, these data support the urgent need for novel, integrated, or otherwise effective dengue prevention and control tools and approaches.

Safety and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (IMOJEV®) in children.

JE-CV (IMOJEV®, Sanofi Pasteur, France) is a live attenuated virus vaccine constructed by inserting coding sequences of the prM and E structural proteins of the Japanese encephalitis SA14-14-2 virus into the genome of yellow fever 17D virus. Primary immunization with JE-CV requires a single dose of the vaccine. This article reviews clinical trials of JE-CV in children aged up to 6 years conducted in countries across South-East Asia. Strong and persistent antibody responses were observed after single primary and booster doses, with 97% of children seroprotected up to five years after booster vaccination. Models of long-term antibody persistence predict a median duration of protection of approximately 30 years after a booster dose. The safety and reactogenicity profiles of JE-CV primary and booster doses are comparable to other widely used childhood vaccines.

Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Human rotavirus vaccine (HRV; i.e., Rotarix) reduced the incidence of severe rotavirus gastroenteritis (RVGE) by 77% (95% Confidence interval: 56-88%) during the first year of life in South Africa. Persistence of HRV-derived protection against RVGE during subsequent rotavirus seasons, although evident in industrialized settings, remains to be established in African settings. This study reports on the efficacy of HRV against severe RVGE over two consecutive rotavirus seasons in South African children. METHODS: A prospective, double-blind, placebo controlled multi-centered trial in South Africa and Malawi randomly assigned infants in a 1:1:1 ratio to receive either two (10 and 14 weeks; HRV_2D) or three (6, 10 and 14 weeks; HRV_3D) doses of HRV or placebo. The primary analysis involved pooling of HRV_2D and HRV_3D arms. Episodes of gastroenteritis caused by wild-type rotavirus were identified through active follow-up surveillance and graded by the Vesikari scale. RESULTS: 1339 infants (447 in the HRV_2D group, 447 in the HRV_3D group and 445 in the placebo group) were enrolled in Year 2 of the study, including 1035 (77.3%) who were followed up over two consecutive rotavirus seasons (i.e., Cohort 2 subjects). Rotarix was associated with ongoing protection against severe RVGE, preventing 2.5 episodes per 100 vaccinated children over two consecutive rotavirus seasons; vaccine efficacy: 59% (95% Confidence interval: 1-83%). An exploratory analysis indicated better immunogenicity (among Cohort 1 subjects) and a higher point-efficacy estimate over two seasons in the HRV_3D compared to HRV_2D arms of the study in Cohort 2 subjects. CONCLUSION: Rotarix is associated with significant reductions in severe gastroenteritis episodes through 2 years of life among South African children. Further research is needed to determine the optimal dosing schedule of Rotarix in providing long-term protection against rotavirus illness in African children.

Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 oral suspension (liquid formulation) in Finnish infants.

The lyophilized formulation of a human rotavirus vaccine, Rotarix™ (RIX4414) is highly immunogenic. In order to comply with the World Health Organization's (WHO) recommendation, a liquid formulation of the vaccine that does not require reconstitution was developed. The immunogenicity, reactogenicity and safety of the liquid formulation were compared with lyophilized formulation in two Finnish studies. In Study A infants aged 6-12 weeks received two doses of the lyophilized or liquid formulation of the vaccine or placebo following a 0,1 month schedule. In Study B, infants aged 10-17 weeks received two doses of either liquid or lyophilized formulation of the vaccine. In both studies, anti-rotavirus IgA antibodies were assessed pre-vaccination and one month post-Dose 2. In Study A, the anti-rotavirus seroconversion rate was 90% (95% CI: 81.2-95.6%) and 83.7% (95% CI: 74.2-90.8%) in the groups that received the liquid and the lyophilized formulation of RIX4414, respectively; the respective anti-rotavirus IgA seroconversion rates in Study B were 88.6% (95% CI: 86.1-90.8%) and 90.5% (95% CI: 86.2-93.8%). Reactogenicity and safety profiles of the two vaccine formulations were similar. Liquid formulation of the rotavirus vaccine allows greater flexibility in supply and reduces logistical costs.

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.

Psorospermium haeckelii: a cause of pseudoparasitosis.

A 42-year-old man had nausea, vomiting, periumbilical pain, tenesmus, and diarrhea shortly after eating seafood. Stool microscopy showed "beaver bodies," or Psorospermium haeckelii, a nonpathogenic algal organism often confused with enteric pathogens and commonly found in the excrement of persons consuming crayfish.

Intestinal secretory immunoglobulin A response to enteroaggregative Escherichia coli in travelers with diarrhea.

We examined stool samples from travelers for secretory immunoglobulin A (sIgA) to enteroaggregative Escherichia coli (EAEC) during episodes of acute diarrhea. Ten paired samples from 10 patients with diarrhea caused by EAEC were examined for the presence of specific sIgA by dot blot and Western blot immunoassays. Five samples were positive by dot blotting, and two samples were positive by Western blotting.

Markers of enteric inflammation in enteroaggregative Escherichia coli diarrhea in travelers.

As part of a traveler's diarrhea study carried out in Guadalajara, Mexico, and Goa, India, we conducted a case control study to evaluate fecal markers of enteric inflammation in three groups. Forty-five cases of enteroaggregative Escherichia coli (EAEC) diarrhea were compared to 56 controls with enterotoxigenic E. coli (ETEC) diarrhea, and 126 controls with diarrhea without identifiable pathogens. For EAEC cases we found fecal leukocytes, occult blood, and lactoferrin in 13 (28.9%), 14 (31.1%), and 27 (60.0%) patients, respectively; for ETEC controls they were 15 (26.8%), 16 (28.6%), and 15 (26.8%) respectively; and for patients without identifiable pathogens 19 (15.1%), 34 (27.0%) and 27 (21.4%) were seen for the presence of a positive fecal lactoferrin test in EAEC cases was statistically significant compared to both control groups. The study provides evidence that EAEC infection is associated with an intestinal inflammatory response.

HIV trends in African blood donors.

OBJECTIVES: To assess trends over the last 12 years in HIV-1/HIV-2 seroprevalence among blood donors in African nations and to correlate trends with national AIDS policies, with the purpose of preventing future cases. METHODS: Using collated data of African seroepidemiologic studies published by the U.S. Bureau of the Census, we established a best-fit linear trend, determined by regression analysis of HIV-1 and HIV-2 seroprevalence values for African blood donors against time, with adjustments for sample size of reported studies. RESULTS: Among 38 nations with sufficient data, 11 showed increases in HIV-1 seroprevalence, six showed decreases and 21 showed no significant changes. Decreases were seen primarily in nations with a high HIV-1 seroprevalence before 1989 (P<0.001, Chi-square). HIV-2 seroprevalence decreased in all nations where it was tested except Nigeria. There was a moderate correlation between decreases in HIV-1 and HIV-2 seroprevalence values (correlation coefficient = 0.39). No significant correlations between HIV policies and subsequent HIV-1 seroprevalence trends among blood donors and HIV patients were detected. CONCLUSIONS: A great disparity exists in trends in HIV-1 seroprevalence among African nations. HIV-2 seroprevalence is consistently decreasing throughout most of West Africa, the exception being Nigeria. The absence of any significant correlation between HIV seroprevalence trends and healthcare policies suggests that other factors are more influential than national policy in determining such trends and, by extrapolation, trends in AIDS prevalence.