In June 2024 a team from Monash University shared that a collaboration with the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) has produced a COVID-19 vaccine that has induced “very long-lasting, protective immunity” against SARS-CoV-2 virus in pre-clinical models. Their paper in Molecular Therapy presents a novel vaccine platform that fuses the receptor-binding domain (RBD) from the SARS-CoV-2 virus spike protein to the Clec9A antibody, which targets a specific subset of dendritic cells. A single shot immunisation resulted in “increased protection over time”.
The need for new vaccines
The authors suggest that safe and effective vaccines are “imperative” to protect “not only against death, but also against long term, debilitating conditions associated with SARS-CoV-2 infection”. Although more than 13 billion doses of COVID-19 vaccines have been administered globally, they face “several challenges”. For example, repeated booster doses are required as SARS-CoV-2 reactive antibodies and T cells “waned over time”.
“New-generation vaccines that can overcome at least some of these limitations are needed to provide broad and durable protection against rapidly evolving SARS-CoV-2 variants.”
Previous research has explored the potential of dendritic cell (DC)-based vaccines, including antigen-pulsed autologous DC and DC-targeting strategies. Targeting antigen vaccine candidates to Clec9A expressed on the type 1 conventional DC (cDC1) subset has “proven promising” in pre-clinical studies. Clec9A is a C-type lectin-like receptor that acts as a damage recognition receptor, identifying filamentous actin exposed when the cell membrane is damaged and facilitates the cross-presentation of dead cell-associated antigens.
Clec9A targeting was found to be “more potent” than targeting of other DC receptors. In the study, the authors engineered a Clec9A-RBD antibody construct by genetically fusing a single copy of ancestral SARS-CoV-2 receptor binding domain (RBD) to each heavy chain of a rat IgG2a mAb specific to mouse Clec9A.
Study findings
In their study, the authors demonstrate that targeting SARS-CoV-2 RBD to Clec9A-expressing DCs (cDC1) resulted in “potent and exceptionally sustained immune responses” after single dose immunisation.
“Importantly, we provided evidence of affinity maturation over time, which led to improved potency and breadth of the humoral immune response against a broad representation of the sarbecovirus family.”
Associate Professor Sylvie Alonso, Principal Investigator of the study, described the results as “very promising”, with the expectation that the work in pre-clinical models is “highly translatable to humans”.
“Our teams in NUS Medicine and Monash University foresee that the exceptional durability of the immune responses induced by the Clec9A targeting technology, when used as a booster vaccine strategy, may address the shortcoming of current mRNA vaccines, chief of which is the rapid waning of immune responses.”
Associate Professor Alonso stated that the next step is to evaluate the vaccine candidate as a booster vaccine in mRNA-vaccinated pre-clinical models.
“We hope to demonstrate that this booster approach will induce long-term protective immunity and avoid the need of multiple (annual) booster shots. Beyond COVID-19, this versatile, rapidly deployable vaccine platform shows promising potential to be part of the pandemic response against diseases caused by unknown pathogens in the future.”
Associate Professor Mireille Lahoud emphasised the “strength of our platform targeting specialised immune cells for vaccine improvement”.
“There remain many diseases where effective vaccines have proven difficult to generate. Validation of this platform provides strong proof-of-concept for application to such challenges.”
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