RT Journal Article SR Electronic T1 Sterilizing Immunity against SARS-CoV-2 Infection in Mice by a Single-Shot and Modified Imidazoquinoline TLR7/8 Agonist-Adjuvanted Recombinant Spike Protein Vaccine JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.23.344085 DO 10.1101/2020.10.23.344085 A1 Sonia Jangra A1 Jana De Vrieze A1 Angela Choi A1 Raveen Rathnasinghe A1 Gabriel Laghlali A1 Annemiek Uvyn A1 Simon Van Herck A1 Lutz Nuhn A1 Kim Deswarte A1 Zifu Zhong A1 Niek Sanders A1 Stefan Lienenklaus A1 Sunil David A1 Shirin Strohmeier A1 Fatima Amanat A1 Florian Krammer A1 Hamida Hammad A1 Bart N. Lambrecht A1 Lynda Coughlan A1 Adolfo GarcĂ­a-Sastre A1 Bruno G. De Geest A1 Michael Schotsaert YR 2020 UL http://biorxiv.org/content/early/2020/10/23/2020.10.23.344085.abstract AB The search for vaccines that protect from severe morbidity and mortality as a result 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. Several vaccine candidates are currently being tested in the clinic. Inactivated virus and recombinant protein vaccines can be safe options but may require adjuvants to induce robust immune responses efficiently. In this work we describe the use of a novel 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). This amphiphile is water soluble and exhibits massive translocation to lymph nodes upon local administration, likely through binding to albumin. IMDQ-PEG-CHOL is used to induce a protective immune response against SARS-CoV-2 after single vaccination with trimeric recombinant SARS-CoV-2 spike protein in the BALB/c mouse model. Inclusion of amphiphilic IMDQ-PEG-CHOL in the SARS-CoV-2 spike vaccine formulation resulted in enhanced immune cell recruitment and activation in the draining lymph node. IMDQ-PEG-CHOL has a better safety profile compared to native soluble IMDQ as the former induces a more localized immune response upon local injection, preventing systemic inflammation. Moreover, IMDQ-PEG-CHOL adjuvanted vaccine induced enhanced ELISA and in vitro microneutralization titers, and a more balanced IgG2a/IgG1 response. To correlate vaccine responses with control of virus replication in vivo, vaccinated mice were challenged with SARS-CoV-2 virus after being sensitized by intranasal adenovirus-mediated expression of the human angiotensin converting enzyme 2 (ACE2) gene. Animals vaccinated with trimeric recombinant spike protein vaccine without adjuvant had lung virus titers comparable to non-vaccinated control mice, whereas animals vaccinated with IMDQ-PEG-CHOL-adjuvanted vaccine controlled viral replication and infectious viruses could not be recovered from their lungs at day 4 post infection. In order to test whether IMDQ-PEG-CHOL could also be used to adjuvant vaccines currently licensed for use in humans, proof of concept was also provided by using the same IMDQ-PEG-CHOL to adjuvant human quadrivalent inactivated influenza virus split vaccine, which resulted in enhanced hemagglutination inhibition titers and a more balanced IgG2a/IgG1 antibody response. Enhanced influenza vaccine responses correlated with better virus control when mice were given a lethal influenza virus challenge. Our results underscore the potential use of IMDQ-PEG-CHOL as an adjuvant to achieve protection after single immunization with recombinant protein and inactivated vaccines against respiratory viruses, such as SARS-CoV-2 and influenza viruses.Competing Interest StatementAG-S is inventor in patents on influenza and COVID-19 vaccines owned by the Icahn Shool of Medicine at Mount Sinai. The laboratory of AG-S has research agreements on the study of viral vaccines and prophylaxis with Avimex, Pfizer and 7Hills Pharma. AG-S is a consultant for Avimex and Esperovax