Vaccine hesitancy in primary care: Building bridges by understanding barriers.

Adult vaccination is an accepted part of health care and diabetes care. In spite of evidence regarding the efficacy and utility of vaccination in preventing disease, we continue to encounter vaccine hesitancy and vaccine skepticism. As physicians, it is our duty to encourage the public to get vaccinated. In this article, we create a simple framework which helps assess the barriers to vaccine acceptance, and create bridges to overcome vaccine hesitancy and skepticism. We use an interesting mnemonic, NARCO, to remind ourselves, and our readers, of the appropriate hierarchy of interviewing related to vaccine acceptance.

COVID-19 virus: the immune reaction to vaccines

The immune system is developed to preserve its hosts from an ever-expanding cluster of pathogenic microbes. The elimination of toxic substances, allergens, or any other harmful existences that come in, passing the mucosal surfaces, is as well the responsibility of this special system. Its ability to distinguish self (our bodies' functioning cells and tissues) from non-self is the key aspect to its ability to mobilize some reaction to an invasion initiated by the stranger substances listed above. To identify and kill unsafe microorganisms, the host applies both natural and versatile systems, our innate and adaptive immune systems. Vaccines are used to combat the current SARS-CoV-2 strain by utilizing immune system mechanisms, specifically the adaptive immune system. Vectored vaccines, protein vaccines, genetic vaccine, and monoclonal antibody for passive vaccination are among the vaccine platforms under consideration for SARS-CoV-2. Each vaccine has its own benefits and drawbacks. This paper is written to describe the three major forms of COVID-19 vaccines, as well as the unique mechanisms of elements of the immune system associated with the virus. © 2023 SPIE.

COVID-19: Agent-Based Simulation-Optimization to Vaccine Center Location Vaccine Allocation Problem

This paper presents an agent-based simulation-optimization modeling and algorithmic framework to determine the optimal vaccine center location and vaccine allocation strategies under budget constraints during an epidemic outbreak. Both simulation and optimization models incorporate population health dynamics, such as susceptible (S), vaccinated (V), infected (I) and recovered (R), while their integrated utilization focuses on the COVID-19 vaccine allocation challenges. We first formulate a dynamic location-allocation mixed-integer programming (MIP) model, which determines the optimal vaccination center locations and vaccines allocated to vaccination centers, pharmacies, and health centers in a multi-period setting in each region over a geographical location. We then extend the agent-based epidemiological simulation model of COVID-19 (Covasim) by adding new vaccination compartments representing people who take the first vaccine shot and the first two shots. The Covasim involves complex disease transmission contact networks, including households, schools, and workplaces, and demographics, such as age-based disease transmission parameters. We combine the extended Covasim with the vaccination center location-allocation MIP model into one single simulation-optimization framework, which works iteratively forward and backward in time to determine the optimal vaccine allocation under varying disease dynamics. The agent-based simulation captures the inherent uncertainty in disease progression and forecasts the refined number of susceptible individuals and infections for the current time period to be used as an input into the optimization. We calibrate, validate, and test our simulation-optimization vaccine allocation model using the COVID-19 data and vaccine distribution case study in New Jersey. The resulting insights support ongoing mass vaccination efforts to mitigate the impact of the pandemic on public health, while the simulation-optimization algorithmic framework could be generalized for other epidemics. [ FROM AUTHOR] Copyright of IISE Transactions is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Enabling mRNA medicine for brain tumors

mRNA is a new class of drugs that has the potential to revolutionize the treatment of brain tumors. Thanks to the COVID-19 mRNA vaccines and numerous therapy-based clinical trials, it is now clear that lipid nanoparticles (LNPs) are a clinically viable means to deliver RNA therapeutics. However, LNP-mediated mRNA delivery to brain tumors remains elusive. Over the past decade, numerous studies have shown that tumor cells communicate with each other via small extracellular vesicles, which are around 100 nm in diameter and consist of lipid bilayer membrane similar to synthetic lipidbased nanocarriers. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain tumors without undue toxicity. We synthesized LNPs using four components similar to the formulation used in the mRNA COVID19 vaccines (Moderna and Pfizer): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. For the in vitro screen, we tested ten classes of helper lipids based on their abundance in extracellular vesicle membranes, commercial availability, and large-scale production feasibility while keeping rest of the LNP components unchanged. The transfection kinetics of GFP mRNA encapsulated in LNPs and doped with 16 mol% of helper lipids was tested using GL261, U87 and SIM-A9 cell lines. Several LNP formations resulted in stable transfection (upto 5 days) of GFP mRNA in all the cell lines tested in vitro. The successful LNP candidates (enabling >80% transfection efficacy) were then tested in vivo to deliver luciferase mRNA to brain tumors via intrathecal administration in a syngeneic glioblastoma (GBM) mouse model, which confirmed luciferase expression in brain tumors in the cortex. LNPs were then tested to deliver Cre recombinase mRNA in syngeneic GBM mouse model genetically modified to express tdTomato under LoxP marker cassette that enabled identification of LNP targeted cells. mRNA was successfully delivered to tumor cells (70-80% transfected) and a range of different cells in the tumor microenvironment, including tumor-associated macrophages (80-90% transfected), neurons (31- 40% transfected), neural stem cells (39-62% transfected), oligodendrocytes (70-80% transfected) and astrocytes (44-76% transfected). Then, LNP formulations were assessed for delivering Cas9 mRNA and CD81 sgRNA (model protein) in murine syngeneic GBM model to enable gene editing in brain tumor cells. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~94% of brain tumor cells in vivo. In conclusion, we have developed a library of safe LNPs that can transfect GBM cells in vivo with high efficacy. This technology can potentially be used to develop novel mRNA therapies for GBM by delivering single or multiple mRNAs and holds great potential as a tool to study brain tumor biology.

AI and the Clinical Immunology/Immunoinformatics for COVID-19

Artificial Intelligence (AI) is contributing to the campaign against the Coronavirus Disease 2019 (COVID-19). Since 2019, more and more AI frameworks and applications in COVID-19 have been proposed, and the recent research has shown that AI is a promising technology because AI can achieve a higher degree of scalability, a more comprehensive and identification of patterns in the vast amount of unstructured and noisy data, accelerated processing power, and strategies to outperform traditional methods in many specific tasks. In this chapter, we focus on the specific AI applications in the clinical immunology/immunoinformatics for COVID-19. More precisely, on one hand, we discuss the application of deep learning in designing SARS-CoV-2 vaccines, and, on the other hand, we discuss the development of a machine learning framework for investigating the SARS-CoV-2 mutations that can help us better respond to the future mutant viruses, including designing more robust vaccines based on such AI approaches. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Optimizing mRNA vaccines and virusmediated CAR T-cell therapy for immuno-oncology: Synthetic tools for gene modification

With the success of mRNA vaccines during the COVID-19 pandemic and CAR T-cell therapies in clinical trials, there is growing opportunity for immunotherapies in the treatment of many types of cancers. Lentiviral vectors have proven effective at delivery of genetic material or gene editing technology for ex vivo processing, but the benefits and promise of Adeno-associated virus (AAV) and mRNA tools for in vivo immunotherapy have garnered recent interest. Here we describe complete synthetic solutions for immuno-oncology research programs using either mRNA-vaccines or virus-mediated cell and gene engineering. These solutions optimize workflows to minimize screening time while maximizing successful research results through: (1) Efficiency in lentiviral packaging with versatility in titer options for high-quality particles. (2) A highthroughput viral packaging process to enable rapid downstream screening. (3) Proprietary plasmid synthesis and preparation techniques to maintain ITR integrity through AAV packaging and improve gene delivery. (4) Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tail. The reported research demonstrates a streamlined approach that improves data quality through innovative synthesis and sequencing methodologies as compared to current standard practices.

Patients Characteristics, Vaccine Uptake, Healthcare Resource Utilization and Costs Associated with Acute COVID-19 during the Omicron Predominant Period in Brazil: A Nationwide Database Study

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has imposed significant burden on Brazil's health system. The present study aims to describe patients' demographic and clinical characteristics, vaccine uptake and assess healthcare resource utilization (HCRU) and costs associated with acute COVID-19 in Brazil during the Omicron predominant period. Method(s): A population-based retrospective study was conducted using the National Health Data Network (RNDS), National Vaccination Campaign against COVID-19 data and surveillance data in public setting. Individuals with positive COVID-19 test results between January-April 2022 were identified. Patients' demographics, comorbidities, vaccination status, HCRU for those who were admitted to hospitals and their associated costs were described by age groups. Result(s): A total of 8,160,715 COVID-19 cases were identified and 2.7% were aged <5 years, 11.6% were 5-19 years, 76.9% were 20-64 years and 8.7% were >= 65 years. The presence of comorbidity was 23.1% with a higher prevalence of comorbidities in the elderly (61.8% for 65-74 years and 71.2% for >=75 years). Regarding COVID -19 vaccination uptake, among those aged <=19 years, 20-64 years and >=65 years, 40.6%, 86.5% and 92.2% had primary series, respectively. Among adults, the booster uptake was 47.3% and 75.8% for those aged 20-64 years and >= 65 years, respectively. Among those with confirmed COVID-19, regardless of vaccination status, 87% were being symptomatic and 1.7% were hospitalized (3.8% in aged <5 years, 4.2% in 5-19 years, 34.3% in 20-64 years and 57.6% in >= 65 years). Among hospitalized patients, 32,6% were admitted to ICU and 80% required mechanical ventilation support. The average cost per day in normal wards and ICU without ventilation was R$291,89 and R$923,90, respectively. Conclusion(s): Our results quantify the public health and economic burden of COVID-19 in Brazil, suggesting substantial healthcare resources required to manage the COVID-19 pandemic.Copyright © 2023

Evaluation of COVID-19 Vaccines in Primary Prevention Against Infections and Reduction in Severity of Illness Following the Outbreak of Sars-Cov-2 Omicron Variant in Shanghai

Objectives: To evaluate COVID-19 vaccines in primary prevention against infections and lessening the severity of illness following the most recent outbreak of the SARS-CoV-2 Omicron variant in Shanghai. Method(s): To investigate whether inactivated vaccines were effective in protecting against COVID-19 infections, we estimated the odds ratio (OR) of the vaccination in COVID-19 cases vs. matched community-based healthy controls. To evaluate the potential benefits of vaccination in lowering the risk of symptomatic infection (vs. asymptomatic), we estimated the relative risk (RR) of symptomatic infections among diagnosed patients. We also applied the multivariate stepwise Logistic regression analyses to measure the risk of disease severity (symptomatic vs. asymptomatic and moderate/severe vs. mild) in COVID-19 patient cohort with vaccination status as an independent variable while controlling for potential confounding factors. Result(s): Out of the 153,544 COVID-19 patients included in the analysis, 118,124 (76.9%) patients had been vaccinated and 143,225(93.3%) were asymptomatic patients. Of the 10,319 symptomatic patients, 10,031(97.2%), 281(2.7%) and 7(0.1%) experienced mild, moderate, and severe infections, respectively. There is no evidence that the vaccination helped protect from infections (OR=0.82, p=0.613). The vaccination, however, offered a small but significant protection against symptomatic infections (RR=0.92, p < 0.001) and halved the risk of moderate/severe infections (OR=0.48, 95% CI: 0.37 - 0.61). Older age (> 60 years) and malignant tumors were significantly associated with moderate/severe infections. Gender also appeared to be a risk factor for symptomatic infections, with females being associated with a lower risk for moderate/severe illness. Conclusion(s): Inactivated COVID-19 vaccines helped provide a small but significant protection against symptomatic infections and halved risk of moderate/severe illness among symptomatic patients. The vaccination was not effective in blocking COVID-19 Omicron variant community spread.Copyright © 2023

Clinical Characteristics of Patients with Sars-Cov-2 Omicron Variant and COVID-19 Vaccination with Clinical Outcome Findings in Shanghai, China: A Single Center, Retrospective, Observational Study

Objectives: This study aimed to determine disease severity, clinical features, clinical outcome in hospitalized patients with the Omicron variant and evaluate the effectiveness of one-dose, two-dose, and three-dose inactivated vaccines in reducing viral loads, disease course, ICU admissions and severe diseases. Method(s): Retrospective cohort analysis was performed on 5,170 adult patients (>=18 years) identified as severe acute respiratory syndrome coronavirus 2 positive with Reverse Transcription Polymerase Chain Reaction admitted at Shanghai Medical Center for Gerontology between March 2022 and June 2022. COVID-19 vaccination effectiveness was assessed using logistic regression models evaluating the association between the risk of vaccination and clinical outcomes, adjusting for confounders. Result(s): Among 5,170 enrolled patients, the median age was 53 years, and 2,861 (55.3%) were male. 71.0% were mild COVID-19 cases, and cough (1,137 [22.0%]), fever (592 [11.5%]), sore throat (510 [9.9%]), and fatigue (334 [6.5%]) were the most common symptoms on the patient's first admission. Ct values increased generally over time and 27.1% patients experienced a high viral load (Ct value< 20) during their stay. 105(2.0%) of these patients were transferred to the intensive care unit after admission. 97.1% patients were cured or showed an improvement in symptoms and 0.9% died in hospital. The median length of hospital stay was 8.7+/-4.5 days. In multivariate logistic analysis, booster vaccination can significantly reduce ICU admissions and decrease the severity of COVID-19 outcome when compared with less doses of vaccine (OR=0.75, 95%CI, 0.62-0.91, P<=0.005;OR=0.99, 95%CI, 0.99-1.00, p<0.001). Conclusion(s): In summary, the most of patients who contracted SARSCoV-2 omicron variant had mild clinical features and patients with vaccination took less time to lower viral loads. As the COVID-19 pandemic progressed, an older and less vaccinated population was associated with higher risk for ICU admission and severe disease.Copyright © 2023

Research progress of nasal mucosal immunization vaccine against COVID-19

Respiratory mucosal immune system is the body's first line of defense against infection. Since the outbreak of novel coronavirus disease 2019 (COVID-19) in 2019, nasal mucosal immune vaccine, with its ability to induce cellular, humoral and mucosal triple immune responses, has become a research hotspot. This article focuses on novel coronavirus, with an understanding of its structure and pathogenesis, a brief introduction to the immune mechanism of nasal mucosa, a summary of the different types of nasal mucosal immune vaccines and their clinical research, aiming to provide some theoretical reference for the development of new vaccines, and exploration of the best methods and strategies to combat COVID-19.

Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses

Delivery of self-amplifying mRNA (SAM) has high potential for infectious disease vaccination due to its self-adjuvanting and dose-sparing properties. Yet a challenge is the susceptibility of SAM to degradation and the need for SAM to reach the cytosol fully intact to enable self-amplification. Lipid nanoparticles are successfully deployed at incredible speed for mRNA vaccination, but aspects such as cold storage, manufacturing, efficiency of delivery, and the therapeutic window can benefit from further improvement. To investigate alternatives to lipid nanoparticles, a class of >200 biodegradable end-capped lipophilic poly(beta-amino ester)s (PBAEs) that enable efficient delivery of SAM in vitro and in vivo as assessed by measuring expression of SAM encoding reporter proteins is developed. The ability of these polymers to deliver SAM intramuscularly in mice is evaluated, and a polymer-based formulation that yields up to 37-fold higher intramuscular (IM) expression of SAM compared to injected naked SAM is identified. Using the same nanoparticle formulation to deliver a SAM encoding rabies virus glycoprotein, the vaccine elicits superior immunogenicity compared to naked SAM delivery, leading to seroconversion in mice at low RNA injection doses. These biodegradable nanomaterials may be useful in the development of next-generation RNA vaccines for infectious diseases.Copyright © 2023 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH.

A Vaccine for the Pandemic of Aging? Conceptual and Ethical Issues

In this chapter, we develop and extend the above analogy by means of a thought experiment in which a vaccine for the pandemic of aging is developed. We ask first, whether the concept of a vaccine for the pandemic of aging is conceptually coherent, and second whether such a vaccine (or similar aging preventive) is ethically desirable. This chapter makes the case that, while there are some clear disanalogies between aging and typical pandemics like the COVID-19 pandemic, there are some striking similarities that advocate for similar degrees of urgency. Moreover, the comparison throws important light on some of the flawed objections to healthy life-extending technologies. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

Characterization of Adaptive Immune Responses to SARS-CoV-2 Updated Bivalent Booster

Bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and Omicron BA.4/5 spike proteins are successful in preventing infection from the original strain and Omicron variants, but the quality of adaptive immune responses is still not well documented. This study aims at characterizing adaptive immune responses to the bivalent booster vaccination in 46 healthy participants. Plasma and PBMC were collected prior and three weeks after bivalent booster. We measured anti-N, anti-S, and RBD IgM, IgA, IgG plasma titers against original, Omicron BA.1, and BA.5 variants (pending) as well as total anti-S IgG titers and surrogate Virus Neutralization capacity against the Alpha, Delta, and BA.1 variant. With spectral flow-cytometry we identified peripheral blood B-cells specific for the RBD of the S-protein of the original and BA.1 variants. T-cell-specific responses were assessed by cytokine release assay after stimulation with SARS-CoV-2 peptides from the original, BA.1, BA.4, and BA.5 variants (pending). Finally, we performed TRB and IGH repertoire studies on sorted CD4+, CD8+, CD19+ lymphocytes, to study breadth of SARS-CoV-2 specific clonotypes (pending). 27/46 participants were analyzed;9 had SARS-CoV-2 infection (COVID+), while 18 are infection naive (COVID-). In both groups, median time since last dose of SARS-CoV-2 vaccine (3rd or 4th) was 11 months. All subjects were positive for anti-S IgG prior to bivalent booster. The COVID + group displayed anti-S IgG pre-booster levels and neutralization against BA.1 higher than the COVID- group. Significant increase post-boost of total anti-S IgG and BA.1 neutralizing activity was detected in the COVID- but not in the COVID+ group;however, no difference in neutralization activity post-boost was detected between the two groups. Furthermore, the COVIDgroup showed significant increase in the frequency of CD19+ and CD27+ switched memory B-cells specific for BA.1 RBD in post-boost compared to pre-boost samples. However, post-boost frequencies of the same B-cells were higher in the COVID+ compared to the COVID- group. These preliminary findings confirm that among individual immunized with the original COVID-19 mRNAvaccine, prior COVID infection provides increased protection against SARS-CoV-2 variants. They also demonstrate that booster immunization with the bivalent vaccine induces robust adaptive immune responses against Omicron variant.[Formula presented][Formula presented]Copyright © 2023 Elsevier Inc.

Budget Impact Analysis of COVID-19 Vaccines on U.S. Medicare and Commercial Health Plans after Depletion of the Federally-Purchased Supply

Objectives: To analyze the budget impact (BI) of Covid-19 vaccines from a mixed U.S commercial and Medicare payer perspective after depletion of the Federally-Purchased Supply (FPS). Method(s): BI analyses were conducted in a hypothetical one-million member health plan with a mixed commercial (55%) and Medicare (45%) population over a one-year time horizon based on the current (January 2023) Covid-19 vaccine recommendations from the Centers for Disease Control and Prevention (CDC). The two scenarios in the model include 1) the health plan does not pay for Covid-19 vaccines, and 2) after the depletion of FPS, the health plan must cover all costs for Covid-19 vaccines. Model inputs include the market shares of available Covid-19 vaccines in the US as of December 2022, Covid-19 vaccine utilization trends stratified into age groups (<12, 12-17, 18-24, 25-49, 50-64, >=65 years old) between commercial and Medicare populations, and predicted Covid-19 vaccine costs. Model inputs were based on the CDC publicly available data, real world evidence, published literature, and expert opinions. Sensitivity analyses (SA) were conducted to test uncertainties arising from the input values in the model. Result(s): The number of members receiving one primary dose, completed Covid-19 vaccine series, one booster dose and two booster doses was estimated at 9,253, 49,720, 594,933 and 29,387, respectively. The incremental Covid-19 vaccine cost per member per month over one year after depletion of the FPS was $5.92 for the commercial population, $8.93 for the Medicare population, and $7.27 for the total population in the health plan. In the SA, the largest effect was observed for the scenario which varied the percentage of population >=65 years old receiving one booster dose. Conclusion(s): The model results indicate that there will be a high budget impact from a mixed U.S commercial and Medicare perspective after depletion of the FPS of Covid-19 vaccines.Copyright © 2023

Fulminant myocarditis following SARS-CoV-2 mRNA vaccination rescued with venoarterial ECMO: A report of two cases

Objectives: Cases of fulminant myocarditis after mRNA COVID-19 vaccination have been reported. The most severe may need venoarterial extracorporeal membrane oxygenation (V-A ECMO) support. Here we report two cases successfully rescued with V-A ECMO. Method(s): We included all the cases supported with V-A ECMO for refractory cardiogenic shock due to myocarditis secondary to a mRNA SARS-COV2 vaccine in the high-volume adult ECMO Program in Vall Hebron University Hospital since January 2020. Result(s): We identified two cases (table). One of them was admitted for out-of-hospital cardiac arrest. In both, a peripheral V-A ECMO was implanted in the cath lab. An intra-aortic balloon pump was needed in one case for left ventricle unloading. Support could be successfully withdrawn in a mean of five days. No major bleeding or thrombosis complications occurred. Definite microscopic diagnosis could be reached in one case (Image, 3). Treatment was the same, using 1000mg of methylprednisolone/day for 3 days. A cardiac magnetic resonance 10 days after admission showed a significant improvement in systolic function and diffuse oedema and subepicardial contrast intake in different segments (Image, 1-2). Both patients were discharged fully recovered. Conclusion(s): V-A ECMO should be established in cases of COVID-19 vaccine-associated myocarditis with refractory cardiogenic shock during the acute phase. (Table Presented).

COVID-19 Vaccine: Knowledge and Acceptance among Obstetric Population in Garhwal Region of Uttarakhand

Background: Coronavirus disease-2019 (COVID-19) poses expectant mothers to a higher risk of serious complications and mortality. Following a risk-benefit review, a number of governmental and professional bodies from across the globe recently approved the COVID-19 vaccination during pregnancy. Aim(s): This study aimed to investigate knowledge, actual acceptance, and concerns about the COVID-19 vaccine among the obstetric population. Material(s) and Method(s): Participants were selected from among the expecting women who came for antenatal checkup during the study period (October 1, 2021-November 30, 2021). About 150 pregnant women who met the inclusion criteria and consented were recruited into the study. Data related to socio-demographic and clinical characteristics as well as knowledge, actual acceptance, and concerns about COVID-19 vaccine were collected through in-person interviews using a prestructured questionnaire. The SPSS version 23 was used to analyze data. The association between the attitude (acceptance and hesitance) of participants toward the COVID-19 vaccine and their sociodemographic and clinical profile was found by Fisher's exact test. Result(s): The actual acceptance of the COVID-19 vaccine among expecting women was 52.0%. The primary motive for accepting COVID-19 immunization was to protect the fetus, followed by the protection of one's own health. A significant association was found between COVID-19 vaccine acceptance and the level of education, socio-economic status, and presence of comorbidities. The leading causes for vaccine reluctance were concerns about the efficacy and safety of the vaccines and lack of awareness about their usage during pregnancy. Conclusion(s): Multifaceted activities are required to promote the effectiveness and safety profile of the COVID-19 vaccine as well as disseminate knowledge about its usage during pregnancy. Clinical significance: Unlike numerous other studies that have investigated the accepting attitude only, the present one has investigated the actual COVID-19 vaccine uptake among the obstetric population.Copyright © The Author(s).