Reactogenic sleepiness after COVID-19 vaccination. A hypothesis involving orexinergic system linked to inflammatory signals

Coronavirus disease 2019 (COVID-19) represents a global healthcare crisis that has led to morbidity and mortality on an unprecedented scale. While studies on COVID-19 vaccines are ongoing, the knowledge about the reactogenic symptoms that can occur after vaccination and its generator mechanisms can be critical for healthcare professionals to improve compliance with the future vaccination campaign. Because sleep and immunity are bidirectionally linked, sleepiness or sleep disturbance side effects reported after some of the COVID-19 vaccines advise an academic research line in the context of physiological or pathological neuroimmune interactions. On the recognized basis of inflammatory regulation of hypothalamic neurons in sickness behavior, we hypothesized that IL-1β, INF-γ and TNF-α pro-inflammatory cytokines inhibit orexinergic neurons promoting sleepiness after peripheral activation of the innate immune system induced by the novel COVID-19 vaccines. In addition, based on knowledge of previous vaccines and disease manifestations of SARS-CoV-2 infection, it also suggests that narcolepsy must be included as potential adverse events of particular interest to consider in pharmacovigilance studies. •Sleepiness or sleep disturbance after COVID-19 vaccination have been reported.•IL-1β, INF-γ and TNF-α may propagate an inflammatory response to the hypothalamus promoting sleepiness.•Orexin (Ox) neurons inhibition could be involved in reactogenic sleepiness after COVID-19 vaccines.•LHA GABA-/Nts-expressing neurons arousal-associated Ox neurons could be critical players.•Sleepiness after COVID-19 vaccination should be an alert to be monitored in pharmacovigilance studies.