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Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

ABSTRACT: Background:The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence. Methods:In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially immune after their first rotavirus diarrhea (RVD) episode. We then simulated trial cohorts to estimate the expected impact of prior exposure on efficacy estimates for varying rotavirus incidence rates and vaccine efficacies. Results:Accounting for natural immunity increased the per-protocol vaccine efficacy estimate against severe RVD from 63.1% (95% confidence interval [CI], 33.0%-79.7%) to 70.2% (95% CI, 44.5%-84.0%) in the postvaccination period, and original year 2 efficacy was underestimated by 14%. The simulations demonstrated that this expected impact increases linearly with RVD incidence, will be greatest for vaccine efficacies near 50%, and can reach 20% in settings with high incidence and low efficacy. Conclusions:High rotavirus incidence leads to predictably lower vaccine efficacy estimates due to the acquisition of natural immunity in unvaccinated children, and this phenomenon should be considered when comparing efficacy estimates across settings. Clinical Trials Registration:NCT01375647.

SUBMITTER: Rogawski ET

PROVIDER: S-EPMC5853827 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

Rogawski Elizabeth T ET Platts-Mills James A JA Colgate E Ross ER Haque Rashidul R Zaman K K Petri William A WA Kirkpatrick Beth D BD

The Journal of infectious diseases 20180301 6

<h4>Background</h4>The low efficacy of rotavirus vaccines in clinical trials performed in low-resource settings may be partially explained by acquired immunity from natural exposure, especially in settings with high disease incidence.<h4>Methods</h4>In a clinical trial of monovalent rotavirus vaccine in Bangladesh, we compared the original per-protocol efficacy estimate to efficacy derived from a recurrent events survival model in which children were considered naturally exposed and potentially ...[more]

PMID: 29514306

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Project description:BackgroundOral, live-attenuated rotavirus vaccines suffer from impaired immunogenicity and efficacy in low-income countries. Increasing the inoculum of vaccine might improve vaccine response, but this approach has been inadequately explored in low-income countries.MethodsWe performed a double-blind, parallel group, randomized controlled trial from June 2017 through June 2018 in the urban Mirpur slum of Dhaka, Bangladesh to compare vaccine take (primary outcome) among healthy infants randomized to receive either the standard dose or double the standard dose of oral Rotarix (GlaxoSmithKline) vaccine at 6 and 10 weeks of life. Infants with congenital malformations, birth or enrollment weight <2000 gm, known immunocompromising condition, enrollment in another vaccine trial, or other household member enrolled in the study were excluded. Infants were randomized using random permuted blocks. Vaccine take was defined as detection of post-vaccination fecal vaccine shedding by real-time reverse transcription polymerase chain reaction with sequence confirmation or plasma rotavirus-specific immunoglobulin A (RV-IgA) seroconversion 4 weeks following the second dose.Results220 infants were enrolled and randomized (110 per group). 97 standard-dose and 92 high-dose infants completed the study per-protocol. For the primary outcome, no significant difference was observed between groups: vaccine take occurred in 62 (67%) high-dose infants versus 69 (71%) standard-dose infants (RR 0.92, 95% CI 0.67-1.24). However, in post-hoc analysis, children with confirmed vaccine replication had significantly increased RV-IgA responses, independent of the intervention. No significant adverse events related to study participation were detected.ConclusionsAdministration of double the standard dose of an oral, live-attenuated rotavirus vaccine (Rotarix) did not improve vaccine take among infants in urban Dhaka, Bangladesh. However, improved immunogenicity in children with vaccine replication irrespective of initial inoculum provides further evidence for the need to promote in-host replication and improved gut health to improve oral vaccine response in low-income settings. ClinicalTrials.gov: NCT02992197.

Project description:Dengue, the most important mosquito-borne viral disease of humans is a recurring global health problem. In Bangladesh, dengue outbreaks are on the increase despite the efforts of government and it is not clear what the understanding of the general Dhaka population towards dengue fever is. Knowledge, attitude and practice (KAP) studies are essential guides in public health interventions. Hence, using KAP, this study aims to assess patient-perspectives with regards to factors associated with dengue, as well as investigate the associated factors between the two corporations in Dhaka. A Hospital-based cross-sectional study of 242 fever patients from two city-corporations in Dhaka (Dhaka North City Corporations, DNCC (n = 91, 37.6%) and Dhaka South City Corporation, DSCC (n = 151, 62.4%) was conducted using pre-tested KAP items. Wilcoxon's Rank Sum was used to determine the KAP by DNCC, DSCC and both corporations and multivariate Poisson regression analyses. The two corporations were analysed separately due to the differences in income distribution, concentration of slums, hospitals and clinics. The study found that more than half of the study population were knowledgeable about dengue (mean percentage scores was 52%), possess an appropriate and acceptable attitude towards the disease (69.2%), and about two thirds of the respondents (71.4%) engaged in practices towards its prevention. After adjusting for the potential cofounders, the factors associated with KAP about dengue fever varied between DNCC and DSCC; with duration of residency and use of mosquito nets were associated with knowledge in the north while income class and age were associated with knowledge and attitude in the south. In the pooled analysis (combining both corporations), knowledge of dengue was associated with good practice towards dengue fever among the respondents. The duration of residence in Dhaka (10+ years), not using mosquito nets and length of time spent in the hospital (7+ days) due to dengue, and decreased knowledge (Adjusted coefficient (β) = -0.01, 95%CI: -0.02, -0.01) were associated with attitude towards dengue in DNCC. On the other hand, middle-high income class, age (40+ years) and increased knowledge were associated with practice towards dengue in DSCC (β = 0.02, 95%CI: 0.01, 0.03). Efforts to increase knowledge about dengue fever through education by the administrations of both corporations would benefit from targeting these high-risk groups for a more sustainable outcome.

Project description:BackgroundDengue virus (DENV) activity has been reported in Dhaka, Bangladesh since the early 1960s with the greatest burden of dengue fever and dengue hemorrhagic fever cases observed in 2000. Since this time, the intensity of dengue activity has varied from year to year, and its determining factors remained relatively unknown. In light of such gaps in knowledge, the main objectives of this study were to determine the magnitude of seroprevalence and seroconversion among the surveyed population, and establish the individual/household level risk factors for the presence of DENV antibodies among all age groups of target populations in the city of Dhaka.Methodology/principal findingsConsidering the lack of fine scale investigations on the factors driving dengue activity in Bangladesh, a prospective cohort study involving serological surveys was undertaken with participant interviews and blood donation across the city of Dhaka in 2012. Study participants were recruited from 12 of 90 wards and blood samples were collected during both the pre-monsoon (n = 1125) and post-monsoon (n = 600) seasons of 2012. The findings revealed that the seroprevalence in all pre-monsoon samples was 80.0% (900/1125) while the seropositivity in the pre-monsoon samples that had paired post-monsoon samples was 83.3% (503/600). Of the 97 paired samples that were negative at the pre-monsoon time point, 56 were positive at the post-monsoon time point. This resulted in a seroprevalence of 93.2% (559/600) among individuals tested during the post-monsoon period. Seroprevalence trended higher with age with children exhibiting a lower seropositivity as compared to adults. Results from this study also indicated that DENV strains were the only flaviviruses circulating in Dhaka in 2012. A multivariate analysis revealed that age, possession of indoor potted plants, and types of mosquito control measures were significant factors associated with DENV seroprevalence; while attendance in public/mass gatherings, and use of mosquito control measures were significantly associated with DENV seroconversion after adjusting for all other variables.Conclusions/significanceOur study suggests that there is a high level of endemic dengue virus circulation in the city of Dhaka which has resulted in significant DENV seroprevalence among its residents. Seropositivity increased with age, however, a substantial proportion of children are at risk for DENV infections. Our serological analysis also documents considerable DENV seroconversion among study participants which indicates that a large proportion of the population in the city of Dhaka were newly exposed to DENV during the study period (pre-and post-monsoon 2012). High levels of seroconversion suggest that there was an intense circulation of DENV in 2012 and this may have resulted in a significant risk for viral associated illness. Findings of our study further indicated that home-based interventions, such as removing indoor potted plants and increased bed net use, in addition to vector control measures in public parks, would reduce exposure to DENV and further decrease risk of viral associated disease.

Dataset Information

Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

Publications

Quantifying the Impact of Natural Immunity on Rotavirus Vaccine Efficacy Estimates: A Clinical Trial in Dhaka, Bangladesh (PROVIDE) and a Simulation Study.

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