Editorial

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Open AccessEditorial

SARS-CoV-2: Advances in Serological Methods and the Understanding of Antibody Escape

by Daniele Focosi and Fabrizio Maggi

Int. J. Mol. Sci. 2023, 24(3), 2488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032488 - 27 Jan 2023

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In this Special Issue, many original contributions concerning serological methods for SARS-CoV-2 were collected, some of them with implications about therapeutics [...] Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

Research

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11 pages, 1061 KiB

Open AccessArticle

Correlation between In Vitro Neutralization Assay and Serological Tests for Protective Antibodies Detection

by Maria Addolorata Bonifacio, Riccardo Laterza, Angela Vinella, Annalisa Schirinzi, Mariangela Defilippis, Francesca Di Serio, Angelo Ostuni, Antonio Fasanella and Maria Addolorata Mariggiò

Int. J. Mol. Sci. 2022, 23(17), 9566; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179566 - 24 Aug 2022

Cited by 9 | Viewed by 1757

Abstract

Serological assays are useful in investigating the development of humoral immunity against SARS-CoV-2 in the context of epidemiological studies focusing on the spread of protective immunity. The plaque reduction neutralization test (PRNT) is the gold standard method to assess the titer of protective [...] Read more.

Serological assays are useful in investigating the development of humoral immunity against SARS-CoV-2 in the context of epidemiological studies focusing on the spread of protective immunity. The plaque reduction neutralization test (PRNT) is the gold standard method to assess the titer of protective antibodies in serum samples. However, to provide a result, the PRNT requires several days, skilled operators, and biosafety level 3 laboratories. Therefore, alternative methods are being assessed to establish a relationship between their outcomes and PRNT results. In this work, four different immunoassays (Roche Elecsys^® Anti SARS-CoV-2 S, Snibe MAGLUMI^® SARS-CoV-2 S-RBD IgG, Snibe MAGLUMI^® 2019-nCoV IgG, and EUROIMMUN^® SARS-CoV-2 NeutraLISA assays, respectively) have been performed on individuals healed after SARS-CoV-2 infection. The correlation between each assay and the reference method has been explored through linear regression modeling, as well as through the calculation of Pearson’s and Spearman’s coefficients. Furthermore, the ability of serological tests to discriminate samples with high titers of neutralizing antibodies (>160) has been assessed by ROC curve analyses, Cohen’s Kappa coefficient, and positive predictive agreement. The EUROIMMUN^® NeutraLISA assay displayed the best correlation with PRNT results (Pearson and Spearman coefficients equal to 0.660 and 0.784, respectively), as well as the ROC curve with the highest accuracy, sensitivity, and specificity (0.857, 0.889, and 0.829, respectively). Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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11 pages, 2630 KiB

Open AccessArticle

SARS-CoV-2 and Immunity: Natural Infection Compared with Vaccination

by Simone Vespa, Pasquale Simeone, Giulia Catitti, Davide Buca, Domenico De Bellis, Laura Pierdomenico, Damiana Pieragostino, Ilaria Cicalini, Piero Del Boccio, Luca Natale, Trevor Owens, Reza Khorooshi, Vincenzo De Laurenzi, Liborio Stuppia and Paola Lanuti

Int. J. Mol. Sci. 2022, 23(16), 8982; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168982 - 11 Aug 2022

Cited by 5 | Viewed by 1976

Abstract

Recently, the protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies. We investigated the anti-spike IgG levels and SARS-CoV-2-specific T cells in 125 donors (90 vaccinated with four different vaccine platforms, 16 individuals with [...] Read more.

Recently, the protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies. We investigated the anti-spike IgG levels and SARS-CoV-2-specific T cells in 125 donors (90 vaccinated with four different vaccine platforms, 16 individuals with a previous natural infection, and 19 not vaccinated donors who did not report previous SARS-CoV-2 infections). Our data show that anti-spike IgG titers were similar between naturally infected subjects and those vaccinated with adenoviral vector vaccines. Of note, all immunized donors produced memory CD4⁺ and/or CD8⁺ T cells. A sustained polyfunctionality of SARS-CoV-2-specific T cells in all immunized donors was also demonstrated. Altogether, our data suggest that the natural infection produces an overall response like that induced by vaccination. Therefore, this detailed immunological evaluation may be relevant for other vaccine efforts especially for the monitoring of novel vaccines effective against emerging virus variants. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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16 pages, 2928 KiB

Open AccessArticle

Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD

by Antonia Sophia Peter, Eva Grüner, Eileen Socher, Kirsten Fraedrich, Elie Richel, Sandra Mueller-Schmucker, Arne Cordsmeier, Armin Ensser, Heinrich Sticht and Klaus Überla

Int. J. Mol. Sci. 2022, 23(15), 8177; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158177 - 25 Jul 2022

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Abstract

Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing [...] Read more.

Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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22 pages, 3178 KiB

Open AccessArticle

Pre-Omicron Vaccine Breakthrough Infection Induces Superior Cross-Neutralization against SARS-CoV-2 Omicron BA.1 Compared to Infection Alone

by Eveline Santos da Silva, Michel Kohnen, Georges Gilson, Therese Staub, Victor Arendt, Christiane Hilger, Jean-Yves Servais, Emilie Charpentier, Olivia Domingues, Chantal J. Snoeck, Markus Ollert, Carole Seguin-Devaux and Danielle Perez-Bercoff

Int. J. Mol. Sci. 2022, 23(14), 7675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147675 - 12 Jul 2022

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Abstract

SARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here, we compared the neutralizing abilities of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of [...] Read more.

SARS-CoV-2 variants raise concern because of their high transmissibility and their ability to evade neutralizing antibodies elicited by prior infection or by vaccination. Here, we compared the neutralizing abilities of sera from 70 unvaccinated COVID-19 patients infected before the emergence of variants of concern (VOCs) and of 16 vaccine breakthrough infection (BTI) cases infected with Gamma or Delta against the ancestral B.1 strain, the Gamma, Delta and Omicron BA.1 VOCs using live virus. We further determined antibody levels against the Nucleocapsid (N) and full Spike proteins, the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the Spike protein. Convalescent sera featured considerable variability in the neutralization of B.1 and in the cross-neutralization of different strains. Their neutralizing capacity moderately correlated with antibody levels against the Spike protein and the RBD. All but one convalescent serum failed to neutralize Omicron BA.1. Overall, convalescent sera from patients with moderate disease had higher antibody levels and displayed a higher neutralizing ability against all strains than patients with mild or severe forms of the disease. The sera from BTI cases fell into one of two categories: half the sera had a high neutralizing activity against the ancestral B.1 strain as well as against the infecting strain, while the other half had no or a very low neutralizing activity against all strains. Although antibody levels against the spike protein and the RBD were lower in BTI sera than in unvaccinated convalescent sera, most neutralizing sera also retained partial neutralizing activity against Omicron BA.1, suggestive of a better cross-neutralization and higher affinity of vaccine-elicited antibodies over virus-induced antibodies. Accordingly, the IC50: antibody level ratios were comparable for BTI and convalescent sera, but remained lower in the neutralizing convalescent sera from patients with moderate disease than in BTI sera. The neutralizing activity of BTI sera was strongly correlated with antibodies against the Spike protein and the RBD. Together, these findings highlight qualitative differences in antibody responses elicited by infection in vaccinated and unvaccinated individuals. They further indicate that breakthrough infection with a pre-Omicron variant boosts immunity and induces cross-neutralizing antibodies against different strains, including Omicron BA.1. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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13 pages, 2780 KiB

Open AccessArticle

Analysis of the Neutralizing Activity of Antibodies Targeting Open or Closed SARS-CoV-2 Spike Protein Conformations

by Gabriel Cia, Fabrizio Pucci and Marianne Rooman

Int. J. Mol. Sci. 2022, 23(4), 2078; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042078 - 14 Feb 2022

Cited by 5 | Viewed by 2176

Abstract

SARS-CoV-2 infection elicits a polyclonal neutralizing antibody (nAb) response that primarily targets the spike protein, but it is still unclear which nAbs are immunodominant and what distinguishes them from subdominant nAbs. This information would however be crucial to predict the evolutionary trajectory of [...] Read more.

SARS-CoV-2 infection elicits a polyclonal neutralizing antibody (nAb) response that primarily targets the spike protein, but it is still unclear which nAbs are immunodominant and what distinguishes them from subdominant nAbs. This information would however be crucial to predict the evolutionary trajectory of the virus and design future vaccines. To shed light on this issue, we gathered 83 structures of nAbs in complex with spike protein domains. We analyzed in silico the ability of these nAbs to bind the full spike protein trimer in open and closed conformations, and predicted the change in binding affinity of the most frequently observed spike protein variants in the circulating strains. This led us to define four nAb classes with distinct variant escape fractions. By comparing these fractions with those measured from plasma of infected patients, we showed that the class of nAbs that most contributes to the immune response is able to bind the spike protein in its closed conformation. Although this class of nAbs only partially inhibits the spike protein binding to the host’s angiotensin converting enzyme 2 (ACE2), it has been suggested to lock the closed pre-fusion spike protein conformation and therefore prevent its transition to an open state. Furthermore, comparison of our predictions with mRNA-1273 vaccinated patient plasma measurements suggests that spike proteins contained in vaccines elicit a different nAb class than the one elicited by natural SARS-CoV-2 infection and suggests the design of highly stable closed-form spike proteins as next-generation vaccine immunogens. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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13 pages, 3375 KiB

Open AccessArticle

Small Structural Proteins E and M Render the SARS-CoV-2 Pseudovirus More Infectious and Reveal the Phenotype of Natural Viral Variants

by Hsin-I Wang, Zih-Shiuan Chuang, Yu-Ting Kao, Yi-Ling Lin, Jian-Jong Liang, Chun-Che Liao, Ching-Len Liao, Michael M. C. Lai and Chia-Yi Yu

Int. J. Mol. Sci. 2021, 22(16), 9087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169087 - 23 Aug 2021

Cited by 14 | Viewed by 3437

Abstract

The SARS-CoV-2 pseudovirus is a commonly used strategy that mimics certain biological functions of the authentic virus by relying on biological legitimacy at the molecular level. Despite the fact that spike (S), envelope (E), and membrane (M) proteins together wrap up the SARS-CoV-2 [...] Read more.

The SARS-CoV-2 pseudovirus is a commonly used strategy that mimics certain biological functions of the authentic virus by relying on biological legitimacy at the molecular level. Despite the fact that spike (S), envelope (E), and membrane (M) proteins together wrap up the SARS-CoV-2 virion, most of the reported pseudotype viruses consist of only the S protein. Here, we report that the presence of E and M increased the virion infectivity by promoting the S protein priming. The S, E, and M (SEM)-coated pseudovirion is spherical, containing crown-like spikes on the surface. Both S and SEM pseudoviruses packaged the same amounts of viral RNA, but the SEM virus bound more efficiently to cells stably expressing the viral receptor human angiotensin-converting enzyme II (hACE2) and became more infectious. Using this SEM pseudovirus, we examined the infectivity and antigenic properties of the natural SARS-CoV-2 variants. We showed that some variants have higher infectivity than the original virus and that some render the neutralizing plasma with lower potency. These studies thus revealed possible mechanisms of the dissemination advantage of these variants. Hence, the SEM pseudovirion provides a useful tool to evaluate the viral infectivity and capability of convalescent sera in neutralizing specific SARS-CoV-2 S dominant variants. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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Review

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14 pages, 2631 KiB

Open AccessReview

Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

by Daniele Focosi, Fabrizio Maggi, Massimo Franchini, Scott McConnell and Arturo Casadevall

Int. J. Mol. Sci. 2022, 23(1), 29; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010029 - 21 Dec 2021

Cited by 28 | Viewed by 3587

Abstract

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the [...] Read more.

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ΔLGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants. Full article

(This article belongs to the Special Issue SARS-CoV-2 Variants, Antibodies and Vaccines)

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