ABSTRACT
In 2020, the WHO launched its first global strategy to accelerate the elimination of cervical cancer, outlining an ambitious set of targets for countries to achieve over the next decade. At the same time, new tools, technologies, and strategies are in the pipeline that may improve screening performance, expand the reach of prophylactic vaccines, and prevent the acquisition, persistence and progression of oncogenic HPV. Detailed mechanistic modelling can help identify the combinations of current and future strategies to combat cervical cancer. Open-source modelling tools are needed to shift the capacity for such evaluations in-country. Here, we introduce the Human papillomavirus simulator (HPVsim), a new open-source software package for creating flexible agent-based models parameterised with country-specific vital dynamics, structured sexual networks, and co-transmitting HPV genotypes. HPVsim includes a novel methodology for modelling cervical disease progression, designed to be readily adaptable to new forms of screening. The software itself is implemented in Python, has built-in tools for simulating commonly-used interventions, includes a comprehensive set of tests and documentation, and runs quickly (seconds to minutes) on a laptop. Performance is greatly enhanced by HPVsim's multiscale modelling functionality. HPVsim is open source under the MIT License and available via both the Python Package Index (via pip install) and GitHub (hpvsim.org).
Subject(s)
Papillomavirus Infections , Software , Uterine Cervical Neoplasms , Humans , Female , Papillomavirus Infections/transmission , Papillomavirus Infections/virology , Uterine Cervical Neoplasms/virology , Uterine Cervical Neoplasms/prevention & control , Computer Simulation , Papillomaviridae/genetics , Papillomaviridae/pathogenicity , Papillomaviridae/physiology , Computational Biology/methods , Models, BiologicalABSTRACT
The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.
Subject(s)
COVID-19 , Models, Biological , SARS-CoV-2 , Systems Analysis , Basic Reproduction Number , COVID-19/etiology , COVID-19/prevention & control , COVID-19/transmission , COVID-19 Testing , COVID-19 Vaccines , Computational Biology , Computer Simulation , Contact Tracing , Disease Progression , Hand Disinfection , Host Microbial Interactions , Humans , Masks , Mathematical Concepts , Pandemics , Physical Distancing , Quarantine , SoftwareABSTRACT
Human papillomavirus (HPV) is the cause of almost all cases of cervical cancer, a disease that kills some 340,000 women per year. The timeline from initial infection with HPV to the onset of invasive cervical cancer spans decades, and observational studies of this process are limited to settings in which treatment of precancerous lesions was withheld or inadequate. Such studies have been critical for understanding the natural history of HPV. Modeling can shed additional insight on the natural history of HPV, especially across geographical settings with varying prevalence of factors known to affect the host-side immune response to HPV, such as HIV and tobacco use. In this study, we create models for the 30 most populous countries in Sub-Saharan Africa, each with country-specific demographic, and behavioral inputs. We found that it was not possible to fit the data if we assumed that the natural history parameters were exactly identical for all countries, even after accounting for demographic and behavioral differences, but that we could achieve a good fit with the addition of a single immunocompetence parameter for each country. Our results indicate that variation in host immune responses may play a role in explaining the differences in the burden of cervical cancer between countries, which in turn implies a greater need for more geographically diverse data collection to understand the natural history of HPV.
Subject(s)
Papillomavirus Infections , Registries , Uterine Cervical Neoplasms , Humans , Female , Uterine Cervical Neoplasms/virology , Uterine Cervical Neoplasms/epidemiology , Papillomavirus Infections/epidemiology , Papillomavirus Infections/virology , Papillomavirus Infections/immunology , Africa South of the Sahara/epidemiology , Adult , Papillomaviridae , Global Health , Prevalence , Middle Aged , CalibrationABSTRACT
Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.
ABSTRACT
Much of the world's population had already been infected with COVID-19 by the time the Omicron variant emerged at the end of 2021, but the scale of the Omicron wave was larger than any that had come before or has happened since, and it left a global imprinting of immunity that changed the COVID-19 landscape. In this study, we simulate a South African population and demonstrate how population-level vaccine effectiveness and efficiency changed over the course of the first 2 years of the pandemic. We then introduce three hypothetical variants and evaluate the impact of vaccines with different properties. We find that variant-chasing vaccines have a narrow window of dominating pre-existing vaccines but that a variant-chasing vaccine strategy may have global utility, depending on the rate of spread from setting to setting. Next-generation vaccines might be able to overcome uncertainty in pace and degree of viral evolution.
Subject(s)
COVID-19 , Vaccines , Humans , COVID-19/prevention & control , Pandemics/prevention & control , SARS-CoV-2ABSTRACT
BACKGROUND: Developing a causal graph is an important step in etiologic research planning and can be used to highlight data flaws and irreparable bias and confounding. As a case study, we consider recent findings that suggest human papillomavirus (HPV) vaccine is less effective against HPV-associated disease among girls living with HIV compared to girls without HIV. OBJECTIVES: To understand the relationship between HIV status and HPV vaccine effectiveness, it is important to outline the key assumptions of the causal mechanisms before designing a study to investigate the effect of the HPV vaccine in girls living with HIV infection. METHODS: We present a causal graph to describe our assumptions and proposed approach to explore this relationship. We hope to obtain feedback on our assumptions before data analysis and exemplify the process for designing causal graphs to inform an etiologic study. CONCLUSION: The approach we lay out in this paper may be useful for other researchers who have an interest in using causal graphs to describe and assess assumptions in their own research before undergoing data collection and/or analysis.
Subject(s)
HIV Infections , Papillomavirus Infections , Papillomavirus Vaccines , Female , HIV Infections/complications , Humans , Papillomavirus Infections/complications , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/therapeutic use , PublishingABSTRACT
Background: The emergence of the Brazilian variant of concern, Gamma lineage (P.1), impacted the epidemiological profile of COVID-19 cases due to its higher transmissibility rate and immune evasion ability. Methods: We sequenced 305 SARS-CoV-2 whole-genomes and performed phylogenetic analyses to identify introduction events and the circulating lineages. Additionally, we use epidemiological data of COVID-19 cases, severe cases, and deaths to measure the impact of vaccination coverage and mortality risk. Results: Here we show that Gamma introduction in São José do Rio Preto, São Paulo, Brazil, was followed by the displacement of seven circulating SARS-CoV-2 variants and a rapid increase in prevalence two months after its first detection in January 2021. Moreover, Gamma variant is associated with increased mortality risk and severity of COVID-19 cases in younger age groups, which corresponds to the unvaccinated population at the time. Conclusions: Our findings highlight the beneficial effects of vaccination indicated by a pronounced reduction of severe cases and deaths in immunized individuals, reinforcing the need for rapid and massive vaccination.
ABSTRACT
Initial COVID-19 containment in the United States focused on limiting mobility, including school and workplace closures. However, these interventions have had enormous societal and economic costs. Here, we demonstrate the feasibility of an alternative control strategy, test-trace-quarantine: routine testing of primarily symptomatic individuals, tracing and testing their known contacts, and placing their contacts in quarantine. We perform this analysis using Covasim, an open-source agent-based model, which has been calibrated to detailed demographic, mobility, and epidemiological data for the Seattle region from January through June 2020. With current levels of mask use and schools remaining closed, we find that high but achievable levels of testing and tracing are sufficient to maintain epidemic control even under a return to full workplace and community mobility and with low vaccine coverage. The easing of mobility restrictions in June 2020 and subsequent scale-up of testing and tracing programs through September provided real-world validation of our predictions. Although we show that test-trace-quarantine can control the epidemic in both theory and practice, its success is contingent on high testing and tracing rates, high quarantine compliance, relatively short testing and tracing delays, and moderate to high mask use. Thus, in order for test-trace-quarantine to control transmission with a return to high mobility, strong performance in all aspects of the program is required.