Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 isolate had detectable but limited neutralizing antibodies against newly circulating SARS-CoV-2 variants of concern. This study highlights the potential of re-infection for recovered COVID-19 patients.

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Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific and neutralizing antibodies in recovered COVID-19 patients

10.21203/rs.3.rs-1073046/v1 ◽

2021 ◽

Author(s):

Jira Chansaenroj ◽

Ritthideach Yorsaeng ◽

Nasamon Wanlapakorn ◽

Chintana Chirathaworn ◽

Natthinee Sudhinaraset ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Symptom Onset ◽

Neutralizing Antibodies ◽

Serum Antibody ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Spike Protein ◽

Immunological Study ◽

Igg Antibody ◽

Vaccine Schedule

Abstract Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule. This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 in a cohort of patients who were previously infected with SARS-CoV-2. Between March and May 2020, 531 individuals with virologically confirmed cases of SARS-CoV-2 infection were enrolled in our immunological study. The neutralizing titers against SARS-CoV-2 were detected in 95.2%, 86.7%, 85.0%, and 85.4% of recovered COVID-19 patients at 3, 6, 9, and 12 months after symptom onset, respectively. The seropositivity rate of anti-S1 IgG, anti-RBD total Ig, anti-S1 IgA, and neutralizing titers remained at 68.6%, 89.6%, 77.1%, and 85.4%, respectively, at 12 months after symptom onset. The half-life of neutralizing titers was estimated at 100.7 days (95% confidence interval = 44.5 – 327.4 days, R2 = 0.106). These results support that the decline in serum antibody levels over time depends on the symptom severity, and the individuals with high IgG antibody titers experienced a significantly longer persistence of SARS-CoV-2-specific antibody responses than those with lower titers.

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Can we predict antibody responses in SARS-CoV-2? A cohort analysis

10.1101/2021.03.15.21253267 ◽

2021 ◽

Author(s):

Mary Gaeddert ◽

Philip Kitchen ◽

Tobias Broger ◽

Stefan Weber ◽

Ralf Bartenschlager ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Severe Disease ◽

Cohort Analysis ◽

Antibody Responses ◽

High Antibody ◽

Igg Antibodies ◽

Rt Pcr ◽

Median Increase ◽

Antibody Titers

AbstractBackgroundAfter infection with severe acute respiratory syndrome coronavirus (SARS-CoV-2), Immunoglobulin G (IgG) antibodies and virus-specific neutralizing antibodies (nAbs) develop. This study describes antibody responses in a cohort of recovered COVID-19 patients to identify predictors.MethodsWe recruited patients with confirmed SARS-CoV-2 infection from Heidelberg, Germany. Blood samples were collected three weeks after COVID-19 symptoms ended. Participants with high antibody titers were invited for follow-up visits. IgG titers were measured by the Euroimmun Assay, and nAbs titers in a SARS-CoV-2 infection-based assay.Results281 participants were enrolled between April and August 2020 with IgG testing, 145 (51.6%) had nAbs, and 35 (12.5%) had follow-up. The median IgG optical density (OD) ratio was 3.1 (Interquartile range (IQR) 1.6-5.1), and 24.1% (35/145) had a nAb titer>1:80. Higher IgG titers were associated with increased age and more severe disease, and higher nAbs were associated with male gender and CT-value of 25-30 on RT-PCR at diagnosis. The median IgG OD ratio on follow-up was 3.7 (IQR 2.9-5.9), a median increase of 0.5 (IQR −0.3-1.7). Six participants with follow-up nAbs all had titers ≤ 1:80.ConclusionsWhile age and disease severity were correlated with IgG responses, predictive factors for nAbs in convalescent patients remain unclear.

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

Science ◽

10.1126/science.abc7520 ◽

2020 ◽

Vol 369 (6506) ◽

pp. 956-963 ◽

Cited By ~ 222

Author(s):

Thomas F. Rogers ◽

Fangzhu Zhao ◽

Deli Huang ◽

Nathan Beutler ◽

Alison Burns ◽

...

Keyword(s):

Animal Model ◽

Severe Acute Respiratory Syndrome ◽

Global Health ◽

Neutralizing Antibodies ◽

Small Animal ◽

Passive Transfer ◽

Antibody Responses ◽

High Dose ◽

Receptor Binding Domain ◽

Small Animal Model

Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–recovered participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design.

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SARS-CoV-2 preS dTM vaccine booster candidates increase functional antibody responses and cross-neutralization against SARS-CoV-2 variants of concern in non-human primates

10.21203/rs.3.rs-871537/v1 ◽

2021 ◽

Author(s):

Vincent Pavot ◽

Catherine Berry ◽

Michael Kishko ◽

Natalie Anosova ◽

Dean Huang ◽

...

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Protein Vaccine ◽

Preclinical Models ◽

Protein Subunit ◽

Vaccine Candidates ◽

Vaccine Booster ◽

Cross Neutralization

Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that partly evade neutralizing antibodies has raised concerns of reduced vaccine effectiveness and increased infection. We previously demonstrated in preclinical models and in human clinical trials that our SARS-CoV-2 recombinant spike protein vaccine adjuvanted with AS03 (CoV2 preS dTM-AS03) elicits robust neutralizing antibody responses in naïve subjects. Here, the objective was to document the potency of various booster vaccine formulations in macaques previously vaccinated with mRNA or protein subunit vaccine candidates. We show that one booster dose of AS03-adjuvanted CoV2 preS dTM, D614 (parental) or B.1.351 (Beta), in monovalent or bivalent (D614 + B.1.351) formulations, significantly boosted pre-existing neutralizing antibodies and elicited high and stable cross-neutralizing antibodies covering the four known SARS-CoV-2 variants of concern (Alpha, Beta, Gamma and Delta) and, unexpectedly, SARS-CoV-1, in primed macaques. Interestingly, the non-adjuvanted CoV2 preS dTM B.1.351 vaccine formulation also significantly boosted and broadened the neutralizing antibody responses. Our findings show that these vaccine candidates used as a booster have the potential to offer cross-protection against a broad spectrum of variants. This has important implications for vaccine control of SARS-CoV-2 variants of concern and informs on the benefit of a booster with our vaccine candidates currently under evaluation in phase 2 and 3 clinical trials (NCT04762680 and NCT04904549).

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CoV-RBD121-NP Vaccine Candidate Protects against Symptomatic Disease Following SARS-CoV-2 Challenge in K18-hACE2 Mice and Induces Protective Responses That Prevent COVID-19-Associated Immunopathology

Vaccines ◽

10.3390/vaccines9111346 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1346

Author(s):

Jennifer K. DeMarco ◽

Joshua M. Royal ◽

William E. Severson ◽

Jon D. Gabbard ◽

Steve Hume ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibodies ◽

Potential Role ◽

Vaccine Candidate ◽

Severe Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Receptor Binding Domain ◽

Symptomatic Disease ◽

Human Igg1

We developed a SARS-CoV-2 vaccine candidate (CoV-RBD121-NP) comprised of a tobacco mosaic virus-like nanoparticle conjugated to the receptor-binding domain of the spike glycoprotein of SARS-CoV-2 fused to a human IgG1 Fc domain. CoV-RBD121-NP elicits strong antibody responses in C57BL/6 mice and is stable for up to 12 months at 2–8 or 22–28 °C. Here, we showed that this vaccine induces a strong neutralizing antibody response in K18-hACE2 mice. Furthermore, we demonstrated that immunization protects mice from virus-associated mortality and symptomatic disease. Our data indicated that a sufficient pre-existing pool of neutralizing antibodies is required to restrict SARS-CoV-2 replication upon exposure and prevent induction of inflammatory mediators associated with severe disease. Finally, we identified a potential role for CXCL5 as a protective cytokine in SARS-CoV-2 infection. Our results suggested that disruption of the CXCL5 and CXCL1/2 axis may be important early components of the inflammatory dysregulation that is characteristic of severe cases of COVID-19.

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Robust neutralizing antibodies to SARS-CoV-2 infection persist for months

Science ◽

10.1126/science.abd7728 ◽

2020 ◽

Vol 370 (6521) ◽

pp. 1227-1230 ◽

Cited By ~ 59

Author(s):

Ania Wajnberg ◽

Fatima Amanat ◽

Adolfo Firpo ◽

Deena R. Altman ◽

Mark J. Bailey ◽

...

Keyword(s):

New York ◽

New York City ◽

Severe Acute Respiratory Syndrome ◽

Antibody Response ◽

York City ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Spike Protein ◽

Global Pandemic

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with millions infected and more than 1 million fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here, on the basis of a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City, we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust immunoglobulin G antibody responses against the viral spike protein. We also show that titers are relatively stable for at least a period of about 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggest that more than 90% of seroconverters make detectable neutralizing antibody responses. These titers remain relatively stable for several months after infection.

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The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients

Science Immunology ◽

10.1126/sciimmunol.abc8413 ◽

2020 ◽

Vol 5 (48) ◽

pp. eabc8413 ◽

Cited By ~ 111

Author(s):

Lakshmanane Premkumar ◽

Bruno Segovia-Chumbez ◽

Ramesh Jadi ◽

David R. Martinez ◽

Rajendra Raut ◽

...

Keyword(s):

Receptor Binding ◽

Neutralizing Antibodies ◽

Clinical Symptoms ◽

Severe Disease ◽

Population Level ◽

Respiratory Illness ◽

Binding Domain ◽

Spike Protein ◽

Receptor Binding Domain ◽

Specific Antibodies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.

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Civets Are Equally Susceptible to Experimental Infection by Two Different Severe Acute Respiratory Syndrome Coronavirus Isolates

Journal of Virology ◽

10.1128/jvi.79.4.2620-2625.2005 ◽

2005 ◽

Vol 79 (4) ◽

pp. 2620-2625 ◽

Cited By ~ 73

Author(s):

Donglai Wu ◽

Changchun Tu ◽

Chaoan Xin ◽

Hua Xuan ◽

Qingwen Meng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Experimental Infection ◽

Neutralizing Antibodies ◽

Virus Isolation ◽

Clinical Symptoms ◽

Genomic Rna ◽

Sars Coronavirus ◽

Nucleotide Deletion ◽

Novel Virus ◽

Viral Genomic Rna

ABSTRACT Severe acute respiratory syndrome (SARS) was caused by a novel virus now known as SARS coronavirus (SARS-CoV). The discovery of SARS-CoV-like viruses in masked palm civets (Paguma larvata) raises the possibility that civets play a role in SARS-CoV transmission. To test the susceptibility of civets to experimental infection by different SARS-CoV isolates, 10 civets were inoculated with two human isolates of SARS-CoV, BJ01 (with a 29-nucleotide deletion) and GZ01 (without the 29-nucleotide deletion). All inoculated animals displayed clinical symptoms, such as fever, lethargy, and loss of aggressiveness, and the infection was confirmed by virus isolation, detection of viral genomic RNA, and serum-neutralizing antibodies. Our data show that civets were equally susceptible to SARS-CoV isolates GZ01 and BJ01.

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The impact of Spike mutations on SARS-CoV-2 neutralization

10.1101/2021.01.15.426849 ◽

2021 ◽

Cited By ~ 9

Author(s):

C Rees-Spear ◽

L Muir ◽

SA Griffith ◽

J Heaney ◽

Y Aldon ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Viral Entry ◽

Neutralizing Antibodies ◽

Protective Efficacy ◽

Polyclonal Antibodies ◽

Antibody Responses ◽

Serum Samples ◽

Neutralization Sensitivity ◽

Cross Neutralization ◽

The Impact

AbstractMultiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2 infection neutralize the virus by focused targeting of Spike and there is limited serum cross-neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B.1.1.7, 501Y.V2 and P.1 lineages, it is critical to understand if antibody responses induced by infection with the original SARS-CoV-2 virus or the current vaccines will remain effective against virus variants. In this study we evaluate neutralization of a series of mutated Spike pseudotypes including a B.1.1.7 Spike pseudotype. The analyses of a panel of Spike-specific monoclonal antibodies revealed that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations. In contrast, polyclonal antibodies in the serum of patients infected in early 2020 remained active against most mutated Spike pseudotypes. The majority of serum samples were equally able to neutralize the B.1.1.7 Spike pseudotype, however potency was reduced in a small number of samples (3 of 36) by 5–10-fold. This work highlights that changes in the SARS-CoV-2 Spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.

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mRNA-1273 and BNT162b2 mRNA vaccines have reduced neutralizing activity against the SARS-CoV-2 Omicron variant

10.1101/2021.12.20.473557 ◽

2021 ◽

Author(s):

Venkata-Viswanadh Edara ◽

Kelly E Manning ◽

Madison Ellis ◽

Lilin Lai ◽

Kathryn M Moore ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Neutralization Assay ◽

Antibody Responses ◽

Spike Protein ◽

Live Virus ◽

Neutralizing Activity ◽

Virus Neutralization Assay ◽

Fold Reduction

The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines generate potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the global emergence of SARS-CoV-2 variants with mutations in the spike protein, the principal antigenic target of these vaccines, has raised concerns over the neutralizing activity of vaccine-induced antibody responses. The Omicron variant, which emerged in November 2021, consists of over 30 mutations within the spike protein. Here, we used an authentic live virus neutralization assay to examine the neutralizing activity of the SARS-CoV-2 Omicron variant against mRNA vaccine-induced antibody responses. Following the 2nd dose, we observed a 30-fold reduction in neutralizing activity against the omicron variant. Through six months after the 2nd dose, none of the sera from naive vaccinated subjects showed neutralizing activity against the Omicron variant. In contrast, recovered vaccinated individuals showed a 22-fold reduction with more than half of the subjects retaining neutralizing antibody responses. Following a booster shot (3rd dose), we observed a 14-fold reduction in neutralizing activity against the omicron variant and over 90% of boosted subjects showed neutralizing activity against the omicron variant. These findings show that a 3rd dose is required to provide robust neutralizing antibody responses against the Omicron variant.

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