Human rotavirus vaccines: too early for the strain to tell

The Lancet ◽  
2008 ◽  
Vol 371 (9619) ◽  
pp. 1144-1145 ◽  
Author(s):  
Keith Grimwood ◽  
Carl D Kirkwood
Keyword(s):  
Rotavirus Vaccines ◽  
Human Rotavirus

scholarly journals Two out of the 11 genes of an unusual human G6P[6] rotavirus isolate are of bovine origin

2008 ◽  
Vol 89 (10) ◽  
pp. 2630-2635 ◽  
Author(s):  
Jelle Matthijnssens ◽  
Mustafizur Rahman ◽  
Marc Van Ranst
Keyword(s):  
Complete Genome ◽  
Bovine Rotavirus ◽  
Rotavirus Vaccines ◽  
Human Rotavirus ◽  
New Gene ◽  
Molecular Origin ◽  
Encoding Gene ◽  
Vp7 Gene

In 2003, we described the first human G6P[6] rotavirus strain (B1711). To investigate further the molecular origin of this strain and to determine the possible reassortments leading to this new gene constellation, the complete genome of strain B1711 was sequenced. SimPlot analyses were conducted to compare strain B1711 with other known rotavirus gene segments, and phylogenetic dendrograms were constructed to analyse the origin of the eleven genome segments of strain B1711. Our analysis indicated that strain B1711 acquired its VP1-, VP2-, VP4-, VP6- and NSP1–5-encoding gene segments from human DS-1-like P[6] rotavirus strains, and its VP3 and VP7 gene segments from a bovine rotavirus strain through reassortment. The introduction of animal–human reassortant strains, which might arise in either of the hosts, into the human rotavirus population is an important mechanism for the generation of rotavirus diversity, and might be a challenge for the current rotavirus vaccines and vaccines under development.

scholarly journals Comparative analysis of the Rotarix™ vaccine strain and G1P[8] rotaviruses detected before and after vaccine introduction in Belgium

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2733 ◽  
Author(s):  
Mark Zeller ◽  
Elisabeth Heylen ◽  
Sana Tamim ◽  
John K. McAllen ◽  
Ewen F. Kirkness ◽  
...  
Keyword(s):  
Vaccine Strain ◽  
Amino Acid Level ◽  
Nsp2 Gene ◽  
Vaccine Introduction ◽  
Rotavirus Vaccines ◽  
Human Rotavirus ◽  
Genotype Constellation ◽  
Before And After ◽  
The Impact ◽  
Universal Mass Vaccination

G1P[8] rotaviruses are responsible for the majority of human rotavirus infections worldwide. The effect of universal mass vaccination with rotavirus vaccines on circulating G1P[8] rotaviruses is still poorly understood. Therefore we analyzed the complete genomes of the Rotarix™ vaccine strain, and 70 G1P[8] rotaviruses, detected between 1999 and 2010 in Belgium (36 before and 34 after vaccine introduction) to investigate the impact of rotavirus vaccine introduction on circulating G1P[8] strains. All rotaviruses possessed a complete Wa-like genotype constellation, but frequent intra-genogroup reassortments were observed as well as multiple different cluster constellations circulating in a single season. In addition, identical cluster constellations were found to circulate persistently over multiple seasons. The Rotarix™ vaccine strain possessed a unique cluster constellation that was not present in currently circulating G1P[8] strains. At the nucleotide level, the VP6, VP2 and NSP2 gene segments of Rotarix™ were relatively distantly related to any Belgian G1P[8] strain, but other gene segments of Rotarix™ were found in clusters also containing circulating Belgian strains. At the amino acid level, the genetic distance between Rotarix™ and circulating Belgian strains was considerably lower, except for NSP1. When we compared the Belgian G1P[8] strains collected before and after vaccine introduction a reduction in the proportion of strains that were found in the same cluster as the Rotarix™ vaccine strain was observed for most gene segments. The reduction in the proportion of strains belonging to the same cluster may be the result of the vaccine introduction, although natural fluctuations cannot be ruled out.

scholarly journals Generation of Simian Rotavirus Reassortants with VP4- and VP7-Encoding Genome Segments from Human Strains Circulating in Africa Using Reverse Genetics

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 201 ◽  
Author(s):  
Alexander Falkenhagen ◽  
Corinna Patzina-Mehling ◽  
Ashish K. Gadicherla ◽  
Amy Strydom ◽  
Hester G. O’Neill ◽  
...  
Keyword(s):  
Cell Culture ◽  
Disease Burden ◽  
Reverse Genetics ◽  
Sub Saharan Africa ◽  
Rotavirus A ◽  
Virus Particles ◽  
Rotavirus Vaccines ◽  
Human Rotavirus ◽  
Sub Saharan ◽  
Infants And Young Children

Human rotavirus A (RVA) causes acute gastroenteritis in infants and young children. The broad use of two vaccines, which are based on RVA strains from Europe and North America, significantly reduced rotavirus disease burden worldwide. However, a lower vaccine effectiveness is recorded in some regions of the world, such as sub-Saharan Africa, where diverse RVA strains are circulating. Here, a plasmid-based reverse genetics system was used to generate simian RVA reassortants with VP4 and VP7 proteins derived from African human RVA strains not previously adapted to cell culture. We were able to rescue 1/3 VP4 mono-reassortants, 3/3 VP7 mono-reassortants, but no VP4/VP7 double reassortant. Electron microscopy showed typical triple-layered virus particles for the rescued reassortants. All reassortants stably replicated in MA-104 cells; however, the VP4 reassortant showed significantly slower growth compared to the simian RVA or the VP7 reassortants. The results indicate that, at least in cell culture, human VP7 has a high reassortment potential, while reassortment of human VP4 from unadapted human RVA strains with simian RVA seems to be limited. The characterized reassortants may be useful for future studies investigating replication and reassortment requirements of rotaviruses as well as for the development of next generation rotavirus vaccines.

scholarly journals Screening of Viral Pathogens from Pediatric Ileal Tissue Samples after Vaccination

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Laura Hewitson ◽  
James B. Thissen ◽  
Shea N. Gardner ◽  
Kevin S. McLoughlin ◽  
Margaret K. Glausser ◽  
...  
Keyword(s):  
Porcine Circovirus ◽  
Recent Infection ◽  
Viral Pathogens ◽  
Tissue Samples ◽  
Rotavirus A ◽  
Microbial Detection ◽  
Rotavirus Vaccines ◽  
Detection Technology ◽  
Human Rotavirus ◽  
Ileal Tissue

In 2010, researchers reported that the two US-licensed rotavirus vaccines contained DNA or DNA fragments from porcine circovirus (PCV). Although PCV, a common virus among pigs, is not thought to cause illness in humans, these findings raised several safety concerns. In this study, we sought to determine whether viruses, including PCV, could be detected in ileal tissue samples of children vaccinated with one of the two rotavirus vaccines. A broad spectrum, novel DNA detection technology, the Lawrence Livermore Microbial Detection Array (LLMDA), was utilized, and confirmation of viral pathogens using the polymerase chain reaction (PCR) was conducted. The LLMDA technology was recently used to identify PCV from one rotavirus vaccine. Ileal tissue samples were analyzed from 21 subjects, aged 15–62 months. PCV was not detected in any ileal tissue samples by the LLMDA or PCR. LLMDA identified a human rotavirus A from one of the vaccinated subjects, which is likely due to a recent infection from a wild type rotavirus. LLMDA also identified human parechovirus, a common gastroenteritis viral infection, from two subjects. Additionally, LLMDA detected common gastrointestinal bacterial organisms from theEnterobacteriaceae,Bacteroidaceae, andStreptococcaceaefamilies from several subjects. This study provides a survey of viral and bacterial pathogens from pediatric ileal samples, and may shed light on future studies to identify pathogen associations with pediatric vaccinations.

scholarly journals Lactobacillus acidophilus and Lactobacillus reuteri modulate cytokine responses in gnotobiotic pigs infected with human rotavirus

2012 ◽  
Vol 3 (1) ◽  
pp. 33-42 ◽  
Author(s):  
M. Azevedo ◽  
W. Zhang ◽  
K. Wen ◽  
A. Gonzalez ◽  
L. Saif ◽  
...  
Keyword(s):  
Lactobacillus Acidophilus ◽  
Lactobacillus Reuteri ◽  
Rotavirus Vaccines ◽  
Cytokine Responses ◽  
Human Rotavirus ◽  
Probiotic Lactic Acid Bacteria ◽  
Th1 And Th2 Cytokines ◽  
Ifn Γ ◽  
Gnotobiotic Pigs ◽  
Th1 And Th2

Probiotic lactic acid bacteria (LAB) have been shown to alleviate inflammation, enhance the immunogenicity of rotavirus vaccines, or reduce the severity of rotavirus diarrhoea. Although the mechanisms are not clear, the differential Th1/Th2/Th3-driving capacities and modulating effects on cytokine production of different LAB strains may be the key. Our goal was to delineate the influence of combining two probiotic strains of Lactobacillus acidophilus and Lactobacillus reuteri on the development of cytokine responses in neonatal gnotobiotic pigs infected with human rotavirus (HRV). We demonstrated that HRV alone, or HRV plus LAB, but not LAB alone, initiated serum cytokine responses, as indicated by significantly higher concentrations of IFN-α, IFN-γ, IL-12, and IL-10 at postinoculation day (PID) 2 in the HRV only and LAB+HRV+ pigs compared to LAB only and LAB-HRV- pigs. Peak cytokine responses coincided with the peak of HRV replication. LAB further enhanced the Th1 and Th2 cytokine responses to HRV infection as indicated by significantly higher concentrations of IL-12, IFN-γ, IL-4 and IL-10 in the LAB+HRV+ pigs compared to the LAB-HRV+ pigs. The LAB+HRV+ pigs maintained relatively constant concentrations of TGF-β compared to the HRV only group which had a significant increase at PID 2 and decrease at PID 7, suggesting a regulatory role of LAB in maintaining gut homeostasis. At PID 28, cytokine secreting cell (CSC) responses, measured by ELISpot, showed increased Th1 (IL-12, IFN-γ) CSC numbers in the LAB+HRV+ and LAB-HRV+ groups compared to LAB only and LAB-HRV- pigs, with significantly increased IL-12 CSCs in spleen and PBMCs and IFN-γ CSCs in spleen of the LAB+HRV+ group. Thus, HRV infection alone, but not LAB alone was effective in inducing cytokine responses but LAB significantly enhanced both Th1 and Th2 cytokines in HRV-infected pigs. LAB may also help to maintain immunological homeostasis during HRV infection by regulating TGF-β production.

Rotavirus vaccines: how they work or don't work

2008 ◽  
Vol 10 ◽  
Author(s):  
Richard L. Ward
Keyword(s):  
T Cells ◽  
Cellular Immunity ◽  
Indirect Effects ◽  
Direct Role ◽  
Live Virus ◽  
Rotavirus Vaccines ◽  
Human Rotavirus ◽  
Helper Function ◽  
Antibody Levels ◽  
Mucosal Immunisation

In 2004 and 2006, two new rotavirus vaccines – Rotarix™and RotaTeq™– were licensed worldwide. Both are live virus vaccines and are composed of either a monovalent attenuated human rotavirus or five bovine–human reassortant rotaviruses, respectively. Studies in humans and animals have reported correlations between rotavirus antibody levels and protection, the most consistent of which has been with rotavirus IgA. Cellular immunity was also found to have a role in protection after live rotavirus immunisation, particularly in mice. However, the primary importance of CD8+T cells may be in resolution of infection and that of CD4+T cells may be their helper function, particularly for antibody production. CD4+T cells have been reported to have a more direct role in protection after mucosal immunisation with non-living rotavirus vaccines, possibly because of direct or indirect effects of the cytokines they generate. Immune effectors have overlapping functions, and protection against rotavirus by either live or non-living vaccines is probably enhanced by this redundancy.

scholarly journals Rotavirus Vaccines: an Overview

2008 ◽  
Vol 21 (1) ◽  
pp. 198-208 ◽  
Author(s):  
Penelope H. Dennehy
Keyword(s):  
Developing Countries ◽  
Control Measure ◽  
The United States ◽  
Rotavirus Vaccine ◽  
Industrialized Countries ◽  
Severe Diarrhea ◽  
Rotavirus Vaccines ◽  
Childhood Morbidity ◽  
Human Rotavirus ◽  
Increased Risk

SUMMARY Rotavirus infection is the most common cause of severe diarrhea disease in infants and young children worldwide and continues to have a major global impact on childhood morbidity and mortality. Vaccination is the only control measure likely to have a significant impact on the incidence of severe dehydrating rotavirus disease. In 1999, a highly efficacious rotavirus vaccine licensed in the United States, RotaShield, was withdrawn from the market after 14 months because of its association with intussusception. Two new live, oral, attenuated rotavirus vaccines were licensed in 2006: the pentavalent bovine-human reassortant vaccine (RotaTeq) and the monovalent human rotavirus vaccine (Rotarix). Both vaccines have demonstrated very good safety and efficacy profiles in large clinical trials in western industrialized countries and in Latin America. Careful surveillance has not revealed any increased risk of intussusception in the vaccinated groups with either vaccine. The new rotavirus vaccines are now introduced for routine use in a number of industrialized and developing countries. These new safe and effective rotavirus vaccines offer the best hope of reducing the toll of acute rotavirus gastroenteritis in both developed and developing countries.

scholarly journals Serial Passaging of the Human Rotavirus CDC-9 Strain in Cell Culture Leads to Attenuation: Characterization from In Vitro and In Vivo Studies

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Theresa Kathrina Resch ◽  
Yuhuan Wang ◽  
Sungsil Moon ◽  
Baoming Jiang
Keyword(s):  
Vero Cells ◽  
Wild Type Virus ◽  
Rotavirus Vaccine ◽  
Type Virus ◽  
Neonatal Rats ◽  
Wild Type ◽  
Rotavirus Vaccines ◽  
Human Rotavirus

ABSTRACT Live oral rotavirus vaccines have been developed by serial passaging in cell culture and found to be safe in infants. However, mechanisms for the adaptation and attenuation of rotavirus vaccines are not fully understood. We prepared a human rotavirus vaccine strain, CDC-9 (G1P[8]), which when grown in MA104 cells to passage 11 or 12 (P11/P12) had no nucleotide or amino acid sequence changes from the original virus in stool. Upon adaptation and passages in Vero cells, the strain underwent five amino acid changes at P28 and one additional change at P44/P45 in the VP4 gene. We performed virologic, immunological, and pathogenic characterization of wild-type CDC-9 virus at P11/P12 and its two mutants at P28 or P44/P45 using in vitro and in vivo model systems. We found that mutants CDC-9 P28 and P44 induced upregulated expression of immunomodulatory cytokines. On the other hand, the two mutant viruses induced lower STAT1 phosphorylation and grew to 2-log-higher titers than wild-type virus in human Caco-2 cells and simian Vero cells. In neonatal rats, CDC-9 P45 showed reduced rotavirus shedding in fecal specimens and did not induce diarrhea compared to wild-type virus and modulated cytokine responses comparably to Rotarix infection. These findings indicate that mutant CDC-9 is attenuated and safe. Our study is the first to provide insight into the possible mechanisms of human rotavirus adaptation and attenuation and supports ongoing efforts to develop CDC-9 as a new generation of rotavirus vaccine for live oral or parenteral administration. IMPORTANCE Mechanisms for in vitro adaptation and in vivo attenuation of human rotavirus vaccines are not known. The present study is the first to comprehensively compare the in vitro growth characteristics, virulence, and host response of a wild-type and an attenuated human rotavirus strain, CDC-9, in Caco-2 cells and neonatal rats. Our study identifies critical sequence changes in the genome that render human rotavirus adapted to growth to high levels in Vero cells and attenuated and safe in neonatal rats; thus, the study supports clinical development of CDC-9 for oral or parenteral vaccination in children.

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