scholarly journals The O-Ag Antibody Response to Francisella Is Distinct in Rodents and Higher Animals and Can Serve as a Correlate of Protection

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1646
Author(s):  
Lauren E. Shoudy ◽  
Prachi Namjoshi ◽  
Gabriela Giordano ◽  
Sudeep Kumar ◽  
Jennifer D. Bowling ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Low Dose ◽  
High Sensitivity ◽  
High Dose ◽  
Live Vaccine Strain ◽  
Plasma Samples ◽  
Vaccine Candidates ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Bona Fide

Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live vaccine strain (LVS) demonstrated ~80% vaccine efficacy against low dose (~50 CFU) challenge; however, protection deteriorated with higher challenge doses (~2000 CFU of SchuS4) and no COPs were established. Here, we describe our efforts to develop clinically relevant, humoral COPs applicable to high-dose, aerosol challenge with S4. First, our serosurvey of LVS-vaccinated Hu and animals revealed that rabbits (Rbs), but not rodents, recapitulate the Hu O-Ag dependent Ab response to Ft. Next, we assayed Rbs immunized with distinct S4-based vaccine candidates (S4ΔclpB, S4ΔguaBA, and S4ΔaroD) and found that, across multiple vaccines, the %O-Ag dep Ab trended with vaccine efficacy. Among S4ΔguaBA-vaccinated Rbs, the %O-Ag dep Ab in pre-challenge plasma was significantly higher in survivors than in non-survivors; a cut-off of >70% O-Ag dep Ab predicted survival with high sensitivity and specificity. Finally, we found this COP in 80% of LVS-vaccinated Hu plasma samples as expected for a vaccine with 80% Hu efficacy. Collectively, the %O-Ag dep Ab response is a bona fide COP for S4ΔguaBA-vaccinated Rb and holds significant promise for guiding vaccine trials with higher animals.

scholarly journals Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

2016 ◽  
Vol 23 (3) ◽  
pp. 228-235 ◽  
Author(s):  
Andrew J. Dunning ◽  
Carlos A. DiazGranados ◽  
Timothy Voloshen ◽  
Branda Hu ◽  
Victoria A. Landolfi ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Vaccine Efficacy ◽  
Standard Dose ◽  
The Elderly ◽  
High Dose ◽  
Efficacy Trial ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Immunologic Assays ◽  
Dose Vaccine

ABSTRACTAlthough a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus—the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.)

scholarly journals Principal surrogates in context of high vaccine efficacy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Andrea Callegaro ◽  
Fabian Tibaldi ◽  
Dean Follmann
Keyword(s):  
Vaccine Efficacy ◽  
Meta Analysis ◽  
Principal Stratification ◽  
Simulation Experiments ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Simulation Results ◽  
The Impact ◽  
Statistical Solutions ◽  
Very High

Abstract Objectives The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. “Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy.” BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

scholarly journals Covid-19 Vaccine Efficacy: Accuracy, Uncertainty and Projection of Cases

2020 ◽  
Author(s):  
Wenjiang Fu ◽  
Jieni Li ◽  
Paul Scheet
Keyword(s):  
Confidence Intervals ◽  
Vaccine Efficacy ◽  
Accuracy Assessment ◽  
Point Estimate ◽  
Societal Impact ◽  
Limited Information ◽  
Interim Report ◽  
Vaccine Candidates ◽  
Vaccine Trials ◽  
Point Estimates

ABSTRACTBackgroundTwo vaccine candidates for coronavirus disease 2019 (Covid-19) have been announced by Pfizer-BioNTech and Moderna with above 90% efficacy. The efficacy of each vaccine changes between reports with no accuracy assessment.MethodsWe examined data in both vaccine trials, provided 95% confidence intervals, and projected the cases that would be prevented in communities of multi-million population.ResultsThe 95% confidence intervals reveal that the true vaccine efficacy could be as low as 86% for stated efficacy of 94.4% in an interim report, indicating the inaccuracy and uncertainty of efficacy point estimate. Both vaccines achieve an efficacy above 89% by the 95% confidence interval in updated reports. The Moderna vaccine would prevent more than 50,260 cases in communities of 1 million people with 1 year exposure.ConclusionsPoint estimates of vaccine efficacy transmit limited information. Corresponding statements of uncertainty, such as confidence intervals, should be provided and included in discussions of societal impact. The Covid-19 vaccines announced to date would prevent a substantial number of cases even at lower ends of the intervals.

Acetaminophen: Neonatal hepatotoxicity due to late pregnancy exposure

1987 ◽  
Vol 45 ◽  
pp. 718-719
Author(s):  
G.A. Miranda ◽  
M.A. Arroyo ◽  
C.A. Lucio ◽  
M. Mongeotti ◽  
S.S. Poolsawat
Keyword(s):  
Low Dose ◽  
Fetal Liver ◽  
Late Pregnancy ◽  
Toxic Chemicals ◽  
Control Group ◽  
High Dose ◽  
Over The Counter ◽  
Liver And Kidney ◽  
Neonatal Liver ◽  
Childbearing Women

Exposure to drugs and toxic chemicals, during late pregnancy, is a common occurrence in childbearing women. Some studies have reported that more than 90% of pregnant women use at least 1 prescription; of this, 60% used more than one. Another study indicated that 80% of the consumed drugs were not prescribed, and of this figure, 95% were “over-the-counter” drugs. Acetaminophen, the safest of all over-the-counter drugs, has been reported to induce fetal liver necrosis in man and animals and to have abortifacient and embryocidal action in mice. This study examines the degree to which acetaminophen affects the neonatal liver and kidney, when a fatty diet is simultaneously fed to the mother during late pregnancy.Timed Swiss Webster female mice were gavaged during late pregnancy (days 16-19) with fat suspended acetaminophen at a high dose, HD = 84.50 mg/kg, and a low dose, LD = 42.25 mg/kg; a control group received fat alone.

Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

1990 ◽  
Vol 48 (3) ◽  
pp. 398-399
Author(s):  
A.M. Andrews ◽  
S.W. Wilson ◽  
A.C. Scallet ◽  
S.F. Ali ◽  
J. Bailey ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Rhesus Monkeys ◽  
Low Dose ◽  
Inhalation Exposure ◽  
Synaptic Cleft ◽  
High Dose ◽  
Withdrawal Time ◽  
Treatment Groups ◽  
Ultrastructural Evidence ◽  
Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

1991 ◽  
Vol 65 (05) ◽  
pp. 504-510 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
Walter Bernini ◽  
Guido Lazzerini ◽  
Giuliana Buti Strata ◽  
...  
Keyword(s):  
Platelet Function ◽  
Low Dose ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Stable Coronary Artery Disease ◽  
High Dose ◽  
Single Drug ◽  
Before And After ◽  
Serum Thromboxane ◽  
Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

1984 ◽  
Vol 52 (03) ◽  
pp. 276-280 ◽  
Author(s):  
Sam Schulman ◽  
Dieter Lockner ◽  
Kurt Bergström ◽  
Margareta Blombäck
Keyword(s):  
Deep Vein Thrombosis ◽  
Oral Anticoagulation ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Signs ◽  
Coagulation Factor ◽  
High Dose ◽  
Vein Thrombosis ◽  
Heparin Treatment ◽  
Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

Effects of Aspirin and Sulfinpyrazone on Thromboxane and Prostacyclin Synthesis in Rabbits

1979 ◽  
Author(s):  
J McDonald ◽  
A Cerskus ◽  
M Ali
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Low Dose ◽  
High Dose ◽  
Prostacyclin Synthesis

Arachidonic acid (AA) or collagen were infused into rabbits causing intravascular platelet aggregation with thrombocytopenia, hypotension and death. Thromboxane and prostacyclin synthesis were measured by radioimmunoassay of plasma TXB2 and 6-keto-PGF1α. The effects of pretreatement with aspirin (ASA) or sulfinpyrazone(SPZ) were assessed.Death in drug-treated rabbits was always associated with elevations of plasma TXB2(1-40 ng/ml) and of 6-keto-PGF1α(1-20 ng/ml). Collagen produced only small elevations of plasma TXB2 compared to AA but protection by ASA correlated better with inhibition of TXB2 and 6-keto-PGF1α synthesis than with inhibition of aggregation. Low dose ASA produced less inhibition of prostacyclin synthesis than high dose ASA but was less effective in preventing thromboxane synthesis and death.

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