Review 1: "Sterilizing Immunity against SARS-CoV-2 Infection in Mice by a Single-Shot and Modified Imidazoquinoline TLR7/8 Agonist-Adjuvanted Recombinant Spike Protein Vaccine"

Yang Shi

doi:doi:10.1162/2e3983f5.6d739b86

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

by Sonia Jangra, Jana De Vrieze, Angela Choi, Raveen Rathnasinghe, Gabriel Laghlali, Annemiek Uvyn, Simon Van Herck, Lutz Nuhn, Kim Deswarte, Zifu Zhong, Niek Sanders, Stefan Lienenklaus, Sunil David, Shirin Strohmeier, Fatima Amanat, Florian Krammer, Hamida Hammad, Bart N. Lambrecht, Lynda Coughlan, Adolfo García-Sastre, Bruno G. De Geest, and Michael Schotsaert

Show Description
dx.doi.org

Description

AbstractThe 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.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

***************************************

Review:

The current preprint manuscript submitted by the group of De Geest and the group of Schotsaert reports on a novel subunit vaccine formulation with a macromolecular adjuvant for SARS-CoV-2, which is a timely contribution as a potential alternative solution for SARS-CoV-2 vaccination. The manuscript covers adjuvant formulation, in vitro and in vivo evaluations of the adjuvant together with the two antigens. The adjuvant IMDQ-PEG-CHOL was synthesized by conjugating a TLR7/8 agonist to cholesterol via a short PEG chain, which overall is water-soluble and can be easily injected. The cholesterol moiety of the conjugate is able to bind to albumin as reported in previous publications from the Irvine group and also recently by the De Geest group. Such conjugate was much more efficiently taken up by antigen-presenting cells such as DCs compared to a water-soluble version of the conjugate without the cholesterol moiety. In mice, after local injection in the footpad, the conjugate IMDQ-CHOL-PEG was shown to drain to lymph node to activate antigen-presenting cells, however, the water-soluble conjugate and the free TLR7/8 agonist displayed very low immunostimulation and massive whole-body inflammation reaction, respectively. It was interesting to observe that the IMDQ-CHOL-PEG was able to significantly boost the vaccination effects of a model human influenza vaccine IVR-180 [Influenza A /Singapore /gp1908 /2015 (H1N1)] in mice as compared to IVR-180 alone or IVR-180 with IMDQ-PEG regarding antibody generation and protection of mice after virus challenge. The exiting results of the work are the vaccination efficiency of the adjuvant IMDQ-CHOL-PEG with SARS-CoV-2 Spike protein and the protection of mice challenged with the virus by the vaccine.

One of the highlights of the system is that the vaccine was highly effective with only one injection. The current vaccines in clinical trials need generally two injections, which doubles the number of formulations required and this will delay the speed to vaccinate a sufficient fraction of the whole population of the world to stop the pandemic. The current adjuvant technology could potentially make the clinically tested vaccines more potent and to reduce the number of antigen materials in the vaccines, which will accelerate the vaccination process. Therefore, the work is of significant importance for the development of SARS-CoV-2 vaccines. In addition, one suggestion from the reviewer to the authors is that cellular immunity should also be considered in future research to better understand how the adjuvant improves the SARS-CoV-2 subunit vaccine in mice.