Modelling the population-level protection conferred by COVID-19 vaccination

Mapping Intimacies ◽

10.1101/2021.03.16.21253742 ◽

2021 ◽

Author(s):

Pranesh Padmanabhan ◽

Rajat Desikan ◽

Narendra M Dixit

Keyword(s):

Mathematical Model ◽

Severe Acute Respiratory Syndrome ◽

Dose Response ◽

Neutralizing Antibodies ◽

Population Level ◽

Response Curves ◽

Post Vaccination ◽

Dose Response Curves ◽

Vaccine Availability

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines work predominantly by eliciting neutralizing antibodies (NAbs), how the protection they confer depends on the NAb response to vaccination is unclear. Here, we collated and analysed in vitro dose-response curves of >70 NAbs and constructed a landscape defining the spectrum of neutralization efficiencies of NAbs elicited. We mimicked responses of individuals by sampling NAb subsets of known sizes from the landscape and found that they recapitulated responses of convalescent patients. Combining individual responses with a mathematical model of within-host SARS-CoV-2 infection post-vaccination, we predicted how the population-level protection conferred would increase with the NAb response to vaccination. Our predictions captured the outcomes of vaccination trials. Our formalism may help optimize vaccination protocols, given limited vaccine availability.

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Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

Archives of Toxicology ◽

10.1007/s00204-021-03015-1 ◽

2021 ◽

Author(s):

Shensheng Zhao ◽

Sebastiaan Wesseling ◽

Bert Spenkelink ◽

Ivonne M. C. M. Rietjens

Keyword(s):

Dose Response ◽

Kinetic Modelling ◽

Ache Inhibition ◽

Response Curves ◽

Alternative Testing ◽

Dose Response Curves ◽

Physiologically Based Kinetic Modelling ◽

Point Of Departure

AbstractThe present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.

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Histamine H2-receptor of human and rabbit parietal cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1987.253.4.g497 ◽

1987 ◽

Vol 253 (4) ◽

pp. G497-G501 ◽

Cited By ~ 1

Author(s):

R. Leth ◽

B. Elander ◽

U. Haglund ◽

L. Olbe ◽

E. Fellenius

Keyword(s):

Dose Response ◽

In Vivo Model ◽

Response Curves ◽

Gastric Glands ◽

Histamine H2 Receptor ◽

Receptor Affinity ◽

H2 Receptor ◽

Dose Response Curves

The histamine H2-receptor on the human parietal cell has been characterized by using dose-response curves and the negative logarithm of the molar concentration of an antagonist (pA2) analyses of cimetidine antagonism of betazole, histamine, and impromidine stimulation in isolated human and rabbit gastric glands. To evaluate the in vitro results, betazole-stimulated gastric acid secretion with and without cimetidine was also studied in healthy subjects. In the in vivo model, individual dose-response curves were shifted to the right with increasing cimetidine concentrations, but this was counteracted by increasing betazole doses, indicating competitive, reversible antagonism. The pA2 values ranged from 6.1 to 6.3. In isolated human gastric glands, impromidine was shown to be eight times more potent than histamine, indicating higher receptor affinity, but the maximally stimulated aminopyrine accumulation was the same as for histamine, and the pA2 values for cimetidine antagonism did not differ significantly, i.e., 5.7 (histamine) and 6.1 (impromidine). In isolated rabbit gastric glands, cimetidine inhibited the histamine- and impromidine-stimulated response with pA2 values of 6.0 and 7.3, respectively. Impromidine was shown to be approximately 100 times more potent than in human gastric glands, whereas histamine had the same potency. This confirms the role of the histamine H2-receptor and suggests a difference between the species concerning receptor affinity.

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AN IN VITRO ASSAY OF CORTICOTROPHIN

Canadian Journal of Biochemistry and Physiology ◽

10.1139/o55-030 ◽

1955 ◽

Vol 33 (2) ◽

pp. 209-216 ◽

Cited By ~ 7

Author(s):

K. W. McKerns ◽

E. Nordstrand

Keyword(s):

Dose Response ◽

In Vitro Assay ◽

Assay Method ◽

Response Curves ◽

Vitro Assay ◽

Rat Adrenals ◽

Assay Design ◽

Dose Response Curves ◽

Gland System

The ability of corticotrophin to increase the corticoid output of rat adrenals in an isolated gland system has been developed as a useful assay method for the measurement of corticotrophin potency. The extra corticoids produced by stimulation are measured in terms of cortisone. Log dose response curves are presented for corticotrophin levels from 0.002 to 0.135 I.U./100 mgm. adrenals. A four point assay design, the precision of corticoid measurements, and the characteristics of the log dose response curves for a number of types of corticotrophin are given. With four measurements of each dose level the average lambda s/b for 20 assays was 0.209 ± 0.085 (S.D.).

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AN IN VITRO ASSAY OF CORTICOTROPHIN

Canadian Journal of Biochemistry and Physiology ◽

10.1139/y55-030 ◽

1955 ◽

Vol 33 (1) ◽

pp. 209-216

Author(s):

K. W. McKerns ◽

E. Nordstrand

Keyword(s):

Dose Response ◽

In Vitro Assay ◽

Assay Method ◽

Response Curves ◽

Vitro Assay ◽

Rat Adrenals ◽

Assay Design ◽

Dose Response Curves ◽

Gland System

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BIOLOGICALLY ACTIVE LUTEINIZING HORMONE (LH) IN PLASMA

Acta Endocrinologica ◽

10.1530/acta.0.0830454 ◽

1976 ◽

Vol 83 (3) ◽

pp. 454-465 ◽

Cited By ~ 23

Author(s):

P. Romaní ◽

D. M. Robertson ◽

E. Diczfalusy

Keyword(s):

Menstrual Cycle ◽

Dose Response ◽

Gel Filtration ◽

Biologically Active ◽

Relative Potency ◽

Response Curves ◽

Plasma Pool ◽

Dose Response Curves ◽

Post Menopausal

ABSTRACT A recently described in vitro bioassay method for the measurement of biologically active LH (Van Damme et al. 1974) has been applied to the plasma of normally menstruating and post-menopausal women. The specificity of the procedure was established according to the following evidence: 1. Parallelism was observed between dose response curves obtained with serial dilutions of a standard LH preparation (HMG 2nd IRP) and plasma pools collected during the follicular phase, at the LH-peak, during the luteal phase and after menopause. 2. There was no evidence for the presence of any synergistic or antagonistic factor in the various plasma specimens. The assay design used to establish this consisted of assaying the standard and plasma pool separately and then together as a mixture followed by an asssessment of the difference (if any) in the potencies obtained. Strict additivity should yield a relative potency of 1.0. Plasma pools which were obtained every 2–3 days throughout the menstrual cycle were assayed using this design against the standard (HMG 2nd IRP) and against a mid-cycle plasma pool obtained at the time of the LH-peak. The latter was also assayed against partially purified plasma fractions obtained from a post-menopausal plasma pool after gel filtration and isoelectric focusing. With the exception of 3 assays, in which the estimates of relative potency were 0.91, 0.94 and 0.95, respectively, in 19 assays of additivity, the fiducial limits always included unity. 3. Non-detectable LH levels were found in the plasma or serum of either hypophysectomized or hypopituitary hypogonadal men or women treated with oestrogen/progestogen combined pills. 4. The presence of calf or human serum in the assay medium is an essential requirement for a valid comparison of standard and unknown preparations. In their absence, non-parallel dose response curves between plasma and standard were obtained. The other established criteria of reliability (sensitivity and precision) were also examined. The method is sufficiently sensitive (3.5–8.0 mIU/ml plasma; HMG (2nd IRP) as standard) for the measurement of LH throughout the cycle. The mean index of precision (λ) in 230 multiple assays was 0.040. It is concluded that the modified bioassay yields valid and reliable estimates of LH when applied to human plasma obtained throughout the menstrual cycle and after menopause.

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Differential response of primary cultures of breast carcinomas to lapatinib in an in vitro chemoresponse assay

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.1115 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 1115-1115

Author(s):

L. M. Hancher ◽

P. R. Ervin ◽

S. L. Brower

Keyword(s):

Cell Lines ◽

Dose Response ◽

Response Rate ◽

Primary Cultures ◽

Breast Carcinomas ◽

Human Breast ◽

Response Curves ◽

Her 2 ◽

Dose Response Curves

1115 Background: Lapatinib (Tykerb) is a small molecule tyrosine kinase inhibitor that targets the intracellular domain of the epidermal growth factor receptor and HER-2, thereby inhibiting both growth and survival signaling pathways. Lapatinib is currently FDA-approved to treat HER-2-positive breast cancer previously treated with anthracycline and taxane therapies and trastuzumab. Due to the low population response rate of lapatinib, an integrated biomarker that can identify patients with an increased likelihood for response would be of great clinical utility. The current study describes an in vitro chemoresponse assay developed to predict sensitivity and resistance of primary cultures of human breast tumor specimens to lapatinib. Methods: The chemoresponse assay (ChemoFx) for lapatinib was developed using four different immortalized carcinoma cell lines (SK-OV3, BT474, MDA-MB-231, MCF7). In addition to cell lines, the chemoresponse assay was also performed on 55 first passage primary cultures of human breast carcinomas. All cultures were confirmed to contain keratin-positive epithelial cells using fluorescence immunocytochemistry. Cell lines and specimens were treated with a 10 dose concentration range of lapatinib for 72 hours and stained with DAPI; remaining live cells were counted on an inverted fluorescent imaging system. Resulting dose-response curves were analyzed and categorized as responsive, intermediate responsive, or non-responsive using a proprietary scoring algorithm. Results: All four cell lines (BT474, MDA-MB-231, MCF7, SK-OV3) were responsive to lapatinib treatment, with EC50 values of approximately 10 uM. Dose-response curves of the 55 primary breast cultures revealed that 9% of the specimens tested were responsive to lapatinib, 15% had an intermediate response, and 76% were non-responsive. These results are consistent with a reported clinical response rate of 10% for lapatinib. Conclusions: Initial results with the described integrated cell-based assay demonstrate that in vitro chemoresponse testing may be useful in predicting patient response to lapatinib. This type of in vitro biomarker is likely to increase the efficacy of the current chemotherapy decision-making process for oncologists and their patients. No significant financial relationships to disclose.

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Use of an in vitro chemoresponse assay to define a subset of colorectal carcinomas responsive to cetuximab

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15127 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15127-e15127

Author(s):

S. D. Rice ◽

P. R. Ervin ◽

S. L. Brower

Keyword(s):

Cell Lines ◽

Dose Response ◽

Response Rate ◽

Primary Cultures ◽

Colorectal Tumor ◽

Colorectal Carcinomas ◽

Response Curves ◽

Drug Mechanism ◽

Dose Response Curves

e15127 Background: Cetuximab (Erbitux) is a chimeric monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor. This interaction interferes with ligand binding and activation of the receptor blocking the downstream signaling of EGFR and impairing cell growth and proliferation. Cetuximab also has been shown to mediate antibody dependent cellular cytotoxicity. Thus, a singular approach to drug mechanism likely would not capture the true effects of cetuximab. Cetuximab is FDA-approved to treat head and neck cancer and colorectal carcinomas and is being evaluated for use in non-small cell lung and endometrial cancer. Due to the low population response rate of cetuximab, an integrated biomarker that can identify patients with an increased likelihood for response would be of great clinical utility. The current study describes an in vitro chemoresponse assay to predict response of primary cultures of human colorectal tumor specimens to cetuximab. Methods: The chemoresponse assay (ChemoFx) was developed using four different immortalized carcinoma cell lines (NCI-H292, NCI-H522, NCI-H1666, Calu3). The chemoresponse assay was also performed on 54 first passage primary cultures of human colorectal tumor specimens. Cell lines and specimens were treated with a 10 dose concentration range of cetuximab for 72 hours, stained with a nuclear dye, and remaining post-treatment live cells were counted. Resulting dose-response curves were analyzed. Results: Two of the examined cell lines showed response to cetuximab treatment; EC50 values for NCI-H292 and NCI-H1666 were 825nM and 13nM, respectively. NCI-H522 and Calu3 were deemed non-responsive to cetuximab. Dose-response curves of the 54 primary colorectal cultures revealed that 8% of the cultures tested were responsive to cetuximab, 22% had an intermediate response, and 70% were deemed non-responsive. These results are consistent with a reported clinical response rate of 11% for cetuximab in colorectal carcinoma patients. Conclusions: Initial results demonstrate that in vitro chemoresponse testing may be useful in predicting patient response to cetuximab. This could increase the efficacy of the current chemotherapy decision-making process for oncologists and their patients. No significant financial relationships to disclose.

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Characterization of sulfidopeptide leukotriene responses in sheep tracheal smooth muscle in vitro

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-121 ◽

1991 ◽

Vol 69 (6) ◽

pp. 805-811 ◽

Cited By ~ 7

Author(s):

K. Tomioka ◽

J. T. Jackowski ◽

W. M. Abraham

Keyword(s):

Smooth Muscle ◽

Dose Response ◽

Tracheal Smooth Muscle ◽

Response Curves ◽

Leukotriene Antagonist ◽

Dose Response Curves ◽

The Right ◽

Glutamyl Transpeptidase

We have investigated the effects of leukotrienes (LTs) on isolated tracheal smooth muscle from sheep sensitive to Ascaris suum antigen. LTC4 and LTD4 produced dose-dependent contractions of sheep trachea, but LTE4 was virtually inactive. YM-17690, a non-analogous LT agonist, produced no contractile response up to 100 μM. Indomethacin (5 μM) had no effect on LTC4- and LTD4-induced contractions. L-Serine borate (45 mM), an inhibitor of γ-glutamyl transpeptidase, shifted the dose–response curve of LTC4 to the left by 161-fold, and L-cysteine (6 mM), an inhibitor of aminopeptidase, shifted the dose–response curves of LTC4 and LTD4 to the left by 67- and 23-fold, respectively. YM-16638 (1 μM), an LT antagonist, shifted the dose–response curves of LTC4 and LTD4 to the right with pKB values of 6.57 and 7.13, respectively. YM-16638 did not affect LTC4-induced contractions of L-serine borate-treated tissues, indicating that the compound acts only on LTD4 receptors in sheep trachea. LTE4 (1 μM) shifted the dose–response curves of LTC4 and LTD4 to the right with pKB values of 6.87 and 7.31, respectively. YM-17690 (10 μM) showed effects similar to LTE4, suggesting that the compound acts as an LTE4 agonist in sheep trachea. These results suggest that in sheep tracheal smooth muscle (a) LTC4 and LTD4 produce contractions, (b) these LT-induced contractions are not mediated by cyclooxygenase products, (c) LTC4 is converted to LTD4 and then to LTE4, and (d) the potency of the LTC4- and LTD4-induced contractions is increased when their conversion to LTE4 is inhibited. This potentiation may result from the inability of LTE4 to contract sheep trachea and (or) its antagonist actions.Key words: leukotriene antagonist, receptors, asthma.

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Regulation of gonadotrophin secretion by inhibin, testosterone and gonadotrophin-releasing hormone in pituitary cell cultures of male monkeys

Journal of Endocrinology ◽

10.1677/joe.0.1590103 ◽

1998 ◽

Vol 159 (1) ◽

pp. 103-110 ◽

Cited By ~ 9

Author(s):

U Fingscheidt ◽

GF Weinbauer ◽

HL Fehm ◽

E Nieschlag

Keyword(s):

Dose Response ◽

Pituitary Cells ◽

Basal Secretion ◽

Response Curves ◽

Gonadotrophin Secretion ◽

Lh Release ◽

Gonadotrophin Releasing Hormone ◽

Dose Response Curves ◽

Male Rhesus

The effects of bovine inhibin, testosterone and GnRH on gonadotrophin secretion by primate pituitary cells were characterized in vitro using pituitaries from six male rhesus monkeys and one male cynomolgus monkey. The effect of inhibin on basal secretion of FSH and LH was investigated. Dose-response curves in monkeys and rats were compared. GnRH dose-response curves in the presence and absence of testosterone were also examined in monkeys. In monkey pituitary cells, testosterone at a concentration of 10(-7) M had no effect on LH or FSH secretion. Inhibin suppressed FSH secretion to 50.8% of that of controls with no effect on LH. In rats, FSH secretion was suppressed to 45.0% of that of controls with a median effective dose (ED50, 95% range) of 1.298 (1.064-1.584) U/ml, compared with 1.024 (0.7204-1.455) U/ml in monkeys. In monkey pituitary cells, LH release was stimulated 9.9-fold and FSH 3.3-fold by GnRH. Testosterone had no effect on basal or GnRH-stimulated gonadotrophin release. These results support the view that the pituitary is not the target organ for the negative feedback action of testosterone in the male. In vitro, inhibin is the major regulator of FSH secretion at the pituitary level.

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