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Register a new userApplication of Quantitative Systems Pharmacology to guide the optimal dosing of COVID-19 vaccines
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Optimal use and distribution of Covid-19 vaccines involves adjustments of dosing. Due to the rapidly-evolving pandemic, such adjustments often need to be introduced before full efficacy data are available. As demonstrated in other areas of drug development, quantitative systems pharmacology (QSP) is well placed to guide such extrapolation in a rational and timely manner. Here we propose for the first time how QSP can be applied real time in the context of COVID-19 vaccine development.
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SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this, outbreak specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. Here, we present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS- CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. UISS is then potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2.
In this paper we propose a novel SEIR stochastic epidemic model. A distinguishing feature of this new model is that it allows us to consider a set up under general latency and infectious period distributions. To some extent, queuing systems with infinitely many servers and a Markov chain with time-varying transition rate are the very technical underpinning of the paper. Although more general, the Markov chain is as tractable as previous models for exponentially distributed latency and infection periods. It is also significantly simpler and more tractable than semi-Markov models with a similar level of generality. Based on the notion of stochastic stability, we derive a sufficient condition for a shrinking epidemic in terms of the queuing systems occupation rate that drives the dynamics. Relying on this condition, we propose a class of ad-hoc stabilising mitigation strategies that seek to keep a balanced occupation rate after a prescribed mitigation-free period. We validate the approach in the light of recent data on the COVID-19 epidemic and assess the effect of different stabilising strategies. The results suggest that it is possible to curb the epidemic with various occupation rate levels, as long as the mitigation is not excessively procrastinated.
Antibody therapeutics and vaccines are among our last resort to end the raging COVID-19 pandemic. They, however, are prone to over 5,000 mutations on the spike (S) protein uncovered by a Mutation Tracker based on over 200,000 genome isolates. It is imperative to understand how mutations would impact vaccines and antibodies in the development. In this work, we study the mechanism, frequency, and ratio of mutations on the S protein. Additionally, we use 56 antibody structures and analyze their 2D and 3D characteristics. Moreover, we predict the mutation-induced binding free energy (BFE) changes for the complexes of S protein and antibodies or ACE2. By integrating genetics, biophysics, deep learning, and algebraic topology, we reveal that most of 462 mutations on the receptor-binding domain (RBD) will weaken the binding of S protein and antibodies and disrupt the efficacy and reliability of antibody therapies and vaccines. A list of 31 vaccine escape mutants is identified, while many other disruptive mutations are detailed as well. We also unveil that about 65% existing RBD mutations, including those variants recently found in the United Kingdom (UK) and South Africa, are binding-strengthen mutations, resulting in more infectious COVID-19 variants. We discover the disparity between the extreme values of RBD mutation-induced BFE strengthening and weakening of the bindings with antibodies and ACE2, suggesting that SARS-CoV-2 is at an advanced stage of evolution for human infection, while the human immune system is able to produce optimized antibodies. This discovery implies the vulnerability of current vaccines and antibody drugs to new mutations. Our predictions were validated by comparison with more than 1,400 deep mutations on the S protein RBD. Our results show the urgent need to develop new mutation-resistant vaccines and antibodies and to prepare for seasonal vaccinations.
From the moment the first COVID-19 vaccines are rolled out, there will need to be a large fraction of the global population ready in line. It is therefore crucial to start managing the growing global hesitancy to any such COVID-19 vaccine. The current approach of trying to convince the nos cannot work quickly enough, nor can the current policy of trying to find, remove and/or rebut all the individual pieces of COVID and vaccine misinformation. Instead, we show how this can be done in a simpler way by moving away from chasing misinformation content and focusing instead on managing the yes--no--not-sure hesitancy ecosystem.
We analyze risk factors correlated with the initial transmission growth rate of the recent COVID-19 pandemic in different countries. The number of cases follows in its early stages an almost exponential expansion; we chose as a starting point in each country the first day $d_i$ with 30 cases and we fitted for 12 days, capturing thus the early exponential growth. We looked then for linear correlations of the exponents $alpha$ with other variables, for a sample of 126 countries. We find a positive correlation, {it i.e. faster spread of COVID-19}, with high confidence level with the following variables, with respective $p$-value: low Temperature ($4cdot10^{-7}$), high ratio of old vs.~working-age people ($3cdot10^{-6}$), life expectancy ($8cdot10^{-6}$), number of international tourists ($1cdot10^{-5}$), earlier epidemic starting date $d_i$ ($2cdot10^{-5}$), high level of physical contact in greeting habits ($6 cdot 10^{-5}$), lung cancer prevalence ($6 cdot 10^{-5}$), obesity in males ($1 cdot 10^{-4}$), share of population in urban areas ($2cdot10^{-4}$), cancer prevalence ($3 cdot 10^{-4}$), alcohol consumption ($0.0019$), daily smoking prevalence ($0.0036$), UV index ($0.004$, 73 countries). We also find a correlation with low Vitamin D levels ($0.002-0.006$, smaller sample, $sim 50$ countries, to be confirmed on a larger sample). There is highly significant correlation also with blood types: positive correlation with types RH- ($3cdot10^{-5}$) and A+ ($3cdot10^{-3}$), negative correlation with B+ ($2cdot10^{-4}$). Several of the above variables are intercorrelated and likely to have common interpretations. We performed a Principal Component Analysis, in order to find their significant independent linear combinations. We also analyzed a possible bias: countries with low GDP-per capita might have less testing and we discuss correlation with the above variables.
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