Rotavirus immune responses and correlates of protection

Abstract

Selected topics in the field of rotavirus immunity are reviewed focusing on recent developments that may improve efficacy and safety of current and future vaccines. Rotaviruses (RVs) have developed multiple mechanisms to evade interferon (IFN)-mediated innate immunity. Compared to more developed regions of the world, protection induced by natural infection and vaccination is reduced in developing countries where, among other factors, high viral challenge loads are common and where infants are infected at an early age. Studies in developing countries indicate that rotavirus-specific serum IgA levels are not an optimal correlate of protection following vaccination, and better correlates need to be identified. Protection against rotavirus following vaccination is substantially heterotypic; nonetheless, a role for homotypic immunity in selection of circulating postvaccination strains needs further study.

Figure 1

Modulation of the host innate immune system by RV. After viral entry, viral replication activates the pathogen recognition receptors RIG-I and MDA-5, which in turn activate the transcription factor IRF3 and NF-κB. These molecules translocate to the nucleus, where they induce the transcription of ISGs and IFN. Viral replication produces NSP1 that can induce proteasomal degradation of IRF3. Through NSP1 dependent and independent mechanisms RV may also block NF-κB translocation. After transcription of IFNs, the dsRNA-dependent protein kinase PKR modulates IFN secretion by an unknown mechanism. Autocrine secreted IFN signals through the IFN receptor to activate transcription factors STAT1, STAT2 and IRF9. These factors translocate to the nucleus and further increase the levels of ISG and IFN transcripts, establishing an “antiviral state”. RV has also been shown to block STAT1 and STAT2 through an unknown mechanism.