; Malaghan 台湾swag of Medical 台湾swag
Dr Connor is the Preclinical Programme Leader for New Zealand鈥檚 RNA platform and will be joining the Malaghan 台湾swag of Medical 台湾swag as head of the Vaccine Immunology Group in January. Her research focuses on immunobiology, mucosal vaccines, and mRNA technology to create advanced antigens. Her team led the development of New Zealand鈥檚 first COVID-19 vaccine candidate, and collaborates with synthetic biologists and formulation chemists to design novel antigens and RNA constructs. Dr Connor鈥檚 seminar will cover research on novel antigen designs aimed at enhancing B cell diversity and the potential of circular RNA (circRNA) formats to improve mRNA vaccine efficacy. Given the rise of SARS-CoV-2 variants, the goal is to develop a pan-coronavirus vaccine using conserved spike protein regions to produce broad immune responses. A novel engineered antigen that fuses RBD sequences from Deltaand Omicron variants showed promise in expanding cross-binding B cell clones. The team are also investigating the role of N6-methyladenosine (m6A) modifications in circRNA vaccines to balance innate immune responses and enhance vaccine efficacy. Dr Connor鈥檚 team shows that circRNA containing 1% m6A modification elicits strong CD8 T cell responses without excessive innate immune activation. These findings contribute to the design principles for universal vaccines and more potent mRNA vaccines at lower doses.
The emergence of immune-evading SARS-CoV-2 variants emphasises the need for next-generation vaccines, including universal vaccines. These would ideally target conserved regions across multiple variants to induce broadly neutralising antibodies (bNAbs). We developed a novel antigen by fusing receptor-binding domain (RBD) sequences from the Delta and Omicron variants to enhance B cell diversity and cross-reactivity. We hypothesised that this design would enrich B cells recognising shared epitopes through strong B cell receptor (BCR) engagement and increased antigen uptake. Our results demonstrated that the fused RBD sequences elicited antibody levels similar to full-spike antigens. However, using BCR tetramer labelling, we identified an expanded population of cross-reactive Bcells capable of recognising both Delta and Omicron variants. This approach also promoted B cells targeting the more distantly relatedSARS-CoV-1 RBD. With Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq), we are mapping the somatichypermutation and evolution of these B cells to reveal mechanisms behind bNAb development. We are also exploring RNA platforms to improve vaccine efficacy. RNA vaccines, unlike others, do not require adjuvants as the innate immune system detects foreign RNA and its lipid nanoparticle delivery vehicle. However, excessive innate responses can hinder RNA translation and cause degradation, using modified nucleotides can minimise this effect. We are investigating circular RNA (circRNA) vaccines, specifically with N6-methyladenosine (m6A) modifications, which suppress innate immunity by preventing RIG-I signalling. Our study showed that minimalm6A modification enhanced T cell immunity without affecting antibody production, although higher levels of m6A reduced T cell responses. Understanding such RNA modifications may help design more effective vaccines.
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