Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Abstract

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials.

From Cell to Symptoms: The Role of SARS-CoV-2 Cytopathic Effects in the Pathogenesis of COVID-19 and Long COVID

“…Moreover, the presence of alterations in cerebral blood vessels could be explained by direct infection by SARS-CoV-2 [193]. This was previously described in two different animal models, in which they observed that the SARS-CoV-2 nsp5 protein induces the cleavage of the essential modulator of NF-κB (NEMO) in infected endothelial cells, inactivating it.…”

“…In addition, previous studies have reported that ventral brain blood vessels may undergo structural alterations in some patients with COVID-19, and morphological changes in microglia were also described. The latter, which are the result of microglial activation, are characterized by a retraction of the projections and an enlargement of the cell body, while alterations in cerebral blood vessels may appear as a consequence of an inflammatory activation of their permeability, which is also observed in other pathologies such as multiple sclerosis [193]. Regarding apoptosis in the dentate gyrus of the hippocampus, it has been previously described that certain infections affecting this region, such as bacterial meningitis, can also induce apoptosis, and learning deficits often occur in survivors [208].…”

“…Since then, several possible routes of spread of the virus to the CNS have been proposed. In addition, it has been accepted that the neurological manifestations observed in COVID-19 patients may be due to direct CNS infection and/or due to side effects of systemic infection, such as hypoxemia or cytokine release syndrome [193]. Consequently, given that the CNS is frequently affected by SARS-CoV-2 infection, it is not surprising that neuropsychiatric symptoms are common in patients with prolonged COVID.…”

“…However, some viruses can enter the CNS by retrograde hematogenous or neuronal routes, leading to debilitating direct immune-mediated pathologies [194]. SARS-CoV-2 virus can enter the nervous system by direct infection of tissue nerve endings and/or by utilizing the axonal transport machinery, as well as enter the CNS directly through the blood-brain barrier [193]. Thus, it uses transmucosal olfactory invasion as a gateway to access the central nervous system, which could be a consequence of ACE2 expression in the olfactory epithelium, specifically in sustentacular cells, Bowman's gland and horizontal basal cells [195].…”

Differential pathogenic and molecular features in neurological infection of SARS‐CoV‐2 Omicron BA.5.2 and BA.2.75 and Delta

“…Possible routes for SARS-CoV-2 invasion into the central nervous system (CNS) include: (1) entry through the nasal cavity to the olfactory bulb and subsequent spreading; (2) disruption of the BBB leading to leakage from blood vessels; and (3) retrograde transmission along neuronal axons. 33 Consequently, we analyzed the infection patterns of the variants in various brain regions and observed higher N proteinpositive signals in the olfactory bulb and cerebellum of Delta-infected brains (Figure 3B). Considering the spatial distance between the two regions, it appears unlikely that the virus originated from the olfactory bulb was directly transmitted to the cerebellum.…”