CoroNAb investigators have made a number of key contributions to SARS-CoV-2 research throughout the project.
PIs McInerney and Murrell at Karolinska Institutet immunized alpacas and generated nanobody libraries, discovering the neutralizing nanobody Ty1. This was foundational for SARS-CoV-2 single-domain antibody research, and has been widely cited. Additionally, the investigators discovered second-generation nanobodies with cross-variant neutralizing breadth and novel modes of neutralization.
Other members of the CoroNAb consortium at Karolinska, led by PIs Karlsson Hedestam and Murrell, have been focused on neutralizing antibody responses and comparing immunogens via serological readouts in both mice and rhesus macaques. Mouse immunization studies compared prefusion-stabilized spike to Receptor Binding Domain (RBD), with the former showing far greater immunogenicity. Later, it was shown that a Beta variant RBD elicited potent cross-neutralization when used as a booster immunogen.
Our pseudovirus neutralization assay, which was itself a distinct aim, has been used across the spectrum of CoroNAb activities, profiling both serum and identified nanobodies, as well as engaging as a key partner in collaborations. Notably, we disseminated the first pseudovirus neutralization results for Omicron, demonstrating that in cohorts with multiple antigenic exposures, the loss of neutralization was not as extreme as initially feared, and have characterized the degree of escape in multiple subsequent omicron sublineages, which was widely discussed in policy venues and the popular press.
Following on from this, in the 3rd reporting period we provided an early demonstration that the emerging variant BA.2.75 did not show substantial immune escape, but its offspring, BA.2.75.2 was extremely resistant to neutralization by antibodies. These results were presented, by invitation, at various venues such as the "Joint ECDC/WHO Euro SARS-CoV-2 virus characterisation working group", and the "Joint EMA-FDA Workshop on the efficacy of monoclonal antibodies in the context of rapidly evolving SARS-CoV-2 variants".
CoroNAb consortium member at ETH Zurich, PI Reddy, combined single-cell RNAseq with a mammalian display platform for antibody screening and optimization, which was used for mAb discovery and optimization, as well as characterizing antibodies from plasma cell populations. This team then published their novel Deep Mutational Learning approach, which combines Machine Learning with Deep Mutational Scanning to characterize and predict the effects of combinations of multiple SARS-CoV-2 mutations on antibody binding.
At Statens Serum Institut, under PI Pedersen, work was focused on the comparison of adjuvants. Multiple adjuvant formulations were characterized by various methods. A mouse immunization study was conducted to examine immune responses from spike immunization with each of these adjuvants. The studies demonstrated that the SARS-CoV-2 spike protein administered with various adjuvants boosted immune responses to the spike protein after a single immunization. Subsequent work used small animal models to investigate protection afforded by intranasal boosting.
At Imperial College London, PI Volz led work involving the development of methodological approaches for tracking the epidemic from genomic data, and building models to infer key parameters that characterize the epidemic. These models have been applied to two research questions: 1) the transmissibility of genetic variants; and 2) phylodynamic models to estimate intervention effect. CoroNAb investigators also developed a model of variant competition dynamics, which is monitored by local and international stakeholders (incl. the ECDC).
Overall, results from CoroNAb have been published, so far, in 28 peer reviewed publications, and presented at key meetings (eg. those by the ECDC and WHO), and widely reported in the popular press.
