Eyal Leshem

Distribution of rotavirus strains and strain-specific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis

BACKGROUND Concerns exist about whether monovalent (RV1) and pentavalent (RV5) rotavirus vaccines provide adequate protection against diverse strains and whether vaccine introduction will lead to selective pressure. We aimed to investigate the distribution of rotavirus strains and strain-specific rotavirus vaccine effectiveness after vaccine introduction. METHODS We did a systematic review of published work to assess the strain-specific effectiveness of RV1 and RV5 rotavirus vaccines. We classified strains as homotypic, partly heterotypic, and fully heterotypic based on the amount of antigen-matching between strain and vaccine. When studies reported vaccine effectiveness against single antigens (G-type or P-type), we categorised them as either single-antigen vaccine type or single-antigen non-vaccine type. Our primary outcome was strain-specific vaccine effectiveness, comparing effectiveness of homotypic strains with fully or partly heterotypic strains. A secondary outcome was the prevalence of rotavirus strains after vaccine introduction. We estimated pooled odds ratios using random-effect regression models, stratified by country income level and vaccine type, and tested for differences in strain-specific vaccine effectiveness. We assessed strain distribution trends from surveillance reports. FINDINGS In high-income countries, RV1 pooled vaccine effectiveness was 94% (95% CI 80-98) against homotypic strains, 71% (39-86) against partly heterotypic strains, and 87% (76-93) against fully heterotypic strains. In middle-income settings, respective pooled data were 59% (36-73), 72% (58-81), and 47% (28-61). In high-income countries, RV5 vaccine effectiveness was 83% (78-87) against homotypic strains, 82% (70-89) against single-antigen vaccine type strains, 82% (70-89) against partly heterotypic strains, and 75% (47-88) against single-antigen non-vaccine type strains. In middle-income settings, RV5 vaccine effectiveness was 70% (58-78) against single-antigen vaccine type strains, 37% (10-56) against partly heterotypic strains, and 87% (38-97) against single-antigen non-vaccine type strains. No difference was noted in vaccine effectiveness for either RV1 or RV5 in any setting (all p>0·05). Prevalent strains in countries using RV1 were G2P[4] (2198 of 4428, 50%) and G1P[8] (953, 22%), and those in countries using RV5 were G1P[8] (1280 of 3875, 33%) and G2P[4] (1169, 30%). Sustained predominance of a single strain was not recorded. INTERPRETATION RV1 and RV5 exert similar effectiveness against homotypic and heterotypic rotavirus strains. Persistence of specific strains was not recorded, suggesting vaccine-induced selective pressure did not occur. Expansion of rotavirus surveillance efforts to low-income countries and ongoing surveillance are crucial to identify emergence of new strains and to assess strain-specific vaccine effectiveness in various settings. FUNDING None.

Rotavirus Vaccines and Health Care Utilization for Diarrhea in the United States (2007–2011)

OBJECTIVES: To examine reductions in diarrhea-associated health care utilization after rotavirus vaccine implementation and to assess direct and indirect effectiveness of vaccination. METHODS: Retrospective cohort analysis of claims data of commercially insured US children aged <5 years. We examined annual pentavalent (RV5) and monovalent (RV1) rotavirus vaccine coverage. We compared rates of diarrhea-associated health care utilization in prevaccine (2001–2006) versus postvaccine introduction (2007–2011) years, compared rates of diarrhea-associated health care utilization in vaccinated versus unvaccinated children and compared rates in unvaccinated children in postvaccine versus prevaccine years. RESULTS: Among children aged <5 years, RV5 and RV1 rotavirus vaccine coverage rates reached 58% and 5%, respectively, by December 31, 2010. Compared with the average rate of rotavirus-coded hospitalizations in 2001–2006, rates were reduced by 75% in 2007–2008, 60% in 2008–2009, 94% in 2009–2010, and 80% in 2010–2011. Compared with unvaccinated children, in 2010–2011, the rate of rotavirus-coded hospitalizations was reduced by 92% among RV5 recipients and 96% among RV1 recipients. Rotavirus-coded hospitalization rate reductions among RV5 recipients versus unvaccinated children ranged from 87% among <1-year-olds to 81% among 4-year-olds. Compared with prevaccine rates in 2001–2006, rotavirus-coded hospitalization rates among unvaccinated children decreased by 50% in 2007–2008, 77% in 2009–2010, and 25% in 2010–2011. CONCLUSIONS: Implementation of rotavirus vaccines has substantially reduced diarrhea health care utilization in US children. Both rotavirus vaccines conferred high protection against rotavirus hospitalizations; RV5 conferred durable protection through the fourth year of life. Vaccination also conferred indirect benefits to unvaccinated children.

Review of global rotavirus strain prevalence data from six years post vaccine licensure surveillance: Is there evidence of strain selection from vaccine pressure?

Comprehensive reviews of pre licensure rotavirus strain prevalence data indicated the global importance of six rotavirus genotypes, G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] and G12P[8]. Since 2006, two vaccines, the monovalent Rotarix (RV1) and the pentavalent RotaTeq (RV5) have been available in over 100 countries worldwide. Of these, 60 countries have already introduced either RV1 or RV5 in their national immunization programs. Post licensure vaccine effectiveness is closely monitored worldwide. This review aimed at describing the global changes in rotavirus strain prevalence over time. The genotype distribution of the nearly 47,000 strains that were characterized during 2007-2012 showed similar picture to that seen in the preceding period. An intriguing finding was the transient predominance of heterotypic strains, mainly in countries using RV1. Unusual and novel antigen combinations continue to emerge, including some causing local outbreaks, even in vaccinated populations. In addition, vaccine strains have been found in both vaccinated infants and their contacts and there is evidence for genetic interaction between vaccine and wild-type strains. In conclusion, the post-vaccine introduction strain prevalence data do not show any consistent pattern indicative of selection pressure resulting from vaccine use, although the increased detection rate of heterotypic G2P[4] strains in some countries following RV1 vaccination is unusual and this issue requires further monitoring.

Severe respiratory illness associated with a nationwide outbreak of enterovirus D68 in the USA (2014): a descriptive epidemiological investigation

Summary Background Enterovirus D68 (EV-D68) has been infrequently reported historically, and is typically associated with isolated cases or small clusters of respiratory illness. Beginning in August, 2014, increases in severe respiratory illness associated with EV-D68 were reported across the USA. We aimed to describe the clinical, epidemiological, and laboratory features of this outbreak, and to better understand the role of EV-D68 in severe respiratory illness. Methods We collected regional syndromic surveillance data for epidemiological weeks 23 to 44, 2014, (June 1 to Nov 1, 2014) and hospital admissions data for epidemiological weeks 27 to 44, 2014, (June 29 to Nov 1, 2014) from three states: Missouri, Illinois and Colorado. Data were also collected for the same time period of 2013 and 2012. Respiratory specimens from severely ill patients nationwide, who were rhinovirus-positive or enterovirus-positive in hospital testing, were submitted between Aug 1, and Oct 31, 2014, and typed by molecular sequencing. We collected basic clinical and epidemiological characteristics of EV-D68 cases with a standard data collection form submitted with each specimen. We compared patients requiring intensive care with those who did not, and patients requiring ventilator support with those who did not. Mantel-Haenszel χ2 tests were used to test for statistical significance. Findings Regional and hospital-level data from Missouri, Illinois, and Colorado showed increases in respiratory illness between August and September, 2014, compared with in 2013 and 2012. Nationwide, 699 (46%) of 1529 patients tested were confirmed as EV-D68. Among the 614 EV-D68-positive patients admitted to hospital, age ranged from 3 days to 92 years (median 5 years). Common symptoms included dyspnoea (n=513 [84%]), cough (n=500 [81%]), and wheezing (n=427 [70%]); 294 (48%) patients had fever. 338 [59%] of 574 were admitted to intensive care units, and 145 (28%) of 511 received ventilator support; 322 (52%) of 614 had a history of asthma or reactive airway disease; 200 (66%) of 304 patients with a history of asthma or reactive airway disease required intensive care compared with 138 (51%) of 270 with no history of asthma or reactive airway disease (p=0·0004). Similarly, 89 (32%) of 276 patients with a history of asthma or reactive airway disease required ventilator support compared with 56 (24%) of 235 patients with no history of asthma or reactive airway disease (p=0·039). Interpretation In 2014, EV-D68 caused widespread severe respiratory illness across the USA, disproportionately affecting those with asthma. This unexpected event underscores the need for robust surveillance of enterovirus types, enabling improved understanding of virus circulation and disease burden. Funding None.

Acute Gastroenteritis Hospitalizations Among US Children Following Implementation of the Rotavirus Vaccine

Acute Gastroenteritis Hospitalizations Among US Children Following Implementation of the Rotavirus Vaccine Routine rotavirus vaccination of US children was implemented in 2006, with 2 or 3 doses recommended before the age of 8 months.1 Previous studies have demonstrated the association of rotavirus vaccine introduction with reductions in health care use during the early postintroduction period or with limited insurance databases.2-4 Because laboratory testing and coding for rotavirus are not routinely performed for patients with diarrhea, we examined both allcause acute gastroenteritis and rotavirus-coded hospitalizations among children younger than 5 years from 2000 through 2012.

Acute Flaccid Myelitis in the United States, August–December 2014: Results of Nationwide Surveillance

BACKGROUND During late summer/fall 2014, pediatric cases of acute flaccid myelitis (AFM) occurred in the United States, coincident with a national outbreak of enterovirus D68 (EV-D68)-associated severe respiratory illness. METHODS Clinicians and health departments reported standardized clinical, epidemiologic, and radiologic information on AFM cases to the Centers for Disease Control and Prevention (CDC), and submitted biological samples for testing. Cases were ≤21 years old, with acute onset of limb weakness 1 August-31 December 2014 and spinal magnetic resonance imaging (MRI) showing lesions predominantly restricted to gray matter. RESULTS From August through December 2014, 120 AFM cases were reported from 34 states. Median age was 7.1 years (interquartile range, 4.8-12.1 years); 59% were male. Most experienced respiratory (81%) or febrile (64%) illness before limb weakness onset. MRI abnormalities were predominantly in the cervical spinal cord (103/118). All but 1 case was hospitalized; none died. Cerebrospinal fluid (CSF) pleocytosis (>5 white blood cells/µL) was common (81%). At CDC, 1 CSF specimen was positive for EV-D68 and Epstein-Barr virus by real-time polymerase chain reaction, although the specimen had >3000 red blood cells/µL. The most common virus detected in upper respiratory tract specimens was EV-D68 (from 20%, and 47% with specimen collected ≤7 days from respiratory illness/fever onset). Continued surveillance in 2015 identified 16 AFM cases reported from 13 states. CONCLUSIONS Epidemiologic data suggest this AFM cluster was likely associated with the large outbreak of EV-D68-associated respiratory illness, although direct laboratory evidence linking AFM with EV-D68 remains inconclusive. Continued surveillance will help define the incidence, epidemiology, and etiology of AFM.

Enterovirus D68 Infection in Children with Acute Flaccid Myelitis, Colorado, USA, 2014

Odds of this viral infection in the nasopharynx were 10 times greater for children with this condition than for controls.

Early Evidence of Impact of Monovalent Rotavirus Vaccine in Togo

Togo introduced monovalent rotavirus vaccine starting 19 June 2014. We compared all-cause acute gastroenteritis (AGE) hospitalizations and rotavirus-associated hospitalizations during the prevaccine period (July 2008-June 2014) to 1 year after vaccine introduction (July 2014-June 2015). The proportion of children with AGE who tested positive for rotavirus declined from 53% (645/1223) in prevaccine years to 36% (68/187) in the postvaccine year (P< .01). The decline only occurred in children <1 year of age who were eligible for vaccination and was greatest during the rotavirus season months, supporting that it was associated with vaccine implementation.

Effectiveness of Pentavalent Rotavirus Vaccine Against a Diverse Range of Circulating Strains in Nicaragua

BACKGROUND Because >60 rotavirus strains have been reported worldwide, concerns exist about strain replacement after the introduction of rotavirus vaccines, particularly in developing countries with diverse strains and lower efficacy. METHODS We used the case-control design in 4 hospitals in Nicaragua to assess strain-specific vaccine effectiveness (VE) of a pentavalent rotavirus vaccine (RotaTeq) against rotavirus diarrhea. Cases were identified through prospective strain surveillance with reverse transcription-polymerase chain reaction for 3 years among children hospitalized for diarrhea, and controls were children negative for rotavirus. RESULTS We enrolled 1178 case-patients, 1082 (92%) with G and P typing, and 4927 controls. A different strain predominated each year with increasing age of the vaccine-eligible cohort during the study period: G2P[4] in 2008 (97%; mean age, 11.9 months), G1P[8] in 2009 (55%; mean age, 17.0 months), and G3P[8] in 2010 (78%; mean age, 17.3 months). Overall VE was 45% (95% confidence interval, 25%-59%). Regardless of the strain, VE estimates were 12%-79% lower among children aged ≥12 months relative to those 6-11 months of age. The lower VE for G3P[8] was related to the higher mean age of cases (17.3 months) compared with the G2P[4] strains (11.9 months), with a significant trend (R(2)= 0.819;P< .001) of declining effectiveness with increasing mean age of the cases. CONCLUSIONS Introduction of RotaTeq did not result in sustained emergence of any particular strain in Nicaragua. Variation in strain-specific effectiveness was due to an age-related decline in effectiveness rather than differences in protection against the observed strains.

Anticipating rotavirus vaccines--a pre-vaccine assessment of incidence and economic burden of rotavirus hospitalizations among children < 5 year of age in Libya, 2012-13.

BackgroundLibya introduced rotavirus vaccine in October 2013. We examined pre-vaccine incidence of rotavirus hospitalizations and associated economic burden among children < 5 years in Libya to provide baseline data for future vaccine impact evaluations.MethodsProspective, hospital-based active surveillance for rotavirus was conducted at three public hospitals in two cities during August 2012 - April 2013. Clinical, demographic and estimated cost data were collected from children <5 hospitalized for diarrhea; stool specimens were tested for rotavirus with a commercial enzyme immunoassay. Annual rotavirus hospitalization incidence rate estimates included a conservative estimate based on the number of cases recorded during the nine months and an extrapolation to estimate 12 months incidence rate. National rotavirus disease and economic burden were estimated by extrapolating incidence and cost data to the national population of children aged <5 years.ResultsA total of 410 children <5 years of age with diarrhea were enrolled, of whom 239 (58%) tested positive rotavirus, yielding an incidence range of 418-557 rotavirus hospitalizations per 100,000 children <5 years of age. Most (86%) rotavirus cases were below two years of age with a distinct seasonal peak in winter (December-March) months. The total cost of treatment for each rotavirus patient was estimated at US