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1.
J Immunol Methods ; : 113328, 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-1977497

ABSTRACT

Monocytes are highly versatile innate immune cells responsible for pathogen clearance, innate immune coordination, and induction of adaptive immunity. Monocytes can directly and indirectly integrate pathogen-destructive instructions and contribute to disease control via pathogen uptake, presentation, or the release of cytokines. Indirect pathogen-specific instructions are conferred via Fc-receptor signaling and triggered by antibody opsonized material. Given the tremendous variation in polyclonal humoral immunity, defining the specific antibody-responses able to arm monocytes most effectively remains incompletely understood. While monocyte cell line-based assays have been used previously, cell lines may not faithfully recapitulate the full biology of monocytes. Thus, here we describe a multifaceted antigen-specific method for probing antibody-dependent primary monocyte phagocytosis (ADMP) and secondary responses. The assay not only reliably captures phagocytic uptake of immune complexes, but also detects unique changes in surface markers and cytokine secretions profiles, poorly detected by monocytic cell lines. The assay captures divergent polyclonal-monocyte recruiting activity across subjects with varying SARS-CoV-2 disease severity and also revealed biological nuances in Fc-mutant monoclonal antibody activity related to differences in Fc-receptor binding. Thus, the ADMP assay is a flexible assay able to provide key insights into the role of humoral immunity in driving monocyte phenotypic transitions and downstream functions across many diseases.

2.
Science ; : eabq0203, 2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1949930

ABSTRACT

The SARS-CoV-2 Omicron variant of concern comprises several sublineages with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1, and BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations lead to enhanced ACE2 binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, and BA.4/5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

3.
PLoS Pathog ; 18(6): e1010592, 2022 06.
Article in English | MEDLINE | ID: covidwho-1910702

ABSTRACT

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , Epitopes , Humans , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic , mRNA Vaccines
4.
Immunol Rev ; 309(1): 8-11, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1909396

ABSTRACT

Pandemics have devastating effects that can be mitigated with the existence of global infrastructure for pandemic preparedness along with the adaptation of existing research studies and establishment of biorepositories early in an outbreak. Observational cohort studies in place prior to a pandemic, that are rapidly scalable in response to emerging infectious diseases, are essential for both the early pandemic response and evaluation of its long-term effects. The ability to quickly collect and share samples from convalescent individuals is also critical for the development of vaccines and therapeutics. We provide a reflection on key lessons learned from establishing a longitudinal observational cohort study during the SARS-CoV-2 pandemic in order to provide guidance for future pandemic preparedness.


Subject(s)
COVID-19 , Pandemics , Cohort Studies , Disease Outbreaks , Humans , Observational Studies as Topic , Pandemics/prevention & control , SARS-CoV-2
5.
PLoS Pathogens ; 18(4), 2022.
Article in English | ProQuest Central | ID: covidwho-1842599

ABSTRACT

Macaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings.

6.
PLoS Pathog ; 18(2): e1010248, 2022 02.
Article in English | MEDLINE | ID: covidwho-1674026

ABSTRACT

Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/immunology , COVID-19/drug therapy , Epitopes/immunology , Humans , Immunization, Passive/methods , Neutralization Tests , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
7.
Elife ; 112022 01 24.
Article in English | MEDLINE | ID: covidwho-1648673

ABSTRACT

Background: Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. Methods: The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue. Results: Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. Conclusions: The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level. Funding: This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.


When SARS-CoV-2 ­ the virus that causes COVID-19 ­ infects our bodies, our immune system reacts by producing small molecules called antibodies that stick to a part of the virus called the spike protein. Vaccines are thought to work by triggering the production of similar antibodies without causing disease. Some of the most effective antibodies against SARS-CoV-2 bind a specific area of the spike protein called the 'receptor binding domain' or RBD. When SARS-CoV-2 evolves it creates a challenge for our immune system: mutations, which are changes in the virus's genetic code, can alter the shape of its spike protein, meaning that existing antibodies may no longer bind to it as effectively. This lowers the protection offered by past infection or vaccination, which makes it harder to tackle the pandemic. As it stands, it is not clear which mutations to the virus's genetic code can affect antibody binding, especially to portions outside the RBD. To complicate things further, the antibodies people produce in response to mild infection, severe infection, and vaccination, while somewhat overlapping, exhibit some differences. Studying these differences could help minimize emergence of mutations that allow the virus to 'escape' the antibody response. A phage display library is a laboratory technique in which phages (viruses that infect bacteria) are used as a 'repository' for DNA fragments that code for a specific protein. The phages can then produce the protein (or fragments of it), and if the protein fragments bind to a target, it can be easily detected. Garrett, Galloway et al. exploited this technique to study how different portions of the SARS-CoV-2 spike protein were bound by antibodies. They made a phage library in which each phage encoded a portion of the spike protein with different mutations, and then exposed the different versions of the protein to antibodies from people who had experienced prior infection, vaccination, or both. The experiment showed that antibodies produced during severe infection or after vaccination bound to similar parts of the spike protein, while antibodies from people who had experienced mild infection targeted fewer areas. Garrett, Galloway et al. also found that mutations that affected the binding of antibodies produced after vaccination were more consistent than mutations that interfered with antibodies produced during infection. While these results show which mutations are most likely to help the virus escape existing antibodies, this does not mean that the virus will necessarily evolve in that direction. Indeed, some of the mutations may be impossible for the virus to acquire because they interfere with the virus's ability to spread. Further studies could focus on revealing which of the mutations detected by Garrett, Galloway et al. are most likely to occur, to guide vaccine development in that direction. To help with this, Garrett, Galloway et al. have made the data accessible to other scientists and the public using a web tool.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Epitopes , Humans , Mass Vaccination
8.
Clin Infect Dis ; 73(11): e4411-e4418, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1561635

ABSTRACT

BACKGROUND: Noninfluenza respiratory viruses are responsible for a substantial burden of disease in the United States. Household transmission is thought to contribute significantly to subsequent transmission through the broader community. In the context of the coronavirus disease 2019 (COVID-19) pandemic, contactless surveillance methods are of particular importance. METHODS: From November 2019 to April 2020, 303 households in the Seattle area were remotely monitored in a prospective longitudinal study for symptoms of respiratory viral illness. Enrolled participants reported weekly symptoms and submitted respiratory samples by mail in the event of an acute respiratory illness (ARI). Specimens were tested for 14 viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using reverse-transcription polymerase chain reaction. Participants completed all study procedures at home without physical contact with research staff. RESULTS: In total, 1171 unique participants in 303 households were monitored for ARI. Of participating households, 128 (42%) included a child aged <5 years and 202 (67%) included a child aged 5-12 years. Of the 678 swabs collected during the surveillance period, 237 (35%) tested positive for 1 or more noninfluenza respiratory viruses. Rhinovirus, common human coronaviruses, and respiratory syncytial virus were the most common. Four cases of SARS-CoV-2 were detected in 3 households. CONCLUSIONS: This study highlights the circulation of respiratory viruses within households during the winter months during the emergence of the SARS-CoV-2 pandemic. Contactless methods of recruitment, enrollment, and sample collection were utilized throughout this study and demonstrate the feasibility of home-based, remote monitoring for respiratory infections.


Subject(s)
COVID-19 , Respiratory Syncytial Virus, Human , Respiratory Tract Infections , Viruses , Child , Humans , Longitudinal Studies , Prospective Studies , Respiratory Tract Infections/epidemiology , SARS-CoV-2
9.
Sci Adv ; 7(46): eabj0274, 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1511407

ABSTRACT

Despite recent studies of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), little is known about how the immune response against SARS-CoV-2 differs from other respiratory infections. We compare the immune signature from hospitalized SARS-CoV-2­infected patients to patients hospitalized prepandemic with influenza or respiratory syncytial virus (RSV). Our in-depth profiling indicates that the immune landscape in SARS-CoV-2 patients is largely similar to flu or RSV patients. Unique to patients infected with SARS-CoV-2 who had the most critical clinical disease were changes in the regulatory T cell (Treg) compartment. A Treg signature including increased frequency, activation status, and migration markers was correlated COVID-19 severity. These findings are relevant as Tregs are considered for therapy to combat the severe inflammation seen in COVID-19 patients. Likewise, having defined the overlapping immune landscapes in SARS-CoV-2, existing knowledge of flu and RSV infections could be leveraged to identify common treatment strategies.

10.
Microbiol Spectr ; 9(2): e0129821, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1476403

ABSTRACT

Wide-scale assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies is critical to understanding population seroprevalence, correlates of protection, and the longevity of vaccine-elicited responses. Most SARS-CoV-2 studies characterize antibody responses in plasma/sera. While reliable and broadly used, these samples pose several logistical restrictions, such as requiring venipuncture for collection and a cold chain for transportation and storage. Dried blood spots (DBS) overcome these barriers as they can be self-collected by fingerstick and mailed and stored at ambient temperature. Here, we evaluate the suitability of DBS for SARS-CoV-2 antibody assays by comparing several antibody responses between paired plasma and DBS from SARS-CoV-2 convalescent and vaccinated individuals. We found that DBS not only reflected plasma antibody binding by enzyme-linked immunosorbent assay (ELISA) and epitope profiles using phage display, but also yielded SARS-CoV-2 neutralization titers that highly correlated with paired plasma. Neutralization measurement was further streamlined by adapting assays to a high-throughput 384-well format. This study supports the adoption of DBS for numerous SARS-CoV-2 binding and neutralization assays. IMPORTANCE Plasma and sera isolated from venous blood represent conventional sample types used for the evaluation of SARS-CoV-2 antibody responses after infection or vaccination. However, collection of these samples is invasive and requires trained personnel and equipment for immediate processing. Once collected, plasma and sera must be stored and shipped at cold temperatures. To define the risk of emerging SARS-CoV-2 variants and the longevity of immune responses to natural infection and vaccination, it will be necessary to measure various antibody features in populations around the world, including in resource-limited areas. A sampling method that is compatible with these settings and is suitable for a variety of SARS-CoV-2 antibody assays is therefore needed to continue to understand and curb the COVID-19 pandemic.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Dried Blood Spot Testing/methods , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Enzyme-Linked Immunosorbent Assay , Epitope Mapping/methods , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Neutralization Tests , SARS-CoV-2
11.
J Clin Virol ; 142: 104916, 2021 09.
Article in English | MEDLINE | ID: covidwho-1313216

ABSTRACT

BACKGROUND: While a growing body of literature describes antibody dynamics in serum, little is known about breast milk antibody titers in the months following SARS-CoV-2 infection. OBJECTIVES: We evaluated the dynamics of the humoral immune response to SARS-CoV-2 in two women who were breastfeeding when infected. We assessed paired breast milk and serum samples for six months post-infection for antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) of the spike protein. RESULTS: Starting at 10 days after symptom onset, IgA antibody levels were persistent over a 6-month time period in human milk. For both mothers, no detectable IgA was found in the samples collected pre-symptom onset. RBD-specific IgG and IgM antibodies in tandem serum collected from the two donors demonstrated stable IgG levels over the six-month time period post-symptom onset. CONCLUSIONS: We found that breastfeeding mothers produced a durable IgA response for up to six months following COVID-19 infection, suggesting an important role for breast milk in protection of infants.


Subject(s)
COVID-19 , Milk, Human , Antibodies, Viral , Breast Feeding , Female , Humans , Infant , SARS-CoV-2
12.
Cell Rep ; 35(8): 109164, 2021 05 25.
Article in English | MEDLINE | ID: covidwho-1227990

ABSTRACT

A major goal of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efforts is to elicit antibody responses that confer protection. Mapping the epitope targets of the SARS-CoV-2 antibody response is critical for vaccine design, diagnostics, and development of therapeutics. Here, we develop a pan-coronavirus phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all known human-infecting coronaviruses in patients with mild or moderate/severe coronavirus disease 2019 (COVID-19). We find that the majority of immune responses to SARS-CoV-2 are targeted to the spike protein, nucleocapsid, and ORF1ab and include sites of mutation in current variants of concern. Some epitopes are identified in the majority of samples, while others are rare, and we find variation in the number of epitopes targeted between individuals. We find low levels of SARS-CoV-2 cross-reactivity in individuals with no exposure to the virus and significant cross-reactivity with endemic human coronaviruses (CoVs) in convalescent sera from patients with COVID-19.


Subject(s)
COVID-19/immunology , Epitopes/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Proteins/immunology , Adult , Aged , Antibodies, Viral/immunology , Binding Sites, Antibody , COVID-19/virology , Cell Surface Display Techniques , Coronavirus/immunology , Cross Reactions , Female , HEK293 Cells , Humans , Immunity , Male , Middle Aged , Nucleocapsid Proteins/immunology , Polyproteins/immunology , Serology , Young Adult
13.
Cell ; 184(11): 2927-2938.e11, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1213071

ABSTRACT

Defining long-term protective immunity to SARS-CoV-2 is one of the most pressing questions of our time and will require a detailed understanding of potential ways this virus can evolve to escape immune protection. Immune protection will most likely be mediated by antibodies that bind to the viral entry protein, spike (S). Here, we used Phage-DMS, an approach that comprehensively interrogates the effect of all possible mutations on binding to a protein of interest, to define the profile of antibody escape to the SARS-CoV-2 S protein using coronavirus disease 2019 (COVID-19) convalescent plasma. Antibody binding was common in two regions, the fusion peptide and the linker region upstream of the heptad repeat region 2. However, escape mutations were variable within these immunodominant regions. There was also individual variation in less commonly targeted epitopes. This study provides a granular view of potential antibody escape pathways and suggests there will be individual variation in antibody-mediated virus evolution.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Epitopes/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Algorithms , COVID-19/therapy , COVID-19/virology , Cell Line , Gene Library , Humans , Immunization, Passive , Mutation , Protein Domains , SARS-CoV-2/genetics , Software , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
14.
JCI Insight ; 6(6)2021 03 22.
Article in English | MEDLINE | ID: covidwho-1097059

ABSTRACT

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.


Subject(s)
Antibodies, Viral/physiology , CD4-Positive T-Lymphocytes/physiology , COVID-19/virology , Hospitalization , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus , Virion , Adult , Aged , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/physiology , Antibodies, Viral/metabolism , CD4-Positive T-Lymphocytes/metabolism , COVID-19/epidemiology , COVID-19/immunology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/immunology , Comorbidity , Diabetes Mellitus/epidemiology , Diabetes Mellitus/immunology , Female , Humans , Immunity, Humoral , Male , Middle Aged , Nucleocapsid , Severity of Illness Index , Viral Envelope , Viral Proteins , Young Adult
16.
J Infect Dis ; 223(2): 197-205, 2021 02 03.
Article in English | MEDLINE | ID: covidwho-1060937

ABSTRACT

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop neutralizing antibodies that target the viral spike protein. In this study, we quantified how levels of these antibodies change in the months after SARS-CoV-2 infection by examining longitudinal samples collected approximately 30-152 days after symptom onset from a prospective cohort of 32 recovered individuals with asymptomatic, mild, or moderate-severe disease. Neutralizing antibody titers declined an average of about 4-fold from 1 to 4 months after symptom onset. This decline in neutralizing antibody titers was accompanied by a decline in total antibodies capable of binding the viral spike protein or its receptor-binding domain. Importantly, our data are consistent with the expected early immune response to viral infection, where an initial peak in antibody levels is followed by a decline to a lower plateau. Additional studies of long-lived B cells and antibody titers over longer time frames are necessary to determine the durability of immunity to SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19/virology , Female , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Young Adult
17.
medRxiv ; 2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-955709

ABSTRACT

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2 which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19. Our data suggest that isolated measurements of the magnitudes of spike-specific immune responses are likely insufficient to anticipate vaccine efficacy in high-risk populations.

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