Beyond the Spike: identification of viral targets of the antibody response to SARS-CoV-2 in COVID-19 patients

Hachim, Asmaa; Kavian, Niloufar; Cohen, Carolyn A.; Chin, Alex Wh; Chu, Daniel K.W.; Mok, Chris Ka Pun; Tsang, Owen Ty; Yeung, Yiu Cheong; Perera, Ranawaka A.P.M.; Poon, Leo L M; Peiris, Malik; Valkenburg, Sophie A.

doi:10.1101/2020.04.30.20085670

Cited by 48 publications

(61 citation statements)

References 37 publications

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“…The presence of such antibodies has been interpreted as cross-reactivity with antigens of coronaviruses causing the common cold (10)(44) (45). Indeed, higher sequence homology at the protein level between SARS-CoV-2 and coronaviruses has been reported for N (particularly N-terminal and central regions), M and S2 (10)(46) (47). Pre-existing SARS-CoV-2-specific T cells have been recently reported and also attributed to cross-reactivity to human coronaviruses previously encountered (48) (49).…”

Section: Discussionmentioning

confidence: 98%

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Dobaño

Vidal

Santano

et al. 2020

Preprint

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Reliable serological tests are required to determine the prevalence of antibodies against SARS-CoV-2 antigens and to characterise immunity to the disease in order to address key knowledge gaps in the context of the COVID-19 pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and ELISA with their higher precision, dynamic range, throughput, miniaturization, cost-efficacy and multiplexing capacity. We developed three qSAT assays to detect IgM, IgA and IgG to a panel of eight SARS-CoV-2 antigens including spike (S), nucleoprotein (N) and membrane (M) protein constructs. The assays were optimized to minimize processing time and maximize signal to noise ratio. We evaluated the performance of the assays using 128 plasmas obtained before the COVID-19 pandemic (negative controls) and 115 plasmas from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 8 were asymptomatic, 58 had mild symptoms and 49 were hospitalized. Pre-existing IgG antibodies recognizing N, M and S2 proteins were detected in negative controls suggestive of cross-reactive to common cold coronaviruses. The best performing antibody isotype/antigen signatures had specificities of 100% and sensitivities of 94.94% at ≥14 days since the onset of symptoms and 96.08% at ≥21 days since the onset of symptoms, with AUC of 0.992 and 0.999, respectively. Combining multiple antibody markers as assessed by qSAT assays has the highest efficiency, breadth and versatility to accurately detect low-level antibody responses for obtaining reliable data on prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity required for vaccine development to combat pandemics like the COVID-19.

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Section: Discussionmentioning

confidence: 98%

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Dobaño

Vidal

Santano

et al. 2020

Preprint

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“…According to current data, S protein cross-reactive antibodies are not produced in the receptor-binding domain region. 46 Moreover, recent studies have found that N protein antibodies appear earlier than those of S protein, 47 which further suggests that early high-response antibodies are unlikely to provide protection against virus entry. Therefore, cross-protection is less likely to occur, but more research is needed to address this possibility.…”

Section: Limitations and Potential Solutionsmentioning

confidence: 99%

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Zheng¹,

Liu

2020

Journal of Medical Virology

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Coronavirus disease 2019 (COVID-19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID-19.After a systematical review of the literature, we propose that cross-reactive antibodies associated with antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV-2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID-19. K E Y W O R D S ADE, antibody-dependent enhancement, coronavirus, cross-reactive antibody, cytokine storm, immunity, mTOR inhibitors, rapamycin How to cite this article: Zheng Y, Li R, Liu S. Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines.

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“…The antibody response generated following SARS-CoV-2 infection is diverse, consisting of multiple isotypes targeting several proteins on the virus surface including the spike protein (and its receptor binding domain) and the nucleoprotein [16]. This complexity of biomarkers provides both a challenge and an opportunity for diagnostics research.…”

Section: Introductionmentioning

confidence: 99%

Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics

Rosado

Pelleau

Cockram

et al. 2020

Preprint

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BackgroundThe antibody response generated following infection with SARS-CoV-2 is expected to decline over time. This may cause individuals with confirmed SARS-CoV-2 infection to test negative according to serological diagnostic tests in the months and years following symptom onset. MethodsA multiplex serological assay was developed to measure IgG and IgM antibody responses to four SARS-CoV-2 Spike (S) antigens: spike trimeric ectodomain (S tri ), its receptor-binding domain (RBD), spike subunit 1 (S1), and spike subunit 2 (S2).Antibody responses were measured in serum samples from patients in French hospitals with RT-qPCR confirmed infection (n = 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic in 2019 (n = 335).The multiplex antibody data was used to train a random forests algorithm for classifying individuals with previous SARS-CoV-2 infection. A mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the potential sensitivity and classification performance of serological diagnostics during the first year following symptom onset. ResultsIgG antibody responses to one S antigen identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 90.3% sensitivity (95% confidence interval (CI); 86.1%, 93.4%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG to four antigens, it was possible to identify infected individuals with 96.1% sensitivity (95% CI; 93.0%, 97.9%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Antibody responses to SARS-CoV-2 increase rapidly 1-2 weeks after symptom onset, with antibody responses predicted to peak within 2-4 weeks. Informed by prior data from other coronaviruses, one year following symptom onset antibody responses are predicted to decay by approximately 60% from the peak response. Depending on the selection of sero-positivity cutoff, we estimate that the sensitivity of serological diagnostics may reduce to 56% -97% after six months, and to 49% -93% after one year. ConclusionSerological signatures based on antibody responses to multiple antigens can provide more accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. Changes in antibody levels over time may cause reductions in the sensitivity of serological diagnostics leading to an underestimation of sero-prevalence. It is essential that data continue to be collected to evaluate this potential risk.

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Beyond the Spike: identification of viral targets of the antibody response to SARS-CoV-2 in COVID-19 patients

Cited by 48 publications

References 37 publications

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Highly sensitive and specific multiplex antibody assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics

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