A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections has continued to fuel the COVID-19 pandemic. To secure at least partial protection in the majority of the population through 1 dose of a COVID-19 vaccine, delayed administration of boosters has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may induce breakthrough infections due to intermittent lapses in protection. Optimizing vaccine dosing schedules to ensure prolonged continuity in protection could thus help control the pandemic. We developed a mechanistic model of immune response to vaccines as an in silico tool for dosing schedule optimization. The model was calibrated with clinical data sets of acquired immunity to COVID-19 mRNA vaccines in healthy and immunocompromised participants and showed robust validation by accurately predicting neutralizing antibody kinetics in response to multiple doses of COVID-19 mRNA vaccines. Importantly, by estimating population vulnerability to breakthrough infections, we predicted tailored vaccination dosing schedules to minimize breakthrough infections, especially for immunocompromised individuals. We identified that the optimal vaccination schedules vary from CDC-recommended dosing, suggesting that the model is a valuable tool to optimize vaccine efficacy outcomes during future outbreaks.

A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines has slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections continues to fuel the pandemic. As a strategy to secure at least partial protection, with a single dose of a given COVID-19 vaccine to maximum possible fraction of the population, delayed administration of subsequent doses (or boosters) has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may jeopardize the attainment of herd immunity due to intermittent lapses in protection. Optimizing vaccine dosing schedules could thus make the difference between periodic occurrence of breakthrough infections or effective control of the pandemic. To this end, we have developed a mechanistic mathematical model of adaptive immune response to vaccines and demonstrated its applicability to COVID-19 mRNA vaccines as a proof-of-concept for future outbreaks. The model was thoroughly calibrated against multiple clinical datasets involving immune response to SARS-CoV-2 infection and mRNA vaccines in healthy and immunocompromised subjects (cancer patients undergoing therapy); the model showed robust clinical validation by accurately predicting neutralizing antibody kinetics, a correlate of vaccine-induced protection, in response to multiple doses of mRNA vaccines. Importantly, we estimated population vulnerability to breakthrough infections and predicted tailored vaccination dosing schedules to maximize protection and thus minimize breakthrough infections, based on the immune status of a sub-population. We have identified a critical waiting window for cancer patients (or, immunocompromised subjects) to allow recovery of the immune system (particularly CD4+ T-cells) for effective differentiation of B-cells to produce neutralizing antibodies and thus achieve optimal vaccine efficacy against variants of concern, especially between the first and second doses. Also, we have obtained optimized dosing schedules for subsequent doses in healthy and immunocompromised subjects, which vary from the CDC-recommended schedules, to minimize breakthrough infections. The developed modeling tool is based on generalized adaptive immune response to antigens and can thus be leveraged to guide vaccine dosing schedules during future outbreaks.

Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following parameter quantification with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we ranked model parameters through sensitivity analysis for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination were simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy after infection.

Do Pandemics Obey the Elliott Wave Principle of Financial Markets?

The Elliott Wave principle is a time-honored, oft-used method for predicting variations in the financial markets. It is based on the notion that human emotions drive financial decisions. In the fight against COVID-19, human emotions are similarly decisive, for instance in that they determine one's willingness to be vaccinated, and/or to follow preventive measures including the wearing of masks, the application of social distancing protocols, and frequent handwashing. On this basis, we postulated that the Elliott Wave Principle may similarly be used to predict the future evolution of the COVID-19 pandemic. We demonstrated that this method reproduces the data pattern especially well for USA (daily new cases). Potential scenarios were then extrapolated, from the best-case corresponding to a rapid, full vaccination of the population, to the utterly disastrous case of slow vaccination, and poor adherence to preventive protocols.

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, physiologically-relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy following infection.

Racial and ethnic disparities in SARS-CoV-2 pandemic: analysis of a COVID-19 observational registry for a diverse US metropolitan population.

INTRODUCTION: Data on race and ethnic disparities for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. We analysed sociodemographic factors associated with higher likelihood of SARS-CoV-2 infection and explore mediating pathways for race and ethnic disparities in the SARS-CoV-2 pandemic. METHODS: This is a cross-sectional analysis of the COVID-19 Surveillance and Outcomes Registry, which captures data for a large healthcare system, comprising one central tertiary care hospital, seven large community hospitals and an expansive ambulatory/emergency care network in the Greater Houston area. Nasopharyngeal samples for individuals inclusive of all ages, races, ethnicities and sex were tested for SARS-CoV-2. We analysed sociodemographic (age, sex, race, ethnicity, household income, residence population density) and comorbidity (Charlson Comorbidity Index, hypertension, diabetes, obesity) factors. Multivariable logistic regression models were fitted to provide adjusted OR (aOR) and 95% CI for likelihood of a positive SARS-CoV-2 test. Structural equation modelling (SEM) framework was used to explore three mediation pathways (low income, high population density, high comorbidity burden) for the association between non-Hispanic black (NHB) race, Hispanic ethnicity and SARS-CoV-2 infection. RESULTS: Among 20 228 tested individuals, 1551 (7.7%) tested positive. The overall mean (SD) age was 51.1 (19.0) years, 62% were females, 22% were black and 18% were Hispanic. NHB and Hispanic ethnicity were associated with lower socioeconomic status and higher population density residence. In the fully adjusted model, NHB (vs non-Hispanic white; aOR, 2.23, CI 1.90 to 2.60) and Hispanic ethnicity (vs non-Hispanic; aOR, 1.95, CI 1.72 to 2.20) had a higher likelihood of infection. Older individuals and males were also at higher risk of infection. The SEM framework demonstrated a significant indirect effect of NHB and Hispanic ethnicity on SARS-CoV-2 infection mediated via a pathway including residence in densely populated zip code. CONCLUSIONS: There is strong evidence of race and ethnic disparities in the SARS-CoV-2 pandemic that are potentially mediated through unique social determinants of health.

Signal quality of single dose gadobenate dimeglumine pulmonary MRA examinations exceeds quality of MRA performed with double dose gadopentetate dimeglumine.

During a recent multi-center trial assessing gadolinium (Gd)-enhanced magnetic resonance angiography (MRA) for diagnosis of acute pulmonary embolism (PE), the Food and Drug Administration announced a risk of nephrogenic sclerosing fibrosis in patients with renal insufficiency who had received intravenous Gd-based MR contrast agents. Although no patients in this trial had renal insufficiency, in cautious response to this announcement, the trial protocol was changed from an intravenous administration of 0.2 mmol/Kg of a conventional Gd-based MR contrast agent to 0.1 mmol/Kg of gadobenate dimeglumine. The study described herein compares the signal quality of pulmonary MRA performed with double dose conventional agent to single dose gadobenate dimeglumine. This study is a retrospective analysis of data from a prospective, multicenter study in men and women ≥18 years with documented presence or absence of PE. The study was approved by the Institutional Review Board at all participating centers, and all patients provided written indication of informed consent. We performed both objective and subjective analysis of pulmonary artery image quality. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in the main pulmonary artery were assessed in single and double dose protocols and compared. SNR and CNR of the main PA were correlated with subjective quality assessment of main/lobar, segmental and subsegmental pulmonary arteries. Although there were individual outliers, both SNR (P = 0.01) and CNR (P = 0.008) were higher in all quartiles for examinations using gadobenate dimeglumine than with gadopentetate dimeglumine. Subjective quality of vascular signal intensity at each vessel order was significantly better for gadobenate dimeglumine (P < 0.0001), and correlated well with SNR and CNR at each order (<0.001). Because of agent high relaxivity, a single dose of gadobenate dimeglumine provides better pulmonary MRA signal quality than double dose of a conventional Gd-based MR contrast agent.

Comparison of 1.5 and 3.0 T for contrast-enhanced pulmonary magnetic resonance angiography.

OBJECTIVE: In a recent multi-center trial of gadolinium contrast-enhanced magnetic resonance angiography (Gd-MRA) for diagnosis of acute pulmonary embolism (PE), two centers utilized a common MRI platform though at different field strengths (1.5T and 3T) and realized a signal-to-noise gain with the 3T platform. This retrospective analysis investigates this gain in signal-to-noise of pulmonary vascular targets. METHODS: Thirty consecutive pulmonary MRA examinations acquired on a 1.5T system at one institution were compared to 30 consecutive pulmonary MRA examinations acquired on a 3T system at a different institution. Both systems were from the same MRI manufacturer and both used the same Gd-MRA pulse sequence, although there were some protocol adjustments made due to field strength differences. Region-of-interests were manually defined on the main pulmonary artery, 4 pulmonary veins, thoracic aorta, and background lung for objective measurement of signal-to-noise, contrast-to-noise, and bolus timing bias between centers. RESULTS: The 3T pulmonary MRA protocol achieved higher spatial resolution yet maintained significantly higher signal-to-noise ratio (≥13%, p = 0.03) in the main pulmonary vessels relative to 1.5T. There was no evidence of operator bias in bolus timing or patient hemodynamic differences between groups. CONCLUSION: Relative to 1.5T, higher spatial resolution Gd-MRA can be achieved at 3T with a sustained or greater signal-to-noise ratio of enhanced vasculature.

Factors in the technical quality of gadolinium enhanced magnetic resonance angiography for pulmonary embolism in PIOPED III.

In a multi-center trial, gadolinium enhanced magnetic resonance angiography (MRA) for diagnosis of acute pulmonary embolism (PE) had a high rate of technically inadequate images. Accordingly, we evaluated the reasons for poor quality MRA of the pulmonary arteries in these patients. We performed a retrospective analysis of the data collected in the PIOPED III study. We assessed the relationship to the proportion of examinations deemed "uninterpretable" by central readers to the clinical centers, MR equipment platform and vendors, degree of vascular opacification in different orders of pulmonary arteries; type, frequency and severity of image artifacts; patient co-morbidities, symptoms and signs; and reader characteristics. Centers, MR equipment vendor and platform, degree of vascular opacification, and motion artifacts influenced the likelihood of central reader determinations that images were "uninterpretable". Neither the reader nor patient characteristics (age, body mass index, respiratory rate, heart rate) correlated with the likelihood of determining examinations "uninterpretable". Vascular opacification and motion artifact are the principal factors influencing MRA interpretability. Some centers obtain better images more consistently, but the reasons for differences between centers are unclear.

Controversies in diagnosis of pulmonary embolism.

The approach to the diagnosis of acute pulmonary embolism (PE) is under constant revision with advances in technology, noninvasive approaches, and increasing awareness of the risks of ionizing radiation. Optimal approaches in some categories of patients are controversial. Data are insufficient for evidence-based recommendations. Therefore, this survey of investigators in the field was undertaken. Even among experts there were marked differences of opinion regarding the approach to the diagnosis of acute PE. Although CT pulmonary angiography was usually the imaging test of choice, the respondents were keenly aware of the dangers of ionizing radiation. In view of advances in scintigraphic diagnosis since the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) trial, ventilation/perfusion (V/Q) lung scans or perfusion scans alone and single photon emission computed tomography (SPECT) V/Q lung scans are often recommended. The choice depends on the patient's age, gender, and complexity of the findings on the plain chest radiograph.

Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III).

BACKGROUND: The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively. OBJECTIVE: To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism. DESIGN: Prospective, multicenter study from 10 April 2006 to 30 September 2008. SETTING: 7 hospitals and their emergency services. PATIENTS: 371 adults with diagnosed or excluded pulmonary embolism. MEASUREMENTS: Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment. RESULTS: Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results. LIMITATION: A high proportion of patients with suspected embolism was not eligible or declined to participate. CONCLUSION: Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures.

CT venous phase venography with 64-detector CT angiography in the diagnosis of acute pulmonary embolism.

The value of computed tomographic (CT) venography in combination with CT pulmonary angiography has been questioned because of the potential dangers of radiation. Accordingly, we retrospectively evaluated the diagnostic yield of 64-detector CT angiography with CT venography. Among patients who routinely underwent CT venography with CT angiography, the CT angiogram showed acute pulmonary embolism (PE) in 206 of 1903 patients (10.8%). A positive CT venogram in a patient with a negative CT angiogram was shown in 25 of 1903 patients (1.3%). Either the CT angiogram or the CT venogram showed venous thromboembolism in 231 of 1903 patients (12.1%). The proportion of patients with venous thromboembolism diagnosed only by a CT venogram was 25 of 231 (10.8%). In conclusion, the proportion of patients with venous thromboembolism diagnosed only by a CT venogram is sufficiently high to merit consideration of its use especially in those at high risk for DVT.

SPECT in acute pulmonary embolism.

The purpose of this review was to evaluate the accuracy of SPECT in acute pulmonary embolism. Sparse data are available on the accuracy of SPECT based on an objective reference test. Several investigations were reported in which the reference standard for the diagnosis of pulmonary embolism was based in part on the results of SPECT or planar ventilation-perfusion (V/Q) imaging. The sensitivity of SPECT in all but one investigation was at least 90%, and specificity also was generally at least 90%. The sensitivity of SPECT in 4 of 5 investigations was higher than that of planar V/Q imaging. The specificity of SPECT was generally higher, equal, or only somewhat lower than that of planar V/Q imaging. Most investigators reported nondiagnostic SPECT V/Q scans in no more than 3% of cases. Methods of obtaining SPECT images, methods of obtaining planar V/Q images, and the criteria for interpretation varied. The general impression is that SPECT is more advantageous than planar V/Q imaging.

Diagnosis of pulmonary embolism in the coronary care unit.

The clinical diagnosis of pulmonary embolism (PE) is difficult in coronary care units (CCUs) because many findings of PE are similar to those of acute coronary syndromes and heart failure. Immobilization of only 1 or 2 days may predispose to PE. Heart failure and acute myocardial infarction add to the risk. Dyspnea may be absent or occur only with exertion. The onset of dyspnea may occur over seconds to days. Orthopnea occurs with PE as well as heart failure. When the clinical probability and results of objective testing are discordant, the posttest probability of PE may be neither sufficiently high nor sufficiently low to permit therapeutic decisions. Objective scoring systems for clinical assessment have not been developed for patients in a CCU. d-dimer is likely to be of little value for the exclusion of PE in CCUs, because elevations occur with heart failure, unstable angina, and myocardial infarction. Computed tomographic pulmonary angiography with venous phase imaging of the low pelvic and proximal leg veins (computed tomographic venography) is recommended for imaging. Scintigraphy in women aged <50 years with normal or nearly normal results on chest x-ray may be the preferred imaging test to reduce the risk for radiation. Echocardiography with leg ultrasonography is a rapidly obtainable combination of bedside tests that may be useful for young patients and patients in extremis. In conclusion, the choice of diagnostic test depends on the clinical probability of PE, the condition of the patient, the availability of diagnostic tests, the risks of iodinated contrast material, radiation exposure, and cost.

Reconstructed 4-chamber views compared with axial imaging for assessment of right ventricular enlargement on CT pulmonary angiograms.

PURPOSE: To test the hypothesis that right enlargement assessed from right ventricular/left ventricular (RV/LV) dimension ratios of computed tomographic (CT) angiograms are equivalent irrespective of whether measured on axial views or reconstructed 4-chamber views. METHODS: RV/LV dimension ratios were calculated from measurements on axial views, manually reconstructed 4-chamber views and computer generated reconstructed 4-chamber views of CT angiograms in 152 patients with PE. RESULTS: Paired readings of the axial view and manually reconstructed 4-chamber view showed agreement with RV/LV > or =1 or RV/LV <1 in 114 of 127 (89.8%). Paired readings also showed agreement in 119 of 127 (93.7%) with axial views and computer generated reconstructed 4-chamber views. The McNemar test showed no statistically significant difference between assessments of RV enlargement (RV/LV > or = 1) with any method. CONCLUSION: Right ventricular enlargement can be determined from axial views on CT angiograms, which are readily and immediately available, without obtaining 4-chamber reconstructed views.