Estimates of Inactivated Influenza Vaccine Effectiveness Among Children in Senegal: Results From 2 Consecutive Cluster-Randomized Controlled Trials in 2010 and 2011.

BACKGROUND: We report results of years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal. METHODS: We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months-10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness. RESULTS: We vaccinated 74% of 12 408 age-eligible children in year 2 (June 2010-April 11) and 74% of 11 988 age-eligible children in year 3 (April 2011-December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (year 2) and 4.2 (year 3) per 100 mITT child vaccinees of IPV villages. In year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% confidence interval [CI], 32.3-67.0), and the population effectiveness was 36.0% (95% CI, 10.2-54.4) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI, 39.0-68.9). In year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The year 3 total effectiveness against LCI was -14.5% (95% CI, -81.2-27.6). Vaccine effectiveness varied by type/subtype of influenza in both years. CONCLUSIONS: IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation. CLINICAL TRIALS REGISTRATION: NCT00893906.

Impact of Rotavirus Vaccine Introduction in Children Less Than 2 Years of Age Presenting for Medical Care With Diarrhea in Rural Matlab, Bangladesh.

BACKGROUND: Following the conclusion of a human rotavirus vaccine (HRV) cluster-randomized, controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age. METHODS: Interrupted time series were used to estimate the impact of HRV introduction. We used diarrheal surveillance collected between 2000 and 2014 within the 2 service delivery areas (International Centre for Diarrhoeal Disease Research, Bangladesh [icddr,b] service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System, administered by icddr,b. Age group-specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea diagnoses of any severity presenting to the hospital. We used 2 models to assess the impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period, using outcomes from control-only villages. RESULTS: Both models demonstrated a downward trend in RV+ diarrheal incidences in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impacts of HRV on RV+ diarrhea incidences in GSA villages were not observed in either model. Differences in population-level impacts between the 2 delivery areas may be due to the varied rotavirus vaccine coverage and presentation rates to the hospital. CONCLUSIONS: This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies are needed of the rotavirus vaccine impact after the nationwide introduction in Bangladesh.

Effectiveness of Seasonal Influenza Vaccination in Children in Senegal During a Year of Vaccine Mismatch: A Cluster-randomized Trial.

BACKGROUND: The population effects of influenza vaccination in children have not been extensively studied, especially in tropical, developing countries. In rural Senegal, we assessed the total (primary objective) and indirect effectiveness of a trivalent inactivated influenza vaccine (IIV3). METHODS: In this double-blind, cluster-randomized trial, villages were randomly allocated (1:1) for the high-coverage vaccination of children aged 6 months through 10 years with either the 2008-09 northern hemisphere IIV3 or an inactivated polio vaccine (IPV). Vaccinees were monitored for serious adverse events. All village residents, vaccinated and unvaccinated, were monitored for signs and symptoms of influenza illness using weekly home visits and surveillance in designated clinics. The primary outcome was all laboratory-confirmed symptomatic influenza. RESULTS: Between 23 May and 11 July 2009, 20 villages were randomized, and 66.5% of age-eligible children were enrolled (3918 in IIV3 villages and 3848 in IPV villages). Follow-up continued until 28 May 2010. There were 4 unrelated serious adverse events identified. Among vaccinees, the total effectiveness against illness caused by the seasonal influenza virus (presumed to all be drifted A/H3N2, based on antigenic characterization data) circulating at high rates among children was 43.6% (95% confidence interval [CI] 18.6-60.9%). The indirect effectiveness against seasonal A/H3N2 was 15.4% (95% CI -22.0 to 41.3%). The total effectiveness against illness caused by the pandemic influenza virus (A/H1N1pdm09) was -52.1% (95% CI -177.2 to 16.6%). CONCLUSIONS: IIV3 provided statistically significant, moderate protection to children in Senegal against circulating, pre-2010 seasonal influenza strains, but not against A/H1N1pdm09, which was not included in the vaccine. No indirect effects were measured. Further study in low-resource populations is warranted. CLINICAL TRIALS REGISTRATION: NCT00893906.

Evaluation of a Booster Dose of Pentavalent Rotavirus Vaccine Coadministered With Measles, Yellow Fever, and Meningitis A Vaccines in 9-Month-Old Malian Infants.

Background: Rotavirus vaccines given to infants are safe and efficacious. A booster dose of rotavirus vaccine could extend protection into the second year of life in low-resource countries. Methods: We conducted an open-label, individual-randomized trial in Bamako, Mali. We assigned 600 infants aged 9-11 months to receive measles vaccine (MV), yellow fever vaccine (YFV), and meningococcal A conjugate vaccine (MenAV) with or without pentavalent rotavirus vaccine (PRV). We assessed the noninferiority (defined as a difference of ≤10%) of seroconversion and seroresponse rates to MV, YFV, and MenAV. We compared the seroresponse to PRV. Results: Seroconversion to MV occurred in 255 of 261 PRV recipients (97.7%) and 246 of 252 control infants (97.6%; difference, 0.1% [95% confidence interval {CI}, -4.0%-4.2%]). Seroresponse to YFV occurred in 48.1% of PRV recipients (141 of 293), compared with 52.2% of controls (153 of 293; difference, -4.1% [95% CI, -12.2%-4.0%]). A 4-fold rise in meningococcus A bactericidal titer was observed in 273 of 292 PRV recipients (93.5%) and 276 of 293 controls (94.2%; difference, -0.7% [95% CI, -5.2%-3.8%]). Rises in geometric mean concentrations of immunoglobulin A and immunoglobulin G antibodies to rotavirus were higher among PRV recipients (118 [95% CI, 91-154] and 364 [95% CI, 294-450], respectively), compared with controls (68 [95% CI, 50-92] and 153 [95% CI, 114-207], respectively). Conclusions: PRV did not interfere with MV and MenAV; this study could not rule out interference with YFV. PRV increased serum rotavirus antibody levels. Clinical Trials Registration: NCT02286895.

Significant Correlation Between the Infant Gut Microbiome and Rotavirus Vaccine Response in Rural Ghana.

BACKGROUND: Rotavirus (RV) is the leading cause of diarrhea-related death in children worldwide and 95% of RV-associated deaths occur in Africa and Asia where RV vaccines (RVVs) have lower efficacy. We hypothesize that differences in intestinal microbiome composition correlate with the decreased RVV efficacy observed in poor settings. METHODS: We conducted a nested, case-control study comparing prevaccination, fecal microbiome compositions between 6-week old, matched RVV responders and nonresponders in rural Ghana. These infants' microbiomes were then compared with 154 age-matched, healthy Dutch infants' microbiomes, assumed to be RVV responders. Fecal microbiome analysis was performed in all groups using the Human Intestinal Tract Chip. RESULTS: We analyzed findings in 78 Ghanaian infants, including 39 RVV responder and nonresponder pairs. The overall microbiome composition was significantly different between RVV responders and nonresponders (FDR, 0.12), and Ghanaian responders were more similar to Dutch infants than nonresponders (P = .002). RVV response correlated with an increased abundance of Streptococcus bovis and a decreased abundance of the Bacteroidetes phylum in comparisons between both Ghanaian RVV responders and nonresponders (FDR, 0.008 vs 0.003) and Dutch infants and Ghanaian nonresponders (FDR, 0.002 vs 0.009). CONCLUSIONS: The intestinal microbiome composition correlates significantly with RVV immunogenicity and may contribute to the diminished RVV immunogenicity observed in developing countries.

Effectiveness of a live oral human rotavirus vaccine after programmatic introduction in Bangladesh: A cluster-randomized trial.

BACKGROUND: Rotavirus vaccines are now globally recommended by the World Health Organization (WHO), but in early 2009 WHO's Strategic Advisory Group of Experts on Immunization reviewed available data and concluded that there was no evidence for the efficacy or effectiveness of a two-dose schedule of the human rotavirus vaccine (HRV; Rotarix) given early at 6 and 10 wk of age. Additionally, the effectiveness of programmatic rotavirus vaccination, including possible indirect effects, has not been assessed in low-resource populations in Asia. METHODS AND FINDINGS: In Bangladesh, we cluster-randomized (1:1) 142 villages of the Matlab Health and Demographic Surveillance System to include two doses of HRV with the standard infant vaccines at 6 and 10 wk of age or to provide standard infant vaccines without HRV. The study was initiated November 1, 2008, and surveillance was conducted concurrently at Matlab Diarrhoea Hospital and two community treatment centers to identify children less than 2 y of age presenting with acute rotavirus diarrhea (ARD) through March 31, 2011. Laboratory confirmation was made by enzyme immunoassay detection of rotavirus antigen in stool specimens. Overall effectiveness of the HRV vaccination program (primary objective) was measured by comparing the incidence rate of ARD among all children age-eligible for vaccination in villages where HRV was introduced to that among such children in villages where HRV was not introduced. Total effectiveness among vaccinees and indirect effectiveness were also evaluated. In all, 6,527 infants were age-eligible for vaccination in 71 HRV villages, and 5,791 in 71 non-HRV villages. In HRV villages, 4,808 (73.7%) infants received at least one dose of HRV. The incidence rate of ARD was 4.10 cases per 100 person-years in non-HRV villages compared to 2.8 per 100 person-years in HRV villages, indicating an overall effectiveness of 29.0% (95% CI, 11.3% to 43.1%). The total effectiveness of HRV against ARD among vaccinees was 41.4% (95% CI, 23.2% to 55.2%). The point estimate for total effectiveness was higher against ARD during the first year of life than during the second (45.2% versus 28.9%), but estimates for the second year of life lacked precision and did not reach statistical significance. Indirect effects were not detected. To check for bias in presentation to treatment facilities, we evaluated the effectiveness of HRV against acute diarrhea associated with enterotoxigenic Escherichia coli; it was 4.0% (95% CI, -46.5% to 37.1%), indicating that bias likely was not introduced. Thirteen serious adverse events were identified among recipients of HRV, but none were considered related to receipt of study vaccine. The main limitation of this study is that it was an open-label study with an observed-only control group (no placebo). CONCLUSIONS: The two-dose HRV rotavirus vaccination program significantly reduced medically attended ARD in this low-resource population in Asia. Protection among vaccinees was similar to that in other low-resource settings. In low-resource populations with high rotavirus incidence, large-scale vaccination across a wide population may be required to obtain the full benefit of rotavirus vaccination, including indirect effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00737503.

A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants.

BACKGROUND: The recommended schedule for receipt of 2-dose human rotavirus vaccine (HRV) coincides with receipt of the first and second doses of diphtheria, pertussis, and tetanus vaccine (ie, 6 and 10 weeks of age, respectively). Alternative schedules and additional doses of HRV have been proposed and may improve vaccine performance in low-income countries. METHODS: In this randomized trial in rural Ghana, HRV was administered at ages 6 and 10 weeks (group 1), 10 and 14 weeks (group 2), or 6, 10, and 14 weeks (group 3). We compared serum antirotavirus immunoglobulin A (IgA) seroconversion (≥20 U/mL) and geometric mean concentrations (GMCs) between group 1 and groups 2 and 3. RESULTS: Ninety-three percent of participants (424 of 456) completed the study per protocol. In groups 1, 2, and 3, the IgA seroconversion frequencies among participants with IgA levels of <20 U/mL at baseline were 28.9%, 37.4%, and 43.4%, respectively (group 1 vs group 3, P = .014; group 1 vs group 2, P = .163). Postvaccination IgA GMCs were 22.1 U/mL, 26.5 U/mL, and 32.6 U/mL in groups 1, 2, and 3, respectively (group 1 vs group 3, P = .038; group 1 vs group 2, P = .304). CONCLUSIONS: A third dose of HRV resulted in increased seroconversion frequencies and GMCs, compared with 2 doses administered at 6 and 10 weeks of age. Since there is no correlate of protection, a postmarketing effectiveness study is required to determine whether the improvement in immune response translates into a public health benefit in low-income countries. CLINICAL TRIALS REGISTRATION: NCT015751.

Noninterference of Rotavirus Vaccine With Measles-Rubella Vaccine at 9 Months of Age and Improvements in Antirotavirus Immunity: A Randomized Trial.

BACKGROUND: The burden of rotavirus morbidity and mortality is high in children aged <5 years in developing countries, and evaluations indicate waning protection from rotavirus immunization in the second year. An additional dose of rotavirus vaccine may enhance the immune response and lengthen the period of protection against disease, but coadministration of this dose should not interfere with immune responses to concurrently given vaccines. METHODS: A total of 480 9-month-old participants from Matlab, Bangladesh, were enrolled in a study with a primary objective to establish noninferiority of concomitant administration of measles-rubella vaccine (MR) and a third dose of human rotavirus vaccine (HRV; MR + HRV), compared with MR given alone. Secondary objectives included noninferiority of rubella antibody seroconversion and evaluating rotavirus IgA/IgG seroresponses in MR + HRV recipients. RESULTS: Two months after vaccination, 75.3% and 74.3% of MR + HRV and MR recipients, respectively, had seroprotective levels of measles virus antibodies; 100.0% and 99.6%, respectively, showed anti-rubella virus immunoglobulin G (IgG) seroprotection. In the MR + HRV group, antirotavirus immunoglobulin A and IgG seropositivity frequencies before vaccination (52.7% and 66.3%, respectively) increased to 69.6% and 88.3% after vaccination. CONCLUSIONS: Vaccine-induced measles and rubella antibody responses are not negatively affected by concomitant administration of HRV. The HRV dose increases antirotavirus serum antibody titers and the proportion of infants with detectable antirotavirus antibody. CLINICAL TRIALS REGISTRATION: NCT01700621.

Effect of human rotavirus vaccine on severe diarrhea in African infants.

BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)

Comparative efficacy of inactivated and live attenuated influenza vaccines.

BACKGROUND: The efficacy of influenza vaccines may vary from year to year, depending on a variety of factors, and may differ for inactivated and live attenuated vaccines. METHODS: We carried out a randomized, double-blind, placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007-2008 influenza season and estimated the absolute and relative efficacies of the two vaccines. RESULTS: A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007. Influenza activity occurred from January through April 2008, with the circulation of influenza types A (H3N2) (about 90%) and B (about 9%). Absolute efficacy against both types of influenza, as measured by isolating the virus in culture, identifying it on real-time polymerase-chain-reaction assay, or both, was 68% (95% confidence interval [CI], 46 to 81) for the inactivated vaccine and 36% (95% CI, 0 to 59) for the live attenuated vaccine. In terms of relative efficacy, there was a 50% (95% CI, 20 to 69) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine. The absolute efficacy against the influenza A virus was 72% (95% CI, 49 to 84) for the inactivated vaccine and 29% (95% CI, -14 to 55) for the live attenuated vaccine, with a relative efficacy of 60% (95% CI, 33 to 77) for the inactivated vaccine. CONCLUSIONS: In the 2007-2008 season, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A (predominately H3N2) in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00538512.)

Using social contact data to improve the overall effect estimate of a cluster-randomized influenza vaccination program in Senegal.

This study estimates the overall effect of two influenza vaccination programs consecutively administered in a cluster-randomized trial in western Senegal over the course of two influenza seasons from 2009-2011. We apply cutting-edge methodology combining social contact data with infection data to reduce bias in estimation arising from contamination between clusters. Our time-varying estimates reveal a reduction in seasonal influenza from the intervention and a nonsignificant increase in H1N1 pandemic influenza. We estimate an additive change in overall cumulative incidence (which was 6.13% in the control arm) of -0.68 percentage points during Year 1 of the study (95% CI: -2.53, 1.18). When H1N1 pandemic infections were excluded from analysis, the estimated change was -1.45 percentage points and was significant (95% CI, -2.81, -0.08). Because cross-cluster contamination was low (0-3% of contacts for most villages), an estimator assuming no contamination was only slightly attenuated (-0.65 percentage points). These findings are encouraging for studies carefully designed to minimize spillover. Further work is needed to estimate contamination - and its effect on estimation - in a variety of settings.

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rotavirus gastroenteritis causes many deaths in infants in sub-Saharan Africa. Because rotavirus vaccines have proven effective in developed countries but had not been tested in developing countries, we assessed efficacy of a pentavalent rotavirus vaccine against severe disease in Ghana, Kenya, and Mali between April, 2007, and March, 2009. METHODS: In our multicentre, double-blind, placebo-controlled trial, undertaken in rural areas of Ghana and Kenya and an urban area of Mali, we randomly assigned infants aged 4-12 weeks without symptoms of gastrointestinal disorders in a 1:1 ratio to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age. Infants with HIV infection were not excluded. Randomisation was done by computer-generated randomisation sequence in blocks of six. We obtained data for gastrointestinal symptoms from parents on presentation to health-care facilities and clinical data were obtained prospectively by clinicians. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11), detected by enzyme immunoassay, arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. FINDINGS: 5468 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=2733) or placebo (n=2735). 2357 infants assigned to vaccine and 2348 assigned to placebo were included in the per-protocol analysis. 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years in the vaccine group, compared with 129 cases in 2585.9 person-years in the placebo group, resulting in a vaccine efficacy against severe rotavirus gastroenteritis of 39.3% (95% CI 19.1-54.7, p=0.0003 for efficacy >0%). Median follow-up in both groups was 527 days starting 14 days after the third dose of vaccine or placebo was given. 42 (1.5%) of 2723 infants assigned to receive vaccine and 45 (1.7%) of 2724 infants assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was gastroenteritis (vaccine 17 [0.6%]; placebo 17 [0.6%]). INTERPRETATION: Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years. We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa. FUNDING: PATH (GAVI Alliance grant) and Merck.

Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam. METHODS: In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4-12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score >or=11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. FINDINGS: 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480-575). 38 cases of severe rotavirus gastroenteritis (Vesikari score >or=11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48.3% (95% CI 22.3-66.1) against severe disease (p=0.0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2.5%) of 1017 infants assigned to receive vaccine and 20 (2.0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1.2%]; placebo 15 [1.5%]). INTERPRETATION: In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use. FUNDING: PATH (GAVI Alliance grant) and Merck.

Hepatitis A vaccine versus immune globulin for postexposure prophylaxis.

BACKGROUND: Hepatitis A vaccine administered to persons after exposure to the hepatitis A virus has not been compared directly with immune globulin, which is known to be highly effective in preventing hepatitis A when given within 2 weeks after exposure to the virus. METHODS: We randomly assigned household and day-care contacts, 2 to 40 years of age, in Almaty, Kazakhstan, to receive one standard age-appropriate dose of hepatitis A vaccine or immune globulin within 14 days after exposure to patients with hepatitis A. Instances of laboratory-confirmed, symptomatic hepatitis A infection occurring between 15 and 56 days after exposure were then assessed during active follow-up of all susceptible contacts. RESULTS: Of 4524 contacts who underwent randomization, 1414 (31%) were susceptible to hepatitis A virus and 1090 were eligible for the per-protocol analysis. Among these contacts, 568 received hepatitis A vaccine and 522 received immune globulin. Most contacts were children (average age, 12 years), and most received prophylaxis during the second week after exposure (average interval after exposure, 10 days). The baseline characteristics of the contacts were similar in the two groups. Symptomatic infection with hepatitis A virus was confirmed in 25 contacts receiving vaccine (4.4%) and in 17 contacts receiving immune globulin (3.3%) (relative risk, 1.35; 95% confidence interval, 0.70 to 2.67). CONCLUSIONS: Low rates of hepatitis A in both groups indicate that hepatitis A vaccine and immune globulin provided good protection after exposure. Although the study's prespecified criterion for noninferiority was met, the slightly higher rates of hepatitis A among vaccine recipients may indicate a true modest difference in efficacy and might be clinically meaningful in some settings. Vaccine has other advantages, including long-term protection, and it may be a reasonable alternative to immune globulin for postexposure prophylaxis in many situations. (ClinicalTrials.gov number, NCT00139139 [ClinicalTrials.gov].).

Rotavirus vaccines for infants in developing countries in Africa and Asia: considerations from a world health organization-sponsored consultation.

The World Health Organization (WHO) and its international partners have prioritized the development of rotavirus vaccines for the past 3 decades. In November 2005, the WHO's Strategic Advisory Group of Experts first reviewed the clinical efficacy data from 2 new live attenuated oral rotavirus vaccines, which demonstrated excellent protective efficacy against severe rotavirus disease in regions where they were evaluated. Despite these successes, the WHO has urged the clinical evaluation of these vaccines in populations of Africa and Asia, where most of the deaths due to rotavirus occur, and has emphasized the need for ongoing postlicensure safety monitoring in countries introducing vaccines. Clinical studies in Africa and Asia will soon provide data on the efficacy of both new vaccines in these populations. A WHO international consultative meeting convened to evaluate how to use these imminent data for the future use of rotavirus vaccines in developing countries. In brief, it was agreed that (1) even vaccines with lesser efficacy in developing countries, compared with industrialized countries, would still lead to substantial public health benefits and would be cost-effective in saving lives in Africa and Asia; (2) criteria, such as the WHO mortality strata and local epidemiology of rotavirus infection, would be appropriate measures for extrapolating the clinical data to other regions and countries; and (3) research toward understanding the programmatic limitations of rotavirus vaccine use may help develop strategies to improve vaccine uptake and overall impact.

Immunogenicity of seasonal inactivated influenza and inactivated polio vaccines among children in Senegal: Results from a cluster-randomized trial.

Data on influenza vaccine immunogenicity in children are limited from tropical developing countries. We recently reported significant, moderate effectiveness of a trivalent inactivated influenza vaccine (IIV) in a controlled, cluster-randomized trial in children in rural Senegal during 2009, a year of H3N2 vaccine mismatch (NCT00893906). We report immunogenicity of IIV3 and inactivated polio vaccine (IPV) from that trial. We evaluated hemagglutination inhibition (HAI) and polio antibody titers in response to vaccination of three age groups (6 through 35 months, 3 through 5 years, and 6 through 8 years). As all children were IIV naïve, each received two vaccine doses, although titers were assessed after only the first dose for subjects aged 6 through 8 years. Seroconversion rates (4-fold titer rise or increase from <1:10 to ≥1:40) were 74-87% for A/H1N1, 76-87% for A/H3N2, and 54-79% for B/Yamagata. Seroprotection rates (HAI titer ≥ 1:40) were 79-88% for A/H1N1, 88-96% for A/H3N2, and 52-74% for B/Yamagata. IIV responses were lowest in the youngest age group, and they were comparable between ages 3 through 5 years after two doses and 6 through 8 years after one dose. We found that baseline seropositivity (HAI titer ≥ 1:10) was an effect modifier of IIV response. Using a seroprotective titer (HAI titer ≥ 1:160) recommended for IIV evaluation in children, we found that among subjects who were seropositive at baseline, 69% achieved seroprotection for both A/H1N1 and A/H3N2, while among those who were seronegative at baseline, seroprotection was achieved in 11% for A/H1N1 and 22% for A/H3N2. The IPV group had high baseline polio antibody seropositivity and appropriate responses to vaccination. Our data emphasize the importance of a two-dose IIV3 series in vaccine naïve children. IIV and IPV vaccines were immunogenic in Senegalese children.

Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines.

BACKGROUND: The efficacy of influenza vaccines may decline during years when the circulating viruses have antigenically drifted from those included in the vaccine. METHODS: We carried out a randomized, double-blind, placebo-controlled trial of inactivated and live attenuated influenza vaccines in healthy adults during the 2004-2005 influenza season and estimated both absolute and relative efficacies. RESULTS: A total of 1247 persons were vaccinated between October and December 2004. Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A (H3N2) virus, the A/California/07/2004-like strain, and of type B viruses from two lineages. The absolute efficacy of the inactivated vaccine against both types of virus was 77% (95% confidence interval [CI], 37 to 92) as measured by isolating the virus in cell culture, 75% (95% CI, 42 to 90) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction, and 67% (95% CI, 16 to 87) as measured by either isolating the virus or observing a rise in the serum antibody titer. The absolute efficacies of the live attenuated vaccine were 57% (95% CI, -3 to 82), 48% (95% CI, -7 to 74), and 30% (95% CI, -57 to 67), respectively. The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses. CONCLUSIONS: In the 2004-2005 season, in which most circulating viruses were dissimilar to those included in the vaccine, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic illnesses from influenza in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00133523.)

Networks of face-to-face social contacts in Niakhar, Senegal.

We present the first analysis of face-to-face contact network data from Niakhar, Senegal. Participants in a cluster-randomized influenza vaccine trial were interviewed about their contact patterns when they reported symptoms during their weekly household surveillance visit. We employ a negative binomial model to estimate effects of covariates on contact degree. We estimate the mean contact degree for asymptomatic Niakhar residents to be 16.5 (95% C.I. 14.3, 18.7) in the morning and 14.8 in the afternoon (95% C.I. 12.7, 16.9). We estimate that symptomatic people make 10% fewer contacts than asymptomatic people (95% C.I. 5%, 16%; p = 0.006), and those aged 0-5 make 33% fewer contacts than adults (95% C.I. 29%, 37%; p < 0.001). By explicitly modelling the partial rounding pattern observed in our data, we make inference for both the underlying (true) distribution of contacts as well as for the reported distribution. We created an estimator for homophily by compound (household) membership and estimate that 48% of contacts by symptomatic people are made to their own compound members in the morning (95% CI, 45%, 52%) and 60% in the afternoon/evening (95% CI, 56%, 64%). We did not find a significant effect of symptom status on compound homophily. We compare our findings to those from other countries and make design recommendations for future surveys.