Development of broadly protective merbecovirus and sarbecovirus countermeasures

About This Grant

ABSTRACT There are two subgenera of βCoVs, Merbecovirus and Sarbecovirus, that cause severe disease in humans, for which broadly protective medical countermeasures are needed. While conserved sites of vulnerability on the virus Spike, called the receptor binding domain (RBD) and stem helix (SH), have been noted for merbecoviruses (MERBs) and sarbecoviruses (SARBs), antibodies to these epitopes tend to be infrequently elicited during infection or with current treatments. Our scientific premise is that nanoparticle (NP) S fragment immunogens elicit high titers of broadly neutralizing antibodies by focusing the immune response on subdominant epitopes. We proposed here to employ our innovative NP design technology to elicit broadly protective immunity against both subgenera of viruses. In rigorous preliminary studies, our RBD NP elicited neutralizing antibodies and protected mice against MERB MERS-CoV and four different SARBs. Also, our RBD NPs elicited neutralizing antibodies against 11 different SARBs, 5 different MERBs, and protected monkeys against SARB and MERB infection. Our central hypothesis is that neutralizing antibody breadth can be increased to cover many viruses within a βCoV subgenera by simultaneously eliciting a polyclonal, high-affinity antibody response to RBD and SH on CoV S. To determine the extent that polyclonal responses are needed, Specific Aim 1 will determine the antibody clonality and immunogenetics features that afford broad MERB and SARB neutralization. No known antibodies that bind to RBD and neutralize both MERBs and SARBs have been identified to date. The work in this aim will define the antibodies that mediate neutralization of each subgenus of viruses in order to understand the structural and genetic basis for how the neutralization breadth of these antibodies is limited within or across subgenera. In Specific Aim 2, we will further optimize our NP immunogens to increase the breadth of antibody response they elicit. Guided by the information about what viral sequences are resistant to the current induced antibodies, new immunogens will be designed using computational structural and bioinformatic approaches. These new immunogens will be tested for the ability to elicit broader neutralizing antibodies in mice than a commercial drug and our earlier immunogen designs. In Specific Aim 3, we will define the Ab responses that correlate with protection against SARBs and MERBs. Successful immunogens will be examined for their ability to elicit protective immunity against both Merbecoviruses and Sarbecoviruses in innovative mouse challenge models uniquely available to this team. Upon completion of this study, its impact will be the elucidation of new design approaches to target and protect against large subgenera of viruses rather than a single virus. Also, the final immunogen designed here, can be manufactured in the future to provide a countermeasure against deadly viruses for which there is no current treatment.