Engineered Receptor Binding Domain Immunogens Elicit Pan-Coronavirus Neutralizing Antibodies Outside the Receptor Binding Motif (preprint)

Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. We find that a cocktail of these homotrimeric sarbecovirus RBDs elicit antibodies to conserved viral epitopes outside of the ACE-2 receptor binding motif. Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. This may be an effective strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.Funding: We acknowledge funding from NIH R01s AI146779 (AGS), AI124378,AI137057 and AI153098 (DL), and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (AGS); training grants: NIGMS T32 GM007753 (BMH and TMC); T32AI007245 (JF); F31 Al138368 (MS). A.B.B. is supported by the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation. This independent research was supported by the Gilead Sciences Research Scholars Program in HIV.Conflict of Interest: Authors declare no competing interests.Ethical Approval: All experiments were conducted with institutional IACUC approval (MGH protocol 2014N000252).

COVID-19 Neutralizing Antibodies Predict Disease Severity and Survival (preprint)

COVID-19 exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, and high anti-RBD antibody levels. While anti-RBD IgG levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting protection from reinfection by this strain. However, SARS-CoV-2 sera was unable to cross-neutralize a highly-homologous pre-emergent bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.Funding: K.L.C. is supported by Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship 1F32AI143480. T.M.C. and B.M.H. were supported by award Number T32GM007753 from the National Institute of General Medical Sciences. J.F. was supported by T32AI007245. A.G.S. was supported by NIH R01 AI146779 and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant. J.A.B. has received research support from Zeus Scientific, bioMerieux, Immunetics, Alere, DiaSorin, the Bay Area Lyme Foundation (BALF), and the National Institute of Allergy and Infectious Diseases (NIAID; Award 1R21AI119457-01) for unrelated projects. J.A.B. has served as a paid consultant to T2 Biosystems, DiaSorin and Roche Diagnostics. A.J.I. is supported by the Lambertus Family Foundation. A.B.B. is supported by the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation. This independent research was supported by the Gilead Sciences Research Scholars Program in HIV. Ethical Approval: Use of patient samples for the development and validation of SARS-CoV-2 diagnostic tests was approved by Partners Institutional Review Board (protocol 2020P000895).