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

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

Household catastrophic healthcare expenditure and impoverishment due to rotavirus gastroenteritis requiring hospitalization in Malaysia.

BACKGROUND: While healthcare costs for rotavirus gastroenteritis requiring hospitalization may be burdensome on households in Malaysia, exploration on the distribution and catastrophic impact of these expenses on households are lacking. OBJECTIVES: We assessed the economic burden, levels and distribution of catastrophic healthcare expenditure, the poverty impact on households and inequities related to healthcare payments for acute gastroenteritis requiring hospitalization in Malaysia. METHODS: A two-year prospective, hospital-based study was conducted from 2008 to 2010 in an urban (Kuala Lumpur) and rural (Kuala Terengganu) setting in Malaysia. All children under the age of 5 years admitted for acute gastroenteritis were included. Patients were screened for rotavirus and information on healthcare expenditure was obtained. RESULTS: Of the 658 stool samples collected at both centers, 248 (38%) were positive for rotavirus. Direct and indirect costs incurred were significantly higher in Kuala Lumpur compared with Kuala Terengganu (US$222 Vs. US$45; p<0.001). The mean direct and indirect costs for rotavirus gastroenteritis consisted 20% of monthly household income in Kuala Lumpur, as compared with only 5% in Kuala Terengganu. Direct medical costs paid out-of-pocket caused 141 (33%) households in Kuala Lumpur to experience catastrophic expenditure and 11 (3%) households to incur poverty. However in Kuala Terengganu, only one household (0.5%) experienced catastrophic healthcare expenditure and none were impoverished. The lowest income quintile in Kuala Lumpur was more likely to experience catastrophic payments compared to the highest quintile (87% vs 8%). The concentration index for out-of-pocket healthcare payments was closer to zero at Kuala Lumpur (0.03) than at Kuala Terengganu (0.24). CONCLUSIONS: While urban households were wealthier, healthcare expenditure due to gastroenteritis had more catastrophic and poverty impact on the urban poor. Universal rotavirus vaccination would reduce both disease burden and health inequities in Malaysia

Incidence of intussusception in Singaporean children aged less than 2 years: A hospital-based prospective study

10.1186/1471-2431-13-161BMC Pediatrics131-BPME

Emergence of double- and triple-gene reassortant G1P[8] rotaviruses possessing a DS-1-like backbone after rotavirus vaccine introduction in Malawi

To combat the high burden of rotavirus gastroenteritis, multiple African countries have introduced rotavirus vaccines into their childhood immunization programs. Malawi incorporated a G1P[8] rotavirus vaccine (Rotarix) into its immunization schedule in 2012. Utilizing a surveillance platform of hospitalized rotavirus gastroenteritis cases, we examined the phylodynamics of G1P[8] rotavirus strains that circulated in Malawi before (1998 to 2012) and after (2013 to 2014) vaccine introduction. Analysis of whole genomes obtained through next-generation sequencing revealed that all randomly selected prevaccine G1P[8] strains sequenced (n = 32) possessed a Wa-like genetic constellation, whereas postvaccine G1P[8] strains (n = 18) had a DS-1-like constellation. Phylodynamic analyses indicated that postvaccine G1P[8] strains emerged through reassortment events between human Wa- and DS-1-like rotaviruses that circulated in Malawi from the 1990s and hence were classified as atypical DS-1-like reassortants. The time to the most recent common ancestor for G1P[8] strains was from 1981 to 1994; their evolutionary rates ranged from 9.7 × 10−4 to 4.1 × 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. IMPORTANCE: The 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 a 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 postvaccine era in Malawi. Three distinct G1P[8] lineages circulated chronologically from 1998 to 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 a limited effect on the 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

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