PT  - JOURNAL ARTICLE
AU  - George W. Carnell
AU  - Katarzyna A. Ciazynska
AU  - David A. Wells
AU  - Xiaoli Xiong
AU  - Ernest T. Aguinam
AU  - Stephen H. McLaughlin
AU  - Donna Mallery
AU  - Soraya Ebrahimi
AU  - Lourdes Ceron-Gutierrez
AU  - Leo C. James
AU  - Rainer Doffinger
AU  - Jonathan L. Heeney
AU  - John A. G. Briggs
TI  - SARS-CoV-2 spike protein arrested in the closed state induces potent neutralizing responses
AID  - 10.1101/2021.01.14.426695
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.14.426695
4099  - http://biorxiv.org/content/early/2021/01/14/2021.01.14.426695.short
4100  - http://biorxiv.org/content/early/2021/01/14/2021.01.14.426695.full
AB  - The majority of SARS-CoV-2 vaccines in use or in advanced clinical development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described that act against both open and closed conformations. The long-term success of vaccination strategies will depend upon inducing antibodies that provide long-lasting broad immunity against evolving, circulating SARS-CoV-2 strains, while avoiding the risk of antibody dependent enhancement as observed with other Coronavirus vaccines. Here we have assessed the results of immunization in a mouse model using an S protein trimer that is arrested in the closed state to prevent exposure of the receptor binding site and therefore interaction with the receptor. We compared this with a range of other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induce a long-lived, strongly neutralizing antibody response as well as T-cell responses. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralising responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, virus-inhibiting immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.Competing Interest StatementThe authors have declared no competing interest.