Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model

Rogers, Thomas F.; Zhao, Fangzhu; Huang, Deli; Beutler, Nathan; Burns, Alison; He, Wanting; Limbo, Oliver; Smith, Chloe N.; Song, Ge; Woehl, Jordan L.; Yang, Linlin; Abbott, Robert G.; Callaghan, Sean; Garcia, Elijah; Hurtado, Jonathan; Parren, Mara; Peng, Linghang; Ramirez, Sydney I.; Ricketts, James; Ricciardi, Michael J.; Rawlings, Stephen A.; Wu, Nicholas C.; Yuan, Meng; Smith, Davey M; Nemazee, David; Teijaro, John R.; Voss, James E.; Wilson, Ian A.; Andrabi, Raiees; Briney, Bryan; Landais, Elise; Sok, Devin; Jardine, Joseph G.; Burton, Dennis R.

doi:10.1126/science.abc7520

Cited by 1,364 publications

(1,791 citation statements)

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“…We chose this viral antigen because of its specificity to SARS-CoV-2, and because anti-RBD antibodies are typically neutralizing. Plaque reduction neutralization tests are the gold standard for assessing neutralizing ability, [23][24][25][26] and ongoing studies are in progress to confirm anti-RBD antibodies are neutralizing in SARS-CoV-2 infection. 27 Some commercially available assays measure the more abundant nucleocapsid protein, which may increase sensitivity to detect a serologic response early in the course of infection, therefore, shifting the seroconversion curve to the left.…”

Section: Negative Results Do Not Completely Preclude Sars-cov-2mentioning

confidence: 99%

Clinical sensitivity and interpretation of PCR and serological COVID‐19 diagnostics for patients presenting to the hospital

et al. 2020

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The diagnosis of COVID‐19 requires integration of clinical and laboratory data. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) diagnostic assays play a central role in diagnosis and have fixed technical performance metrics. Interpretation becomes challenging because the clinical sensitivity changes as the virus clears and the immune response emerges. Our goal was to examine the clinical sensitivity of two most common SARS‐CoV‐2 diagnostic test modalities, polymerase chain reaction (PCR) and serology, over the disease course to provide insight into their clinical interpretation in patients presenting to the hospital. We conducted a single‐center, retrospective study. To derive clinical sensitivity of PCR, we identified 209 PCR‐positive SARS‐CoV‐2 patients with multiple PCR test results (624 total PCR tests) and calculated daily sensitivity from date of symptom onset or first positive test. Clinical sensitivity of PCR decreased with days post symptom onset with >90% clinical sensitivity during the first 5 days after symptom onset, 70%‐71% from Days 9 to 11, and 30% at Day 21. To calculate daily clinical sensitivity by serology, we utilized 157 PCR‐positive patients with a total of 197 specimens tested by enzyme‐linked immunosorbent assay for IgM, IgG, and IgA anti‐SARS‐CoV‐2 antibodies. In contrast to PCR, serological sensitivity increased with days post symptom onset with >50% of patients seropositive by at least one antibody isotype after Day 7, >80% after Day 12, and 100% by Day 21. Taken together, PCR and serology are complimentary modalities that require time‐dependent interpretation. Superimposition of sensitivities over time indicate that serology can function as a reliable diagnostic aid indicating recent or prior infection.

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Section: Negative Results Do Not Completely Preclude Sars-cov-2mentioning

confidence: 99%

Clinical sensitivity and interpretation of PCR and serological COVID‐19 diagnostics for patients presenting to the hospital

et al. 2020

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“…Most recent strategies to prevent SARS-CoV-2 entry into the host cell aim at blocking the ACE2-RBD interaction. High-affinity monoclonal antibodies, many identified from convalescent patients, are leading the way as potential therapeutics (22)(23)(24)(25)(26)(27)(28)(29). While highly effective in vitro, these agents are expensive to produce by mammalian cell expression and need to be intravenously administered by healthcare professionals (30).…”

Section: Discussionmentioning

confidence: 99%

An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation

Schoof

Faust

Saunders

et al. 2020

Preprint

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Without an effective prophylactic solution, infections from SARS-CoV-2 continue to rise worldwide with devastating health and economic costs. SARS-CoV-2 gains entry into host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). Disruption of this interaction confers potent neutralization of viral entry, providing an avenue for vaccine design and for therapeutic antibodies. Here, we develop single-domain antibodies (nanobodies) that potently disrupt the interaction between the SARS-CoV-2 Spike and ACE2. By screening a yeast surface-displayed library of synthetic nanobody sequences, we identified a panel of nanobodies that bind to multiple epitopes on Spike and block ACE2 interaction via two distinct mechanisms. Cryogenic electron microscopy (cryo-EM) revealed that one exceptionally stable nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for SARS-CoV-2 Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains stability and function after aerosolization, lyophilization, and heat treatment. These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

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“…Recent studies have shown that related, potently neutralizing monoclonal antibodies that recognize the SARS-CoV-2 receptor binding domain (RBD) are often elicited in SARS-CoV-2 infection (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). These antibodies have great potential to be clinically impactful in the treatment and prevention of SARS-CoV-2 infection.…”

Section: Introductionmentioning

confidence: 99%

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Weisblum

Schmidt

Zhang

et al. 2020

Preprint

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Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

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Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model

Cited by 1,364 publications

References 26 publications

Clinical sensitivity and interpretation of PCR and serological COVID‐19 diagnostics for patients presenting to the hospital

Clinical sensitivity and interpretation of PCR and serological COVID‐19 diagnostics for patients presenting to the hospital

An ultra-potent synthetic nanobody neutralizes SARS-CoV-2 by locking Spike into an inactive conformation

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

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