Poster Presentation Australasian RNA Biology and Biotechnology Association 2026 Conference

Engineering antigenic breadth against SARS-CoV-2 by pairing divergent RBDs within a single mRNA immunogen (#130)

Joanna Kuang 1 , Isabelle Montgomerie 1 , Rebecca E McKenzie 1 , Olga R Palmer 1 , Ngarangi C Mason 1 , Theresa E Pankhurst 2 , Sarah L Draper 3 , Sventja von Daake 1 , David A Eccles 1 , Thomas Bird 1 , Abby L Martin 1 , Issac Green 1 , Lydia White 1 , Zoe Robinson 1 , Andrew J Marshall 3 , Jordan J Minnell 1 , Sam J Small 1 , Ian F Hermans 1 , Gavin F Painter 3 , James E Ussher 4 , Miguel E Quinones-Mateu 5 , Wayne M Patrick 6 , Davide Comoletti 6 , Lisa M Connor 1
  1. Malaghan Institute of Medical Research, Wellington, New Zealand
  2. Babraham Institute, Cambridge, United kingdom
  3. Ferrier Research Institute, Wellington
  4. University of Otago, Dunedin, New Zealand
  5. Western University , London, Ontario, Canada
  6. Victoria University of Wellington, Wellington, New Zealand

The use of RNA technology as a tool in therapeutics and preventative vaccine development is rapidly growing. The recent successes of messenger RNA (mRNA) vaccines have been driven by advances in in-vitro production of RNA molecules, bioinformatic tools and further development of ionisable lipid nanoparticles (iLNP). In contrast to conventional vaccine types, mRNA vaccines are highly adaptable allowing for changes to the target antigen encoded by the RNA sequence, without changing the standard production process drastically.

Vaccines capable of eliciting broadly neutralising antibodies (bnAbs) are a major goal for pandemic preparedness. A challenge across vaccine fields is how to deliberately recruit the rare B cell clones that recognise conserved epitopes shared across diverse viral variants. BnAbs have been known to frequently emerge through extensive somatic hypermutation during affinity maturation, here we describe an alternative, mechanism for bnAb selection. We designed an mRNA vaccine in which two antigenically distinct SARS-CoV-2 variant's (Omicron and Delta; O-Δ) receptor binding domains (RBDs) are physically fused on a single polypeptide. This design is predicted to favour B cell antigen receptors capable of engaging conserved epitopes on both RBDs with enhanced avidity. In mice, immunisation elicited potent antibody responses and increased the frequency of cross-reactive B cells, recognising Delta, Omicron, and the 2002 pandemic strain SARS-CoV RBDs.

This work highlights the modularity of RNA vaccine design, demonstrating its capacity to incorporate multiple antigenic variants within a single construct while enabling the rapid evaluation of design features such as transmembrane domains and epitope combinations which can ultimately elicit a larger number of bnAb-prone B cells. Through the New Zealand RNA platform, these modular design capabilities can be readily applied across a wide range of collaborative projects, supporting researchers through New Zealand in the development of RNA-based therapeutics and vaccines.