Elevated SARS-CoV-2 Antibodies Distinguish Severe Disease in Early COVID-19 Infection

AbstractBackgroundSARS-CoV-2 has caused over 36,000,000 cases and 1,000,000 deaths globally. Comprehensive assessment of the multifaceted anti-viral antibody response is critical for diagnosis, differentiation of severe disease, and characterization of long-term immunity. Initial observations suggest that severe disease is associated with higher antibody levels and greater B cell/plasmablast responses. A multi-antigen immunoassay to define the complex serological landscape and clinical associations is essential.MethodsWe developed a multiplex immunoassay and evaluated serum/plasma from adults with RT-PCR-confirmed SARS-CoV-2 infections during acute illness (N=52) and convalescence (N=69); and pre-pandemic (N=106) and post-pandemic (N=137) healthy adults. We measured IgA, IgG, and/or IgM against SARS-CoV-2 Nucleocapsid (N), Spike domain 1 (S1), receptor binding domain (S1-RBD) and S1-N-terminal domain (S1-NTD).ResultsTo diagnose infection, the combined [IgA+IgG+IgM] or IgG for N, S1, and S1-RBD yielded AUC values −0.90 by ROC curves. From days 6-30 post-symptom onset, the levels of antigen-specific IgG, IgA or [IgA+IgG+IgM] were higher in patients with severe/critical compared to mild/moderate infections. Consistent with excessive concentrations of antibodies, a strong prozone effect was observed in sera from severe/critical patients. Notably, mild/moderate patients displayed a slower rise and lower peak in anti-N and anti-S1 IgG levels compared to severe/critical patients, but anti-RBD IgG and neutralization responses reached similar levels at 2-4 months.ConclusionThis SARS-CoV-2 multiplex immunoassay measures the magnitude, complexity and kinetics of the antibody response against multiple viral antigens. The IgG and combined-isotype SARS-CoV-2 multiplex assay is highly diagnostic of acute and convalescent disease and may prognosticate severity early in illness.One Sentence SummaryIn contrast to patients with moderate infections, those with severe COVID-19 develop prominent, early antibody responses to S1 and N proteins.

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Serum IgG levels in children 6 months after SARS-CoV-2 infection and comparison with adults

European Journal of Pediatrics ◽

10.1007/s00431-021-04124-w ◽

2021 ◽

Author(s):

Silvia Bloise ◽

Alessia Marcellino ◽

Alessia Testa ◽

Anna Dilillo ◽

Saverio Mallardo ◽

...

Keyword(s):

Antibody Response ◽

Clinical Manifestations ◽

Antibody Responses ◽

Serological Tests ◽

Gene Characterization ◽

Children And Parents ◽

Antibody Levels ◽

Serum Igg Levels

AbstractSince the outbreak of SARS-CoV-2 among the population has occurred quite recently, there is a lack of evidence on the long-term duration of antibody response, especially in children. It is therefore crucial to clarify this aspect, considering its implications in the development of successful surveillance strategies, therapies, and vaccinations. The aim of this study was to assess the antibody response in a children group after SARS-CoV-2 infection, and to compare it with that of their parents affected by SARS-CoV-2 infection. We enrolled 12 children and their parents, both groups being affected by COVID-19 in April 2020. In the children’s group, we collected real-time RT-PCR cycle threshold (Ct) values and gene characterization of first nasal-throat swab at the time of diagnosis (T0); 30 days after the diagnosis (T30), we performed blood tests to detect anti-SARS-CoV-2 IgM and IgG. Finally, 180 days after the diagnosis (T180), we measured anti-SARS-CoV-2 IgG in both children and parents. In children, antibody levels declined significantly at 180 days (T180) after first measurement (T30). There were no significant differences in IgG level related to age, sex, and clinical manifestations. We found a significant correlation between IgG titers at T30 and Ct value of gene N. Children showed a lower level of antibodies against SARS-CoV-2 at T180 compared to their parents.Conclusion: Antibody responses in children waned 180 days after SARS-CoV-2 infection, and at the same time, their parents showed a different antibody response to the virus. These results highlight that serological tests should be used with caution in surveillance strategies among the general population. What is known:• Currently is not known how long antibody response will be maintained or if it protects from reinfection.• Recent reports in adults suggest that antibodies to SARS-CoV-2 declined several months after infection, but data are missing in pediatric age. What is new:• We showed that antibody responses to SARS-CoV-2 wane several months after infection also in children with quantitative differences in antibody levels between children and adults.• In this context, serological tests should be used with caution in surveillance strategies.

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Declining Levels of Neutralizing Antibodies Against SARS-CoV-2 in Convalescent COVID-19 Patients One Year Post Symptom Onset

Frontiers in Immunology ◽

10.3389/fimmu.2021.708523 ◽

2021 ◽

Vol 12 ◽

Author(s):

Tiandan Xiang ◽

Boyun Liang ◽

Yaohui Fang ◽

Sihong Lu ◽

Sumeng Li ◽

...

Keyword(s):

Symptom Onset ◽

Neutralizing Antibodies ◽

Natural Infection ◽

Protein S ◽

Igg Antibodies ◽

Neutralizing Activity ◽

Specific Igg ◽

One Year ◽

Kinetics Of

Major advances have been made in understanding the dynamics of humoral immunity briefly after the acute coronavirus disease 2019 (COVID-19). However, knowledge concerning long-term kinetics of antibody responses in convalescent patients is limited. During a one-year period post symptom onset, we longitudinally collected 162 samples from 76 patients and quantified IgM and IgG antibodies recognizing the nucleocapsid (N) protein or the receptor binding domain (RBD) of the spike protein (S). After one year, approximately 90% of recovered patients still had detectable SARS-CoV-2-specific IgG antibodies recognizing N and RBD-S. Intriguingly, neutralizing activity was only detectable in ~43% of patients. When neutralization tests against the E484K-mutated variant of concern (VOC) B.1.351 (initially identified in South Africa) were performed among patients who neutralize the original virus, the capacity to neutralize was even further diminished to 22.6% of donors. Despite declining N- and S-specific IgG titers, a considerable fraction of recovered patients had detectable neutralizing activity one year after infection. However, neutralizing capacities, in particular against an E484K-mutated VOC were only detectable in a minority of patients one year after symptomatic COVID-19. Our findings shed light on the kinetics of long-term immune responses after natural SARS-CoV-2 infection and argue for vaccinations of individuals who experienced a natural infection to protect against emerging VOC.

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Effects of Loigolactobacillus coryniformis K8 CECT 5711 on the Immune Response of Elderly Subjects to COVID-19 Vaccination: A Randomized Controlled Trial

Nutrients ◽

10.3390/nu14010228 ◽

2022 ◽

Vol 14 (1) ◽

pp. 228

Author(s):

Anxo Fernández-Ferreiro ◽

Francisco J. Formigo-Couceiro ◽

Roi Veiga-Gutierrez ◽

Jose A. Maldonado-Lobón ◽

Ana M. Hermida-Cao ◽

...

Keyword(s):

Immune Response ◽

Controlled Trial ◽

Severe Disease ◽

Nursing Home Residents ◽

Vaccination Schedule ◽

Elderly Subjects ◽

Double Blind ◽

Iga Antibody ◽

Specific Igg ◽

Antibody Levels

Elderly people are particularly vulnerable to COVID-19, with a high risk of developing severe disease and a reduced immune response to the COVID-19 vaccine. A randomized, placebo-controlled, double-blind trial to assess the effect of the consumption of the probiotic Loigolactobacillus coryniformis K8 CECT 5711 on the immune response generated by the COVID-19 vaccine in an elderly population was performed. Two hundred nursing home residents >60 yrs that had not COVID-19 were randomized to receive L. coryniformis K8 or a placebo daily for 3 months. All volunteers received a complete vaccination schedule of a mRNA vaccine, starting the intervention ten days after the first dose. Specific IgG and IgA antibody levels were analyzed 56 days after the end of the immunization process. No differences between the groups were observed in the antibody levels. During the intervention, 19 subjects had COVID-19 (11 receiving K8 vs. 8 receiving placebo, p = 0.457). Subgroup analysis in these patients showed that levels of IgG were significantly higher in those receiving K8 compared to placebo (p = 0.038). Among subjects >85 yrs that did not get COVID-19, administration of K8 tended to increase the IgA levels (p = 0.082). The administration of K8 may enhance the specific immune response against COVID-19 and may improve the COVID-19 vaccine-specific responses in elderly populations.

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IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients

Cells ◽

10.3390/cells9122676 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2676

Author(s):

Léonie A. N. Staats ◽

Hella Pfeiffer ◽

Jasmin Knopf ◽

Aylin Lindemann ◽

Julia Fürst ◽

...

Keyword(s):

Severe Disease ◽

Fatal Outcome ◽

Adaptive Immune Response ◽

Extracellular Dna ◽

Neutrophil Extracellular Trap ◽

Organ Injury ◽

Reactive Protein ◽

Patient Groups ◽

Specific Igg ◽

Antibody Levels

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.

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Kinetics of antibody response to Coxiella burnetii infection (Q fever): Estimation of the seroresponse onset from antibody levels

Epidemics ◽

10.1016/j.epidem.2015.07.001 ◽

2015 ◽

Vol 13 ◽

pp. 37-43 ◽

Cited By ~ 10

Author(s):

C.C.H. Wielders ◽

P.F.M. Teunis ◽

M.H.A. Hermans ◽

W. van der Hoek ◽

P.M. Schneeberger

Keyword(s):

Antibody Response ◽

Coxiella Burnetii ◽

Q Fever ◽

Antibody Levels ◽

Kinetics Of

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More rapid, robust and sustainable antibody responses to mRNA COVID-19 vaccine in convalescent COVID-19 individuals

10.1101/2021.08.04.21261561 ◽

2021 ◽

Author(s):

Sabrina E Racine-Brzostek ◽

Jim Yee ◽

Ashley Sukhu ◽

Yuqing Qiu ◽

Sophie Rand ◽

...

Keyword(s):

Longitudinal Study ◽

Antibody Response ◽

Real World ◽

Neutralizing Antibodies ◽

Vaccine Dose ◽

Antibody Responses ◽

Antibody Levels

Longitudinal studies are needed to evaluate the SARS-CoV-2 mRNA vaccine antibody response under real-world conditions. This longitudinal study investigated the quantity and quality of SARS-CoV-2 antibody response in 846 specimens from 350 subjects: comparing BNT162b2-vaccinated individuals (19 previously diagnosed with COVID-19 [RecoVax]; 49 never been diagnosed [NaiveVax]) to 122 hospitalized unvaccinated (HospNoVax) and 160 outpatient unvaccinated (OutPtNoVax) COVID-19 patients. NaiveVax experienced a delay in generating SARS-CoV-2 total antibody levels (TAb) and neutralizing antibodies (SNAb) after the 1st vaccine dose (D1), but a rapid increase in antibody levels was observed after the 2nd dose (D2). However, these never reached the robust levels observed in RecoVax. In fact, NaiveVax TAb and SNAb levels decreased 4-weeks post-D2 (p=0.003;p<0.001). For the most part, RecoVax TAb persisted throughout this study, after reaching maximal levels 2-weeks post-D2; but SNAb decreased significantly ~6-months post-D1 (p=0.002). Although NaiveVax avidity lagged behind that of RecoVax for most of the follow-up periods, NaiveVax did reach similar avidity by ~6-months post-D1. These data suggest that one vaccine dose elicits maximal antibody response in RecoVax and may be sufficient. Also, despite decreasing levels in TAb and SNAb overtime, long-term avidity maybe a measure worth evaluating and possibly correlating to vaccine efficacy.

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Seven-month kinetics of SARS-CoV-2 antibodies and protective role of pre-existing antibodies to seasonal human coronaviruses on COVID-19

10.1101/2021.02.22.21252150 ◽

2021 ◽

Author(s):

Natalia Ortega ◽

Marta Ribes ◽

Marta Vidal ◽

Rocío Rubio ◽

Ruth Aguilar ◽

...

Keyword(s):

Protective Role ◽

Neutralization Capacity ◽

Care Workers ◽

Neutralizing Capacity ◽

Human Coronaviruses ◽

Antibody Levels ◽

The Impact ◽

Kinetics Of ◽

Over Time

AbstractUnraveling the long-term kinetics of antibodies to SARS-CoV-2 and its determinants, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 and four HCoV antigens were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed-up for 6 months. Seroprevalence increased over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, were stable over time, except IgG to nucleocapsid antigen and IgM levels that waned. After the peak response, anti-spike antibody levels increased from ∼150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. Pre-existing antibodies to alpha-HCoV were lower in individuals who subsequently seroconverted for SARS-CoV-2. IgG and IgA to HCoV were significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

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Antibody Responses in Elderly Residential Care Persons following COVID-19 mRNA Vaccination

10.1101/2021.04.07.21254925 ◽

2021 ◽

Author(s):

David A Nace ◽

Kevin E Kip ◽

Octavia M Peck Palmer ◽

Michael R Shurin ◽

Katie Mulvey ◽

...

Keyword(s):

Antibody Response ◽

Assisted Living ◽

Independent Living ◽

Long Term Care ◽

Linear Regression Analysis ◽

Antibody Responses ◽

Personal Care ◽

Term Care ◽

Antibody Levels

Objective COVID-19 disproportionately impacts older adults residing at long-term care facilities. Data regarding antibody response to COVID-19 vaccines in this population is limited. Our objective was to quantify the presence and magnitude of antibody response in older, vaccinated residents at assisted living, personal care, and independent living facilities. Design A cross-sectional quality improvement study was conducted March 15-April 1, 2021 in the Pittsburgh region. Setting and Population Participants were volunteers at assisted living, personal care, and independent living facilities, who received mRNA COVID-19 vaccine. Conditions that obviate immune responses were exclusionary criteria. Methods Sera were collected to measure IgG anti-SARS-CoV-2 antibody level with reflex to total anti-SARS-CoV-2 immunoglobulin levels. Descriptive statistics, Pearson correlation coefficients, and multiple linear regression analysis were performed to evaluate relationships between factors potentially associated with antibody levels. Results All participants (N=70) had received two rounds of vaccination for COVID-19 and were found to have antibodies to SARS-CoV-2. There was wide variation in relative levels of antibodies as determined by extinction coefficients. Antibody levels trended lower in male sex, advanced age, steroid medications, and longer length of time from vaccination. Conclusions and Implications Higher functioning long-term care residents mounted detectable antibody responses when vaccinated with COVID-19 mRNA-based vaccines. This study provides preliminary information on level of population risk of assisted living, personal care, and independent living residents which can inform reopening strategies. Data suggests some degree of immunity is present during the immediate period following vaccination. However, protective effects of such vaccination programs remain to be determined in larger studies. Clinical protection is afforded not just by pre-formed antibody levels, but by ongoing adaptive immunity, which is known to be decreased in older individuals. Thus, the implications of these levels of antibodies in preventing COVID-19 disease must be determined by clinical follow-up.

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Interpreting serological surveys using mixture models: the seroepidemiology of measles, mumps and rubella in England and Wales at the beginning of the 21st century

Epidemiology and Infection ◽

10.1017/s0950268806006340 ◽

2006 ◽

Vol 134 (6) ◽

pp. 1303-1312 ◽

Cited By ~ 55

Author(s):

A. J. VYSE ◽

N. J. GAY ◽

L. M. HESKETH ◽

R. PEBODY ◽

P. MORGAN-CAPNER ◽

...

Keyword(s):

Antibody Response ◽

Natural Infection ◽

England And Wales ◽

Frequency Distributions ◽

The United Kingdom ◽

Specific Frequency ◽

Quantitative Results ◽

Specific Igg ◽

Antibody Levels ◽

Age Range

A mixture modelling technique is applied to age-specific frequency distributions of quantitative results from serological surveys for measles, mumps and rubella using samples collected across the age range in England and Wales in 2000. In accordance with previous studies the analysis suggests that the antibody response to natural infection is stronger than that produced by vaccination, that vaccine-induced antibody levels wane with time and that levels of vaccine-induced antibody response vary for each virus infection being strongest for rubella and weakest for mumps. The current mumps epidemic in the United Kingdom is focused in cohorts born during 1982–1987 who were too old to have received routine MMR vaccination. In the cohort born in 1981–1985 the model estimates that 7·5% have no evidence of mumps specific IgG and 24·9% have the lowest level of detectable antibody. The similar proportions of mumps antibody in these categories among cohorts with opportunity for 1 or 2 doses of vaccine is a concern, as the degree to which these individuals are protected is unclear. Investigations into the efficacy of two doses of a mumps containing vaccine should be a priority during the current epidemic.

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Anti-Leptospira immunoglobulin profiling in mice reveals strain specific IgG and persistent IgM responses associated with virulence and renal colonization

10.1101/2020.11.26.399667 ◽

2020 ◽

Author(s):

Frédérique Vernel-Pauillac ◽

Gerald Murray ◽

Ben Adler ◽

Ivo G. Boneca ◽

Catherine Werts

Keyword(s):

Immune Response ◽

Antibody Response ◽

Post Infection ◽

Severe Disease ◽

Humoral Response ◽

Antibody Responses ◽

High Dose ◽

Leptospira Interrogans ◽

Homologous Challenge

AbstractLeptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected, zoonotic reemerging disease. Humans are sensitive hosts and may develop severe disease. Some animal species, such as rats and mice can become asymptomatic renal carriers. More than 350 leptospiral serovars have been identified, classified on the basis of the antibody response directed against the lipopolysaccharide (LPS). Similarly to whole inactivated bacteria used as human vaccines, this response is believed to confer only short-term, serogroup-specific protection. The immune response of hosts against leptospires has not been thoroughly studied and correlates of protection would be required to test vaccine candidates. In this work, we studied the immunoglobulin (Ig) profiles in mice infected with L. interrogans over time to determine whether this humoral response confers long-term protection after homologous challenge six months post-infection.Groups of mice were injected intraperitoneally with 2×107 leptospires of one of three pathogenic serovars (Manilae, Copenhageni or Icterohaemorrhagiae), attenuated mutants or heat-killed bacteria. Leptospira-specific immunoglobulin (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection were measured by ELISA. Strikingly, we found sustained high levels of IgM in mice infected with the pathogenic Manilae and Copenhageni strains, both colonizing the kidney. In contrast, the Icterohaemorrhagiae strain did not lead to kidney colonization, even at high dose, and triggered a classical IgM response that peaked at day 8 post-infection and disappeared. The virulent Manilae and Copenhageni serovars elicited high levels and similar profiles of IgG subclasses in contrast to Icterohaemorrhagiae strains that stimulated weaker antibody responses. Inactivated heat-killed Manilae strains elicited very low responses. However, all mice pre-injected with leptospires challenged with high doses of homologous bacteria did not develop acute leptospirosis, and all antibody responses were boosted after challenge. Furthermore, we showed that 2 months post challenge, mice pre-infected with the M895 Manilae LPS mutant or heat-killed bacterin were completely protected against renal colonization. In conclusion, we observed a sustained IgM response potentially associated with chronic leptospiral renal infection. We also demonstrated in mice different profiles of protective antibody response after L. interrogans infection, depending on the serovar and virulence of strains.Author summaryLeptospira interrogans is a pathogenic spirochete responsible for leptospirosis, a neglected zoonotic reemerging disease. The immune response of hosts against these bacteria has not been thoroughly studied. Here, we studied over 6 months the immunoglobulin (Ig) profiles in mice infected with L. interrogans and determined whether this humoral response confers long-term protection after homologous challenge six months after primary infection. Groups of mice were infected intraperitoneally with 2×107 bacteria of one of three different pathogenic serovars (Manilae, Copenhageni and Icterohaemorrhagiae) and some corresponding attenuated avirulent mutants. We measured by ELISA each type of Leptospira-specific Ig (IgA, IgM, IgG and 4 subclasses) produced in the first weeks up to 6 months post-infection. We showed different profiles of antibody response after L. interrogans challenge in mice, depending on the serovar and virulence of strains. However, all infected mice, including the ones harboring low antibody levels, like mice vaccinated with an inactivated, heat-killed strain, were protected against leptospirosis after challenge. Notably, we also showed an unusual sustained IgM response associated with chronic leptospiral colonization. Altogether, this long-term immune protection is different from what is known in humans and warrants further investigation.

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