Evidence for antibody as a protective correlate for COVID-19 vaccines

Though eleven novel COVID-19 vaccines have demonstrated efficacy, additional affordable, scalable, and deliverable vaccines are needed to meet unprecedented global demand. With placebo-controlled efficacy trials becoming infeasible due to the roll out of licensed vaccines, a correlate of protection is urgently needed to provide a path for regulatory approval of novel vaccines. To assess whether antibody titers may reasonably predict efficacy, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (ρ= 0.79) and binding antibody titer and efficacy (ρ = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. This correlation is strengthened by substituting post-hoc analyses for efficacy against the ancestral strain (D614G), where available. Together with an accumulating body of evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.

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Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A/H3N2 Influenza Disease

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv067 ◽

2015 ◽

Vol 2 (2) ◽

Cited By ~ 22

Author(s):

Anne Benoit ◽

Jiri Beran ◽

Jeanne-Marie Devaster ◽

Meral Esen ◽

Odile Launay ◽

...

Keyword(s):

Characteristic Curve ◽

Fold Increase ◽

Correlate Of Protection ◽

Pooled Data ◽

Trivalent Influenza Vaccine ◽

Inhibition Antibody ◽

Antibody Titers ◽

H3n2 Influenza ◽

Antibody Levels ◽

The Relationship

Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods. Data on the occurrence of laboratory-confirmed influenza and HI levels pre- and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged ≥65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to ide.jpegy a potential cutoff titer between protection and no protection. Results. The baseline odds ratio of A/H3N2 disease was higher for subjects aged ≥65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions. The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.

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Discrete SARS-CoV-2 antibody titers track with functional humoral stability

Nature Communications ◽

10.1038/s41467-021-21336-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yannic C. Bartsch ◽

Stephanie Fischinger ◽

Sameed M. Siddiqui ◽

Zhilin Chen ◽

Jingyou Yu ◽

...

Keyword(s):

Cellular Response ◽

Asymptomatic Infection ◽

Activity Level ◽

Antibody Activity ◽

Significant Heterogeneity ◽

Antibody Titers ◽

Binding Antibody ◽

And Function ◽

The Relationship

AbstractAntibodies serve as biomarkers of infection, but if sustained can confer long-term immunity. Yet, for most clinically approved vaccines, binding antibody titers only serve as a surrogate of protection. Instead, the ability of vaccine induced antibodies to neutralize or mediate Fc-effector functions is mechanistically linked to protection. While evidence has begun to point to persisting antibody responses among SARS-CoV-2 infected individuals, cases of re-infection have begun to emerge, calling the protective nature of humoral immunity against this highly infectious pathogen into question. Using a community-based surveillance study, we aimed to define the relationship between titers and functional antibody activity to SARS-CoV-2 over time. Here we report significant heterogeneity, but limited decay, across antibody titers amongst 120 identified seroconverters, most of whom had asymptomatic infection. Notably, neutralization, Fc-function, and SARS-CoV-2 specific T cell responses were only observed in subjects that elicited RBD-specific antibody titers above a threshold. The findings point to a switch-like relationship between observed antibody titer and function, where a distinct threshold of activity—defined by the level of antibodies—is required to elicit vigorous humoral and cellular response. This response activity level may be essential for durable protection, potentially explaining why re-infections occur with SARS-CoV-2 and other common coronaviruses.

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Relationship between Anti-Spike Protein Antibody Titers and SARS-CoV-2 In Vitro Virus Neutralization in Convalescent Plasma

10.1101/2020.06.08.138990 ◽

2020 ◽

Cited By ~ 8

Author(s):

Eric Salazar ◽

Suresh V. Kuchipudi ◽

Paul A. Christensen ◽

Todd N. Eagar ◽

Xin Yi ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Spike Protein ◽

Virus Neutralization ◽

Strong Positive Correlation ◽

Antibody Titers ◽

Asymptomatic Individuals ◽

The Relationship ◽

Recommended Level ◽

Better Than

AbstractNewly emerged pathogens such as SARS-CoV-2 highlight the urgent need for assays that detect levels of neutralizing antibodies that may be protective. We studied the relationship between anti-spike ectodomain (ECD) and anti-receptor binding domain (RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by two different in vitro assays using convalescent plasma samples obtained from 68 COVID-19 patients, including 13 who donated plasma multiple times. Only 23% (16/68) of donors had been hospitalized. We also studied 16 samples from subjects found to have anti-spike protein IgG during surveillance screening of asymptomatic individuals. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers, and in vitro VN titer. Anti-RBD plasma IgG correlated slightly better than anti-ECD IgG titer with VN titer. The probability of a VN titer ≥160 was 80% or greater with anti-RBD or anti-ECD titers of ≥1:1350. Thirty-seven percent (25/68) of convalescent plasma donors lacked VN titers ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease either VN or IgG titers. Analysis of 2,814 asymptomatic adults found 27 individuals with anti-RBD or anti-ECD IgG titers of ≥1:1350, and evidence of VN ≥1:160. Taken together, we conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titer of ≥1:1350 may provide critical information about protection against COVID-19 disease.

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Controversies Surrounding Vitamin D: Focus on Supplementation and Cancer

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16020189 ◽

2019 ◽

Vol 16 (2) ◽

pp. 189 ◽

Cited By ~ 16

Author(s):

Salvatore Minisola ◽

Federica Ferrone ◽

Vittoria Danese ◽

Veronica Cecchetti ◽

Jessica Pepe ◽

...

Keyword(s):

Vitamin D ◽

Serum Levels ◽

Vitamin D Supplementation ◽

Hydroxyvitamin D ◽

Final Agreement ◽

Number Of Publications ◽

Meta Analyses ◽

Post Hoc ◽

The Relationship

There has recently been a huge number of publications concerning various aspects of vitamin D, from the physiological to therapeutic fields. However, as a consequence of this very fast-growing scientific area, some issues still remain surrounded by uncertainties, without a final agreement having been reached. Examples include the definitions of vitamin D sufficiency and insufficiency, (i.e., 20 vs. 30 ng/mL), the relationship between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone, (i.e., linear vs. no linear), the referent to consider, (i.e., total vs. free determination), the utility of screening versus universal supplementation, and so on. In this review, the issues related to vitamin D supplementation in subjects with documented hypovitaminosis, and the role of vitamin D in cancer will be concisely considered. Daily, weekly, or monthly administration of cholecalciferol generally leads to essentially similar results in terms of an increase in 25(OH)D serum levels. However, we should also consider possible differences related to a number of variables, (i.e., efficiency of intestinal absorption, binding to vitamin D binding protein, and so on). Thus, adherence to therapy may be more important than the dose regimen chosen in order to allow long-term compliance in a sometimes very old population already swamped by many drugs. It is difficult to draw firm conclusions at present regarding the relationship between cancer and vitamin D. In vitro and preclinical studies seem to have been more convincing than clinical investigations. Positive results in human studies have been mainly derived from post-hoc analyses, secondary end-points or meta-analyses, with the last showing not a decrease in cancer incidence but rather in mortality. We must therefore proceed with a word of caution. Until it has been clearly demonstrated that there is a causal relationship, these positive “non-primary, end-point results” should be considered as a background for generating new hypotheses for future investigations.

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Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053711 ◽

1982 ◽

Vol 40 ◽

pp. 210-211

Author(s):

M.J. Murphy ◽

R.R. Price ◽

J.C. Sloman

Keyword(s):

Cultured Cells ◽

Human Tumor ◽

Cell Type ◽

Tumor Mass ◽

Initial Cell ◽

Cloning Assay ◽

Human Tumor Cloning ◽

The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

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Plasminogen Depletion during Streptokinase Treatment or Two-Chain Urokinase Incubation Correlates with Decreased Clot Lysability Ex Vivo and In Vitro

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649714 ◽

1993 ◽

Vol 70 (06) ◽

pp. 0998-1004 ◽

Cited By ~ 13

Author(s):

Páll T Önundarson ◽

H Magnús Haraldsson ◽

Lena Bergmann ◽

Charles W Francis ◽

Victor J Marder

Keyword(s):

Myocardial Infarction ◽

Ex Vivo ◽

Time Dependent ◽

State Variables ◽

Thrombolytic Treatment ◽

Direct Proportion ◽

Plasmin Activity ◽

Plasma Exposure ◽

The Relationship

SummaryThe relationship between lytic state variables and ex vivo clot lysability was investigated in blood drawn from patients during streptokinase administration for acute myocardial infarction. A lytic state was already evident after 5 min of treatment and after 20 min the plasminogen concentration had decreased to 24%, antiplasmin to 7% and fibrinogen 0.2 g/1. Lysis of radiolabeled retracted clots in the patient plasmas decreased from 37 ± 8% after 5 min to 21 ± 8% at 10 min and was significantly lower (8 ± 9%, p <0.005) in samples drawn at 20, 40 and 80 min. Clot lysability correlated positively with the plasminogen concentration (r = 0.78, p = 0.003), but not with plasmin activity. Suspension of radiolabeled clots in normal plasma pre-exposed to 250 U/ml two-chain urokinase for varying time to induce an in vitro lytic state was also associated with decreasing clot lysability in direct proportion with the duration of prior plasma exposure to urokinase. The decreased lysability correlated with the time-dependent reduction in plasminogen concentration (r = 0.88, p <0.0005). Thus, clot lysability decreases in conjunction with the development of the lytic state and the associated plasminogen depletion. The lytic state may therefore limit reperfusion during thrombolytic treatment.

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Monitoring Anticoagulant Therapy by Activated Partial Thromboplastin Time: Hirudin Assessment

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648943 ◽

1994 ◽

Vol 72 (05) ◽

pp. 685-692 ◽

Cited By ~ 43

Author(s):

Michael T Nurmohamed ◽

René J Berckmans ◽

Willy M Morriën-Salomons ◽

Fenny Berends ◽

Daan W Hommes ◽

...

Keyword(s):

Whole Blood ◽

Partial Thromboplastin Time ◽

Ex Vivo ◽

Fold Increase ◽

Heparin Therapy ◽

Activated Partial Thromboplastin Time ◽

Recombinant Hirudin ◽

Interindividual Differences ◽

The Relationship

SummaryBackground. Recombinant hirudin (RH) is a new anticoagulant for prophylaxis and treatment of venous and arterial thrombosis. To which extent the activated partial thromboplastin time (APTT) is suitable for monitoring of RH has not been properly evaluated. Recently, a capillary whole blood device was developed for bed-side monitoring of the APTT and it was demonstrated that this device was suitable to monitor heparin therapy. However, monitoring of RH was not evaluated.Study Objectives. To evaluate in vitro and ex vivo the responsiveness and reproducibility for hirudin monitoring of the whole blood monitor and of plasma APTT assays, which were performed with several reagents and two conventional coagulometers.Results. Large interindividual differences in hirudin responsiveness were noted in both the in vitro and the ex vivo experiments. The relationship between the APTT, expressed as clotting time or ratio of initial and prolonged APTT, and the hirudin concentration was nonlinear. A 1.5-fold increase of the clotting times was obtained at 150-200 ng/ml plasma. However, only a 2-fold increase was obtained at hirudin levels varying from 300 ng to more than 750 ng RH/ml plasma regardless of the assays. The relationship linearized upon logarithmic conversion of the ratio and the hirudin concentration. Disregarding the interindividual differences, and presuming full linearity of the relationship, all combinations were equally responsive to hirudin.Conclusions. All assays were equally responsive to hirudin. Levels up to 300 ng/ml plasma can be reliably estimated with each assay. The manual device may be preferable in situations where rapid availability of test results is necessary.

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Thickness of endometrium: predictor of the effectiveness of IVF/ICSI programs (literature review)

GYNECOLOGY ◽

10.26442/2079-5696_20.1.113-116 ◽

2018 ◽

Vol 20 (1) ◽

pp. 113-116

Author(s):

L A Bagdasaryan ◽

I E Korneyeva

Keyword(s):

Assisted Reproductive Technologies ◽

Endometrial Thickness ◽

Molecular Genetic ◽

Uterine Cavity ◽

Reproductive Technologies ◽

Genetic Characteristics ◽

Vitro Fertilization ◽

Need To Evaluate ◽

The Relationship

The aim of the study is to systematically analyze the data available in the modern literature on the relationship between endometrial thickness and the frequency of pregnancy in the program of assisted reproductive technologies (ART). Materials and methods. The review includes data from foreign and domestic articles found in PubMed on this topic. Results. The article presents data on the relationship between the thickness of the endometrium and the frequency of pregnancy in ART programs. The greatest number of studies is devoted to the evaluation of the relationship between the thickness of the endometrium and the frequency of pregnancy on the day of the ovulation trigger. Data are presented on the existence of a correlation between the thickness of the endometrium measured on the day of the ovulation trigger and the frequency of clinical pregnancy, as well as data on the need to evaluate the structure of the endometrium and the state of subendometric blood flow. The importance of multilayered (three-layered) endometrium as a prognostic marker of success in in vitro fertilization/intracytoplasmic sperm injection programs in the ovum is emphasized. The conclusion. The thickness of the endometrium can not be used as an argument for canceling the cycle or abolishing embryo transfer to the uterine cavity. Further studies in this direction are needed with a study of the morphological and molecular genetic characteristics of the endometrium, which in the future will allow us to evaluate the relationship between the thickness of the endometrium and the probability of pregnancy.

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