Jennifer J. Hull

Association between pentavalent rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua.

CONTEXT Pentavalent rotavirus vaccine (RV5), a live, oral attenuated vaccine, prevented 98% of severe rotavirus diarrhea in a trial conducted mainly in Finland and the United States. Nicaragua introduced RV5 in 2006, providing the first opportunity to assess the association between vaccination and rotavirus disease in a developing country. OBJECTIVE To assess the association between RV5 vaccination and subsequent rotavirus diarrhea requiring overnight admission or intravenous hydration. DESIGN, SETTING, AND PARTICIPANTS Case-control evaluation in 4 hospitals in Nicaragua from June 2007 to June 2008. Cases were children age-eligible to receive RV5 who were admitted or required intravenous hydration for laboratory-confirmed rotavirus diarrhea. For each case (n = 285), 1 to 3 neighborhood (n = 840) and hospital (n = 690) controls were selected. MAIN OUTCOME MEASURES Primary outcome was the association of RV5 and rotavirus diarrhea requiring overnight admission or intravenous hydration in the emergency department. Secondary analysis further classified disease as severe and very severe. We computed the matched odds ratio of vaccination in cases vs controls. Vaccine effectiveness was estimated using the formula 1 - matched odds ratio x 100%. RESULTS Of the 285 rotavirus cases, 265 (93%) required hospitalization; 251 (88%) received intravenous hydration. A single rotavirus strain (G2P[4]) was identified in 88% of the cases. Among cases and controls, respectively, 18% and 12% were unvaccinated, 12% and 15% received 1 dose of RV5, 15% and 17% received 2 doses, and 55% and 57% received 3 doses. Vaccination with 3 doses was associated with a lower risk of rotavirus diarrhea requiring overnight admission or intravenous hydration (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.36-0.82). Of the 285 rotavirus cases, 191 (67%) were severe and 54 (19%) were very severe. A progressively lower risk of severe (OR, 0.42; 95% CI, 0.26-0.70) and very severe rotavirus diarrhea (OR, 0.23; 95% CI, 0.08-0.61) was observed after RV5 vaccination. Thus, effectiveness of 3 doses of RV5 against rotavirus disease requiring admission or treatment with intravenous hydration was 46% (95% CI, 18%-64%); against severe rotavirus diarrhea, 58% (95% CI, 30%-74%); and against very severe rotavirus diarrhea, 77% (95% CI, 39%-92%). CONCLUSION Vaccination with RV5 was associated with a lower risk of severe rotavirus diarrhea in children younger than 2 years in Nicaragua but to a lesser extent than that seen in clinical trials in industrialized countries.

Effectiveness of Pentavalent Rotavirus Vaccine in a Large Urban Population in the United States

OBJECTIVE: The goal was to assess the effectiveness of complete (3-dose) or partial (1- or 2-dose) immunization with pentavalent rotavirus vaccine (RV5) against rotavirus acute gastroenteritis (AGE) in US clinical practice. METHODS: A case-control evaluation was conducted in February through June 2008 at an emergency department in Houston, Texas. Case patients with rotavirus AGE (N = 90) were identified through testing for rotavirus in fecal specimens obtained from 205 children 15 days through 23 months of age presenting with AGE. Control groups included rotavirus-negative AGE patients (N = 115), concurrently enrolled patients with acute respiratory infection (ARI) (N = 228), and up to 10 age- and zip code-matched children sampled from the Houston-Harris County Immunization Registry (HHCIR) for each case patient >8 months of age. Immunization data were obtained from parent records, health care providers, and/or the HHCIR. Vaccine effectiveness was calculated as 1 minus odds of RV5 vaccination for case patients versus control patients, after adjustment for age at presentation and birth date. RESULTS: The vaccine effectiveness of a complete RV5 series was 89% (95% confidence interval [CI]: 70%–96%) and 85% (95% CI: 55%–95%) with rotavirus-negative AGE and ARI control patients, respectively. Immunization data were available for 44% of case patients (n = 40) from the HHCIR; the estimated 3-dose vaccine effectiveness with these HHCIR control patients was 82% (95% CI: 19%–96%). A complete RV5 series conferred 100% protection (95% CI: 71%–100%) against severe rotavirus disease requiring hospitalization and 96% protection (95% CI: 72%–99%) against disease requiring intravenous hydration. Vaccine effectiveness of 1 and 2 doses against hospitalization and emergency department visits was 69% (95% CI: 13%–89%) and 81% (95% CI: 13%–96%), respectively, using rotavirus-negative AGE and ARI control groups combined. CONCLUSIONS: In this setting, a complete series of RV5 was highly effective against severe rotavirus AGE. Partial immunization also conferred substantial protection.

United States rotavirus strain surveillance from 2005 to 2008: genotype prevalence before and after vaccine introduction.

Background: A live, attenuated rotavirus vaccine, RotaTeq®, was approved in 2006 for immunization of infants in the United States. To monitor the distribution of rotavirus genotypes before and after vaccine introduction, the Centers for Disease Control and Prevention conducted strain surveillance with the National Rotavirus Strain Surveillance System. Methods: Over 3 rotavirus seasons, 2005–2006, 2006–2007, and 2007–2008, National Rotavirus Strain Surveillance System laboratories collected rotavirus-positive stool specimens and submitted them to the Centers for Disease Control and Prevention. Rotavirus strains were G- and P-genotyped by multiplex reverse transcription-polymerase chain reaction or nucleotide sequencing. Results: During 2005–2006 and 2006–2007 seasons, G1 was the dominant G-type but in the 2007–2008 season, G3 replaced G1 as the most frequently detected strain. Four genotypes, G1P[8], G2P[4], G3P[8], and G9P[8] were detected in every season. Uncommon strains observed during the study period were G2P[8], G1P[6], G2P[6], G4P[6], G1P[4], G3P[9], G12P [6], and G12P[8]. The mean age of rotavirus cases in the 2007–2008 season increased significantly in patients less than 3 years old compared with the 2 previous seasons. Conclusions: The increased overall prevalence of G3P [8] strains in 2007–2008, the first rotavirus season with reasonable rotavirus vaccine coverage, was consistent with Australian reports of G3 dominance following RotaTeq introduction. However, these strain changes in both countries have occurred in the context of large declines in severe rotavirus disease and we cannot rule out that they are simply the result of naturally occurring changes in rotavirus strain prevalence. These findings underscore the need for careful monitoring of strains to assess possible vaccine pressure-induced changes and vaccine effectiveness against various rotavirus genotypes.

Novel human rotavirus genotype G5P[7] from child with diarrhea, Cameroon.

We report characterization of a genotype G5P[7] human rotavirus (HRV) from a child in Cameroon who had diarrhea. Sequencing of all 11 gene segments showed similarities to >5 genes each from porcine and human rotaviruses. This G5P[7] strain exemplifies the importance of heterologous animal rotaviruses in generating HRV genetic diversity through reassortment.

G and P Types of Circulating Rotavirus Strains in the United States during 1996–2005: Nine Years of Prevaccine Data

BACKGROUND Rotavirus vaccine was recommended for routine use among US infants in 2006. To provide prevaccine data, we conducted strain surveillance for 9 consecutive seasons during 1996-2005. METHODS Using reverse-transcriptase polymerase chain reaction genotyping and nucleotide sequencing, we determined P/G genotypes of >3100 rotavirus strains collected in up to 12 cities each year from different US regions. RESULTS The most prevalent strain globally, P[8] G1, was the most prevalent each year in the United States (overall, 78.5% of strains; range, 60.0%-93.9%), and 9.2% of the samples were P[4] G2, 3.6% were P[8] G9, 1.7% were P[8] G3, and 0.8% were P[8] G4. Genotype P[6] G9, which emerged in 1995, was detected continuously for several seasons (from 1996-1997 to 2000-2001, 0.2%-5.4%) but was not identified in the subsequent 4 seasons. Single or a few detections of rare genotypes (eg, P[6] G12, P[9] G6, and P[9] G3) were observed during several rotavirus seasons at frequencies of 0.5%-1.7% and, overall, comprised 0.6% of all the samples from the entire surveillance period. Several globally common strains in addition to G1, especially G2 and G9, circulated at high prevalence (33%-62%) in some cities during certain years. CONCLUSIONS Almost 85% of strains during 1996-2005 had either a G or P antigen that is present in both RotaTeq (Merck) and Rotarix (GlaxoSmithKline). Monitoring of strains after introduction of rotavirus vaccines is important.

Detection of fecal shedding of rotavirus vaccine in infants following their first dose of pentavalent rotavirus vaccine

Studies on rotavirus vaccine shedding and its potential transmission within households including immunocompromised individuals are needed to better define the potential risks and benefits of vaccination. We examined fecal shedding of pentavalent rotavirus vaccine (RV5) for 9 days following the first dose of vaccine in infants between 6 and 12 weeks of age. Rotavirus antigen was detected by enzyme immunoassay (EIA), and vaccine-type rotavirus was identified by nucleotide sequencing based on genetic relatedness to the RV5 VP6 gene. Stool from 22 (21.4%) of 103 children contained rotavirus antigen-positive specimens on ≥ 1 post-vaccination days. Rotavirus antigen was detected as early as post-vaccination day 3 and as late as day 9, with peak numbers of shedding on post-vaccination days 6 through 8. Vaccine-type rotavirus was detected in all 50 antigen-positive specimens and 8 of 8 antigen-negative specimens. Nine (75%) of 12 EIA-positive and 1 EIA-negative samples tested culture-positive for vaccine-type rotavirus. Fecal shedding of rotavirus vaccine virus after the first dose of RV5 occurred over a wide range of post-vaccination days not previously studied. These findings will help better define the potential for horizontal transmission of vaccine virus among immunocompromised household contacts of vaccinated infants for future studies.

Molecular characterization of a rare, human-porcine reassortant rotavirus strain, G11P[6], from Ecuador.

The Pan-American Health Organization established a rotavirus pre-vaccination disease burden and strain surveillance network in Latin America and the Caribbean in 2004. During strain surveillance in Ecuador in 2005–2006, a rare rotavirus genotype, G11P[6], was detected among common strains. Sequencing and phylogenetic analysis of this strain identified a novel lineage of the G11 VP7 gene, most closely related to A253 (91.8% nt identity), a porcine rotavirus strain identified in Venezuela. Most genes of this strain clustered with porcine, human-porcine or bovine-porcine reassortant strains; only VP6 and perhaps NSP2 genes were more closely related to cognate genes of human rotaviruses. Thus, this strain was likely generated by gene reassortment between porcine and human parental strains. Our study provides further evidence that animal rotaviruses play an important role in genetic and antigenic diversity of rotaviruses pathogenic for humans.

Phylogenetic analysis of novel G12 rotaviruses in the United States: A molecular search for the origin of a new strain

Rotavirus serotype G12 was initially identified in the Philippines in 1987 and was not described again until it reemerged more than 13 years later. G12 strains were first detected in the United States in 2002 and have recently assumed a worldwide distribution. The high similarity between the sequence of the major outer capsid VP7 gene of human G12 strains and the single porcine G12 isolate raised the prospect that human strains may have arisen through reassortment with porcine strains or, alternatively, that the porcine strain originally came from humans. We sequenced portions of the remaining 10 segments of two human G12 strains (G12P[8] and G12P[6]) and a currently circulating common strain (G1P[8]) identified during the 2005–2006 surveillance season and compared the sequences with those of strains available through GenBank. By comparison, the three strains were all Wa‐like and not porcine‐like. A newly outlined classification system proposed genotypes for each gene segment based on nucleotide similarity. Using this approach, gene segments VP1–3, VP6 and NSP1–5 grouped within the same genotype, indicating that the three strains analyzed were closely related. These results suggest that the novel G12P[8] strain could have been formed by the solitary introduction of a VP7 gene into a globally common rotavirus strain, G1P[8]. Classifying rotavirus strains based only on VP7 (G) and VP4 (P) genotype potentially underestimates diversity and sequence analysis of the other segments is required to assess the complete genetic relationships between strains. J. Med. Virol. 81:736–746, 2009

Genomic characterization of human rotavirus G10 strains from the African Rotavirus Network: relationship to animal rotaviruses.

Global rotavirus surveillance has led to the detection of many unusual human rotavirus (HRV) genotypes. The aim of this study was to elucidate the genetic and evolutionary relationships of short fragments of all 11 gene segments of G10 HRV strains identified in West Africa through the African Rotavirus Network (ARN) system. During 1998-2004 surveillance within the ARN, we identified 5 G10 P[8] HRV strains. Fragments of all 11 gene segments of these G10 strains were sequenced. Phylogenetic and sequence analyses of each gene segment revealed high nucleotide similarities amongst the ARN strains (97-100%) except in the case of the VP1(85-96%) and NSP2 genes (87.8-99.7%) where some strains were divergent. All genes of the ARN strains were classified as Wa-like (genotype 1) with the exception of their VP7 gene of all strains (genotype G10) and the VP6 gene of a single strain, 6755/2002/ARN (DS-1 like, genotype 2). While classified as Wa-like, the NSP2 genes of four of the ARN strains occupied a distinct sub-lineage related to simian strain Tuch, while the NSP2 of strain 6755/2002/ARN and NSP5 genes of all strains were closely related to the cognate genes of both human and animal strains belonging to the Wa-like genogroup. Although these findings help to elucidate the evolution of ARN G10 strains, additional sequence studies of cognate animal rotavirus genes are needed to determine irrefutably the specific origin of those genes relative to both human and animal rotavirus strains.

Sequencing and phylogenetic analysis of the coding region of six common rotavirus strains: Evidence for intragenogroup reassortment among co-circulating G1P[8] and G2P[4] strains from the United States†‡

The segmented genome of rotaviruses provides an opportunity for rotavirus strains to generate a large genetic diversity through reassortment; however, this mechanism is considered to play little role in the generation of mosaic gene constellations between Wa‐like and DS‐1‐like strains in genes other than the neutralization antigens. A pilot study was undertaken to analyze these two epidemiologically important strains at the genomic level in order to (i) identify intergenogroup reassortment and (ii) to make available additional reference genome sequences of G1P[8] and G2P[4] for future genomics analyses. The full or nearly complete coding region of all 11 genes for 3 G1P[8] (LB2719, LB2758, and LB2771) and 3 G2P[4] (LB2744, LB2764, and LB2772) strains isolated from children hospitalized with severe diarrhea in Long Beach, California, where these strains were circulating at comparable rates during 2005–2006 are described in this study. Based on the full‐genome classification system, all G1P[8] strains had a conserved genomic constellation: G1‐P[8]‐I1‐R1‐C1‐M1‐A1‐N1‐T1‐E1‐E1‐H1 and were mostly identical to the few Wa‐like strains whose genome sequences have already been determined. Similarly, the genome sequences of the 3 G2P[4] strains were highly conserved: G2‐P[4]‐I2‐R2‐C2‐M2‐A2‐N2‐T2‐E2‐E2‐H2 and displayed an overall lesser genetic divergence with reference DS‐1‐like strains. While intergenogroup reassortment was not seen between the G1P[8] and G2P[4] strains studied here, evidence for intragenogroup reassortment events was identified. Similar studies in the post‐rotavirus genomic era will help uncover whether intergenogroup reassortment affecting the backbone genes could play a significant role in any potential vaccine breakthrough events by evading immunity of vaccinated children. J. Med. Virol. 83:532–539, 2011.