Broad neutralization of pandemic threat coronaviruses

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ABSTRACT-OVERALL The recurrent emergence of coronaviruses from animal reservoirs, and the resulting COVID19 pandemic, necessitates the development of interventions that can target diverse pandemic-threat coronaviruses. Vaccines are among the most powerful means for mitigating viral epidemics but require significant breadth to maximize the probability of effectiveness against unknown viral threats. Currently, first generation vaccines are being deployed to combat SARS-CoV-2, but their effectiveness against emergent SARS-CoV-2 variants and, importantly, against other potential zoonotic coronaviruses is unknown. This program will focus on neutralizing antibodies as a demonstrated and key component of protective immune responses. The Program will improve preparedness against coronaviruses, employing a progressive multistep approach to increase the breadth of vaccine protection. A key component of the research will be to comprehend how neutralizing antibody responses, elicited in humans following natural infection or vaccination, target the SARS-CoV-2 envelope spike and how antibody evolution leads to increased potency and breadth. The identification and characterization of epitopes targeted by SARS-CoV-2 neutralizing antibodies, using multiple approaches, will guide the design of immunogens that aim to elicit neutralizing antibodies targeting as diverse a spectrum of coronaviruses as possible. Several immunogens and delivery strategies will be tested in mice and hamsters that will be challenged with authentic SARS-CoV-2 or a panoply of newly developed challenge models incorporating divergent coronavirus spike proteins. Antibodies elicited in these animals will be analyzed and compared with those found in SARS-CoV-2 immunized humans and immunogens progressively refined and down-selected with the goal of performing vaccine-challenge experiments in nonhuman primates with the most promising candidates. The expertise of each participating team is highly complementary and the program will capitalize and build on the already existing scientific synergy to ensure the efficient and timely completion of the goals.