Direct and indirect effects of rotavirus vaccination: Comparing predictions from transmission dynamic models

Early observations from countries that have introduced rotavirus vaccination suggest that there may be indirect protection for unvaccinated individuals, but it is unclear whether these benefits will extend to the long term. Transmission dynamic models have attempted to quantify the indirect protection that might be expected from rotavirus vaccination in developed countries, but results have varied. To better understand the magnitude and sources of variability in model projections, we undertook a comparative analysis of transmission dynamic models for rotavirus. We fit five models to reported rotavirus gastroenteritis (RVGE) data from England and Wales, and evaluated outcomes for short- and long-term vaccination effects. All of our models reproduced the important features of rotavirus epidemics in England and Wales. Models predicted that during the initial year after vaccine introduction, incidence of severe RVGE would be reduced 1.8-2.9 times more than expected from the direct effects of the vaccine alone (28-50% at 90% coverage), but over a 5-year period following vaccine introduction severe RVGE would be reduced only by 1.1-1.7 times more than expected from the direct effects (54-90% at 90% coverage). Projections for the long-term reduction of severe RVGE ranged from a 55% reduction at full coverage to elimination with at least 80% coverage. Our models predicted short-term reductions in the incidence of RVGE that exceeded estimates of the direct effects, consistent with observations from the United States and other countries. Some of the models predicted that the short-term indirect benefits may be offset by a partial shifting of the burden of RVGE to older unvaccinated individuals. Nonetheless, even when such a shift occurs, the overall reduction in severe RVGE is considerable. Discrepancies among model predictions reflect uncertainties about age variation in the risk and reporting of RVGE, and the duration of natural and vaccine-induced immunity, highlighting important questions for future research

Determination of a Viral Load Threshold To Distinguish Symptomatic versus Asymptomatic Rotavirus Infection in a High-Disease-Burden African Population

We evaluated quantitative real-time PCR to establish the diagnosis of rotavirus gastroenteritis in a high-disease-burden population in Malawi using enzyme immunoassay as the gold standard diagnostic test. In 146 children with acute gastroenteritis and 65 asymptomatic children, we defined a cutoff point in the threshold cycle value (26.7) that predicts rotavirus-attributable gastroenteritis in this population. These data will inform the evaluation of direct and indirect rotavirus vaccine effects in Africa

Household Transmission of Rotavirus in a Community with Rotavirus Vaccination in Quininde, Ecuador

Background: We studied the transmission of rotavirus infection in households in peri-urban Ecuador in the vaccination era. Methods: Stool samples were collected from household contacts of child rotavirus cases, diarrhea controls and healthy controls following presentation of the index child to health facilities. Rotavirus infection status of contacts was determined by RT-qPCR. We examined factors associated with transmissibility (index-case characteristics) and susceptibility (householdcontact characteristics). Results: Amongst cases, diarrhea controls and healthy control household contacts, infection attack rates (iAR) were 55%, 8% and 2%, (n = 137, 130, 137) respectively. iARs were higher from index cases with vomiting, and amongst siblings. Disease ARs were higher when the index child was ,18 months and had vomiting, with household contact ,10 years and those sharing a room with the index case being more susceptible. We found no evidence of asymptomatic infections leading to disease transmission. Conclusion: Transmission rates of rotavirus are high in households with an infected child, while background infections are rare. We have identified factors associated with transmission (vomiting/young age of index case) and susceptibility (young age/sharing a room/being a sibling of the index case). Vaccination may lead to indirect benefits by averting episodes or reducing symptoms in vaccinees

Hospitalizations associated with rotavirus gastroenteritis in Spain, 2001–2005

<p>Abstract</p> <p>Background</p> <p>This study aims to describe and analyze hospital admissions in Spain due to rotavirus infections among children aged 5 years or under during the period 2001–2005, along with the associated health cost.</p> <p>Methods</p> <p>To update estimates of rotavirus hospitalizations rates in Spain, we conducted a retrospective study of 5 years of national hospitalization data associated with acute gastroenteritis using the Minimum Basic Data Set.</p> <p>Results</p> <p>During the study period, a total of 17.1% of all admissions due to acute gastroenteritis of any etiology in children aged ≤ 5 years were attributable to rotavirus infection as determined by the rotavirus-specific International Classification of Diseases, ninth revision, Clinical Modification code. A mean incidence of 135 hospital admissions attributable to rotavirus per 100,000 children aged ≤ 5 years was found. Hospitalizations associated with rotavirus had a marked winter-time seasonality. The estimated cost of hospital admission attributable to rotavirus has risen from 3 million euros estimated for 2001 to almost 7 million euros estimated in 2005.</p> <p>Conclusion</p> <p>Rotavirus gastroenteritis remains an important cause of hospitalizations in Spanish children, mostly during the winter season.</p

Emergence of Double- and Triple-Gene Reassortant G1P[8]Rotaviruses Possessing a DS-1-Like Backbone after RotavirusVaccine Introduction in Malawi

To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunisation programmes. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix™) into its immunisation schedule in 2012. Utilising a surveillance platform of hospitalised rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 - 2012) and after (2013 - 2014) vaccine introduction. Analysis of whole genomes obtained through next generation sequencing revealed that all randomly-selected pre-vaccine G1P[8] strains sequenced (n=32) possessed a Wa-like genetic constellation, whereas post-vaccine G1P[8] strains (n=18) had a DS-1-like constellation. Phylodynamic analyses indicated that post-vaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990's, hence classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981-1994; their evolutionary rates ranged from 9.7 x 10(-4)-4.1 x 10(-3) nucleotide/substitutions/site/year. Three distinct G1P[8] lineages chronologically replaced each other between 1998 and 2014. Genetic drift was the likely driver for lineage turnover in 2005, whereas replacement in 2013 was due to reassortment. Amino acid substitution within the outer glycoprotein VP7 of G1P[8] strains had no impact on the structural conformation of the antigenic regions, suggesting that it is unlikely that they would affect recognition by vaccine-induced neutralizing antibodies. While the emergence of DS-1-like G1P[8] rotavirus reassortants in Malawi was therefore likely due to natural genotype variation, vaccine effectiveness against such strains needs careful evaluation.ImportanceThe error-prone RNA-dependent RNA polymerase and the segmented RNA genome predispose rotaviruses to genetic mutation and genome reassortment, respectively. These evolutionary mechanisms generate novel strains and have the potential to lead to the emergence of vaccine-escape mutants. While multiple African countries have introduced rotavirus vaccine, there are few data describing the evolution of rotaviruses that circulated before and after vaccine introduction. We report the emergence of atypical DS-1-like G1P[8] strains during the post-vaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998-2014; mutation and reassortment drove lineage turnover in 2005 and 2013, respectively. Amino acid substitutions within the outer capsid VP7 glycoprotein did not affect the structural conformation of mapped antigenic sites, suggesting limited effect in recognition of G1 specific vaccine-derived antibodies. The genes that constitute the remaining genetic backbone may play important roles in immune evasion, and vaccine effectiveness against such atypical strains needs careful evaluation

Klebsiella pneumoniae bacteraemia complicating rotavirus gastroenteritis in two infants with glucocorticoid deficiency

Rotavirus gastroenteritis was complicated by Klebsiella Pneumoniae bacteraemia in two infants with glucocorticoid deficient conditions who were treated with 'stress dose' hydrocortisone during their illness. Delayed healing in the context of glucocorticoid administration combined with damage from rotavirus infection may result in increased risk of mucosal invasion by gastrointestinal bacteria and subsequent enteric gram-negative bacteraemia

Burden of rotavirus gastroenteritis in the Middle Eastern and North African pediatric population

<p>Abstract</p> <p>Background</p> <p>Rotavirus gastroenteritis (RVGE) is the most common cause of severe childhood diarrhea worldwide. Objectives were to estimate the burden of RVGE among children less than five years old in the Middle East (Bahrain, Iran, Iraq, Israel, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Syria, UAE, Yemen), North Africa (Algeria, Egypt, Libya, Morocco, Tunisia) and Turkey.</p> <p>Methods</p> <p>A comprehensive literature search was conducted in major databases on the epidemiology and burden of rotavirus among children less than five years old between 1999 and 2009. Data from each country was extracted and compared.</p> <p>Results</p> <p>The search identified 43 studies. RVGE was identified in 16-61% of all cases of acute gastroenteritis, with a peak in the winter. RVGE-related hospitalization rates ranged from 14% to 45%, compared to 14%-28% for non-RVGE. Annually, RVGE caused up to 112 fatalities per 100,000 in certain countries in the region. Hospitalization costs ranged from $1.8 to$4.6 million annually, depending on the country. The most recent literature available showed that G1P[8] was the most prevalent genotype combination in 8 countries (range 23%-56%). G2P[4] was most prevalent in 4 countries (26%-48%). G9P[8] and G4P[8] were also frequently detected.</p> <p>Conclusions</p> <p>RVGE is a common disease associated with significant morbidity, mortality, and economic burden. Given the variety and diverse rotavirus types in the region, use of a vaccine with broad and consistent serotype coverage would be important to help decrease the burden of RVGE in the Middle East and North Africa.</p

Prevalence and factors associated with rotavirus infection among children admitted with acute diarrhea in Uganda

<p>Abstract</p> <p>Background</p> <p>Rotavirus remains the commonest cause of severe dehydrating diarrhea among children worldwide. Children in developing countries die more because of several factors including poorer access to hydration therapy and greater prevalence of malnutrition. Hitherto, the magnitude of rotavirus disease in Uganda has remained unknown. This study was therefore done to determine the prevalence and factors associated with rotavirus infection among children aged 3-59 months admitted with acute diarrhea to paediatric emergency ward of Mulago Hospital, Uganda</p> <p>Methods</p> <p>Three hundred and ninety children, aged between 3-59 months with acute diarrhoea were recruited. The clinical history, socio-demographic characteristics, physical examination findings and laboratory investigations were recorded. Stool samples were tested for rotavirus antigens using the DAKO IDEIA rotavirus EIA detection kit.</p> <p>Results</p> <p>The prevalence of rotavirus infection was 45.4%. On multivariate analysis rotavirus was significantly associated with a higher education (above secondary) level of the mother [OR 1.8; 95% CI 1.1-2.7]; dehydration [OR 1.8; 95% CI 1.1-3.0] and breastfeeding [OR 2.6; 95% CI 1.4-4.0]. Although age was significantly associated with rotavirus on bivariate analysis; this association disappeared on multivariate analysis. No significant association was found between rotavirus infection and nutritional status, HIV status and attendance of day care or school.</p> <p>Conclusions</p> <p>Rotavirus infection is highly prevalent among children with acute diarrhoea admitted to Mulago Hospital in Uganda.</p

Cost-effectiveness of introducing a rotavirus vaccine in developing countries: The case of Mexico

<p>Abstract</p> <p>Background</p> <p>In developing countries rotavirus is the leading cause of severe diarrhoea and diarrhoeal deaths in children under 5. Vaccination could greatly alleviate that burden, but in Mexico as in most low- and middle-income countries the decision to add rotavirus vaccine to the national immunisation program will depend heavily on its cost-effectiveness and affordability. The objective of this study was to assess the cost-effectiveness of including the pentavalent rotavirus vaccine in Mexico's national immunisation program.</p> <p>Methods</p> <p>A cost-effectiveness model was developed from the perspective of the health system, modelling the vaccination of a hypothetical birth cohort of 2 million children monitored from birth through 60 months of age. It compares the cost and disease burden of rotavirus in an unvaccinated cohort of children with one vaccinated as recommended at 2, 4, and 6 months.</p> <p>Results</p> <p>Including the pentavalent vaccine in the national immunisation program could prevent 71,464 medical visits (59%), 5,040 hospital admissions (66%), and 612 deaths from rotavirus gastroenteritis (70%). At US$10 per dose and a cost of administration of US$13.70 per 3-dose regimen, vaccination would cost US$122,058 per death prevented, US$4,383 per discounted life-year saved, at a total net cost of US$74.7 million dollars to the health care system. Key variables influencing the results were, in order of importance, case fatality, vaccine price, vaccine efficacy, serotype prevalence, and annual loss of efficacy. The results are also very sensitive to the discount rate assumed when calculated per life-year saved.</p> <p>Conclusion</p> <p>At prices below US$15 per dose, the cost per life-year saved is estimated to be lower than one GNP per capita and hence highly cost effective by the WHO Commission on Macroeconomics and Health criteria. The cost-effectiveness estimates are highly dependent upon the mortality in the absence of the vaccine, which suggests that the vaccine is likely to be significantly more cost-effective among poorer populations and among those with less access to prompt medical care – such that poverty reduction programs would be expected to reduce the future cost-effectiveness of the vaccine.</p