Thursday, April 3, 2025
4/3/2025
Synergistic Nanobodies for Pandemic Preparedness - Project Summary Betacoronaviruses (beta-CoVs), including SARS-CoV-1, MERS-CoV, and SARS-CoV-2, have reshaped our understanding of pandemic preparedness. These viruses demonstrate a remarkable ability to mutate and evade defenses, continuing to infect populations worldwide despite extensive vaccination efforts and antiviral therapies. The chameleon-like nature of SARS-CoV-2, particularly its modifications to the Spike protein, consistently outpaces existing countermeasures, necessitating new strategies. This proposal introduces a pioneering class of nanobodies (Nbs), engineered from the immune system of llamas, designed to provide comprehensive protection against all beta-CoVs. These biologics not only advance treatment but also signify a pivotal step in pandemic preparedness, equipping us to outpace the relentless evolution of beta-CoVs. Our innovation lies in developing multivalent, synergistic combinations of broad-spectrum, high-efficacy Nbs. By harnessing these combinations, we amplify their efficacy and scope, concurrently increasing their resistance to viral mutations. Administered intranasally or directly to the lungs, these Nbs serve as both prophylactics and therapeutic agents. Our first Aim is to strategically expand upon our proven repertoires to identify, isolate, and characterize a much larger and more diverse repertoire of Nbs that collectively are strongly neutralizing across the beta-CoVs. We will use cutting-edge methods to produce diverse Nbs from llamas exposed to spike proteins of various beta- CoVs, selecting those with high affinity, specificity, and stability. We aim to discover synergistic, escape-resistant Nb pairs through combination testing and structural analysis. In our second Aim, we will optimize critical parameters important for developing broadly neutralizing Nb combinations and derivatives for human use. We will evaluate the in vivo synergistic potential of Nbs targeting major threats like MERS-CoV and SARS-CoV-2, and engineer Nbs to optimize their properties and efficacy in preparation for clinical trials. Deploying these pre- programmed Nbs at an outbreak's onset will protect first responders and medical personnel, reduce hospital surges, limit transmission, and buy time for new vaccine development and rollout. They will also provide crucial support to immunocompromised individuals, safeguarding the most vulnerable from the start. We hypothesize that our synergistic Nb combinations will introduce new beta-CoV neutralization methods, effectively prevent and treat infections, and maintain efficacy against emerging beta-CoV threats.
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