Mathematical Modeling of Vaccines That Prevent SARS-CoV-2 Transmission

SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.

Download Full-text

Vaccines that prevent SARS-CoV-2 transmission may prevent or dampen a spring wave of COVID-19 cases and deaths in 2021

10.1101/2020.12.13.20248120 ◽

2020 ◽

Author(s):

David A. Swan ◽

Ashish Goyal ◽

Chloe Bracis ◽

Mia Moore ◽

Elizabeth Krantz ◽

...

Keyword(s):

Viral Load ◽

Vaccine Efficacy ◽

Breakthrough Infection ◽

Vaccine Trials ◽

Peak Viral Load ◽

Waning Immunity ◽

Protection Against Infection ◽

Mediated Reduction ◽

Epidemic Wave ◽

Roll Out

Ongoing SARS-CoV-2 vaccine trials assess vaccine efficacy against disease (VEDIS), the ability of a vaccine to block symptomatic COVID-19. They will only partially discriminate whether VEDIS is mediated by preventing infection as defined by the detection of virus in the airways (vaccine efficacy against infection defined as VESUSC), or by preventing symptoms despite breakthrough infection (vaccine efficacy against symptoms or VESYMP). Vaccine efficacy against infectiousness (VEINF), defined as the decrease in secondary transmissions from infected vaccine recipients versus from infected placebo recipients, is also not being measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna and Pfizer vaccines, which have observed VEDIS>90%, mediate VEDIS predominately by complete protection against infection, then prevention of a fourth epidemic wave in the spring of 2021, and associated reduction of subsequent cases and deaths by 60%, is likely to occur assuming rapid enough vaccine roll out. If high VEDIS is explained primarily by reduction in symptoms, then VEINF>50% will be necessary to prevent or limit the extent of this fourth epidemic wave. The potential added benefits of high VEINF would be evident regardless of vaccine allocation strategy and would be enhanced if vaccine roll out rate is low or if available vaccines demonstrate waning immunity. Finally, we demonstrate that a 1.0 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve VEINF=60% and that human challenge studies with 104 infected participants, or clinical trials in a university student population could estimate VESUSC, VESYMP and VEINF using viral load metrics.

Download Full-text

Faculty Opinions recommendation of The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718520402.793498145 ◽

2014 ◽

Author(s):

Chris Robertson

Keyword(s):

Clinical Trials ◽

Vaccine Efficacy ◽

Gold Standard ◽

Controlled Clinical Trials ◽

Accuracy And Precision

Download Full-text

COVID-19: Are Experimental Drugs Cure or Ill?

Current Drug Safety ◽

10.2174/1574886316666210727150127 ◽

2021 ◽

Vol 16 ◽

Author(s):

Bensu Karahalil ◽

Aylin Elkama

Keyword(s):

Clinical Trials ◽

Severe Acute Respiratory Syndrome ◽

Adverse Effects ◽

Antiviral Treatment ◽

Herd Immunity ◽

Mortality Rates ◽

Death Rates ◽

Experimental Drugs ◽

Combined Use ◽

The World

Background: Coronavirus disease 2019 (COVID-19) is a new strain of coronavirus. It is characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has quickly influenced all over the world since it spreads easily. Common symptoms are fever, cough, difficulty in breathing and muscle aches. Despite the urgent need to find an effective antiviral treatment, already available agents are being used alone or in combination all over the world. At the beginning of the pandemic, death rates of infection caused by COVID-19 are high but "is COVID-19 responsible for all deaths?", or “are there any contributions of the frequently used drugs in this period to these deaths?” Surely herd immunity plays a major role and has the contribution in the decline in mortality rates. Meanwhile, it is kept in mind that due to safety concerns, changes have also been made to the dosage and combined use of frequently used drugs. Objective: In this review, answers to two questions above and the safety of treatments, toxicities of agents involving chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopiravir/ritonavir, sarilumab, tocilizumab, siltuximab, corticosteroids and bromhexine which are the most frequently used in both Turkey and all over the world will be summarized. Conclusion: Among these drugs favipiravir seems the most promising drug due to more tolerable adverse effects. More clinical trials with large sample sizes are needed to find the most effective and safe drug for COVID-19 treatment.

Download Full-text

Will the Large-scale Vaccination Succeed in Containing the COVID-19 Epidemic and How Soon?

10.1101/2021.04.16.21255543 ◽

2021 ◽

Author(s):

Shilei Zhao ◽

Tong Sha ◽

Yongbiao Xue ◽

Chung-I Wu ◽

Hua Chen

Keyword(s):

United States Of America ◽

Vaccine Efficacy ◽

Large Scale ◽

Herd Immunity ◽

Vaccination Rate ◽

Epidemic Dynamics ◽

Intervention Measures ◽

Vaccination Scheme ◽

Mutant Strains ◽

Promising Solution

The availability of vaccines provides a promising solution to containing the COVID-19 pandemic. Here, we develop an epidemiological model to quantitatively analyze and predict the epidemic dynamics of COVID-19 under vaccination. The model is applied to the daily released numbers of confirmed cases of Israel and United States of America to explore and predict the trend under vaccination based on their current epidemic status and intervention measures. For Israel, of which 53.83% of the population was fully vaccinated, under the current intensity of NPIs and vaccination scheme, the pandemic is predicted to end between May 14, 2021 to May 16, 2021 depending on an immunity duration between 180 days and 365 days; Assuming no NPIs after March 24, 2021, the pandemic will ends later, between July 4, 2021 to August 26, 2021. For USA, if we assume the current vaccination rate (0.268% per day) and intensity of NPIs, the pandemic will end between February 3, 2022 and August 17, 2029 depending on an immunity duration between 180 days and 365 days. However, assuming an immunity duration of 180 days and with no NPIs, the pandemic will not end, and instead reach an equilibrium state with a proportion of the population remaining actively infected. Overall the daily vaccination rate should be chosen according to the vaccine efficacy and the immunity duration to achieve herd immunity. In some situations, vaccination alone cannot stop the pandemic, and NPIs are necessary both to supplement vaccination and accelerate the end of the pandemic. Considering that vaccine efficacy and duration of immunity may be reduced for new mutant strains, it is necessary to remain cautiously optimistic about the prospect of the pandemic under vaccination.

Download Full-text

Complementary role of mathematical modeling in preclinical glioblastoma: differentiating poor drug delivery from drug insensitivity

10.1101/2021.12.07.471540 ◽

2021 ◽

Author(s):

Javier C. Urcuyo ◽

Susan Christine Massey ◽

Andrea Hawkins-Daarud ◽

Bianca-Maria Marin ◽

Danielle M. Burgenske ◽

...

Keyword(s):

Mathematical Modeling ◽

Drug Delivery ◽

Clinical Trials ◽

Treatment Response ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Significant Heterogeneity ◽

Current Standard ◽

Modeling Approach ◽

Blood Brain

AbstractGlioblastoma is the most malignant primary brain tumor with significant heterogeneity and a limited number of effective therapeutic options. Many investigational targeted therapies have failed in clinical trials, but it remains unclear if this results from insensitivity to therapy or poor drug delivery across the blood-brain barrier. Using well-established EGFR-amplified patient-derived xenograft (PDX) cell lines, we investigated this question using an EGFR-directed therapy. With only bioluminescence imaging, we used a mathematical model to quantify the heterogeneous treatment response across the three PDX lines (GBM6, GBM12, GBM39). Our model estimated the primary cause of intracranial treatment response for each of the lines, and these findings were validated with parallel experimental efforts. This mathematical modeling approach can be used as a useful complementary tool that can be widely applied to many more PDX lines. This has the potential to further inform experimental efforts and reduce the cost and time necessary to make experimental conclusions.Author summaryGlioblastoma is a deadly brain cancer that is difficult to treat. New therapies often fail to surpass the current standard of care during clinical trials. This can be attributed to both the vast heterogeneity of the disease and the blood-brain barrier, which may or may not be disrupted in various regions of tumors. Thus, while some cancer cells may develop insensitivity in the presence of a drug due to heterogeneity, other tumor areas are simply not exposed to the drug. Being able to understand to what extent each of these is driving clinical trial results in individuals may be key to advancing novel therapies. To address this challenge, we used mathematical modeling to study the differences between three patient-derived tumors in mice. With our unique approach, we identified the reason for treatment failure in each patient tumor. These results were validated through rigorous and time-consuming experiments, but our mathematical modeling approach allows for a cheaper, quicker, and widely applicable way to come to similar conclusions.

Download Full-text

Demographics, perceptions, and socioeconomic factors affecting influenza vaccination among adults in the United States

PeerJ ◽

10.7717/peerj.5171 ◽

2018 ◽

Vol 6 ◽

pp. e5171 ◽

Cited By ~ 17

Author(s):

Kaja M. Abbas ◽

Gloria J. Kang ◽

Daniel Chen ◽

Stephen R. Werre ◽

Achla Marathe

Keyword(s):

United States ◽

Health Insurance ◽

Influenza Vaccination ◽

Vaccine Efficacy ◽

Herd Immunity ◽

The United States ◽

Vaccine Cost ◽

Factors Affecting ◽

Vaccination Rates ◽

Healthy People 2020

Objective The study objective is to analyze influenza vaccination status by demographic factors, perceived vaccine efficacy, social influence, herd immunity, vaccine cost, health insurance status, and barriers to influenza vaccination among adults 18 years and older in the United States. Background Influenza vaccination coverage among adults 18 years and older was 41% during 2010–2011 and has increased and plateaued at 43% during 2016–2017. This is below the target of 70% influenza vaccination coverage among adults, which is an objective of the Healthy People 2020 initiative. Methods We conducted a survey of a nationally representative sample of adults 18 years and older in the United States on factors affecting influenza vaccination. We conducted bivariate analysis using Rao-Scott chi-square test and multivariate analysis using weighted multinomial logistic regression of this survey data to determine the effect of demographics, perceived vaccine efficacy, social influence, herd immunity, vaccine cost, health insurance, and barriers associated with influenza vaccination uptake among adults in the United States. Results Influenza vaccination rates are relatively high among adults in older age groups (73.3% among 75 + year old), adults with education levels of bachelor’s degree or higher (45.1%), non-Hispanic Whites (41.8%), adults with higher incomes (52.8% among adults with income of over $150,000), partnered adults (43.2%), non-working adults (46.2%), and adults with internet access (39.9%). Influenza vaccine is taken every year by 76% of adults who perceive that the vaccine is very effective, 64.2% of adults who are socially influenced by others, and 41.8% of adults with health insurance, while 72.3% of adults without health insurance never get vaccinated. Facilitators for adults getting vaccinated every year in comparison to only some years include older age, perception of high vaccine effectiveness, higher income and no out-of-pocket payments. Barriers for adults never getting vaccinated in comparison to only some years include lack of health insurance, disliking of shots, perception of low vaccine effectiveness, low perception of risk for influenza infection, and perception of risky side effects. Conclusion Influenza vaccination rates among adults in the United States can be improved towards the Healthy People 2020 target of 70% by increasing awareness of the safety, efficacy and need for influenza vaccination, leveraging the practices and principles of commercial and social marketing to improve vaccine trust, confidence and acceptance, and lowering out-of-pocket expenses and covering influenza vaccination costs through health insurance.

Download Full-text

Epidemiological Impact of SARS-CoV-2 Vaccination: Mathematical Modeling Analyses

Vaccines ◽

10.3390/vaccines8040668 ◽

2020 ◽

Vol 8 (4) ◽

pp. 668 ◽

Cited By ~ 2

Author(s):

Monia Makhoul ◽

Houssein H. Ayoub ◽

Hiam Chemaitelly ◽

Shaheen Seedat ◽

Ghina R. Mumtaz ◽

...

Keyword(s):

Mathematical Modeling ◽

Vaccine Development ◽

Severe Disease ◽

Herd Immunity ◽

Social Contact ◽

Population Level ◽

Contact Rate ◽

Disease Case ◽

Major Outbreak ◽

Vaccine Impact

This study aims to inform SARS-CoV-2 vaccine development/licensure/decision-making/implementation, using mathematical modeling, by determining key preferred vaccine product characteristics and associated population-level impacts of a vaccine eliciting long-term protection. A prophylactic vaccine with efficacy against acquisition (VES) ≥70% can eliminate the infection. A vaccine with VES <70% may still control the infection if it reduces infectiousness or infection duration among those vaccinated who acquire the infection, if it is supplemented with <20% reduction in contact rate, or if it is complemented with herd-immunity. At VES of 50%, the number of vaccinated persons needed to avert one infection is 2.4, and the number is 25.5 to avert one severe disease case, 33.2 to avert one critical disease case, and 65.1 to avert one death. The probability of a major outbreak is zero at VES ≥70% regardless of the number of virus introductions. However, an increase in social contact rate among those vaccinated (behavior compensation) can undermine vaccine impact. In addition to the reduction in infection acquisition, developers should assess the natural history and disease progression outcomes when evaluating vaccine impact.

Download Full-text