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.

Genetic and Structural Analysis of SARS-CoV-2 Spike Protein for Universal Epitope Selection.

Evaluation of immunogenic epitopes for universal vaccine development in the face of ongoing SARS-CoV-2 evolution remains a challenge. Herein, we investigate the genetic and structural conservation of an immunogenically relevant epitope (C662-C671) of spike (S) protein across SARS-CoV-2 variants to determine its potential utility as a broad-spectrum vaccine candidate against coronavirus diseases. Comparative sequence analysis, structural assessment, and molecular dynamics simulations of C662-C671 epitope were performed. Mathematical tools were employed to determine its mutational cost. We found that the amino acid sequence of C662-C671 epitope is entirely conserved across the observed major variants of SARS-CoV-2 in addition to SARS-CoV. Its conformation and accessibility are predicted to be conserved, even in the highly mutated Omicron variant. Costly mutational rate in the context of energy expenditure in genome replication and translation can explain this strict conservation. These observations may herald an approach to developing vaccine candidates for universal protection against emergent variants of coronavirus.

Is the worst of the COVID-19 global pandemic yet to come? Application of financial mathematics as candidate predictive tools.

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 the COVID-19 global pandemic, 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 personal 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 for various countries and the world (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, 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.