Socioeconomic determinants and reasons for non-acceptance to vaccination recommendations during the 3rd - 5th waves of the COVID-19 pandemic in Hungary.

BACKGROUND: In Hungary, although six types of vaccines were widely available, the percentage of people receiving the primary series of COVID-19 vaccination remained below the EU average. This paper investigates the reasons for Hungary's lower vaccination coverage by exploring changing attitudes towards vaccination, socio-demographic determinants, and individual reasons for non-acceptance during the 3rd - 5th pandemic waves of COVID-19. METHODS: The study's empirical analysis is based on representative surveys conducted in Hungary between February 19, 2021, and June 30, 2022. The study used a total of 17 surveys, each with a sample size of at least 1000 respondents. Binomial logistic regression models were used to investigate which socio-demographic characteristics are most likely to influence vaccine hesitancy in Hungary. The study analysed 2506 open-ended responses to identify reasons for vaccine non-acceptance. The responses were categorised into four main categories and 13 sub-categories. RESULTS: Between the third and fifth wave of the pandemic, attitudes towards COVID-19 vaccination have significantly changed. Although the proportion of vaccinated individuals has increased steadily, the percentage of individuals who reported not accepting the vaccine has remained almost unchanged. Socio-demographic characteristics were an important determinant of the observed vaccine hesitancy, although they remained relatively stable over time. Individuals in younger age groups and those with lower socioeconomic status were more likely to decline vaccination, while those living in the capital city were the least likely. A significant reason behind vaccine refusal can undoubtedly be identified as lack of trust (specifically distrust in science), facing an information barrier and the perception of low personal risk. CONCLUSION: Although compulsory childhood vaccination coverage is particularly high in Hungary, voluntary adult vaccines, such as the influenza and COVID-19 vaccines, are less well accepted. Vaccine acceptance is heavily affected by the social-demographic characteristics of people. Mistrust and hesitancy about COVID-19 vaccines, if not well managed, can easily affect people's opinion and acceptance of other vaccines as well. Identifying and understanding the complexity of how vaccine hesitancy evolved during the pandemic can help to understand and halt the decline in both COVID-19 and general vaccine confidence by developing targeted public health programs to address these issues.

Deviation from the recommended schedule: optimal dosing interval for a two-dose vaccination programme.

Optimizing vaccination impact during an emerging disease becomes crucial when vaccine supply is limited, and robust protection requires multiple doses. Facing this challenge during the early stages of the COVID-19 vaccine deployment, a pivotal policy question arose: whether to administer a single dose to a larger proportion of the population by deferring the second dose, or to prioritize stronger protection for a smaller subset of the population with the established dosing interval from clinical trials. Using a delay-differential model and considering waning immunity and distribution capacity, we compared these strategies. We found that the efficacy of the first dose significantly influences the impact of delaying the second dose. Even for a relatively low efficacy of the first dose, a delayed strategy may outperform vaccination with the recommended dosing interval in reducing short-term hospitalizations and deaths despite increase in infections. The optimal delay, however, depends on the specific outcome measured and timelines within which the vaccination strategy is evaluated. We found transition lines for the relative reduction of infection, hospitalization and death below which vaccination with the recommended schedule is the preferred strategy. In a realistic parameter space, our results highlight scenarios in which the conclusions of previous studies are invalid.

Autopsy findings in cancer patients infected with SARS-CoV-2 show a milder presentation of COVID-19 compared to non-cancer patients.

COVID-19, caused by SARS-CoV-2, manifests with differing severity across distinct patient subgroups, with outcomes influenced by underlying comorbidities such as cancer, which may cause functional and compositional alterations of the immune system during tumor progression. We aimed to investigate the association of SARS-CoV-2 infection and its complications with cancer in a large autopsy series and the role of COVID-19 in the fatal sequence leading to death. A total of 2641 adult autopsies were investigated, 539 of these were positive for SARS-CoV-2. Among the total number of patients analyzed, 829 had active cancer. Overall, the cohort included 100 patients who simultaneously had cancer and SARS-CoV-2 infection. The course of COVID-19 was less severe in cancer patients, including a significantly lower incidence of viral and bacterial pneumonia, occurring more frequently as a contributory disease or coexisting morbidity, or as SARS-CoV-2 positivity without viral disease. SARS-CoV-2 positivity was more frequent among non-metastatic than metastatic cancer cases, and in specific tumor types including hematologic malignancies. COVID-19 was more frequently found to be directly involved in the fatal sequence in patients undergoing active anticancer therapy, but less frequently in perioperative status, suggesting that the underlying malignancy and consequent surgery are more important factors leading to death perioperatively than viral disease. The course of COVID-19 in cancer patients was milder and balanced during the pandemic. This may be due to relative immunosuppressed status, and the fact that even early/mild viral infections can easily upset their condition, leading to death from their underlying cancer or its complications.

Impact and cost-effectiveness analyses of vaccination for prevention of respiratory syncytial virus disease among older adults in Ontario: A Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Two prefusion F protein-based vaccines, Arexvy and Abrysvo, have been approved by Health Canada for protecting older adults against respiratory syncytial virus (RSV)-associated lower respiratory tract disease. We estimated the health benefits and cost-effectiveness of these vaccines under a publicly funded single-dose vaccination program in Ontario that targets residents of long-term care homes (LTCHs). Additionally, we evaluated an extended program that broadens vaccination to include community-dwelling older adults. METHODS: A discrete-event simulation model was parameterised with the burden of RSV disease including outpatient care, hospitalisation, and death among adults aged 60 years or older in Ontario, Canada. Accounting for direct and indirect costs (in 2023 Canadian dollars) associated with RSV-related outcomes, we calculated the net monetary benefit using quality-adjusted life-year (QALY) gained, and determined the range of price-per-dose (PPD) for vaccination programs to be cost-effective from both healthcare and societal perspectives over two RSV seasons. The incremental cost-effectiveness ratio (ICER) was calculated to estimate the additional costs required to gain one QALY. RESULTS: Using a willingness-to-pay of $50,000 per QALY gained, we found that vaccinating 90% of residents in LTCHs with Arexvy would be cost-effective from a societal perspective for a PPD up to $163, producing a mean ICER value of $49,984 (95% CI: $47,539 to $52,704) per QALY gained with a two-year budget impact of $463,468 per 100,000 older adults. The reduction of hospitalizations was estimated at 7.0% compared to the no-vaccination scenario. Extending the program to include community-dwelling older adults with a 74% coverage akin to influenza vaccination, Arexvy remains cost-effective for a PPD up to $139, with a mean ICER value of $49,698 (95% CI: 48,022 to 51,388) per QALY gained and a two-year budget impact of $8.63 million. Compared to the no-vaccination scenario, the extended program resulted in a 57.3% reduction in RSV-related hospitalisations. CONCLUSIONS: Vaccinating residents of LTCHs against RSV disease would be cost-effective depending on PPD; extending the program to community-dwelling older adults would provide substantial health benefits, averting significant direct healthcare costs and productivity losses.

Real-time estimation of the effective reproduction number of COVID-19 from behavioral data.

Monitoring the effective reproduction number [Formula: see text] of a rapidly unfolding pandemic in real-time is key to successful mitigation and prevention strategies. However, existing methods based on case numbers, hospital admissions or fatalities suffer from multiple measurement biases and temporal lags due to high test positivity rates or delays in symptom development or administrative reporting. Alternative methods such as web search and social media tracking are less directly indicating epidemic prevalence over time. We instead record age-stratified anonymous contact matrices at a daily resolution using a longitudinal online-offline survey in Hungary during the first two waves of the COVID-19 pandemic. This approach is innovative, cheap, and provides information in near real-time for estimating [Formula: see text] at a daily resolution. Moreover, it allows to complement traditional surveillance systems by signaling periods when official monitoring infrastructures are unreliable due to observational biases.

Real-Time Monitoring of the Effectiveness of Six COVID-19 Vaccines against Laboratory-Confirmed COVID-19 in Hungary in 2021 Using the Screening Method.

Several studies have reported the waning effectiveness of COVID-19 vaccines. This study aims to demonstrate the applicability of the screening method for estimating vaccine effectiveness (VE) in a pandemic. We report VE in Hungary, estimated with the screening method, in 2021, covering a period of Alpha and the Delta variant, including the booster dose roll-out. Hungary is in a unique position to use six different vaccines in the same population. All vaccines provided a high level of protection initially, which declined over time. While the picture is different in each age group, the waning of immunity is apparent for all vaccines, especially in the younger age groups and the Sinopharm, Sputnik-V, and AstraZeneca vaccines, which performed similarly. This is clearly reversed by booster doses, more prominent for those three vaccines, where the decline in protection is more evident. Overall, two vaccines, Pfizer/BioNTech and Moderna, tend to produce the best results in all age groups, even with waning immunity considered. Using the screening method in future pandemic waves is worthwhile, especially in countries struggling with a lack of resources or when there is a need to deliver VE results within a short timeframe due to urgent decision-making.

Adaptive group testing in a compartmental model of COVID-19.

Various measures have been implemented around the world to prevent the spread of SARS-CoV-2. A potential tool to reduce disease transmission is regular mass testing of a high percentage of the population, possibly with pooling (testing a compound of several samples with one single test). We develop a compartmental model to study the applicability of this method and compare different pooling strategies: regular and Dorfman pooling. The model includes isolated compartments as well, from where individuals rejoin the active population after some time delay. We develop a method to optimize Dorfman pooling depending on disease prevalence and establish an adaptive strategy to select variable pool sizes during the course of the epidemic. It is shown that optimizing the pool size can avert a significant number of infections. The adaptive strategy is much more efficient, and may prevent an epidemic outbreak even in situations when a fixed pool size strategy can not.

Dynamics of an SIRWS model with waning of immunity and varying immune boosting period.

SIRS models capture transmission dynamics of infectious diseases for which immunity is not lifelong. Extending these models by a W compartment for individuals with waning immunity, the boosting of the immune system upon repeated exposure may be incorporated. Previous analyses assumed identical waning rates from R to W and from W to S. This implicitly assumes equal length for the period of full immunity and of waned immunity. We relax this restriction, and allow an asymmetric partitioning of the total immune period. Stability switches of the endemic equilibrium are investigated with a combination of analytic and numerical tools. Then, continuation methods are applied to track bifurcations along the equilibrium branch. We find rich dynamics: Hopf bifurcations, endemic double bubbles, and regions of bistability. Our results highlight that the length of the period in which waning immunity can be boosted is a crucial parameter significantly influencing long term epidemiological dynamics.

A single early introduction governed viral diversity in the second wave of SARS-CoV-2 epidemic in Hungary.

Retrospective evaluation of past waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic is key for designing optimal interventions against future waves and novel pandemics. Here, we report on analysing genome sequences of SARS-CoV-2 from the first two waves of the epidemic in 2020 in Hungary, mirroring a suppression and a mitigation strategy, respectively. Our analysis reveals that the two waves markedly differed in viral diversity and transmission patterns. Specifically, unlike in several European areas or in the USA, we have found no evidence for early introduction and cryptic transmission of the virus in the first wave of the pandemic in Hungary. Despite the introduction of multiple viral lineages, extensive community spread was prevented by a timely national lockdown in March 2020. In sharp contrast, the majority of the cases in the much larger second wave can be linked to a single transmission lineage of the pan-European B.1.160 variant. This lineage was introduced unexpectedly early, followed by a 2-month-long cryptic transmission before a soar of detected cases in September 2020. Epidemic analysis has revealed that the dominance of this lineage in the second wave was not associated with an intrinsic transmission advantage. This finding is further supported by the rapid replacement of B.1.160 by the alpha variant (B.1.1.7) that launched the third wave of the epidemic in February 2021. Overall, these results illustrate how the founder effect in combination with the cryptic transmission, instead of repeated international introductions or higher transmissibility, can govern viral diversity.

Understanding hesitancy with revealed preferences across COVID-19 vaccine types.

Many countries have secured larger quantities of COVID-19 vaccines than their population is willing to take. The abundance and the large variety of vaccines created not only an unprecedented intensity of vaccine related public discourse, but also a historical moment to understand vaccine hesitancy better. Yet, the heterogeneity of hesitancy by vaccine types has been neglected in the existing literature so far. We address this problem by analysing the acceptance and the assessment of five vaccine types. We use information collected with a nationally representative survey at the end of the third wave of the COVID-19 pandemic in Hungary. During the vaccination campaign, individuals could reject the assigned vaccine to wait for a more preferred alternative that enables us to quantify revealed preferences across vaccine types. We find that hesitancy is heterogenous by vaccine types and is driven by individuals' trusted source of information. Believers of conspiracy theories are more likely to evaluate the mRNA vaccines (Pfizer and Moderna) unacceptable. Those who follow the advice of politicians are more likely to evaluate vector-based (AstraZeneca and Sputnik) or whole-virus vaccines (Sinopharm) acceptable. We argue that the greater selection of available vaccine types and the free choice of the individual are desirable conditions to increase the vaccination rate in societies.

Modeling waning and boosting of COVID-19 in Canada with vaccination.

SARS-CoV-2, the causative agent of COVID-19, has caused devastating health and economic impacts around the globe since its appearance in late 2019. The advent of effective vaccines leads to open questions on how best to vaccinate the population. To address such questions, we developed a model of COVID-19 infection by age that includes the waning and boosting of immunity against SARS-CoV-2 in the context of infection and vaccination. The model also accounts for changes to infectivity of the virus, such as public health mitigation protocols over time, increases in the transmissibility of variants of concern, changes in compliance to mask wearing and social distancing, and changes in testing rates. The model is employed to study public health mitigation and vaccination of the COVID-19 epidemic in Canada, including different vaccination programs (rollout by age), and delays between doses in a two-dose vaccine. We find that the decision to delay the second dose of vaccine is appropriate in the Canadian context. We also find that the benefits of a COVID-19 vaccination program in terms of reductions in infections is increased if vaccination of 15-19 year olds are included in the vaccine rollout.

In Silico Evaluation of Paxlovid's Pharmacometrics for SARS-CoV-2: A Multiscale Approach.

Paxlovid is a promising, orally bioavailable novel drug for SARS-CoV-2 with excellent safety profiles. Our main goal here is to explore the pharmacometric features of this new antiviral. To provide a detailed assessment of Paxlovid, we propose a hybrid multiscale mathematical approach. We demonstrate that the results of the present in silico evaluation match the clinical expectations remarkably well: on the one hand, our computations successfully replicate the outcome of an actual in vitro experiment; on the other hand, we verify both the sufficiency and the necessity of Paxlovid's two main components (nirmatrelvir and ritonavir) for a simplified in vivo case. Moreover, in the simulated context of our computational framework, we visualize the importance of early interventions and identify the time window where a unit-length delay causes the highest level of tissue damage. Finally, the results' sensitivity to the diffusion coefficient of the virus is explored in detail.

Reconstructing social mixing patterns via weighted contact matrices from online and representative surveys.

The unprecedented behavioural responses of societies have been evidently shaping the COVID-19 pandemic, yet it is a significant challenge to accurately monitor the continuously changing social mixing patterns in real-time. Contact matrices, usually stratified by age, summarise interaction motifs efficiently, but their collection relies on conventional representative survey techniques, which are expensive and slow to obtain. Here we report a data collection effort involving over [Formula: see text] of the Hungarian population to simultaneously record contact matrices through a longitudinal online and sequence of representative phone surveys. To correct non-representative biases characterising the online data, by using census data and the representative samples we develop a reconstruction method to provide a scalable, cheap, and flexible way to dynamically obtain closer-to-representative contact matrices. Our results demonstrate that although some conventional socio-demographic characters correlate significantly with the change of contact numbers, the strongest predictors can be collected only via surveys techniques and combined with census data for the best reconstruction performance. We demonstrate the potential of combined online-offline data collections to understand the changing behavioural responses determining the future evolution of the outbreak, and to inform epidemic models with crucial data.

Microsimulation based quantitative analysis of COVID-19 management strategies.

Pandemic management requires reliable and efficient dynamical simulation to predict and control disease spreading. The COVID-19 (SARS-CoV-2) pandemic is mitigated by several non-pharmaceutical interventions, but it is hard to predict which of these are the most effective for a given population. We developed the computationally effective and scalable, agent-based microsimulation framework PanSim, allowing us to test control measures in multiple infection waves caused by the spread of a new virus variant in a city-sized societal environment using a unified framework fitted to realistic data. We show that vaccination strategies prioritising occupational risk groups minimise the number of infections but allow higher mortality while prioritising vulnerable groups minimises mortality but implies an increased infection rate. We also found that intensive vaccination along with non-pharmaceutical interventions can substantially suppress the spread of the virus, while low levels of vaccination, premature reopening may easily revert the epidemic to an uncontrolled state. Our analysis highlights that while vaccination protects the elderly from COVID-19, a large percentage of children will contract the virus, and we also show the benefits and limitations of various quarantine and testing scenarios. The uniquely detailed spatio-temporal resolution of PanSim allows the design and testing of complex, specifically targeted interventions with a large number of agents under dynamically changing conditions.

A hybrid PDE-ABM model for viral dynamics with application to SARS-CoV-2 and influenza.

We propose a hybrid partial differential equation-agent-based (PDE-ABM) model to describe the spatio-temporal viral dynamics in a cell population. The virus concentration is considered as a continuous variable and virus movement is modelled by diffusion, while changes in the states of cells (i.e. healthy, infected, dead) are represented by a stochastic ABM. The two subsystems are intertwined: the probability of an agent getting infected in the ABM depends on the local viral concentration, and the source term of viral production in the PDE is determined by the cells that are infected. We develop a computational tool that allows us to study the hybrid system and the generated spatial patterns in detail. We systematically compare the outputs with a classical ODE system of viral dynamics, and find that the ODE model is a good approximation only if the diffusion coefficient is large. We demonstrate that the model is able to predict SARS-CoV-2 infection dynamics, and replicate the output of in vitro experiments. Applying the model to influenza as well, we can gain insight into why the outcomes of these two infections are different.

Global analysis of a cancer model with drug resistance due to Lamarckian induction and microvesicle transfer.

Development of resistance to chemotherapy in cancer patients strongly effects the outcome of the treatment. Due to chemotherapeutic agents, resistance can emerge by Darwinian evolution. Besides this, acquired drug resistance may arise via changes in gene expression. A recent discovery in cancer research uncovered a third possibility, indicating that this phenotype conversion can occur through the transfer of microvesicles from resistant to sensitive cells, a mechanism resembling the spread of an infectious agent. We present a model describing the evolution of sensitive and resistant tumour cells considering Darwinian selection, Lamarckian induction and microvesicle transfer. We identify three threshold parameters which determine the existence and stability of the three possible equilibria. Using a simple Dulac function, we give a complete description of the dynamics of the model depending on the three threshold parameters. We also establish an agent based model as a spatial version of the ODE model and compare the outputs of the two models. We find that although the ODE model does not provide spatial information about the structure of the tumour, it is capable to determine the outcome in terms of tumour size and distribution of cell types. We demonstrate the possible effects of increasing drug concentration, and characterize the possible bifurcation sequences. Our results show that the presence of microvesicle transfer cannot ruin a therapy that otherwise leads to extinction, however it may doom a partially successful therapy to failure.

Primary and secondary clarithromycin resistance in Helicobacter pylori and mathematical modeling of the role of macrolides.

Clarithromycin is a macrolide antibiotic widely used for eradication of Helicobacter pylori infection, and thus resistance to this antibiotic is a major cause of treatment failure. Here, we present the results of a retrospective observational study of clarithromycin resistance (Cla-res) in 4744 H. pylori-infected patients from Central Hungary. We use immunohistochemistry and fluorescence in situ hybridization on fixed gastric tissue samples to determine H. pylori infection and to infer Cla-res status, respectively. We correlate this information with macrolide dispensing data for the same patients (available through a prescription database) and develop a mathematical model of the population dynamics of Cla-res H. pylori infections. Cla-res is found in 5.5% of macrolide-naive patients (primary Cla-res), with no significant sex difference. The model predicts that this primary Cla-res originates from transmission of resistant bacteria in 98.7% of cases, and derives from spontaneous mutations in the other 1.3%. We find an age-dependent preponderance of female patients among secondary (macrolide-exposed) clarithromycin-resistant infections, predominantly associated with prior use of macrolides for non-eradication purposes. Our results shed light into the sources of primary resistant cases, and indicate that the growth rate of Cla-res prevalence would likely decrease if macrolides were no longer used for purposes other than H. pylori eradication.

Fleeing lockdown and its impact on the size of epidemic outbreaks in the source and target regions - a COVID-19 lesson.

The COVID-19 pandemic forced authorities worldwide to implement moderate to severe restrictions in order to slow down or suppress the spread of the disease. It has been observed in several countries that a significant number of people fled a city or a region just before strict lockdown measures were implemented. This behavior carries the risk of seeding a large number of infections all at once in regions with otherwise small number of cases. In this work, we investigate the effect of fleeing on the size of an epidemic outbreak in the region under lockdown, and also in the region of destination. We propose a mathematical model that is suitable to describe the spread of an infectious disease over multiple geographic regions. Our approach is flexible to characterize the transmission of different viruses. As an example, we consider the COVID-19 outbreak in Italy. Projection of different scenarios shows that (i) timely and stricter intervention could have significantly lowered the number of cumulative cases in Italy, and (ii) fleeing at the time of lockdown possibly played a minor role in the spread of the disease in the country.

COVID-19 Seroprevalence in Canada Modelling Waning and Boosting COVID-19 Immunity in Canada a Canadian Immunization Research Network Study.

COVID-19 seroprevalence changes over time, with infection, vaccination, and waning immunity. Seroprevalence estimates are needed to determine when increased COVID-19 vaccination coverage is needed, and when booster doses should be considered, to reduce the spread and disease severity of COVID-19 infection. We use an age-structured model including infection, vaccination and waning immunity to estimate the distribution of immunity to COVID-19 in the Canadian population. This is the first mathematical model to do so. We estimate that 60-80% of the Canadian population has some immunity to COVID-19 by late Summer 2021, depending on specific characteristics of the vaccine and the waning rate of immunity. Models results indicate that increased vaccination uptake in age groups 12-29, and booster doses in age group 50+ are needed to reduce the severity COVID-19 Fall 2021 resurgence.

Nonlinear model predictive control with logic constraints for COVID-19 management.

The management of COVID-19 appears to be a long-term challenge, even in countries that have managed to suppress the epidemic after their initial outbreak. In this paper, we propose a model predictive approach for the constrained control of a nonlinear compartmental model that captures the key dynamical properties of COVID-19. The control design uses the discrete-time version of the epidemic model, and it is able to handle complex, possibly time-dependent constraints, logical relations between model variables and multiple predefined discrete levels of interventions. A state observer is also constructed for the computation of non-measured variables from the number of hospitalized patients. Five control scenarios with different cost functions and constraints are studied through numerical simulations, including an output feedback configuration with uncertain parameters. It is visible from the results that, depending on the cost function associated with different policy aims, the obtained controls correspond to mitigation and suppression strategies, and the constructed control inputs are similar to real-life government responses. The results also clearly show the key importance of early intervention, the continuous tracking of the susceptible population and that of future work in determining the true costs of restrictive control measures and their quantitative effects.