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

Abstract

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.

Keywords: COVID-19 vaccines; Narcolepsy; Orexin; Reactogenicity; Sleep.

Fig. 1

Schematic diagram illustrating the hypothetical implication of the orexinergic system in reactogenic sleepiness after COVID-19 vaccines. (A) After vaccination, inflammation is triggered by antigen and potential adjuvant present in the vaccine formulation. Then pro-inflammatory cytokines are released by activated resident innate immune cells at the periphery, which recruit immune cells, mainly hematogenous neutrophils, releasing directly acting hyperalgesic mediators on nociceptors. This fast neural route via the spinal nociceptive pathway transmits the signal to the brain neurons, producing pro-inflammatory cytokines by microglial cells. In addition, pathogen-associated molecular patterns (PAMPs) and circulating cytokines (slower humoral pathway) activate phagocytic and endothelial cells in the circumventricular organs (CVOs) and choroid plexus, respectively, leading to the production of brain cytokines that diffuse through the deficient blood-brain barrier (BBB) into the brain parenchyma. In both cases, the action of brain pro-inflammatory cytokines can be mediated by prostaglandins or nitric oxide. Brain parenchyma inflammatory milieu (increased of pro-inflammatory cytokines as somnogenic TNF-α and IL-1β) indirectly inhibits the activity of orexin (Ox) neurons during periods of wakefulness and arousal, leading to sleepiness. (B) Several central pathways could subserve its effects on wake-promoting neurons. (1) Lateral hypothalamic area (LHA) neurotensin (Nts)-expressing GABAergic neurons could mediate the suppression of Ox neuron activity, leading to hypersomnolence, resembling hypothalamic inflammation that induces sickness-associated lethargy. (2) Somnogenic IL-1β could directly activate a subset of GABAergic ventrolateral preoptic area (VLPO) sleep-promoting neurons inhibiting Ox neurons. (3) Pro-inflammatory cytokines stimulate astrocyte activation, and astrocyte-derived ATP may be hydrolyzed into adenosine (AD) by ATP-degrading enzymes in VLPO, perifornical (PF)-LHA, and other cholinergic, histaminergic and noradrenergic arousal-related neurons, promoting sleep. Adenosine via adenosine A2 receptors (A2R) directly activates GABAergic VLPO neurons as well as via adenosine A1 receptors (A1R) inhibit GABAergic interneurons, which disinhibit VLPO sleep-promoting neurons, possibly galaninergic. ATP via P2X7 receptors induces IL-1β, INF-γ, and TNF-α release from microglia increasing brain pro-inflammatory cytokines. (4) AD also induces inhibitory influence via A1R on Ox neurons at presynaptic terminals reducing calcium-dependent glutamate release and at the soma of Ox neurons, inhibiting voltage-dependent calcium channels. (5) Inhibitory inputs (inhibitory feedback) on Ox neurons under a central inflammatory context could also be provided from the serotonergic dorsal raphe (DR) nucleus, the noradrenergic locus coeruleus (LC), the dopaminergic ventral periaqueductal gray (vPAG), which are activated by lipopolysaccharide (LPS) experimental treatment.