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1.
J Virol ; 96(9): e0002622, 2022 May 11.
Article in English | MEDLINE | ID: covidwho-1784768

ABSTRACT

Humoral immunity is a major component of the adaptive immune response against viruses and other pathogens with pathogen-specific antibody acting as the first line of defense against infection. Virus-specific antibody levels are maintained by continual secretion of antibody by plasma cells residing in the bone marrow. This raises the important question of how the virus-specific plasma cell population is stably maintained and whether memory B cells are required to replenish plasma cells, balancing their loss arising from their intrinsic death rate. In this study, we examined the longevity of virus-specific antibody responses in the serum of mice following acute viral infection with three different viruses: lymphocytic choriomeningitis virus (LCMV), influenza virus, and vesicular stomatitis virus (VSV). To investigate the contribution of memory B cells to the maintenance of virus-specific antibody levels, we employed human CD20 transgenic mice, which allow for the efficient depletion of B cells with rituximab, a human CD20-specific monoclonal antibody. Mice that had resolved an acute infection with LCMV, influenza virus, or VSV were treated with rituximab starting at 2 months after infection, and the treatment was continued for up to a year postinfection. This treatment regimen with rituximab resulted in efficient depletion of B cells (>95%), with virus-specific memory B cells being undetectable. There was an early transient drop in the antibody levels after rituximab treatment followed by a plateauing of the curve with virus-specific antibody levels remaining relatively stable (half-life of 372 days) for up to a year after infection in the absence of memory B cells. The number of virus-specific plasma cells in the bone marrow were consistent with the changes seen in serum antibody levels. Overall, our data show that virus-specific plasma cells in the bone marrow are intrinsically long-lived and can maintain serum antibody titers for extended periods of time without requiring significant replenishment from memory B cells. These results provide insight into plasma cell longevity and have implications for B cell depletion regimens in cancer and autoimmune patients in the context of vaccination in general and especially for COVID-19 vaccines. IMPORTANCE Following vaccination or primary virus infection, virus-specific antibodies provide the first line of defense against reinfection. Plasma cells residing in the bone marrow constitutively secrete antibodies, are long-lived, and can thus maintain serum antibody levels over extended periods of time in the absence of antigen. Our data, in the murine model system, show that virus-specific plasma cells are intrinsically long-lived but that some reseeding by memory B cells might occur. Our findings demonstrate that, due to the longevity of plasma cells, virus-specific antibody levels remain relatively stable in the absence of memory B cells and have implications for vaccination.


Subject(s)
Antibodies, Viral , Lymphocytic Choriomeningitis , Rituximab , Animals , Antibodies, Viral/blood , Humans , Immunity, Humoral , Immunologic Memory , Lymphocytic Choriomeningitis/immunology , Mice , Mice, Transgenic , Orthomyxoviridae Infections/immunology , Plasma Cells/cytology , Rhabdoviridae Infections/immunology , Rituximab/pharmacology
2.
Microbiol Spectr ; 9(2): e0141621, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1495015

ABSTRACT

The rapid worldwide spread of SARS-CoV-2 has accelerated research and development for controlling the COVID-19 pandemic. A multi-coronavirus protein microarray was created containing full-length proteins, overlapping protein fragments of various lengths, and peptide libraries from SARS-CoV-2 and four other human coronaviruses. Sera from confirmed COVID-19 patients as well as unexposed individuals were applied to multicoronavirus arrays to identify specific antibody reactivity. High-level IgG, IgM, and IgA reactivity to structural proteins S, M, and N of SARS-CoV-2, as well as accessory proteins such as ORF3a and ORF7a, were observed that were specific to COVID-19 patients. Antibody reactivity against overlapping 100-, 50-, and 30-amino acid fragments of SARS-CoV-2 proteins was used to identify antigenic regions. Numerous proteins of SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and the endemic human coronaviruses HCoV-NL63 and HCoV-OC43 were also more reactive with IgG, IgM, and IgA in COVID-19 patient sera than in unexposed control sera, providing further evidence of immunologic cross-reactivity between these viruses. Whereas unexposed individuals had minimal reactivity against SARS-CoV-2 proteins that poorly correlated with reactivity against HCoV-NL63 and HCoV-OC43 S2 and N proteins, COVID-19 patient sera had higher correlation between SARS-CoV-2 and HCoV responses, suggesting that de novo antibodies against SARS-CoV-2 cross-react with HCoV epitopes. Array responses were compared with validated spike protein-specific IgG enzyme-linked immunosorbent assays (ELISAs), showing agreement between orthologous methods. SARS-CoV-2 microneutralization titers were low in the COVID-19 patient sera but correlated with array responses against S and N proteins. The multi-coronavirus protein microarray is a useful tool for mapping antibody reactivity in COVID-19 patients. IMPORTANCE With novel mutant SARS-CoV-2 variants of concern on the rise, knowledge of immune specificities against SARS-CoV-2 proteins is increasingly important for understanding the impact of structural changes in antibody-reactive protein epitopes on naturally acquired and vaccine-induced immunity, as well as broader topics of cross-reactivity and viral evolution. A multi-coronavirus protein microarray used to map the binding of COVID-19 patient antibodies to SARS-CoV-2 proteins and protein fragments as well as to the proteins of four other coronaviruses that infect humans has shown specific regions of SARS-CoV-2 proteins that are highly reactive with patient antibodies and revealed cross-reactivity of these antibodies with other human coronaviruses. These data and the multi-coronavirus protein microarray tool will help guide further studies of the antibody response to COVID-19 and to vaccination against this worldwide pandemic.


Subject(s)
Antibodies, Viral/immunology , Coronavirus NL63, Human/immunology , Coronavirus OC43, Human/immunology , Epitopes/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , SARS-CoV-2/immunology , Antibodies, Viral/blood , Binding Sites, Antibody/immunology , COVID-19/immunology , Coronavirus Nucleocapsid Proteins/immunology , Cross Reactions/immunology , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Phosphoproteins/immunology , Protein Array Analysis , Spike Glycoprotein, Coronavirus/immunology , Viral Proteins/immunology , Viroporin Proteins/immunology
3.
J Infect Dis ; 224(5): 771-776, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1410005

ABSTRACT

We aimed to characterize presence of culturable virus in clinical specimens during acute illness, and antibody kinetics up to 6 months after symptom onset, among 14 early patients with coronavirus disease 2019 in the United States. We isolated viable severe acute respiratory syndrome coronavirus 2 from real-time reverse-transcription polymerase chain reaction-positive respiratory specimens collected during days 0-8 after onset, but not after. All 13 patients with 2 or more serum specimens developed anti-spike antibodies; 12 developed detectable neutralizing antibodies. We did not isolate virus after detection of neutralizing antibodies. Eight participants provided serum at 6 months after onset; all retained detectable anti-spike immunoglobulin G, and half had detectable neutralizing antibodies. Two participants reported not feeling fully recovered at 6 months.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/immunology , Seroconversion/physiology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19/virology , Follow-Up Studies , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Spike Glycoprotein, Coronavirus/immunology , United States
4.
Clin Infect Dis ; 72(12): e1004-e1009, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1269561

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), was first identified in Wuhan, China, in December 2019, with subsequent worldwide spread. The first US cases were identified in January 2020. METHODS: To determine if SARS-CoV-2-reactive antibodies were present in sera prior to the first identified case in the United States on 19 January 2020, residual archived samples from 7389 routine blood donations collected by the American Red Cross from 13 December 2019 to 17 January 2020 from donors resident in 9 states (California, Connecticut, Iowa, Massachusetts, Michigan, Oregon, Rhode Island, Washington, and Wisconsin) were tested at the Centers for Disease Control and Prevention for anti-SARS-CoV-2 antibodies. Specimens reactive by pan-immunoglobulin (pan-Ig) enzyme-linked immunosorbent assay (ELISA) against the full spike protein were tested by IgG and IgM ELISAs, microneutralization test, Ortho total Ig S1 ELISA, and receptor-binding domain/ACE2 blocking activity assay. RESULTS: Of the 7389 samples, 106 were reactive by pan-Ig. Of these 106 specimens, 90 were available for further testing. Eighty-four of 90 had neutralizing activity, 1 had S1 binding activity, and 1 had receptor-binding domain/ACE2 blocking activity >50%, suggesting the presence of anti-SARS-CoV-2-reactive antibodies. Donations with reactivity occurred in all 9 states. CONCLUSIONS: These findings suggest that SARS-CoV-2 may have been introduced into the United States prior to 19 January 2020.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Blood Donors , China , Connecticut , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G , Iowa , Massachusetts , Michigan , Oregon , Rhode Island , Spike Glycoprotein, Coronavirus , Washington , Wisconsin
5.
Public Health Rep ; 136(1): 88-96, 2021.
Article in English | MEDLINE | ID: covidwho-894953

ABSTRACT

OBJECTIVES: Widespread global transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19), continues. Many questions remain about asymptomatic or atypical infections and transmission dynamics. We used comprehensive contact tracing of the first 2 confirmed patients in Illinois with COVID-19 and serologic SARS-CoV-2 antibody testing to determine whether contacts had evidence of undetected COVID-19. METHODS: Contacts were eligible for serologic follow-up if previously tested for COVID-19 during an initial investigation or had greater-risk exposures. Contacts completed a standardized questionnaire during the initial investigation. We classified exposure risk as high, medium, or low based on interactions with 2 index patients and use of personal protective equipment (PPE). Serologic testing used a SARS-CoV-2 spike enzyme-linked immunosorbent assay on serum specimens collected from participants approximately 6 weeks after initial exposure to either index patient. The 2 index patients provided serum specimens throughout their illness. We collected data on demographic, exposure, and epidemiologic characteristics. RESULTS: Of 347 contacts, 110 were eligible for serologic follow-up; 59 (17% of all contacts) enrolled. Of these, 53 (90%) were health care personnel and 6 (10%) were community contacts. Seventeen (29%) reported high-risk exposures, 15 (25%) medium-risk, and 27 (46%) low-risk. No participant had evidence of SARS-CoV-2 antibodies. The 2 index patients had antibodies detected at dilutions >1:6400 within 4 weeks after symptom onset. CONCLUSIONS: In serologic follow-up of the first 2 known patients in Illinois with COVID-19, we found no secondary transmission among tested contacts. Lack of seroconversion among these contacts adds to our understanding of conditions (ie, use of PPE) under which SARS-CoV-2 infections might not result in transmission and demonstrates that SARS-CoV-2 antibody testing is a useful tool to verify epidemiologic findings.


Subject(s)
COVID-19/epidemiology , COVID-19/transmission , Contact Tracing/statistics & numerical data , Health Personnel/statistics & numerical data , Occupational Exposure/statistics & numerical data , COVID-19/immunology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Illinois/epidemiology , Male , Pandemics , Personal Protective Equipment , Risk Assessment , SARS-CoV-2
6.
Clin Infect Dis ; 72(9): 1645-1648, 2021 05 04.
Article in English | MEDLINE | ID: covidwho-633824

ABSTRACT

Among 249 healthcare personnel who worked in hospital units with COVID-19 patients for 1 month, 19 (7.6%) tested positive for SARS-CoV-2 antibodies. Only 11 (57.9%) of the 19 personnel with positive serology reported symptoms of a prior illness, suggesting asymptomatic healthcare personnel could be an important source of SARS-CoV-2 transmission.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Delivery of Health Care , Health Personnel , Humans , Patient Care , Seroepidemiologic Studies , Tennessee/epidemiology
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