Glycan masking of a non-neutralising epitope enhances neutralising antibodies targeting the RBD of SARS-CoV-2 and its variants
George Carnell, Martina Billmeier, Sneha Vishwanath, Maria Suau Sans, Hannah Wein, Charlotte George, Patrick Neckermann, Joanne Marie M. Del Rosario, Alex Sampson, Sebastian Einhauser, Ernest T. Aguinam, Matteo Ferrari, Paul Tonks, Angalee Nadesalingam, Anja Schütz, Chloe Qingzhou Huang, David A. Wells, Minna Paloniemi, Ingo Jordan, Diego Cantoni, David Peterhoff, Benedikt Asbach, Volker Sandig, Nigel Temperton, Rebecca Kinsley, Ralf Wagner, Jonathan L. Heeney
Abstract
The accelerated development of the first generation COVID-19 vaccines has saved millions of lives, and potentially more from the long-term sequelae of SARS-CoV-2 infection. The most successful vaccine candidates have used the full-length SARS-CoV-2 spike protein as an immunogen. As expected of RNA viruses, new variants have evolved and quickly replaced the original wild-type SARS-CoV-2, leading to escape from natural infection or vaccine induced immunity provided by the original SARS-CoV-2 spike sequence. Next generation vaccines that confer specific and targeted immunity to broadly neutralising epitopes on the SARS-CoV-2 spike protein against different variants of concern (VOC) offer an advance on current booster shots of previously used vaccines. Here, we present a targeted approach to elicit antibodies that neutralise both the ancestral SARS-CoV-2, and the VOCs, by introducing a specific glycosylation site on a non-neutralising epitope of the RBD. The addition of a specific glycosylation site in the RBD based vaccine candidate focused the immune response towards other broadly neutralising epitopes on the RBD. We further observed enhanced cross-neutralisation and cross-binding using a DNA-MVA CR19 prime-boost regime, thus demonstrating the superiority of the glycan engineered RBD vaccine candidate across two platforms and a promising candidate as a broad variant booster vaccine.