Neonatal rotavirus vaccine (RV3-BB) immunogenicity and safety in a neonatal and infant administration schedule in Malawi: a randomised, double-blind, four-arm parallel group dose-ranging study.

Background: Rotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P[6] rotavirus vaccine administered in a neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants.

Methods: We did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi.

Rotavirus specific maternal antibodies and immune response to RV3-BB rotavirus vaccine in central java and yogyakarta, Indonesia.

Background: Placental or breast milk maternal antibodies can potentially reduce oral rotavirus vaccine efficacy in developing countries. We aimed to examine the relationship between the level of rotavirus specific immunoglobulin A (IgA) and neutralising antibodies (NA) in colostrum and breast milk and cord IgG, with cumulative vaccine take following one and three doses of oral RV3-BB rotavirus vaccine within a Phase IIb trial in Indonesia.

Methods: 196 infants received three doses of RV3-BB in a randomized, double-blinded trial, using a neonatal schedule (first dose at 0-5 days of age, n = 61), an infant schedule (first dose at ~ 8 weeks of age, n = 67) or placebo (n = 68).

Human Neonatal Rotavirus Vaccine (RV3-BB) Produces Vaccine Take Irrespective of Histo-Blood Group Antigen Status.

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.

Immunogenicity of four doses of oral poliovirus vaccine when co-administered with the human neonatal rotavirus vaccine (RV3-BB).

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.

Australian Rotavirus Surveillance Program: Annual Report, 2017.

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.

Molecular characterisation of rotavirus strains detected during a clinical trial of the human neonatal rotavirus vaccine (RV3-BB) in Indonesia.

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.

Serological responses to rotavirus NSP2 following administration of RV3-BB human neonatal rotavirus vaccine.

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.

Etiology of Severe Acute Watery Diarrhea in Children in the Global Rotavirus Surveillance Network Using Quantitative Polymerase Chain Reaction.

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).

Rotavirus shedding following administration of RV3-BB human neonatal rotavirus vaccine.

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).

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand.

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.

Options for improving effectiveness of rotavirus vaccines in developing countries.

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%.

Emergence of a novel equine-like G3P[8] inter-genogroup reassortant rotavirus strain associated with gastroenteritis in Australian children.

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.

Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial.

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.

Genome-Wide Evolutionary Analyses of G1P[8] Strains Isolated Before and After Rotavirus Vaccine Introduction.

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.

Characterization of a G1P[8] rotavirus causing an outbreak of gastroenteritis in the Northern Territory, Australia, in the vaccine era.

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.

Novel porcine-like human G26P[19] rotavirus identified in hospitalized paediatric diarrhoea patients in Ho Chi Minh City, Vietnam.

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).

HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research.

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.

Genetic characterization of a novel G3P[14] rotavirus strain causing gastroenteritis in 12 year old Australian child.

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.

Novel G10P[14] rotavirus strain, northern territory, Australia.

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.

Reduced basal transcriptional activity of central nervous system-derived HIV type 1 long terminal repeats.

New evidence indicates that astrocytes of the central nervous system (CNS) are extensively infected with human immunodeficiency virus type 1 (HIV-1) in vivo. Although no new virus is produced, this nonproductive or restricted infection contributes to the pathogenesis of HIV-associated dementia (HAD) and compromises virus eradication strategies. The HIV-1 long terminal repeat (LTR) plays a critical role in regulating virus production from infected cells.

CD4 and MHC class 1 down-modulation activities of nef alleles from brain- and lymphoid tissue-derived primary HIV-1 isolates.

Human immunodeficiency virus type 1 (HIV-1) nef undergoes adaptive evolution in the central nervous system (CNS), reflecting altered requirements for HIV-1 replication in macrophages/microglia and brain-specific immune selection pressures. The role of Nef in HIV-1 neurotropism and pathogenesis of HIV-associated dementia (HAD) is unclear. In this study, we characterized 82 nef alleles cloned from brain, cerebral spinal fluid, spinal cord, and blood/lymphoid tissue-derived HIV-1 isolates from seven subjects with HAD.