Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays

Sholukh, Anton M.; Fioré-Gartland, Andrew; Ford, Emily; Miner, Maurine D.; Hou, Yixuan J.; Tse, Longping V.; Kaiser, Hannah; Zhu, Haiying; Lu, J.; Madarampalli, Bhanupriya; Park, Arnold; Lempp, Florian A.; Germain, Russell St.; Bossard, Emily L.; Kee, Jia Jin; Diem, Kurt; Stuart, Andrew B.; Rupert, Peter B.; Brock, Chance; Buerger, Matthew; Doll, Margaret K.; Randhawa, April; Stamatatos, Leonidas; Strong, Roland K.; McLaughlin, Colleen C.; Huang, Meei‐Li; Jerome, Keith R.; Baric, Ralph S.; Montefiori, David C.; Corey, Lawrence

doi:10.1128/jcm.00527-21

Cited by 78 publications

(82 citation statements)

References 72 publications

(78 reference statements)

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“…Pseudo-typed and chimeric viruses have been used most frequently because it is simpler to introduce mutations into a plasmid encoding just the spike gene compared with using a clinical virus isolate or a recombinant virus generated using a system that requires either multiple plasmids or bacterial or yeast artificial chromosomes 119,120 . Although the results of neutralization experiments using pseudo-typed viruses, VSV-based chimeric viruses and full-length SARS-CoV-2 usually yield similar results 97,107,125,126 , full-length viruses are expected to be more reliable and can be studied in animal models 127 .…”

Section: In Vitro Selection and Neutralization Experimentsmentioning

confidence: 99%

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The biological and clinical significance of emerging SARS-CoV-2 variants

et al. 2021

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Among the many unprecedented aspects of the SARS-CoV-2 pandemic is the intense virological monitoring that has occurred, with more than two million virus isolates having undergone partial or complete genomic sequencing. Initially, genetic sequencing suggested that SARS-CoV-2 was exceptionally well adapted to humans, spreading rapidly with little evidence for natural selection among circulating viruses. This changed during the later months of 2020, with the first reports of emergent SARS-CoV-2 variants associated with increased transmissibility, disease severity and escape from humoral immunity.In this Review, we create a framework for understanding SARS-COV-2 variants by describing fundamental aspects of SARS-CoV-2 evolution, the structure and function of the SARS-CoV-2 spike protein and the laboratory methods used to characterize spike variants. We then describe the biological properties and epidemiological characteristics of these variants and their associated mutations. Lastly, we describe the types of study required for the research, clinical and public health communities to respond to the new threat posed by emerging SARS-CoV-2 variants. Given the wide public interest in this topic, we provide a box of key points. We also provide a repository of the SARS-CoV-2 variant neutralization data discussed in this Review (Stanford University Coronavirus Antiviral & Resistance Database -Susceptibility Data). SARS-CoV-2 evolutionCoronaviruses contain an exonuclease enzyme that reduces their replication error rate by about 15-fold to 20-fold in vitro, resulting in an in vivo viral mutation rate about 10-fold lower than that of influenza 1-3 . Nonetheless, they accumulate mutations and generate further diversity through the process of recombination when variants with different mutations infect the same host [4][5][6] . Recombination between different SARS-related coronaviruses is likely to have led to the emergence of SARS-CoV-2 (ref. 7 ) and, although it can be difficult to detect owing to the similarity of most sequences, recombination is occurring to some extent among circulating SARS-CoV-2 variants 6,8 . Additionally, host-mediated RNA editing by APOBeC and ADAr enzymes, as evidenced by the dominance of C to U changes in specific dinucleotide contexts, contributes to SARS-CoV-2 diversity 9,10 .Although it had been previously assumed that waning immunity explained the observation that people are commonly reinfected with endemic common-cold coronaviruses 11 , recent studies suggest that antigenic drift also contributes to the lack of long-lasting protection following coronavirus infections 12,13 . HCoV-229E and HCoV-OC43 sequences over a 30-year period demonstrate a ladder-like phylogenetic tree topology consistent with the emergence of novel variants sweeping

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Section: In Vitro Selection and Neutralization Experimentsmentioning

confidence: 99%

“…antibodies. In summarizing the results of neutralizing experiments, we have also pooled results obtained using pseudo-typed, chimeric and infectious viruses as the results of these assays are usually concordant 97,107,125,126 .…”

Section: Deep Mutational Scanningmentioning

confidence: 99%

The biological and clinical significance of emerging SARS-CoV-2 variants

et al. 2021

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“…In seeking to establish a CoP for COVID-19 vaccines, both Earle et al 11 and Khoury et al 12 initially showed only a weak relationship between efficacy and reported nAb or binding antibody (bAb) titers 11,12 . This poor association could be explained by the high variation observed between the selected assays used by different studies 17,18 . This variability was partially mitigated by calibrating the assays against panels of human convalescent sera (HCS) run within the same study.…”

Section: Clinical Data Support Nab As a Biomarker Of Protectionmentioning

confidence: 99%

Scientific rationale for developing potent RBD-based vaccines targeting COVID-19

et al. 2021

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Vaccination of the global population against COVID-19 is a great scientific, logistical, and moral challenge. Despite the rapid development and authorization of several full-length Spike (S) protein vaccines, the global demand outweighs the current supply and there is a need for safe, potent, high-volume, affordable vaccines that can fill this gap, especially in low- and middle-income countries. Whether SARS-CoV-2 S-protein receptor-binding domain (RBD)-based vaccines could fill this gap has been debated, especially with regards to its suitability to protect against emerging viral variants of concern. Given a predominance for elicitation of neutralizing antibodies (nAbs) that target RBD following natural infection or vaccination, a key biomarker of protection, there is merit for selection of RBD as a sole vaccine immunogen. With its high-yielding production and manufacturing potential, RBD-based vaccines offer an abundance of temperature-stable doses at an affordable cost. In addition, as the RBD preferentially focuses the immune response to potent and recently recognized cross-protective determinants, this domain may be central to the development of future pan-sarbecovirus vaccines. In this study, we review the data supporting the non-inferiority of RBD as a vaccine immunogen compared to full-length S-protein vaccines with respect to humoral and cellular immune responses against both the prototype pandemic SARS-CoV-2 isolate and emerging variants of concern.

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“…Determinants of protective immunity against SARS-CoV-2 infection require the development of well-standardized, reproducible high-throughput antibody assays which can pinpoint people who are at a particular risk. They may also provide information on how often booster vaccinations might be needed and help in developing improved vaccines and immunotherapies [177][178][179]. Nevertheless, there are significant concerns about only using the antibody response in coronavirus infections as a sole metric of protective immunity [180].…”

Section: What Are Strong and Measurable Correlations Between Protection And Disease?mentioning

confidence: 99%

Immune Responses against SARS-CoV-2—Questions and Experiences

et al. 2021

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Understanding immune reactivity against SARS-CoV-2 is essential for coping with the COVID-19 pandemic. Herein, we discuss experiences and open questions about the complex immune responses to SARS-CoV-2. Some people react excellently without experiencing any clinical symptoms, they do not get sick, and they do not pass the virus on to anyone else (“sterilizing” immunity). Others produce antibodies and do not get COVID-19 but transmit the virus to others (“protective” immunity). Some people get sick but recover. A varying percentage develops respiratory failure, systemic symptoms, clotting disorders, cytokine storms, or multi-organ failure; they subsequently decease. Some develop long COVID, a new pathologic entity similar to fatigue syndrome or autoimmunity. In reality, COVID-19 is considered more of a systemic immune–vascular disease than a pulmonic disease, involving many tissues and the central nervous system. To fully comprehend the complex clinical manifestations, a profound understanding of the immune responses to SARS-CoV-2 is a good way to improve clinical management of COVID-19. Although neutralizing antibodies are an established approach to recognize an immune status, cellular immunity plays at least an equivalent or an even more important role. However, reliable methods to estimate the SARS-CoV-2-specific T cell capacity are not available for clinical routines. This deficit is important because an unknown percentage of people may exist with good memory T cell responsibility but a low number of or completely lacking peripheral antibodies against SARS-CoV-2. Apart from natural immune responses, vaccination against SARS-CoV-2 turned out to be very effective and much safer than naturally acquired immunity. Nevertheless, besides unwanted side effects of the currently available vector and mRNA preparations, concerns remain whether these vaccines will be strong enough to defeat the pandemic. Altogether, herein we discuss important questions, and try to give answers based on the current knowledge and preliminary data from our laboratories.

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Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays

Cited by 78 publications

References 72 publications

The biological and clinical significance of emerging SARS-CoV-2 variants

The biological and clinical significance of emerging SARS-CoV-2 variants

Scientific rationale for developing potent RBD-based vaccines targeting COVID-19

Immune Responses against SARS-CoV-2—Questions and Experiences

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