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EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314575


COVID-19 vaccines already in use or in clinical development may have safety concerns, limited immunogenicity in high-risk groups or reduced efficacy against emerging SARS-CoV-2 variants. In addition, although the neurotropism of SARS-CoV-2 is well established, the vaccine strategies currently developed have not taken into account the protection of the central nervous system. Here, we generated a transgenic mouse strain expressing the human Angiotensin Converting Enzyme 2, with unprecedented brain as well as lung permissibility to SARS-CoV-2 replication. Using this stringent transgenic model, we demonstrated that a non-integrative lentiviral vector, encoding for the spike glycoprotein of the ancestral Wuhan SARS-CoV-2, used in intramuscular prime and intranasal boost elicits sterilizing protection of lung and brain against both the Wuhan and the most genetically distant Manaus P.1 SARS-CoV-2 variants. Beyond the induction of strong neutralizing antibodies, the mechanism underlying this broad protection spectrum involves a robust protective spike-specific CD8+ T-cell immunity, unaffected by the recent mutations accumulated in the emerging SARS-CoV-2 variants.

Preprint in English | bioRxiv | ID: ppbiorxiv-478159


As the COVID-19 pandemic continues and new SARS-CoV-2 variants of concern emerge, the adaptive immunity initially induced by the first-generation COVID-19 vaccines wains and needs to be strengthened and broadened in specificity. Vaccination by the nasal route induces mucosal humoral and cellular immunity at the entry point of SARS-CoV-2 into the host organism and has been shown to be the most effective for reducing viral transmission. The lentiviral vaccination vector (LV) is particularly suitable for this route of immunization because it is non-cytopathic, non-replicative and scarcely inflammatory. Here, to set up an optimized cross-protective intranasal booster against COVID-19, we generated an LV encoding stabilized Spike of SARS-CoV-2 Beta variant (LV::SBeta-2P). mRNA vaccine-primed and -boosted mice, with waning primary humoral immunity at 4 months post-vaccination, were boosted intranasally with LV::SBeta-2P. Strong boost effect was detected on cross-sero-neutralizing activity and systemic T-cell immunity. In addition, mucosal anti-Spike IgG and IgA, lung resident B cells, and effector memory and resident T cells were efficiently induced, correlating with complete pulmonary protection against the SARS-CoV-2 Delta variant, demonstrating the suitability of the LV::SBeta-2P vaccine candidate as an intranasal booster against COVID-19.

Preprint in English | bioRxiv | ID: ppbiorxiv-429211


Non-integrative, non-cytopathic and non-inflammatory lentiviral vectors are particularly suitable for mucosal vaccination and recently emerge as a promising strategy to elicit sterilizing prophylaxis against SARS-CoV-2 in preclinical animal models. Here, we demonstrate that a single intranasal administration of a lentiviral vector encoding a prefusion form of SARS-CoV-2 spike glycoprotein induces full protection of respiratory tracts and totally avoids pulmonary inflammation in the susceptible hamster model. More importantly, we generated a new transgenic mouse strain, expressing the human Angiotensin Converting Enzyme 2, with unprecedent brain permissibility to SARS-CoV-2 replication and developing a lethal disease in <4 days post infection. Even though the neurotropism of SARS-CoV-2 is now well established, so far other vaccine strategies under development have not taken into the account the protection of central nervous system. Using our highly stringent transgenic model, we demonstrated that an intranasal booster immunization with the developed lentiviral vaccine candidate achieves full protection of both respiratory tracts and brain against SARS-CoV-2.

Preprint in English | bioRxiv | ID: ppbiorxiv-214049


To develop a vaccine candidate against COVID-19, we generated a Lentiviral Vector (LV), eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, conferred only partial protection, despite an intense serum neutralizing activity. However, targeting the immune response to the respiratory tract through an intranasal boost with this LV resulted in > 3 log10 decrease in the lung viral loads and avoided local inflammation. Moreover, both integrative and non-integrative LV platforms displayed a strong vaccine efficacy and inhibited lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and restitute the human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of the LV-based vaccination against SARS-CoV-2 and designate the intranasal immunization as a powerful approach against COVID-19. HighlightsA lentiviral vector encoding for Spike predicts a promising COVID-19 vaccine Targeting the immune response to the upper respiratory tract is key to protection Intranasal vaccination induces protective mucosal immunity against SARS-CoV-2 Lung anti-Spike IgA responses correlate with protection and reduced inflammation