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1.
International Journal of Molecular Sciences ; 23(8):4341, 2022.
Article in English | MDPI | ID: covidwho-1792663

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global public health crisis. Effective COVID-19 vaccines developed by Pfizer-BioNTech, Moderna, and Astra Zeneca have made significant impacts in controlling the COVID-19 burden, especially in reducing the transmission of SARS-CoV-2 and hospitalization incidences. In view of the emergence of new SARS-CoV-2 variants, vaccines developed against the Wuhan strain were less effective against the variants. Neutralizing antibodies produced by B cells are a critical component of adaptive immunity, particularly in neutralizing viruses by blocking virus attachment and entry into cells. Therefore, the identification of protective linear B-cell epitopes can guide epitope-based peptide designs. This study reviews the identification of SARS-CoV-2 B-cell epitopes within the spike, membrane and nucleocapsid proteins that can be incorporated as potent B-cell epitopes into peptide vaccine constructs. The bioinformatic approach offers a new in silico strategy for the mapping and identification of potential B-cell epitopes and, upon in vivo validation, would be useful for the rapid development of effective multi-epitope-based vaccines. Potent B-cell epitopes were identified from the analysis of three-dimensional structures of monoclonal antibodies in a complex with SARS-CoV-2 from literature mining. This review provides significant insights into the elicitation of potential neutralizing antibodies by potent B-cell epitopes, which could advance the development of multi-epitope peptide vaccines against SARS-CoV-2.

2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329767

ABSTRACT

The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced neutralizing antibody responses for key variants in an Asian volunteer cohort. We demonstrate a reduction in neutralizing antibody titres across all groups six months post-vaccination and show a marked reduction in the serological binding and neutralizing response targeting Omicron compared to other viral variants. We also highlight the increase in cross-protective neutralizing antibody responses against Omicron induced by a third dose (booster) of vaccine. These data illustrate how key virological factors such as immune escape mutation combined with host factors such as age and sex of the vaccinated individuals influence the strength and duration of cross-protective serological immunity for COVID-19.

4.
Vaccines (Basel) ; 10(2)2022 Jan 31.
Article in English | MEDLINE | ID: covidwho-1667380

ABSTRACT

SARS-CoV-2-specific antibody responses are engendered in human milk after BNT162b2 vaccination. However, the emergence of variants of concern (VOCs) raises concerns about the specificity of and potential cross-protection mediated by milk antibody responses, which are crucial for passive immunity transferred from breastfeeding mothers to their infants. In this study, we collected milk samples at three different time points pre- and post-vaccination, and measured milk IgA antibody binding to the receptor binding domain (RBD) of the original Wuhan-Hu-1 strain, and the four VOCs, namely Alpha, Beta, Gamma and Delta. We report a significant level of anti-RBD IgA in milk collected at 4-6 weeks after the second dose of vaccination compared to pre-vaccination. We observed around a 30% reduction in binding to most VOCs, including the major circulating Delta variant, compared to the original Wuhan-Hu-1 strain. As COVID-19 vaccines may take some time to be approved for infants, these individuals remain at risk for severe disease and rely mainly on transferred passive immunity. Our findings support the current recommendations for vaccinating lactating women with the aim of transferring mucosal immunity to breastfeeding infants.

5.
Bioengineering & Translational Medicine ; n/a(n/a):e10293, 2022.
Article in English | Wiley | ID: covidwho-1649299

ABSTRACT

There is clinical need for a quantifiable point-of-care (PoC) SARS-CoV-2 neutralizing antibody (nAb) test that is adaptable with the pandemic's changing landscape. Here, we present a rapid and semi-quantitative nAb test that uses finger stick or venous blood to assess the nAb response of vaccinated population against wild-type, alpha, beta, gamma, and delta variant receptor binding domains. It captures a clinically relevant range of nAb levels, and effectively differentiates pre-vaccination, post 1st dose and post 2nd dose vaccination samples within 10 minutes. The data observed against alpha, beta, gamma, and delta variants agrees with published results evaluated in established serology tests. Finally, our test revealed a substantial reduction in nAb level for beta, gamma, and delta variants between early BNT162b2 vaccination group (within 3 months) and later vaccination group (post 3 months). This test is highly suited for PoC settings and provides an insightful nAb response in a post-vaccinated population. This article is protected by copyright. All rights reserved.

6.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295347

ABSTRACT

We detected the presence of SARS-CoV-2 specific IgA against all major VOCs in milk out to 6 weeks after D2 of BNT162b2. These likely confer some protection to the breastfed infants, who are ineligible for vaccination and are at risk of severe COVID-19. However, we detected significantly reduced milk IgA binding to VOCs, including the globally dominant Delta variant, suggesting reduced protection for breastfeeding infants. Additionally, these antibodies were significantly reduced by as early as 4-6 weeks after D2.

8.
NPJ Vaccines ; 6(1): 105, 2021 Aug 19.
Article in English | MEDLINE | ID: covidwho-1366818

ABSTRACT

Lactating women can produce protective antibodies in their milk after vaccination, which has informed antenatal vaccination programs for diseases such as influenza and pertussis. However, whether SARS-CoV-2-specific antibodies are produced in human milk as a result of COVID-19 vaccination is still unclear. In this study, we show that lactating mothers who received the BNT162b2 vaccine secreted SARS-CoV-2-specific IgA and IgG antibodies into milk, with the most significant increase at 3-7 days post-dose 2. Virus-specific IgG titers were stable out to 4-6 weeks after dose 2. In contrast, SARS-CoV-2-specific IgA levels showed substantial decay. Vaccine mRNA was detected in few milk samples (maximum of 2 ng/ml), indicative of minimal transfer. Additionally, infants who consumed post-vaccination human milk had no reported adverse effects up to 28 days post-ingestion. Our results define the safety and efficacy profiles of the vaccine in this demographic and provide initial evidence for protective immunity conferred by milk-borne SARS-CoV-2-specific antibodies. Taken together, our study supports recommendations for uninterrupted breastfeeding subsequent to mRNA vaccination against COVID-19.

9.
PLoS One ; 16(6): e0253487, 2021.
Article in English | MEDLINE | ID: covidwho-1280634

ABSTRACT

Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , COVID-19/therapy , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/metabolism , COVID-19/immunology , COVID-19/virology , Chemokines/blood , Chemokines/genetics , Chlorocebus aethiops , Convalescence , Cricetinae , Cytokines/blood , Cytokines/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Immunoglobulin G/isolation & purification , Macaca mulatta , Male , Mice, Transgenic , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Viral Load
10.
Elife ; 102021 02 08.
Article in English | MEDLINE | ID: covidwho-1069944

ABSTRACT

The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat [HR]) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the prefusion state. Our findings provide a dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral-host membrane fusion. Thus, protease docking sites flanking the S1/S2 cleavage site represent alternate allosteric hotspot targets for potential therapeutic development.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Allosteric Site , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Binding Sites , COVID-19/metabolism , Humans , Mass Spectrometry/methods , Molecular Dynamics Simulation , Protein Binding , Protein Processing, Post-Translational , Proteolysis , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization
11.
Nat Rev Immunol ; 20(6): 363-374, 2020 06.
Article in English | MEDLINE | ID: covidwho-141459

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.


Subject(s)
Coronavirus Infections , Pandemics , Pneumonia, Viral , Animals , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Coronavirus Infections/virology , Disease Progression , Humans , Inflammation/etiology , Inflammation/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2
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