Pandemic influenza poses a constant threat to domestic and global public health with the potential of high morbidity and mortality. Pandemic virus-matched vaccines, though potentially highly efficacious, require a lead time before they can be mass-produced and distributed to the population. For this reason, mitigation strategies that provide protection ahead of widespread viral transmission are highly desirable. Here, we model the impact of a broadly cross-reactive seasonal influenza vaccine on pandemic influenza spread in the U.S. Our findings indicate that as the cross-protective efficacy of the seasonal vaccine against the pandemic variant increases, total hospitalizations are concomitantly reduced. For example, we find that even at typical seasonal vaccine uptake and modest vaccine efficacies against infection and hospitalization with the pandemic variant, total hospitalizations can be decreased by 30% or more across the scenarios considered. In addition, the hospitalization risk for recipients is at least 35% lower than the risk experienced by unvaccinated persons. These results demonstrate that a broadly protective influenza vaccine could serve as a critical component of pandemic preparedness strategies.

Introduction Emerging infectious diseases (EIDs) cause significant health and economic burdens in the USA and globally. Existing methods and analyses fall short of what is required to prioritise diseases for health technology research and development (R&D), including for medical countermeasure (MCM) development within rapid response frameworks by the Center for Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services.Methods We developed a method for quantifying and ranking health and economic disease burdens (‘full burdens’) and applied it to 15 high-priority EIDs for 223 countries and territories, including the USA and US territories, historically from 2000 to 2022 and prospectively from 2025 to 2034. Health burdens consisted of disability-adjusted life-year losses, converted into monetary values using the value of a statistical life-year. Economic burdens consisted of direct and indirect costs during the acute stage of illness for hospitalised cases. We computed unweighted and weighted burden measures, the latter controlling for global disparities in ability-to-pay to avoid EID burdens. We projected future disease burdens using Monte Carlo simulation.Results Pandemics caused the largest historical and projected unweighted and weighted full burdens in the USA and globally. Among non-pandemics, across unweighted and weighted burdens, dengue and cholera imposed the largest historical and projected full burdens globally; West Nile Virus imposed the largest historical and projected full burdens in the USA, and dengue imposed the largest historical full burdens in the US territories. Weighted full burdens exceeded five times the unweighted ones. Regionally, the Americas and Africa faced the largest per capita weighted burdens while the Western Pacific region faced the smallest.Conclusion R&D priority-setting, including MCM development, depends on multiple criteria, including disease burdens. Our full burden quantification methods and results, along with other such criteria, can inform optimal priority-setting.

To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic-viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose-response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12-24 hours post symptom onset, the predicted transmission mitigation was 39.9-56.4% for baloxavir and 26.6-38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36-48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8-28.3% for baloxavir and 0.8-19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed-some animals exhibited large fluctuations in viral load after cART cessation-the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

Introduction. Timely availability of effective influenza vaccine will be critical to mitigate the next influenza pandemic. The mission of Biomedical Advanced Research and Development Authority (BARDA) is to develop medical countermeasures against pandemics, including influenza and other health security threats.Areas covered. Despite considerable gains in pandemic vaccine preparedness since 2009, old and new challenges threaten the pandemic influenza response capabilities of the U.S. Government: insufficient U.S.-based vaccine production, two-dose vaccination regimen, logistically complex adjuvanted formulation, and sustained surge manufacturing capacity despite no commercial market for pandemic vaccines. Although the coronavirus disease 2019 (COVID-19) pandemic has re-exposed these gaps in preparedness and response, previous investments into flexible influenza vaccine technologies proved to be critical to accelerate COVID-19 vaccine development.Expert opinion. BARDA addresses these challenges by implementing a pandemic influenza vaccine strategy with two key goals: 1) accelerating vaccine development and production (faster) and 2) improving vaccine performance (better). This strategy involves an end-to-end approach, including increasing manufacturing and fill-finish capacity; improving release testing speed; and funding clinical trials to improve current vaccine utilization. As demonstrated by the COVID-19 response, continued investments into this pandemic influenza vaccine strategy will further enhance the ability to respond to future emerging pandemic pathogens.

This cohort study evaluates the first 22 months of implementation of the Cherokee Nation Heath Services community-based program designed to eliminate hepatitis C virus (HCV) infection.

In addition to physical ailments and the possibility of viral persistence in reproductive organs, female Ebola survivors face significant stigma and associated psychological health issues. Programs to meet the varied reproductive health needs of female Ebola survivors are critical, but lack historical models. This chapter, therefore, identifies successful programs to address the needs of young adult women with other communicable diseases, namely HIV and hepatitis. First, Ebola survivors’ risk of transmission is addressed by reporting the current knowledge of transmission potential among female Ebola survivors and programs to prevent transmission for other chronic viral infections. Subsequently, the chapter presents programs intended to educate the broader community about HIV and hepatitis and to offer support for those infected. Recent efforts to help Ebola survivors in Liberia are then described, focusing on the experiences of pregnant Ebola survivors and the PREVAIL Natural History Study and birth cohort study. Finally, the chapter supplies recommendations to utilize available information about Ebola and other infections to prevent transmission and to provide education and support for female Ebola survivors. These recommendations include the provision of public awareness and education campaigns, guidance regarding reproductive choices, medical precautions and protocols, supportive environments, and therapeutic relationships with health care practitioners and peer mentors.

Background Oral pre-exposure prophylaxis (PrEP) prevents HIV infection in men who have sex with men (MSM); however, adherence is an ongoing concern. Long-acting injectable PrEP is being tested in phase 3 trials and could address challenges associated with adherence. We examined the potential effectiveness of long-acting injectable PrEP compared with oral PrEP in MSM. Methods We used an agent-based model to simulate HIV transmission in a dynamic network of 11 245 MSM in Atlanta, GA, USA. We used raw data from studies in macaque models and pharmacokinetic data from safety trials to estimate the time-varying efficacy of long-acting injectable PrEP. The effect of long-acting injectable PrEP on the cumulative number of new HIV infections over 10 years (2015-24) was compared with no PrEP and daily oral PrEP across a range of coverage levels. Sensitivity analyses were done with varying maximum efficacy and drug half-life values. Findings In the absence of PrEP, the model predicted 2374 new HIV infections (95% simulation interval [SI] 2345-2412) between 2015 and 2024. The cumulative number of new HIV infections was reduced in all scenarios in which MSM received long-acting injectable PrEP compared with oral PrEP. At a coverage level of 35%, compared with no PrEP, long-acting injectable PrEP led to a 44% reduction in new HIV infections (1044 new infections averted [95% SI 1018-1077]) versus 33% (792 infections averted [763-821]) for oral PrEP. The relative benefit of long-acting injectable PrEP was sensitive to the assumed efficacy of injections received every 8 weeks, discontinuation rates, and terminal drug half-life. Interpretation Long-acting injectable PrEP has the potential to produce larger reductions in HIV transmission in MSM than oral PrEP. However, the real-world, population-level impact of this approach will depend on uptake of this prevention method and its effectiveness, as well as retention of patients in clinical care. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

Background. While the 2015-2016 Zika epidemics prompted accelerated vaccine development, decision makers need to know the potential economic value of vaccination strategies. Methods. We developed models of Honduras, Brazil, and Puerto Rico, simulated targeting different populations for Zika vaccination (women of childbearing age, school-aged children, young adults, and everyone) and then introduced various Zika outbreaks. Sensitivity analyses varied vaccine characteristics. Results. With a 2% attack rate ($5 vaccination), compared to no vaccination, vaccinating women of childbearing age cost $314-$1664 per case averted ($790-$4221/disability-adjusted life-year [DALY] averted) in Honduras, and saved $847-$1644/case averted in Brazil, and $3648-$4177/case averted in Puerto Rico, varying with vaccination coverage and efficacy (societal perspective). Vaccinating school-aged children cost $718-$1849/case averted (<=$5002/DALY averted) in Honduras, saved $819-$1609/case averted in Brazil, and saved $3823-$4360/case averted in Puerto Rico. Vaccinating young adults cost $310-$1666/case averted ($731-$4017/DALY averted) in Honduras, saved $953-$1703/case averted in Brazil, and saved $3857-$4372/case averted in Puerto Rico. Vaccinating everyone averted more cases but cost more, decreasing cost savings per case averted. Vaccination resulted in more cost savings and better outcomes at higher attack rates. Conclusions. When considering transmission, while vaccinating everyone naturally averted the most cases, specifically targeting women of childbearing age or young adults was the most cost-effective.

Introduction Schistosomiasis is a chronic parasitic trematode disease that affects over 240 million people worldwide. The Schistosoma lifecycle is complex, involving transmission via specific intermediate-host freshwater snails. Predictive mathematical models of Schistosoma transmission have often chosen to simplify or ignore the details of environmental human-snail interaction in their analyses. Schistosome transmission models now aim to provide better precision for policy planning of elimination of transmission. This heightens the importance of including the environmental complexity of vector-pathogen interaction in order to make more accurate projections. Methodology and principal findings We propose a nonlinear snail force of infection (FOI) that takes into account an intermediate larval stage (miracidium) and snail biology. We focused, in particular, on the effects of snail force of infection (FOI) on the impact of mass drug administration (MDA) in human communities. The proposed (modified) model was compared to a conventional model in terms of their predictions. A longitudinal dataset generated in Kenya field studies was used for model calibration and validation. For each sample community, we calibrated modified and conventional model systems, then used them to model outcomes for a range of MDA regimens. In most cases, the modified model predicted more vigorous post-MDA rebound, with faster relapse to baseline levels of infection. The effect was pronounced in higher risk communities. When compared to observed data, only the modified system was able to successfully predict persistent rebound of Schistosoma infection. Conclusion and significance The observed impact of varying location-specific snail inputs sheds light on the diverse MDA response patterns noted in operational research on schistosomiasis control, such as the recent SCORE project. Efficiency of human-to-snail transmission is likely to be much higher than predicted by standard models, which, in practice, will make local elimination by implementation of MDA alone highly unlikely, even over a multi-decade period.

On June 1, 2017, the Healthy California Act was approved by the California Senate to establish universal, single-payer coverage to California residents in an effort to improve access to and efficiency in health care. Universal health care would extend coverage to the 14.7 million Californians currently uninsured or underinsured; however, political hesitation remains regarding the feasibility of universal health care at both the state and federal levels. This article proposes a model for universal coverage combined with a single-payer financial system in the state of California. Universal health care ensures continuous access to health services regardless of preexisting conditions and economic situation. Economic benefits to implementing universal health care include enhanced productivity from a healthier workforce, universal screening for costly chronic conditions such as colorectal cancer, and reduction in individuals filing for bankruptcy due to medical expenses. Universal single-payer health care is projected to reduce health care spending by $37.5 billion annually in California. The proposed plan can increase quality of care at a reduced cost compared with private insurance plans through 3 mechanisms. First, the proposed model increases incentives for preventive care by removing the potential for customers to move between insurers and thus avoids a systemic undervaluation of prevention stemming from downstream benefits not benefiting the initial private insurer. Second, administrative costs that currently account for 25% of US hospital expenditures can be significantly reduced through streamlined payment processes and consolidated bureaucratic functions. Third, California as a unified purchaser of health care will have increased negotiating power with pharmaceutical companies. Opposition to universal health care contends that quality and efficiency will erode with government involvement, and individual choices will be restricted. Despite the fact that the United States has the highest per-capita health expenditure in the world, 34 other countries that provide a form of universal health care score higher than the United States on the Health Access and Quality Index, a metric that quantifies amenable mortality. While it is necessarily true that there is less choice in selecting an insurer, billing and insurance-related expenses are shown to be 6 times higher for private insurance than for public programs such as Medicare and Medicaid. Troubling trends such as soaring premiums, expenditures, and an emerging mental health epidemic show that there is room for improvement in our current privatized health care system. Popularity of single-payer health care is currently increasing on a national scale, and should a model such as the one proposed here be implemented in California, it would likely be transformational for other states watching as California takes the lead.

Background: Mosquito-borne and sexually transmitted Zika virus has become widespread across Central and South America and the Caribbean. Many Zika vaccine candidates are under active development. Objective: To quantify the effect of Zika vaccine prioritization of females aged 9 to 49 years, followed by males aged 9 to 49 years, on incidence of prenatal Zika infections. Design: A compartmental model of Zika transmission between mosquitoes and humans was developed and calibrated to empirical estimates of country-specific mosquito density. Mosquitoes were stratified into susceptible, exposed, and infected groups; humans were stratified into susceptible, exposed, infected, recovered, and vaccinated groups. Age-specific fertility rates, Zika sexual transmission, and country-specific demographics were incorporated. Setting: 34 countries and territories in the Americas with documented Zika outbreaks. Target Population: Males and females aged 9 to 49 years. Intervention: Age-and sex-targeted immunization using a Zika vaccine with 75% efficacy. Measurements: Annual prenatal Zika infections. Results: For a base-case vaccine efficacy of 75% and vaccination coverage of 90%, immunizing females aged 9 to 49 years (the World Health Organization target population) would reduce the incidence of prenatal infections by at least 94%, depending on the country-specific Zika attack rate. In regions where an outbreak is not expected for at least 10 years, vaccination of women aged 15 to 29 years is more efficient than that of women aged 30 years or older. Limitation: Population-level modeling may not capture all local and neighborhood-level heterogeneity in mosquito abundance or Zika incidence. Conclusion: A Zika vaccine of moderate to high efficacy may virtually eliminate prenatal infections through a combination of direct protection and transmission reduction. Efficiency of age-specific targeting of Zika vaccination depends on the timing of future outbreaks.

Purpose: In the wake of a nuclear detonation, individuals with acute radiation syndrome will be a significant source of morbidity and mortality. Mathematical modeling can compare response strategies developed for real-world chaotic conditions after a nuclear blast in order to identify optimal strategies for administering effective treatment to these individuals. To maximize responders' abilities to save lives it is critical to understand how treatment efficacy is impacted by real-world conditions and levels of supportive care. To illustrate the importance of these factors, we developed a mathematical model of cytokine administration 24 h after the blast with varying levels of supportive care described in the primary literature.Conclusion: The results highlight the proportionally higher life-saving benefit of administering cytokines to individuals with a moderate to high dose of radiation exposure, compared to those with a lower dose. However, the fidelity of mathematical models is dependent on the primary data informing them. We describe the data needed to fully explore the impact of timing, dosage, and fractional benefit of cytokines and supportive care treatment in non-optimal situations that could be seen after a nuclear detonation. Studies addressing these types of knowledge gaps are essential to evaluating the relative efficacy of countermeasures to refine existing plans and help develop new strategies and priorities.

BACKGROUND:The use of poor quality antimalarial medicines, including the use of non-recommended medicines for treatment such as sulfadoxine-pyrimethamine (SP) monotherapy, undermines malaria control and elimination efforts. Furthermore, the use of subtherapeutic doses of the active ingredient(s) can theoretically promote the emergence and transmission of drug resistant parasites.METHODS:We developed a deterministic compartmental model to quantify the impact of antimalarial medicine quality on the transmission of SP resistance, and validated it using sensitivity analysis and a comparison with data from Kenya collected in 2006. We modelled human and mosquito population dynamics, incorporating two Plasmodium falciparum subtypes (SP-sensitive and SP-resistant) and both poor quality and good quality (artemether-lumefantrine) antimalarial use.FINDINGS:The model predicted that an increase in human malaria cases, and among these, an increase in the proportion of SP-resistant infections, resulted from an increase in poor quality SP antimalarial use, whether it was full- or half-dose SP monotherapy.INTERPRETATION:Our findings suggest that an increase in poor quality antimalarial use predicts an increase in the transmission of resistance. This highlights the need for stricter control and regulation on the availability and use of poor quality antimalarial medicines, in order to offer safe and effective treatments, and work towards the eradication of malaria.

Chikungunya, a re-emerging arbovirus transmitted to humans by Aedes aegypti and Ae. albopictus mosquitoes, causes debilitating disease characterized by an acute febrile phase and chronic joint pain. Chikungunya has recently spread to the island of St. Martin and subsequently throughout the Americas. The disease is now affecting 42 countries and territories throughout the Americas. While chikungunya is mainly a tropical disease, the recent introduction and subsequent spread of Ae. albopictus into temperate regions has increased the threat of chikungunya outbreaks beyond the tropics. Given that there are currently no vaccines or treatments for chikungunya, vector control remains the primary measure to curtail transmission. To investigate the effectiveness of a containment strategy that combines disease surveillance, localized vector control and transmission reduction measures, we developed a model of chikungunya transmission dynamics within a large residential neighborhood, explicitly accounting for human and mosquito movement. Our findings indicate that prompt targeted vector control efforts combined with measures to reduce transmission from symptomatic cases to mosquitoes may be highly effective approaches for controlling outbreaks of chikungunya, provided that sufficient detection of chikungunya cases can be achieved.

To quantify the effect of hospital and community-based transmission and control measures on Clostridium difficile infection (CDI), we constructed a transmission model within and between hospital, community, and long-term care-facility settings. By parameterizing the model from national databases and calibrating it to C. difficile prevalence and CDI incidence, we found that hospitalized patients with CDI transmit C. difficile at a rate 15 (95% CI 7.2-32) times that of asymptomatic patients. Long-term care facility residents transmit at a rate of 27% (95% CI 13%-51%) that of hospitalized patients, and persons in the community at a rate of 0.1% (95% CI 0.062%-0.2%) that of hospitalized patients. Despite lower transmission rates for asymptomatic carriers and community sources, these transmission routes have a substantial effect on hospital-onset CDI because of the larger reservoir of hospitalized carriers and persons in the community. Asymptomatic carriers and community sources should be accounted for when designing and evaluating control interventions.

Every year in the United States more than 12,000 women are diagnosed with cervical cancer, a disease principally caused by human papillomavirus (HPV). Bivalent and quadrivalent HPV vaccines protect against 66% of HPV-associated cervical cancers, and a new nonavalent vaccine protects against an additional 15% of cervical cancers. However, vaccination policy varies across states, and migration between states interdependently dilutes state-specific vaccination policies. To quantify the economic and epidemiological impacts of switching to the nonavalent vaccine both for individual states and for the nation as a whole, we developed a model of HPV transmission and cervical cancer incidence that incorporates state-specific demographic dynamics, sexual behavior, and migratory patterns. At the national level, the nonavalent vaccine was shown to be cost-effective compared with the bivalent and quadrivalent vaccines at any coverage despite the greater per-dose cost of the new vaccine. Furthermore, the nonavalent vaccine remains cost-effective with up to an additional 40% coverage of the adolescent population, representing 80% of girls and 62% of boys. We find that expansion of coverage would have the greatest health impact in states with the lowest coverage because of the decreasing marginal returns of herd immunity. Our results show that if policies promoting nonavalent vaccine implementation and expansion of coverage are coordinated across multiple states, all states benefit both in health and in economic terms.

BACKGROUND:The effectiveness of interferon-free direct-acting antivirals (DAA) in treating chronic hepatitis C virus (HCV) is limited by low screening and treatment rates, particularly among people who inject drugs (PWIDs).METHODS:To evaluate the levels of screening and treatment with interferon-free DAAs that are required to control HCV incidence and HCV-associated morbidity and mortality, we developed a transmission model, stratified by age and by injection drug use, and calibrated it to epidemiological data in the United States from 1992 to 2014. We quantified the impact of administration of DAAs at current and at enhanced screening and treatment rates, focusing on outcomes of HCV incidence, prevalence, compensated and decompensated cirrhosis, hepatocellular carcinoma, liver transplants, and mortality from 2015 to 2040.RESULTS:Increasing annual treatment of patients 4-fold-from the approximately 100 000 treated historically to 400 000-is predicted to prevent 526 084 (95% confidence interval, 466 615-593 347) cases of cirrhosis and 256 315 (201 589-316 114) HCV-associated deaths. By simultaneously increasing treatment capacity and increasing the number of HCV infections diagnosed, total HCV prevalence could fall to as low as 305 599 (222 955-422 110) infections by 2040. Complete elimination of HCV transmission in the United States through treatment with DAAs would require nearly universal screening of PWIDs, with an annual treatment rate of at least 30%.CONCLUSIONS:Interferon-free DAAs are projected to achieve marked reductions in HCV-associated morbidity and mortality. Aggressive expansion in HCV screening and treatment, particularly among PWIDs, would be required to eliminate HCV in the United States.

Using geo-referenced case data, we present spatial and spatio-temporal cluster analyses of the early spread of the 2013-2015 chikungunya virus (CHIKV) in Dominica, an island in the Caribbean. Spatial coordinates of the locations of the first 417 reported cases observed between December 15th, 2013 and March 11th, 2014, were captured using the Global Positioning System (GPS). We observed a preponderance of female cases, which has been reported for CHIKV outbreaks in other regions. We also noted statistically significant spatial and spatio-temporal clusters in highly populated areas and observed major clusters prior to implementation of intensive vector control programs suggesting early vector control measures, and education had an impact on the spread of the CHIKV epidemic in Dominica. A dynamical identification of clusters can lead to local assessment of risk and provide opportunities for targeted control efforts for nations experiencing CHIKV outbreaks.

Effective control of schistosomiasis remains a challenging problem for endemic areas of the world. Given knowledge of the biology of transmission and past experience with mass drug administration (MDA) programs, it is important to critically evaluate the likelihood that MDA programs will achieve substantial reductions in Schistosoma prevalence. In implementing the World Health Organization Roadmap for Neglected Tropical Diseases it would useful for policymaking to model projections of the status of Schistosoma control in MDA-treated areas in the next 5–10 years.