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1.
Nat Commun ; 13(1): 4615, 2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-2036813

ABSTRACT

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.


Subject(s)
COVID-19 , Viral Vaccines , Aged , Antibodies, Viral , Antibody Formation , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Middle Aged , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , mRNA Vaccines
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296939

ABSTRACT

Efficient COVID-19 vaccines have been developed in record time. Here, we present findings from a comprehensive and integrated analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 mRNA vaccine. Two vaccine doses induced high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of delta variant was less efficient than that of the Wuhan strain. Age stratified analyses identified a group of low antibody responders where individuals ≥ 60 years were overrepresented. Waning of the antibody and cellular responses was observed in 30% of the vaccinees after six months. However, age did not influence the waning of these responses. Taken together, while individuals ≥ 60 years old took longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at six months post-vaccination. However, the higher proportion of older individuals in the group of antibody low responders and the lower antibody reactivity the Delta variant call for a booster immunization to increase immune responses and protection.

4.
Front Immunol ; 12: 710217, 2021.
Article in English | MEDLINE | ID: covidwho-1555700

ABSTRACT

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of "long COVID-19", and defines key cells and cytokines that delineate true and quasi-convalescent states.


Subject(s)
COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , COVID-19/complications , Cohort Studies , Convalescence , Female , Humans , Male , Middle Aged
5.
J Clin Immunol ; 42(2): 214-229, 2022 02.
Article in English | MEDLINE | ID: covidwho-1544509

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that have become dominant as the pandemic progresses bear the ORF8 mutation together with multiple spike mutations. A 382-nucleotide deletion (Δ382) in the ORF7b and ORF8 regions has been associated with milder disease phenotype and less systemic inflammation in COVID-19 patients. However, its impact on host immunity against SARS-CoV-2 remains undefined. Here, RNA-sequencing was performed to elucidate whole blood transcriptomic profiles and identify contrasting immune signatures between patients infected with either wildtype or Δ382 SARS-CoV-2 variant. Interestingly, the immune landscape of Δ382 SARS-CoV-2 infected patients featured an increased adaptive immune response, evidenced by enrichment of genes related to T cell functionality, a more robust SARS-CoV-2-specific T cell immunity, as well as a more rapid antibody response. At the molecular level, eukaryotic initiation factor 2 signaling was found to be upregulated in patients bearing Δ382, and its associated genes were correlated with systemic levels of T cell-associated and pro-inflammatory cytokines. This study provides more in-depth insight into the host-pathogen interactions of ORF8 with great promise as a therapeutic target to combat SARS-CoV-2 infection.


Subject(s)
Adaptive Immunity/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Cytokines/immunology , Host-Pathogen Interactions/immunology , Humans , Inflammation/immunology , Mutation/immunology , Pandemics/prevention & control , T-Lymphocytes/immunology
8.
EMBO Mol Med ; 13(6): e14045, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1219070

ABSTRACT

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS-CoV-2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS-CoV-2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood. Systemic levels of pro-inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro-inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus-specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS-CoV-2 was observed in asymptomatic patients. In addition, asymptomatic COVID-19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro-inflammatory and more protective immune responses against SARS-CoV-2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID-19.


Subject(s)
COVID-19/pathology , Carrier State/immunology , Biomarkers/metabolism , Brain-Derived Neurotrophic Factor/metabolism , COVID-19/immunology , COVID-19/virology , Carrier State/pathology , Carrier State/virology , Cytokines/metabolism , Humans , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , SARS-CoV-2/isolation & purification , Th17 Cells/cytology , Th17 Cells/immunology , Th17 Cells/metabolism , Transcriptome , Up-Regulation , Vascular Endothelial Growth Factor D/metabolism
9.
Elife ; 102021 03 23.
Article in English | MEDLINE | ID: covidwho-1146275

ABSTRACT

Numerous reports of vascular events after an initial recovery from COVID-19 form our impetus to investigate the impact of COVID-19 on vascular health of recovered patients. We found elevated levels of circulating endothelial cells (CECs), a biomarker of vascular injury, in COVID-19 convalescents compared to healthy controls. In particular, those with pre-existing conditions (e.g., hypertension, diabetes) had more pronounced endothelial activation hallmarks than non-COVID-19 patients with matched cardiovascular risk. Several proinflammatory and activated T lymphocyte-associated cytokines sustained from acute infection to recovery phase, which correlated positively with CEC measures, implicating cytokine-driven endothelial dysfunction. Notably, we found higher frequency of effector T cells in our COVID-19 convalescents compared to healthy controls. The activation markers detected on CECs mapped to counter receptors found primarily on cytotoxic CD8+ T cells, raising the possibility of cytotoxic effector cells targeting activated endothelial cells. Clinical trials in preventive therapy for post-COVID-19 vascular complications may be needed.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/etiology , Endothelium, Vascular/pathology , Lymphocyte Activation , Adult , Aged , COVID-19/immunology , COVID-19/pathology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/pathology , Cytokines/immunology , Endothelial Cells/immunology , Endothelial Cells/pathology , Endothelium, Vascular/immunology , Female , Humans , Male , Middle Aged , Risk Factors
10.
Clin Transl Immunology ; 10(2): e1241, 2021.
Article in English | MEDLINE | ID: covidwho-1095258

ABSTRACT

OBJECTIVES: The emergence of a SARS-CoV-2 variant with a point mutation in the spike (S) protein, D614G, has taken precedence over the original Wuhan isolate by May 2020. With an increased infection and transmission rate, it is imperative to determine whether antibodies induced against the D614 isolate may cross-neutralise against the G614 variant. METHODS: Antibody profiling against the SARS-CoV-2 S protein of the D614 variant by flow cytometry and assessment of neutralising antibody titres using pseudotyped lentiviruses expressing the SARS-CoV-2 S protein of either the D614 or G614 variant tagged with a luciferase reporter were performed on plasma samples from COVID-19 patients with known D614G status (n = 44 infected with D614, n = 6 infected with G614, n = 7 containing all other clades: O, S, L, V, G, GH or GR). RESULTS: Profiling of the anti-SARS-CoV-2 humoral immunity reveals similar neutralisation profiles against both S protein variants, albeit waning neutralising antibody capacity at the later phase of infection. Of clinical importance, patients infected with either the D614 or G614 clade elicited a similar degree of neutralisation against both pseudoviruses, suggesting that the D614G mutation does not impact the neutralisation capacity of the elicited antibodies. CONCLUSIONS: Cross-reactivity occurs at the functional level of the humoral response on both the S protein variants, which suggests that existing serological assays will be able to detect both D614 and G614 clades of SARS-CoV-2. More importantly, there should be negligible impact towards the efficacy of antibody-based therapies and vaccines that are currently being developed.

12.
Nat Commun ; 11(1): 5243, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-872700

ABSTRACT

SARS-CoV-2 is the novel coronavirus responsible for the current COVID-19 pandemic. Severe complications are observed only in a small proportion of infected patients but the cellular mechanisms underlying this progression are still unknown. Comprehensive flow cytometry of whole blood samples from 54 COVID-19 patients reveals a dramatic increase in the number of immature neutrophils. This increase strongly correlates with disease severity and is associated with elevated IL-6 and IP-10 levels, two key players in the cytokine storm. The most pronounced decrease in cell counts is observed for CD8 T-cells and VD2 γδ T-cells, which both exhibit increased differentiation and activation. ROC analysis reveals that the count ratio of immature neutrophils to VD2 (or CD8) T-cells predicts pneumonia onset (0.9071) as well as hypoxia onset (0.8908) with high sensitivity and specificity. It would thus be a useful prognostic marker for preventive patient management and improved healthcare resource management.


Subject(s)
Betacoronavirus/immunology , CD8-Positive T-Lymphocytes/immunology , Neutrophils/immunology , Receptors, Antigen, T-Cell, gamma-delta/immunology , Biomarkers/blood , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Flow Cytometry , Humans , Immunophenotyping/methods , Interleukin-10/blood , Interleukin-6/blood , Lymphocyte Count , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2 , Severity of Illness Index
14.
EBioMedicine ; 58: 102911, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-662643

ABSTRACT

BACKGROUND: Given the unceasing worldwide surge in COVID-19 cases, there is an imperative need to develop highly specific and sensitive serology assays to define exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). METHODS: Pooled plasma samples from PCR positive COVID-19 patients were used to identify linear B-cell epitopes from a SARS-CoV-2 peptide library of spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins by peptide-based ELISA. Hit epitopes were further validated with 79 COVID-19 patients with different disease severity status, 13 seasonal human CoV, 20 recovered SARS patients and 22 healthy donors. FINDINGS: Four immunodominant epitopes, S14P5, S20P2, S21P2 and N4P5, were identified on the S and N viral proteins. IgG responses to all identified epitopes displayed a strong detection profile, with N4P5 achieving the highest level of specificity (100%) and sensitivity (>96%) against SARS-CoV-2. Furthermore, the magnitude of IgG responses to S14P5, S21P2 and N4P5 were strongly associated with disease severity. INTERPRETATION: IgG responses to the peptide epitopes can serve as useful indicators for the degree of immunopathology in COVID-19 patients, and function as higly specific and sensitive sero-immunosurveillance tools for recent or past SARS-CoV-2 infections. The flexibility of these epitopes to be used alone or in combination will allow for the development of improved point-of-care-tests (POCTs). FUNDING: Biomedical Research Council (BMRC), the A*ccelerate GAP-funded project (ACCL/19-GAP064-R20H-H) from Agency of Science, Technology and Research (A*STAR), and National Medical Research Council (NMRC) COVID-19 Research fund (COVID19RF-001) and CCGSFPOR20002. ATR is supported by the Singapore International Graduate Award (SINGA), A*STAR.


Subject(s)
B-Lymphocytes/immunology , Coronavirus Infections/diagnosis , Epitopes/immunology , Nucleocapsid Proteins/immunology , Pneumonia, Viral/diagnosis , Spike Glycoprotein, Coronavirus/immunology , Adult , Biomarkers/blood , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/immunology , Epitopes/blood , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/immunology , Serologic Tests/methods
15.
Nat Commun ; 11(1): 2806, 2020 06 01.
Article in English | MEDLINE | ID: covidwho-459009

ABSTRACT

Given the ongoing SARS-CoV-2 pandemic, identification of immunogenic targets against the coronavirus spike glycoprotein will provide crucial advances towards the development of sensitive diagnostic tools and potential vaccine candidate targets. In this study, using pools of overlapping linear B-cell peptides, we report two IgG immunodominant regions on SARS-CoV-2 spike glycoprotein that are recognised by sera from COVID-19 convalescent patients. Notably, one is specific to SARS-CoV-2, which is located in close proximity to the receptor binding domain. The other region, which is localised at the fusion peptide, could potentially function as a pan-SARS target. Functionally, antibody depletion assays demonstrate that antibodies targeting these immunodominant regions significantly alter virus neutralisation capacities. Taken together, identification and validation of these neutralising B-cell epitopes will provide insights towards the design of diagnostics and vaccine candidates against this high priority coronavirus.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Sequence , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 , Coronavirus Infections/blood , Epitopes, B-Lymphocyte , Humans , Immunodominant Epitopes , Immunoglobulin G/blood , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
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