Sterilizing Immunity against SARS‐CoV‐2 Infection in Mice by a Single‐Shot and Lipid Amphiphile Imidazoquinoline TLR7/8 Agonist‐Adjuvanted Recombinant Spike Protein Vaccine**

Abstract

The search for vaccines that protect from severe morbidity and mortality because of infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus that causes coronavirus disease 2019 (COVID‐19) is a race against the clock and the virus. Here we describe an amphiphilic imidazoquinoline (IMDQ‐PEG‐CHOL) TLR7/8 adjuvant, consisting of an imidazoquinoline conjugated to the chain end of a cholesterol‐poly(ethylene glycol) macromolecular amphiphile. It is water‐soluble and exhibits massive translocation to lymph nodes upon local administration through binding to albumin, affording localized innate immune activation and reduction in systemic inflammation. The adjuvanticity of IMDQ‐PEG‐CHOL was validated in a licensed vaccine setting (quadrivalent influenza vaccine) and an experimental trimeric recombinant SARS‐CoV‐2 spike protein vaccine, showing robust IgG2a and IgG1 antibody titers in mice that could neutralize viral infection in vitro and in vivo in a mouse model.

A Combination Adjuvant for the Induction of Potent Antiviral Immune Responses for a Recombinant SARS-CoV-2 Protein Vaccine

“…Passive transfer studies performed in NHPs suggest only low NAb titers are necessary for protection against homologous challenge ( 17 ). As the amount of serum transferred was small (150 μl/mouse), it is likely that with such high NAb titers, the number of vaccinations required for instilling sterilizing immunity can be reduced to two or even one with NE/IVT, as we have reported for IM SARS-CoV-2 vaccination in mice with a TLR7/8 agonist as adjuvant which induced significantly lower NAb titers ( 59 ). The ability of NE/IVT to improve cross-variant protection induced with just the S1 subunit, particularly towards a variant with the N501Y mutation shared by several of the highly transmissible variants of concern, supports its potential for improving the breadth of protection of current vaccine candidates.…”

Mechanisms of SARS-CoV-2 entry into cells

“…Of these, TLR3, TLR7, TLR8 and TLR9 mount antiviral immune responses: TLR3 recognizes double-stranded RNA viruses, TLR9 recognizes unmethylated CpG in viral DNA, and, relevant to coronaviruses, TLR7 and TLR8 bind G/U-rich single-stranded viral RNA. TLR7 and TLR8 reside in the endosomes and were shown to induce proinflammatory cytokines in response to SARS-CoV and SARS-CoV-2 RNA 146 , 147 . TLR7 and TLR8 are both expressed in lung tissue.…”

A reverse vaccinology and immunoinformatics approach for designing a multiepitope vaccine against SARS-CoV-2

“…Output data from molecular dynamic simulations can be used to evaluate vaccine stability by simulation in vivo , wherein a study, the evaluation of TLR7/8 stimulation as in vivo , showed that injection of recombinant spike protein candidate vaccine in a mouse model induced the production of IgG2a and IgG1. (Jangra et al 2021 ).…”

“…Although COVID-19 disease is still a relatively new disease and requires more clinical findings, studies have shown the importance of TLR7/8 stimulation in COVID-19 vaccines. In one study, Imidazoquinolines was used as an adjuvant in a SARS-CoV-2 recombinant spike protein vaccine to enhance TLR7/8 stimulation, and the results showed that the vaccine led to product the robust IgG2a and IgG1 antibody titers in a mouse model and neutralized viral infection in both in vitro and in vivo (Jangra et al 2021 ). Responses of Th1 and CD8 + T cells have been shown also against HIV-1 Gag protein as RNA viral infection by TLR7/8 agonist (Wille-Reece et al 2005a , 2005b ).…”