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Rotavirus

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kvanderwaal edited this page Jul 16, 2019 · 67 revisions

Group

Notes

1)Immunology

In a seminal paper, Velazquez et al. [80] followed up 200 healthy children over their first 2 years of life for the occurrence of RV disease and for associated immune responses. Primary RV infection typically resulted in AGE, but protection developed against subsequent RV infections, with a progressively lower risk of disease. No moderate or severe disease was observed after 2 RV infections.

Immunity after neonatal RV infection did not confer protection from reinfection [86–88], but in some cases, it protected against severe clinical disease

The majority of RV-specific B cells circulating in the blood in children express the gut-specific homing receptor α4β7 [106, 107], suggesting local protective action.

RV infection is a relatively poor inducer of cytokine-secreting, virus-specific CD8+ cells [114], although these cells are present in the peripheral blood in most adults [115]. Circulating RV-specific T-helper (Th) cells are detected in blood samples from infants during the convalescent phase [26, 27]. Dendritic cells infected with RV in vitro can stimulate RV-specific T cells to secrete Th1 cytokines [116, 117] and have been shown to produce IFN-γ after infection with rhesus RV [117] but are less efficient in presenting antigens in infants and young children than in adults [114]. The role of cell-mediated immune responses for protection in humans remains to be explored.

Rotavirus dsRNA stable in environment

  1. Genetic diversity:

  • Different species
  • Epidemiological studies (largely hospital based) have shown that 5 rotavirus genotypes (G1P[8], G3P[8], G4P[8], G2P[4], and G9P[8]) have been the most common types causing severe disease in children in most countries during the last 20 years
  • Genotypes vary across years cycling 3-7 years (rotavirus a)

  • Phylogenies do not show as strong of genetic drift as influenza, partly because lower mutation rate and dsRNA
  • Because of lower homotypic immunity than influenza, promotes coexistence of strains rather than sequential replacement of strains within subtypes

  • Emergence of new clades after vaccination programs started

These mechanisms include (1) accumulation of point mutations (genetic drift) that can lead to antigenic changes; (2) reassortment that lead to viruses with novel genetic and antigenic characteristics, which can occur as a result of exchange between 2 human strains or human and animal strains; (3) direct transmission of animal strains into a human host; and (4) gene rearrangement (eg, deletions, duplications, and insertions) into coding or noncoding regions, primarily of nonstructural genes

10 VP7 and 7 VP4

nABs against outer glycoprotein g and p assignment serotypes G1 accounts for 75% of isolates G1P8

2008 WGS genotyping Multiple Genes used to classify

Immune response B and T VP4 and VP7 neutralize

  1. Population dynamics:

  • G1P[8] is the dominant strain in most parts of the world, but occasionally other strains dominate

  • Cycles are typically 3-11 years

  • Modeled the strength of homo- and heterotypic immunity and its impact on coexistence and cyclic dynamics -- Model based on reduced susceptibility and infectiousness (Rel. risk for homotypic reinfection: 0.01-0.5, Rel. risk for heterotypic reinfection: 0.5-1.0). -- After infection with 2 types, assumed that host was immune to all

  • Found that shorter cycles occur if relative risk to homotypic strain is weaker (A)

  • Introduced vaccination which either provided stronger immunity to G1P[8] or equal immunity against all

  • Preferential immunity against G1P[8] lead to the dominance of other strains (B, C)

  • Equal immunity against all lead to continued dominance of G1P[8] (D,E)

  • Emergence of novel strains

  • (A) Vaccine protects preferentially to G1P[8], with some protection to new strain

  • (B) Vaccine provides no protection against new strain

  • (C/D) - Equal protection against current strains but weak against new strain. In (C), new strain now cycles with G1P[8]

Outstanding questions:

  • Heterotypic immunity - cross-neutralization panels and antigenic cartography
  • Can a new strain invade in absence of vaccination?
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