Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability

Abstract

The rapid spread of SARS-CoV-2 has a significant impact on global health, travel and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent COVID-19 patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3 and VH1-24 gene usage. A subset of the antibodies were able to potently inhibit authentic SARS-CoV-2 infection as low as 0.007 μg/mL. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.

Engineered ACE2 receptor traps potently neutralize SARS-CoV-2

“…Variants 310 and 313 displayed the most neutralization potency, with IC50s of approximately 90 ng/ml and 73 ng/ml, respectively ( Figure 4F, Table S4). This neutralization potency is comparable to recently reported antibodies isolated from convalescent COVID-19 patients (6,39). None of the ACE2 variants induced cytotoxicity in uninfected cells at the concentrations used in the neutralization assay ( Figure S12).…”

Measuring SARS-CoV-2 neutralizing antibody activity using pseudotyped and chimeric viruses

“…This finding may be because they are single-cycle assays, or perhaps because pseudotyped virions may have lower spike density than SARS-CoV-2. Notably, pseudoviruses employed by other investigators sometimes exhibit increased sensitivity to mAbs as compared with SARS-CoV-2, and sometimes their potencies against both virus types are closely matched (Brouwer et al, 2020;Cao et al, 2020;Ju et al, 2020;Wec et al, 2020;Zost et al, 2020 Preprint).…”

“…Effective vaccination and administration of cloned human mAbs may be more successful than prior natural infection and convalescent plasma in providing antibody-based protection from SARS-CoV-2 infection. Indeed, recent work from our own laboratories and others has shown that closely related, highly potent, neutralizing mAbs targeting the SARS-CoV-2 receptorbinding domain (RBD) can be isolated from multiple convalescent donors (Brouwer et al, 2020;Cao et al, 2020;Chen et al, 2020b;Chi et al, 2020 Preprint;Robbiani et al, 2020;Ju et al, 2020;Rogers et al, 2020;Seydoux et al, 2020 Preprint;Shi et al, 2020;Wec et al, 2020;Wu et al, 2020b;Zost et al, 2020 Preprint). Potent antibodies can be isolated from individuals with high or unexceptional plasma neutralizing titers, suggesting that natural infection in some individuals does not induce sufficient B cell expansion and maturation to generate high levels of such antibodies (Robbiani et al, 2020;Wu et al, 2020a Preprint).…”

Presence and strength of binding of IgM, IgG and IgA antibodies against SARS-CoV-2 during CoViD-19 infection

“…The quality of the immune response is not only determined by the quantity of antibodies but also by the overall strength of binding of the pool of potential neutralizing antibodies that binds to the relevant immunogenic proteins of the Corona virus. Recently it was shown that the most potent, highest a nity neutralizing antibodies were directed to the receptor-binding domain (RBD) [9]. This RBD of SARS-CoV-2 domain binds to the angiotensin converting enzyme2 (ACE2) receptor expressed by target cells.…”

“…In a US study [11] the calculated a nity difference between SARS-CoV and SARS-CoV-2 was even 10-20 times. The two most potent neutralizing monoclonal antibodies against RBD in a Dutch study had an equilibrium dissociation constant K D of 47 and 60 pM [9]. Generally, an antibody in that range will effectively block the virus monovalently.…”