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1.
J Infect Dis ; 2019 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-31763671

RESUMEN

BACKGROUND: VP4 [P] genotype binding specificities of rotaviruses and differential expression of histo-blood group antigens (HBGAs) between populations may contribute to reduced efficacy against severe rotavirus disease. P[6]-based rotavirus vaccines could broaden protection in such settings, particularly in Africa, where the Lewis-negative phenotype and P[6] rotavirus strains are common. METHODS: The association between HBGA status and G3P[6] rotavirus vaccine (RV3-BB) take was investigated in a phase 2A study of RV3-BB vaccine involving 46 individuals in Dunedin, New Zealand, during 2012-2014. FUT2 and FUT3 genotypes were determined from DNA extracted from stool specimens, and frequencies of positive cumulative vaccine take, defined as an RV3-BB serum immune response (either immunoglobulin A or serum neutralizing antibody) and/or stool excretion of the vaccine strain, stratified by HBGA status were determined. RESULTS: RV3-BB produced positive cumulative vaccine take in 29 of 32 individuals (91%) who expressed a functional FUT2 enzyme (the secretor group), 13 of 13 (100%) who were FUT2 null (the nonsecretor group), and 1 of 1 with reduced FUT2 activity (i.e., a weak secretor); in 37 of 40 individuals (93%) who expressed a functional FUT3 enzyme (the Lewis-positive group) and 3 of 3 who were FUT3 null (the Lewis-negative group); and in 25 of 28 Lewis-positive secretors (89%), 12 of 12 Lewis-positive nonsecretors (100%), 2 of 2 Lewis-negative secretors, and 1 of 1 Lewis-negative weak secretor. CONCLUSIONS: RV3-BB produced positive cumulative vaccine take irrespective of HBGA status. RV3-BB has the potential to provide an improved level of protection in settings where P[6] rotavirus disease is endemic, irrespective of the HBGA profile of the population.

2.
Vaccine ; 37(49): 7233-7239, 2019 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-31607604

RESUMEN

BACKGROUND: The RV3-BB human neonatal rotavirus vaccine was developed to provide protection from severe rotavirus disease from birth. The aim of this study was to investigate the potential for mutual interference in the immunogenicity of oral polio vaccine (OPV) and RV3-BB. METHODS: A randomized, placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB, with the first dose given at 0-5 days (neonatal schedule) or ~8 weeks (infant schedule), or placebo. Two sub-studies assessed the immunogenicity of RV3-BB when co-administered with either trivalent OPV (OPV group, n = 282) or inactivated polio vaccine (IPV group, n = 333). Serum samples were tested for antibodies to poliovirus strains 1, 2 and 3 by neutralization assays following doses 1 and 4 of OPV. RESULTS: Sero-protective rates to poliovirus type 1, 2 or 3 were similar (range 0.96-1.00) after four doses of OPV co-administered with RV3-BB compared with placebo. Serum IgA responses to RV3-BB were similar when co-administered with either OPV or IPV (difference in proportions OPV vs IPV: sIgA responses; neonatal schedule 0.01, 95% CI -0.12 to 0.14; p = 0.847; infant schedule -0.10, 95% CI -0.21 to -0.001; p = 0.046: sIgA GMT ratio: neonatal schedule 1.23, 95% CI 0.71-2.14, p = 0.463 or infant schedule 1.20, 95% CI 0.74-1.96, p = 0.448). CONCLUSIONS: The co-administration of OPV with RV3-BB rotavirus vaccine in a birth dose strategy did not reduce the immunogenicity of either vaccine. These findings support the use of a neonatal RV3-BB vaccine where either OPV or IPV is used in the routine vaccination schedule.

3.
Artículo en Inglés | MEDLINE | ID: mdl-31315165

RESUMEN

This report, from the Australian Rotavirus Surveillance Program and collaborating laboratories Australia-wide, describes the rotavirus genotypes identified in children and adults with acute gastroenteritis during the period 1 January to 31 December 2017. During this period, 2,285 faecal specimens were referred for rotavirus G and P genotype analysis, including 1,103 samples that were confirmed as rotavirus positive. Of these, 1,014/1,103 were wildtype rotavirus strains and 89/1,103 were identified as rotavirus vaccine-like. Genotype analysis of the 1,014 wildtype rotavirus samples from both children and adults demonstrated that G2P[4] was the dominant genotype nationally, identified in 39% of samples, followed by equine-like G3P[8] and G8P[8] (25% and 16% respectively). Multiple outbreaks were recorded across Australia, including G2P[4] (Northern Territory, Western Australia, and South Australia), equine-like G3P[8] (New South Wales), and G8P[8] (New South Wales and Victoria). This year also marks the change in the Australian National Immunisation Program to the use of Rotarix exclusively, on 1 July 2017.


Asunto(s)
Monitoreo Epidemiológico , Infecciones por Rotavirus/epidemiología , Rotavirus/patogenicidad , Adolescente , Factores de Edad , Australia/epidemiología , Niño , Preescolar , Brotes de Enfermedades , Heces/virología , Gastroenteritis/epidemiología , Gastroenteritis/virología , Genotipo , Humanos , Lactante , Recién Nacido , Nueva Gales del Sur , Northern Territory , Vigilancia de la Población , Rotavirus/clasificación , Rotavirus/genética , Australia del Sur , Victoria , Australia Occidental , Adulto Joven
4.
Vaccine ; 36(39): 5872-5878, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30145099

RESUMEN

BACKGROUND: The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. The aim of the current study was to characterise the rotavirus strains causing gastroenteritis during the Indonesian Phase IIb efficacy trial. METHODS: A randomized, double-blind placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), or the first dose given at ∼8 weeks after birth (infant schedule), or placebo (placebo schedule). Stool samples from episodes of gastroenteritis were tested for rotavirus using EIA testing, positive samples were genotyped by RT-PCR. Full genome sequencing was performed on two representative rotavirus strains. RESULTS: There were 1110 episodes of acute gastroenteritis of any severity, 105 episodes were confirmed as rotavirus gastroenteritis by EIA testing. The most common genotype identified was G3P[8] (90/105), the majority (52/56) of severe (Vesikari score ≥11) rotavirus gastroenteritis episodes were due to the G3P[8] strain. Full genome analysis of two representative G3P[8] samples demonstrated the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, P[8] VP4 and a genogroup 2 backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. The complete genome of the Indonesian equine-like G3P[8] strain demonstrated highest genetic identity to G3P[8] strains circulating in Hungary and Spain. CONCLUSIONS: The dominant circulating strain during the Indonesian Phase IIb efficacy trial of the RV3-BB vaccine was an equine-like G3P[8] strain. The equine-like G3P[8] strain is an emerging cause of severe gastroenteritis in Indonesia and in other regions.


Asunto(s)
Gastroenteritis/virología , Virus Reordenados/aislamiento & purificación , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/uso terapéutico , Rotavirus/aislamiento & purificación , Administración Oral , Método Doble Ciego , Heces/virología , Femenino , Gastroenteritis/epidemiología , Genoma Viral , Genotipo , Humanos , Indonesia , Recién Nacido , Masculino , Filogenia , Virus Reordenados/clasificación , Rotavirus/clasificación , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/prevención & control
5.
J Infect Dis ; 218(4): 546-554, 2018 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-29790933

RESUMEN

Background: Introduction of rotavirus vaccines into national immunization programs (NIPs) could result in strain selection due to vaccine-induced selective pressure. This study describes the distribution and diversity of rotavirus genotypes before and after rotavirus vaccine introduction into the Australian NIP. State-based vaccine selection facilitated a unique comparison of diversity in RotaTeq and Rotarix vaccine states. Methods: From 1995 to 2015, the Australian Rotavirus Surveillance Program conducted genotypic analysis on 13051 rotavirus-positive samples from children <5 years of age, hospitalized with acute gastroenteritis. Rotavirus G and P genotypes were determined using serological and heminested multiplex reverse-transcription polymerase chain reaction assays. Results: G1P[8] was the dominant genotype nationally in the prevaccine era (1995-2006). Following vaccine introduction (2007-2015), greater genotype diversity was observed with fluctuating genotype dominance. Genotype distribution varied based on the vaccine implemented, with G12P[8] dominant in states using RotaTeq, and equine-like G3P[8] and G2P[4] dominant in states and territories using Rotarix. Conclusions: The increased diversity and differences in genotype dominance observed in states using RotaTeq (G12P[8]), and in states and territories using Rotarix (equine-like G3P[8] and G2P[4]), suggest that these vaccines exert different immunological pressures that influence the diversity of rotavirus strains circulating in Australia.


Asunto(s)
Variación Genética , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/administración & dosificación , Rotavirus/clasificación , Rotavirus/aislamiento & purificación , Australia/epidemiología , Preescolar , Monitoreo Epidemiológico , Femenino , Genotipo , Técnicas de Genotipaje , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Reacción en Cadena de la Polimerasa Multiplex , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rotavirus/genética , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/inmunología , Serotipificación , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología
6.
Hum Vaccin Immunother ; 14(8): 2082-2087, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29688121

RESUMEN

Serum rotavirus IgA responses are an imperfect non-mechanistic correlate of protection, and the lack of an accurate serological marker is a challenge to the development of new rotavirus vaccines. Serological responses to rotavirus NSP2 occur following wild-type infection; however, it is unknown if serological responses to NSP2 occur following administration of rotavirus vaccines. The phase IIa immunogenicity trial of RV3-BB provided an opportunity to investigate the serological responses to NSP2 following vaccination. Healthy, full-term babies (n = 96) were previously recruited as part of a phase IIa safety and immunogenicity trial in Dunedin, New Zealand between January 2012 and April 2014. Participants received three doses of oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Serum IgA and IgG antibody responses to total RV3-BB and NSP2 protein (RV3-BB) were assessed using ELISA. Despite significant serum IgA response against total RV3-BB, we were unable to demonstrate a significant serological response to NSP2 in participants receiving RV3-BB when compared to placebo. Heterotypic antibodies against multiple NSP2 genotypes were detected following RV3-BB vaccination. Our data demonstrates that while serological responses to NSP2 were detectable in a subset of participants, it is a less useful marker when compared to total rotavirus serum IgA response.


Asunto(s)
Inmunogenicidad Vacunal , Proteínas de Unión al ARN/inmunología , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/inmunología , Rotavirus/inmunología , Proteínas no Estructurales Virales/inmunología , Administración Oral , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Biomarcadores/análisis , Genotipo , Humanos , Esquemas de Inmunización , Lactante , Recién Nacido , Nueva Zelanda , Proteínas de Unión al ARN/genética , Rotavirus/genética , Infecciones por Rotavirus/inmunología , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/administración & dosificación , Pruebas Serológicas/métodos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Proteínas no Estructurales Virales/genética
7.
N Engl J Med ; 378(8): 719-730, 2018 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-29466164

RESUMEN

BACKGROUND: A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization. RESULTS: Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group. CONCLUSIONS: RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).


Asunto(s)
Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/inmunología , Administración Oral , Método Doble Ciego , Heces/virología , Femenino , Gastroenteritis/epidemiología , Gastroenteritis/virología , Humanos , Esquemas de Inmunización , Indonesia , Lactante , Recién Nacido , Análisis de Intención de Tratar , Masculino , Rotavirus/aislamiento & purificación , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/efectos adversos , Resultado del Tratamiento
8.
J Infect Dis ; 216(2): 220-227, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28838152

RESUMEN

Background: The etiology of acute watery diarrhea remains poorly characterized, particularly after rotavirus vaccine introduction. Methods: We performed quantitative polymerase chain reaction for multiple enteropathogens on 878 acute watery diarrheal stools sampled from 14643 episodes captured by surveillance of children <5 years of age during 2013-2014 from 16 countries. We used previously developed models of the association between pathogen quantity and diarrhea to calculate pathogen-specific weighted attributable fractions (AFs). Results: Rotavirus remained the leading etiology (overall weighted AF, 40.3% [95% confidence interval {CI}, 37.6%-44.3%]), though the AF was substantially lower in the Americas (AF, 12.2 [95% CI, 8.9-15.6]), based on samples from a country with universal rotavirus vaccination. Norovirus GII (AF, 6.2 [95% CI, 2.8-9.2]), Cryptosporidium (AF, 5.8 [95% CI, 4.0-7.6]), Shigella (AF, 4.7 [95% CI, 2.8-6.9]), heat-stable enterotoxin-producing Escherichia coli (ST-ETEC) (AF, 4.2 [95% CI, 2.0-6.1]), and adenovirus 40/41 (AF, 4.2 [95% CI, 2.9-5.5]) were also important. In the Africa Region, the rotavirus AF declined from 54.8% (95% CI, 48.3%-61.5%) in rotavirus vaccine age-ineligible children to 20.0% (95% CI, 12.4%-30.4%) in age-eligible children. Conclusions: Rotavirus remained the leading etiology of acute watery diarrhea despite a clear impact of rotavirus vaccine introduction. Norovirus GII, Cryptosporidium, Shigella, ST-ETEC, and adenovirus 40/41 were also important. Prospective surveillance can help identify priorities for further reducing the burden of diarrhea.


Asunto(s)
Diarrea/epidemiología , Diarrea/microbiología , Diarrea/virología , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/uso terapéutico , África/epidemiología , Asia/epidemiología , Brasil/epidemiología , Preescolar , Heces/microbiología , Heces/virología , Femenino , Salud Global , Humanos , Lactante , Modelos Logísticos , Masculino , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Organización Mundial de la Salud
9.
Hum Vaccin Immunother ; 13(8): 1908-1915, 2017 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-28481726

RESUMEN

The RV3-BB human neonatal rotavirus vaccine aims to provide protection from severe rotavirus disease from birth. A phase IIa safety and immunogenicity trial was undertaken in Dunedin, New Zealand between January 2012 and April 2014. Healthy, full-term (≥ 36 weeks gestation) babies, who were 0-5 d old were randomly assigned (1:1:1) to receive 3 doses of oral RV3-BB vaccine with the first dose given at 0-5 d after birth (neonatal schedule), or the first dose given at about 8 weeks after birth (infant schedule), or to receive placebo (placebo schedule). Vaccine take (serum immune response or stool shedding of vaccine virus after any dose) was detected after 3 doses of RV3-BB vaccine in >90% of participants when the first dose was administered in the neonatal and infant schedules. The aim of the current study was to characterize RV3-BB shedding and virus replication following administration of RV3-BB in a neonatal and infant vaccination schedule. Shedding was defined as detection of rotavirus by VP6 reverse transcription polymerase chain reaction (RT-PCR) in stool on days 3-7 after administration of RV3-BB. Shedding of rotavirus was highest following vaccination at 8 weeks of age in both neonatal and infant schedules (19/30 and 17/27, respectively). Rotavirus was detected in stool on days 3-7, after at least one dose of RV3-BB, in 70% (21/30) of neonate, 78% (21/27) of infant and 3% (1/32) placebo participants. In participants who shed RV3-BB, rotavirus was detectable in stool on day 1 following RV3-BB administration and remained positive until day 4-5 after administration. The distinct pattern of RV3-BB stool viral load demonstrated using a NSP3 quantitative qRT-PCR in participants who shed RV3-BB, suggests that detection of RV3-BB at day 3-7 was the result of replication rather than passage through the gastrointestinal tract.


Asunto(s)
Heces/virología , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/administración & dosificación , Rotavirus/aislamiento & purificación , Replicación Viral , Esparcimiento de Virus , Administración Oral , Anticuerpos Antivirales/sangre , Antígenos Virales/genética , Proteínas de la Cápside/genética , Método Doble Ciego , Femenino , Humanos , Esquemas de Inmunización , Inmunogenicidad Vacunal , Recién Nacido , Intestinos/virología , Masculino , Nueva Zelanda/epidemiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rotavirus/genética , Rotavirus/inmunología , Rotavirus/fisiología , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/efectos adversos , Vacunación/efectos adversos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Carga Viral
10.
Hum Vaccin Immunother ; 13(5): 1126-1135, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28059609

RESUMEN

BACKGROUND: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. METHODS: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0-5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. RESULTS: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). CONCLUSIONS: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.


Asunto(s)
Anticuerpos Antivirales/sangre , Inmunidad Materno-Adquirida , Infecciones por Rotavirus/inmunología , Vacunas contra Rotavirus/inmunología , Anticuerpos Neutralizantes/sangre , Calostro/inmunología , Costo de Enfermedad , Heces/virología , Femenino , Humanos , Inmunoglobulina A/sangre , Lactante , Recién Nacido , Masculino , Leche Humana/inmunología , Nueva Zelanda/epidemiología , Embarazo , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/administración & dosificación , Vacunas Atenuadas/inmunología
11.
Hum Vaccin Immunother ; 13(4): 921-927, 2017 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-27835052

RESUMEN

Rotavirus gastroenteritis is a leading global cause of mortality and morbidity in young children due to diarrhea and dehydration. Over 85% of deaths occur in developing countries. In industrialised countries, 2 live oral rotavirus vaccines licensed in 2006 quickly demonstrated high effectiveness, dramatically reducing severe rotavirus gastroenteritis admissions in many settings by more than 90%. In contrast, the same vaccines reduced severe rotavirus gastroenteritis by only 30-60% in developing countries, but have been proven life-saving. Bridging this "efficacy gap" offers the possibility to save many more lives of children under the age of 5. The reduced efficacy of rotavirus vaccines in developing settings may be related to differences in transmission dynamics, as well as host luminal, mucosal and immune factors. This review will examine strategies currently under study to target the issue of reduced efficacy and effectiveness of oral rotavirus vaccines in developing settings.


Asunto(s)
Gastroenteritis/prevención & control , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/inmunología , Países en Desarrollo , Gastroenteritis/epidemiología , Humanos , Infecciones por Rotavirus/epidemiología , Resultado del Tratamiento
12.
J Gen Virol ; 97(2): 403-410, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26588920

RESUMEN

During 2013, a novel equine-like G3P[8] rotavirus emerged as the dominant strain in Australian children with severe rotavirus gastroenteritis. Full genome analysis demonstrated that the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, a P[8] VP4 and a genogroup 2 backbone I2-R2-C2-M2-A2-N2-T2-E2-H2. The genome constellation of the equine-like G3P[8] was distinct to Australian and global G3P[8] strains. Phylogenetic analysis demonstrated a genetic relationship to multiple gene segments of Japanese strains RVA/JPN/S13-30/2013/G3P[4] and RVA/Human-wt/JPN/HC12016/2012/G1P[8]. The Australian equine-like G3P[8] strain displayed a distinct VP7 antigenic profile when compared with the previously circulating Australian G3P[8] strains. Identification of similar genes in strains from several geographical regions suggested the equine-like G3P[8] strain was derived by multiple reassortment events between globally co-circulating strains from both human and animal sources. This study reinforces the dynamic nature of rotavirus strains and illustrates the potential for novel human/animal reassortant strains to emerge within the human population.


Asunto(s)
Gastroenteritis/virología , Genotipo , Virus Reordenados/clasificación , Virus Reordenados/genética , Infecciones por Rotavirus/virología , Rotavirus/clasificación , Rotavirus/genética , Animales , Antígenos Virales/genética , Australia , Proteínas de la Cápside/genética , Niño , Preescolar , Análisis por Conglomerados , Genoma Viral , Humanos , Datos de Secuencia Molecular , Filogenia , ARN Viral/genética , Virus Reordenados/aislamiento & purificación , Rotavirus/aislamiento & purificación , Análisis de Secuencia de ADN , Homología de Secuencia
13.
Genome Biol Evol ; 7(9): 2473-83, 2015 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-26254487

RESUMEN

Rotaviruses are the most important etiological agent of acute gastroenteritis in young children worldwide. Among the first countries to introduce rotavirus vaccines into their national immunization programs were Belgium (November 2006) and Australia (July 2007). Surveillance programs in Belgium (since 1999) and Australia (since 1989) offer the opportunity to perform a detailed comparison of rotavirus strains circulating pre- and postvaccine introduction. G1P[8] rotaviruses are the most prominent genotype in humans, and a total of 157 G1P[8] rotaviruses isolated between 1999 and 2011 were selected from Belgium and Australia and their complete genomes were sequenced. Phylogenetic analysis showed evidence of frequent reassortment among Belgian and Australian G1P[8] rotaviruses. Although many different phylogenetic subclusters were present before and after vaccine introduction, some unique clusters were only identified after vaccine introduction, which could be due to natural fluctuation or the first signs of vaccine-driven evolution. The times to the most recent common ancestors for the Belgian and Australian G1P[8] rotaviruses ranged from 1846 to 1955 depending on the gene segment, with VP7 and NSP4 resulting in the most recent estimates. We found no evidence that rotavirus population size was affected after vaccine introduction and only six amino acid sites in VP2, VP3, VP7, and NSP1 were identified to be under positive selective pressure. Continued surveillance of G1P[8] strains is needed to determine long-term effects of vaccine introductions, particularly now rotavirus vaccines are implemented in the national immunization programs of an increasing number of countries worldwide.


Asunto(s)
Evolución Molecular , Vacunas contra Rotavirus , Rotavirus/genética , Australia , Bélgica , Preescolar , Genes Virales , Genoma Viral , Genotipo , Humanos , Filogenia , Rotavirus/clasificación , Rotavirus/aislamiento & purificación
14.
Lancet Infect Dis ; 15(12): 1389-97, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26318715

RESUMEN

BACKGROUND: Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. METHODS: This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. FINDINGS: 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. INTERPRETATION: RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. FUNDING: Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.


Asunto(s)
Anticuerpos Antivirales/sangre , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/administración & dosificación , Rotavirus/inmunología , Vacunación , Método Doble Ciego , Femenino , Humanos , Esquemas de Inmunización , Inmunoglobulina A/sangre , Lactante , Recién Nacido , Masculino , Nueva Zelanda , Infecciones por Rotavirus/sangre , Infecciones por Rotavirus/inmunología , Infecciones por Rotavirus/virología , Vacunas Atenuadas
15.
J Neurovirol ; 21(3): 290-300, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25060300

RESUMEN

Human immunodeficiency virus type-1 (HIV-1) invades the central nervous system (CNS) during acute infection which can result in HIV-associated neurocognitive disorders in up to 50% of patients, even in the presence of combination antiretroviral therapy (cART). Within the CNS, productive HIV-1 infection occurs in the perivascular macrophages and microglia. Astrocytes also become infected, although their infection is restricted and does not give rise to new viral particles. The major barrier to the elimination of HIV-1 is the establishment of viral reservoirs in different anatomical sites throughout the body and viral persistence during long-term treatment with cART. While the predominant viral reservoir is believed to be resting CD4(+) T cells in the blood, other anatomical compartments including the CNS, gut-associated lymphoid tissue, bone marrow, and genital tract can also harbour persistently infected cellular reservoirs of HIV-1. Viral latency is predominantly responsible for HIV-1 persistence and is most likely governed at the transcriptional level. Current clinical trials are testing transcriptional activators, in the background of cART, in an attempt to purge these viral reservoirs and reverse viral latency. These strategies aim to activate viral transcription in cells constituting the viral reservoir, so they can be recognised and cleared by the immune system, while new rounds of infection are blocked by co-administration of cART. The CNS has several unique characteristics that may result in differences in viral transcription and in the way latency is established. These include CNS-specific cell types, different transcription factors, altered immune surveillance, and reduced antiretroviral drug bioavailability. A comprehensive understanding of viral transcription and latency in the CNS is required in order to determine treatment outcomes when using transcriptional activators within the CNS.


Asunto(s)
Encéfalo/virología , Reservorios de Enfermedades/virología , Infecciones por VIH/virología , VIH-1/fisiología , Activación Transcripcional/fisiología , Humanos , Latencia del Virus/fisiología
16.
J Gen Virol ; 95(Pt 12): 2727-33, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25121549

RESUMEN

During a hospital-based diarrhoeal disease study conducted in Ho Chi Minh City, Vietnam from 2009 to 2010, we identified four symptomatic children infected with G26P[19] rotavirus (RV)--an atypical variant that has not previously been reported in human gastroenteritis. To determine the genetic structure and investigate the origin of this G26P[19] strain, the whole genome of a representative example was characterized, revealing a novel genome constellation: G26-P[19]-I5-R1-C1-M1-A8-N1-T1-E1-H1. The genome segments were most closely related to porcine (VP7, VP4, VP6 and NSP1) and Wa-like porcine RVs (VP1-3 and NSP2-5). We proposed that this G26P[19] strain was the product of zoonotic transmission coupled with one or more reassortment events occurring in human and/or animal reservoirs. The identification of such strains has potential implications for vaccine efficacy in south-east Asia, and outlines the utility of whole-genome sequencing for studying RV diversity and zoonotic potential during disease surveillance.


Asunto(s)
Diarrea/virología , Infecciones por Rotavirus/virología , Rotavirus/clasificación , Rotavirus/aislamiento & purificación , Preescolar , Diarrea/epidemiología , Genotipo , Humanos , Pacientes Internos , Datos de Secuencia Molecular , Filogenia , Rotavirus/genética , Infecciones por Rotavirus/epidemiología , Vietnam/epidemiología
17.
Infect Genet Evol ; 28: 434-45, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25152486

RESUMEN

Outbreaks of rotavirus diarrhea cause a large disease burden in the Alice Springs region of the Northern Territory, Australia. The introduction of the rotavirus vaccine Rotarix® has been associated with an increase in detection of G2P[4] strains in many countries. However, G2P[4] emergence has also been observed in vaccine-naive countries, suggesting a general global increase in the circulation of G2P[4] strains. A G2P[4] rotavirus outbreak occurred in 2009, 28 months after the introduction of the Rotarix® vaccine and 43 children were hospitalized. Pre-vaccine introduction, G2P[4] strains were observed associated with large outbreaks in 1999 and 2004. To determine the genetic relationship between these strains whole genome sequence analysis was conducted on representative strains from each of the G2P[4] outbreaks, in 1999, 2004 and 2009. Phylogenetic analysis revealed the majority of genes from 2009 outbreak strain clustered with contemporary global strains, while the VP7 gene clustered with contemporary and older strains and was antigenically distinct to the majority of contemporary global G2P[4] strains; suggesting the strain was an intragenogroup reassortant. The 1999 and 2009 strains appear to share similar evolutionary origins, and both had a high degree of genetic identity to previously identified Australian and global strains. Conversely, the 2004 outbreak strain was more divergent in comparison to Australian and global strains. The 1999 and 2004 outbreaks likely occurred due to the accumulation of immunologically naïve children in the population following low levels of G2P[4] rotavirus disease in the community in the years prior to each outbreak. The 2009 outbreak was associated with moderate vaccine coverage in the population and vaccine efficacy against the strain was low. The circulation of this unusual strain in the population combined with low vaccine coverage and diminished vaccine efficacy likely contributed to the outbreak occurring in this population.


Asunto(s)
Gastroenteritis/epidemiología , Infecciones por Rotavirus/epidemiología , Rotavirus/clasificación , Rotavirus/genética , Secuencia de Aminoácidos , Preescolar , Brotes de Enfermedades , Evolución Molecular , Femenino , Gastroenteritis/historia , Gastroenteritis/virología , Genes Virales , Genoma Viral , Genotipo , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Northern Territory/epidemiología , Filogenia , Infecciones por Rotavirus/historia , Infecciones por Rotavirus/virología , Alineación de Secuencia , Análisis de Secuencia de ADN
18.
Infect Genet Evol ; 25: 97-109, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24780429

RESUMEN

A genotype G3P[14] rotavirus strain was identified in a 12year old child presenting to the Emergency Department of the Royal Children's Hospital, Melbourne, with gastroenteritis. G3P[14] strains have been previously identified in rabbits in Japan, China, the USA and Italy and a single lapine-like strain from a child in Belgium. Full genome sequence analysis of RVA/Human-wt/AUS/RCH272/2012/G3P[14] (RCH272) revealed that the strain contained the novel genome constellation G3-P[14]-I2-R3-C3-M3-A9-N2-T6-E2-H3. The genome was genetically divergent to previously characterized lapine viruses and the genes were distantly related to a range of human bovine-like strains and animal strains of bovine, bat and canine/feline characteristics. The VP4, VP6, NSP2, NSP3, NSP4 and NSP5 genes of RCH272 clustered within bovine lineages in the phylogenetic analysis and shared moderate genetic similarity with an Australian bovine-like human strain RVA/Human-tc/AUS/MG6/1993/G6P[14]. Bayesian coalescent analysis suggested these genes of RCH272 and RVA/Human-tc/AUS/MG6/1993/G6P[14] were derived from a population of relatively homogenous bovine-like ancestral strains circulating between 1943 and 1989. The VP7, VP1, VP2 and NSP1 genes shared moderate genetic similarity with the Chinese strain RVA/Bat-tc/CHN/MSLH14/2011/G3P[3] and the VP3 gene clustered within a lineage comprised of canine and feline strains. This strain may represent the direct transmission from an unknown host species or be derived via multiple reassortment events between strains originating from various species. The patient lived in a household containing domesticated cats and dogs and in close proximity to a colony of Gray-headed Flying-foxes. However, without screening numerous animal populations it is not possible to determine the origins of this strain.


Asunto(s)
Gastroenteritis/virología , Infecciones por Rotavirus/virología , Rotavirus/clasificación , Rotavirus/genética , Adolescente , Animales , Australia , Gatos , Perros , Evolución Molecular , Genoma Viral , Humanos , Masculino , Filogenia , ARN Viral , Infecciones por Rotavirus/transmisión , Análisis de Secuencia de ARN
19.
Emerg Microbes Infect ; 3(7): e47, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26038746

RESUMEN

In 2010, a large outbreak of rotavirus gastroenteritis occurred in the Alice Springs region of the Northern Territory, Australia. The outbreak occurred 43 months after the introduction of the G1P[8] rotavirus vaccine Rotarix(®). Forty-three infants were hospitalized during the outbreak and analysis of fecal samples from each infant revealed a G1P[8] rotavirus strain. The outbreak strain was adapted to cell culture and neutralization assays were performed using VP7 and VP4 neutralizing monoclonal antibodies. The outbreak strain exhibited a distinct neutralization resistance pattern compared to the Rotarix(®) vaccine strain. Whole genome sequencing of the 2010 outbreak virus strain demonstrated numerous amino acid differences compared to the Rotarix(®) vaccine strain in the characterized neutralization epitopes of the VP7 and VP4 proteins. Phylogenetic analysis of the outbreak strain revealed a close genetic relationship to global strains, in particular RVA/Human-wt/BEL/BE0098/2009/G1P[8] and RVA/Human-wt/BEL/BE00038/2008/G1P[8] for numerous genes. The 2010 outbreak strain was likely introduced from a globally circulating population of strains rather than evolving from an endemic Australian strain. The outbreak strain possessed antigenic differences in the VP7 and VP4 proteins compared to the Rotarix(®) vaccine strain. The outbreak was associated with moderate vaccine coverage and possibly low vaccine take in the population.

20.
Emerg Infect Dis ; 19(8): 1324-7, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23876354

RESUMEN

We identified a genotype G10P[14] rotavirus strain in 5 children and 1 adult with acute gastroenteritis from the Northern Territory, Australia. Full genome sequence analysis identified an artiodactyl-like (bovine, ovine, and camelid) G10-P[14]-I2-R2-C2-M2-A11-N2-T6-E2-H3 genome constellation. This finding suggests artiodactyl-to-human transmission and strengthens the need to continue rotavirus strain surveillance.


Asunto(s)
Gastroenteritis/virología , Infecciones por Rotavirus/virología , Rotavirus/genética , Enfermedad Aguda , Anciano de 80 o más Años , Antígenos Virales/genética , Proteínas de la Cápside/genética , Preescolar , Genoma Viral , Humanos , Lactante , Tipificación de Secuencias Multilocus , Northern Territory , Filogenia , Rotavirus/clasificación
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