Innate resistance to viral infections can be attributed to mutations in genes involved in the immune response, or to the receptor/ligand. A remarkable example of the latter is the recently described Mendelian trait resistance to clinically important and globally predominating genotypes of rotavirus, the most common agent of severe dehydrating gastroenteritis in children worldwide. This resistance appears to be rotavirus genotype-dependent and is mainly mediated by histo-blood group antigens (HBGAs), which function as a receptor or attachment factors on gut epithelial surfaces. HBGA synthesis is mediated by fucosyltransferases and glycosyltransferases under the genetic control of the FUT2 (secretor), FUT3 (Lewis), and ABO (H) genes on chromosome 19. Significant genotypic and phenotypic diversity of HBGA expression exists between different human populations. This genetic diversity has an effect on genotype-specific susceptibility, molecular epidemiology, and vaccine take. Here, we will discuss studies on genetic susceptibility to rotavirus infection and place them in the context of population susceptibility, rotavirus epidemiology, vaccine take, and public health impact.

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.

This qualitative review on rotavirus infection and its complications in the central nervous system (CNS) aims to understand the gut–brain mechanisms that give rise to CNS driven symptoms such as vomiting, fever, feelings of sickness, convulsions, encephalitis, and encephalopathy. There is substantial evidence to indicate the involvement of the gut–brain axis in symptoms such as vomiting and diarrhea. The underlying mechanisms are, however, not rotavirus specific, they represent evolutionarily conserved survival mechanisms for protection against pathogen entry and invasion. The reviewed studies show that rotavirus can exert effects on the CNS trough nervous gut–brain communication, via the release of mediators, such as the rotavirus enterotoxin NSP4, which stimulates neighboring enterochromaffin cells in the intestine to release serotonin and activate both enteric neurons and vagal afferents to the brain. Another route to CNS effects is presented through systemic spread via lymphatic pathways, and there are indications that rotavirus RNA can, in some cases where the blood brain barrier is weakened, enter the brain and have direct CNS effects. CNS effects can also be induced indirectly as a consequence of systemic elevation of toxins, cytokines, and/or other messenger molecules. Nevertheless, there is still no definitive or consistent evidence for the underlying mechanisms of rotavirus-induced CNS complications and more in-depth studies are required in the future.

Viral infections have a major impact on physiology and behavior. The clinical symptoms of human rotavirus and norovirus infection are primarily diarrhea, fever, and vomiting, but several other sickness symptoms, such as nausea, loss of appetite, and stress response are never or rarely discussed.

Rotavirus and norovirus cause acute gastroenteritis with severe diarrhoea and vomiting, symptoms that may lead to severe dehydration and death. The objective of this randomized double-blinded placebo-controlled study was to investigate whether ondansetron, a serotonin receptor antagonist could attenuate rotavirus- and norovirus-induced vomiting and diarrhoea, which would facilitate oral rehydration and possibly accelerate recovery and reduce need for hospitalization. Children with acute gastroenteritis, aged 6 months to 16 years where enrolled (n = 104) and randomized to one single oral dose (0.15mg/kg) of ondansetron (n = 52) or placebo (n = 52). The number of diarrhoea and vomiting episodes during the 24 hours following treatment was reported as well as the number of days with symptoms. Pathogens in faeces were diagnosed by real-time PCR. Outcome parameters were analyzed for rotavirus- and norovirus-positive children. One dose of oral ondansetron reduced duration of rotavirus clinical symptoms (p = 0.014), with a median of two days. Furthermore, ondansetron reduced diarrhea episodes, most pronounced in children that had been sick for more than 3 days before treatment (p = 0.028). Ondansetron may be a beneficial treatment for children with rotavirus gastroenteritis. European Clinical Trial Database EudraCT 2011-005700-15.