Recent Advances in Nanodrug Delivery Systems Production, Efficacy, Safety, and Toxicity.

In the last three decades, the development of nanoparticles or nano-formulations as drug delivery systems has emerged as a promising tool to overcome the limitations of conventional delivery, potentially to improve the stability and solubility of active molecules, promote their transport across the biological membranes, and prolong circulation times to increase efficacy of a therapy. Despite several nano-formulations having applications in drug delivery, some issues concerning their safety and toxicity are still debated. This chapter describes the recent available information regarding safety, toxicity, and efficacy of nano-formulations for drug delivery. Several key factors can influence the behavior of nanoparticles in a biological environment, and their evaluation is crucial to design non-toxic and effective nano-formulations. Among them, we have focused our attention on materials and methods for their preparation (including the innovative microfluidic technique), mechanisms of interactions with biological systems, purification of nanoparticles, manufacture impurities, and nano-stability. This chapter places emphasis on the utilization of in silico, in vitro, and in vivo models for the assessment and prediction of toxicity associated with these nano-formulations. Furthermore, the chapter includes specific examples of in vitro and in vivo studies conducted on nanoparticles, illustrating their application in this field.

Determinants of protective humoral response to mRNA-1273 and BNT162b2 vaccines in peritoneal dialysis patients: a prospective cohort study.

Patients with chronic kidney disease (CKD) on dialysis have a higher mortality rate associated with SARS-CoV-2 infection. Although vaccines are now available, the protective response rates and determinants of humoral response to the vaccine are poorly described in patients on peritoneal dialysis. This was a prospective observational study describing the response rates of detectable and standardized protective antibody titers one month after each mRNA vaccine dose in a cohort of 88 patients on peritoneal dialysis. We found that the vast majority of patients produced protective levels of antibodies (73%) one month after the second vaccine dose. In the multivariate analysis, the single determinant for an adequate humoral response was the weekly Kt/V, a surrogate of dialysis dose. The response rate was higher, but not significantly, with the mRNA-1273 than with the BNT162b2 vaccine one month after the second dose (78.7 vs. 46.2%, respectively, p = 0.02). We found that patients on peritoneal dialysis had a satisfactory humoral response rate, which was much higher than in transplant recipients. PD patients with a poor humoral response, particularly those with a low wKT/V, may benefit from an additional dose of vaccine.

Quality by design for mRNA platform purification based on continuous oligo-dT chromatography.

Oligo-deoxythymidine (oligo-dT) ligand-based affinity chromatography is a robust method for purifying mRNA drug substances within the manufacturing process of mRNA-based products, including vaccines and therapeutics. However, the conventional batch mode of operation for oligo-dT chromatography has certain drawbacks that reduce the productivity of this process. Here, we report a new continuous oligo-dT chromatography process for the purification of in vitro transcribed mRNA, which reduces losses, improves the efficiency of oligo-dT resin use, and intensifies the chromatography process. Furthermore, the quality by design (QbD) framework was used to establish a design space for the newly developed method. The optimization of process parameters (PPs), including salt type, salt concentration, load flow rate and mRNA load concentration both in batch and the continuous mode, achieved a greater than 90% yield (mRNA recovery) along with greater than 95% mRNA integrity and greater than 99% purity. The productivity of continuous chromatography was estimated to be 5.75-fold higher, and the operating cost was estimated 15% lower, when compared with batch chromatography. Moreover, the QbD framework was further used to map the relationship between critical quality attributes and key performance indicators as a function of critical process parameters and critical material attributes.

Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID-19.

Messenger RNA (mRNA) vaccines represent a new class of vaccines that has been shown to be highly effective during the COVID-19 pandemic and that holds great potential for other preventative and therapeutic applications. While it is known that the transcriptional activity of various genes is altered following mRNA vaccination, identifying and studying gene networks could reveal important scientific insights that might inform future vaccine designs. In this study, we conducted an in-depth weighted gene correlation network analysis of the blood transcriptome before and 24 h after the second and third vaccination with licensed mRNA vaccines against COVID-19 in humans, following a prime vaccination with either mRNA or ChAdOx1 vaccines. Utilizing this unsupervised gene network analysis approach, we identified distinct modular networks of co-varying genes characterized by either an expressional up- or downregulation in response to vaccination. Downregulated networks were associated with cell metabolic processes and regulation of transcription factors, while upregulated networks were associated with myeloid differentiation, antigen presentation, and antiviral, interferon-driven pathways. Within this interferon-associated network, we identified highly connected hub genes such as STAT2 and RIGI and associated upstream transcription factors, potentially playing important regulatory roles in the vaccine-induced immune response. The expression profile of this network significantly correlated with S1-specific IgG levels at the follow-up visit in vaccinated individuals. Those findings could be corroborated in a second, independent cohort of mRNA vaccine recipients. Collectively, results from this modular gene network analysis enhance the understanding of mRNA vaccines from a systems immunology perspective. Influencing specific gene networks could lead to optimized vaccines that elicit augmented vaccine responses.

The Potential of mRNA Vaccines to Fight Against Viruses.

Vaccines have always been a critical tool in preventing infectious diseases. However, the development of traditional vaccines often takes a long time and may struggle to address the challenge of rapidly mutating viruses. The emergence of mRNA technology has brought revolutionary changes to vaccine development, particularly in rapidly responding to the threat of emerging viruses. The global promotion of mRNA vaccines against severe acute respiratory syndrome coronavirus 2 has demonstrated the importance of mRNA technology. Also, mRNA vaccines targeting viruses such as influenza, respiratory syncytial virus, and Ebola are under development. These vaccines have shown promising preventive effects and safety profiles in clinical trials, although the duration of immune protection is still under evaluation. However, the development of mRNA vaccines also faces many challenges, such as stability, efficacy, and individual differences in immune response. Researchers adopt various strategies to address these challenges. Anyway, mRNA vaccines have shown enormous potential in combating viral diseases. With further development and technological maturity, mRNA vaccines are expected to have a profound impact on public health and vaccine equity. This review discussed the potential of mRNA vaccines to fight against viruses, current progress in clinical trials, challenges faced, and future prospects, providing a comprehensive scientific basis and reference for future research.

The self-assembled nanoparticle-based multi-epitope influenza mRNA vaccine elicits protective immunity against H1N1 and B influenza viruses in mice.

Introduction: The influenza virus is recognized as the primary cause of human respiratory diseases, with the current influenza vaccine primarily offering strain-specific immunity and limited protection against drifting strains. Considering this, the development of a broad-spectrum influenza vaccine capable of inducing effective immunity is considered the future direction in combating influenza. Methods: The present study proposes a novel mRNA-based multi-epitope influenza vaccine, which combines three conserved antigens derived from the influenza A virus. The antigens consist of M2 ion channel's extracellular domain (M2e), the conserved epitope of located in HA2 of hemagglutinin (H1, H3, B), and HA1 of hemagglutinin. At the same time, trimeric sequences and ferritin were conjugated separately to investigate the immune effects of antigen multivalent presentation. Results: Immunization studies conducted on C57BL/6 mice with these vaccines revealed that they can elicit both humoral immunity and CD4+ and CD8+ T cell responses, which collectively contribute to enhancing cross-protective effects. The virus challenge results showed that vaccinated groups had significantly reduced lung damage, lower viral loads in the lungs, nasal turbinates, and trachea, as well as decreased levels of pro-inflammatory cytokines. Conclusion: These findings clearly demonstrate the wide range of protective effects provided by these vaccines against H1N1 and B influenza viruses. The present finding highlights the potential of mRNA-based influenza vaccines encoding conserved proteins as a promising strategy for eliciting broad-spectrum protective humoral and cellular immunity against H1N1 and B influenza viruses.

Validation of an HPLC-CAD method for measuring the lipid content of novel LNP-encapsulated COVID-19 mRNA vaccines.

Lipid nanoparticles (LNPs) are frequently employed as mRNA vaccine delivery vehicles. LNPs are made up of four types of lipids: cationic lipid, PEG-lipid conjugate, zwitterionic helper phospholipid, and cholesterol. LNP distribution efficiency is significantly impacted by lipid composition, which also controls LNP stability and bilayer fluidity. The various lipids used in the formulation system have distinct properties and contents. To aid in the development of new drugs and vaccines, we developed and validated an HPLC-CAD method for identifying and determining the amounts of four lipids in Yuxi Watson Biotechnology Co., Ltd.'s LNP-encapsulated COVID-19 mRNA vaccines (OmicronXBB.1.5).

mRNA-Based Cancer Vaccines: Advancements and Prospects.

The success of mRNA COVID-19 vaccines has reinvigorated research and interest in mRNA-based cancer vaccines. Despite promising results in clinical trials, therapeutic mRNA-based cancer vaccines have not yet been approved for human use. These vaccines are designed to trigger tumor regression, establish enduring antitumor memory, and mitigate adverse reactions. However, challenges such as tumor-induced immunosuppression and immunoresistance significantly hinder their application. Here, we provide an overview of the recent advances of neoantigen discovery and delivery systems for mRNA vaccines, focusing on improving clinical efficacy. Additionally, we summarize the recent clinical advances involving mRNA cancer vaccines and discuss prospective strategies for overcoming immuneresistance.

Spleen-Targeted mRNA Vaccine Doped with Manganese Adjuvant for Robust Anticancer Immunity In Vivo.

The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn2+) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.

Acute autoimmune hepatitis following COVID-19 mRNA vaccination: A population-based study using electronic health records in Singapore.

Reports of coronavirus disease 2019 (COVID-19) vaccine-induced autoimmune hepatitis (AIH) have been largely limited to case reports and case series. To further investigate the association between COVID-19 mRNA vaccination and AIH, we conducted a nationwide study using observed-over-expected (O/E) and Self-Controlled Case Series (SCCS) analyses for acute presentations of AIH (AAIH) warranting admission. Patients were included if they had one or more of the following hepatitis-related signs and symptoms (fever, lethargy, jaundice or abdominal pain) reported up to 3 months prior to admission, deranged liver function tests [alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than three times the upper limit of laboratory reference ranges], as well as biopsy results characteristic of AIH or response to steroid treatment for cases which did not undergo biopsy. Seventy-six patients fulfilled our case definition of AAIH within the study period from 1 January 2019 to 28 February 2023, with 6 patients having an estimated onset of AAIH within 42 days of COVID-19 mRNA vaccination. All 6 patients were females aged 40 years and above. In the O/E analysis, the rate ratios of AAIH among females aged 40 years and above in the primary cohort were 1.12 (95% confidence interval (CI) 0.14-9.40) and 1.06 (95% CI 0.24-4.74) in the 21 days and 42 days following vaccination respectively. In the SCCS analysis, we did not observe any statistically significant increase in incidence of AAIH in the 21 and 42 days following COVID-19 mRNA vaccination for both the primary and supplementary cohorts, as well as in the subgroup analysis involving females aged 40 years and above. Our findings suggest that COVID-19 mRNA vaccination does not appear to be associated with increased risk of AAIH requiring admissions in the population, although larger studies are required to confirm these findings.

Myocarditis Associated with COVID-19 Vaccination.

Myocarditis after the COVID-19 vaccine is one of the important adverse events following immunization, observed mainly after mRNA-based vaccines. Importantly, post-vaccination myocarditis was less common than myocarditis after SARS-CoV-2 infection, as it was scored at 19.7 per 1,000,000 doses and 2.76 per 1000 infections. Predominantly, its course was benign and, compared with the myocarditis after COVID-19 infection, significantly fewer patients developed heart failure or died among patients with post-vaccination myocarditis. The group at highest risk of myocarditis related to COVID-19 vaccination were young males who received a second dose of an mRNA vaccine. It was observed that, among mRNA vaccines, specifically mRNA-1273 was associated with a higher risk of myocarditis. The mechanism underlying myocarditis after COVID-19 vaccination is still under investigation and certain processes are being considered. Currently, some follow-up assessments of patients who developed vaccine-induced myocarditis are available and suggest a favorable prognosis. The aim of this review is to discuss the most recent data on myocarditis after COVID-19 vaccination considering its epidemiology, clinical presentation, diagnosis, management, relative risk of myocarditis compared with SARS-CoV-2 infection, potential underlying mechanism, and follow-up data of patients who developed post-vaccination myocarditis.

Neonatal and maternal outcomes of mRNA versus Non-mRNA COVID-19 vaccines in pregnant patients: a systematic review and meta-analysis.

Objective: To compare the effectiveness and safety of non-mRNA versus mRNA COVID-19 vaccines on pregnant women and their newborns in a systematic review with meta-analysis. Data sources: We searched PubMed, Embase, and Cochrane Central in May 2023. Study selection: The search strategy yielded 4451 results, 16 studies were fully reviewed. We selected case-control studies analysing non-mRNA versus mRNA vaccines. Data collection and analysis: we assessed the risk of bias using the Cochrane Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool. Standardised mean differences were pooled using random-effect models. Data synthesis: We identified 8 prospective and retrospective studies with a total of 32,153 patients. Non-mRNA vaccines were associated with a higher incidence of fever (OR 2.67; 95% CI 2.08-3.43; p<0.001), and a lower incidence of fetal or neonatal death (OR 0.16; 95% CI 0.08-0.33; p<0.001). In subgroup analyses, the Jansen vaccine (Ad26.COV2.S) was found to have a higher rate of premature labor/delivery (OR 4.48; 95% CI 1.45-13.83; p=0.009) and missed/spontaneous abortion (OR 1.90; 95% CI 1.09-3.30; p=0.02), as compared with the Pfizer (BNT162b2) vaccine. Conclusion: non-mRNA vaccines are associated with a lower incidence of fetal or neonatal death among pregnant women who receive a Covid19 vaccine, although at an increased rate of pyrexia compared with mRNA vaccines. Other studies are required for better assessment. PROSPERO: CRD42023421814.

Influencing Canadian young adults to receive additional COVID-19 vaccination shots: the efficacy of brief video interventions focusing on altruism and individualism.

Younger adults, aged 18-39 years, exhibit low COVID-19 additional vaccine (i.e., vaccination beyond the original 2-dose series) uptake recommended in Canada. No study has examined how altruistic and individualistic messaging can influence COVID-19 additional dose intentions. The present study aimed to estimate the efficacy of altruism and individualism-based videos on vaccine intentions and to explore the multivariable associations between vaccine related individual psychosocial factors and intention to receive the COVID-19 vaccine. Using a web-based survey in a three-arm, pre-post randomized control trial design, we recruited Canadians aged 18-39 years in both English and French. Participants were randomly allocated in a 1:1:1 ratio to receive the active control (COVID-19 general information), control + altruism or control + altruism + individualism. The video interventions were developed with a media company, based on results of a focus group study conducted previously. The measurement of COVID-19 additional dosage intentions before and after completing the interventions was informed by the multistage Precaution Adoption Process Model. The McNemar Chi-square was used to evaluate within-group changes, and the Pearson Chi-square test was used to evaluate between-group changes post-intervention. The measurement of various psychosocial factors was informed by use of validated scale and self-report questions. We employed a generalized Structural Equation Model to evaluate the associations between COVID-19 vaccine intentions and the psychosocial factors. Analyses were performed on 3,431 participants (control: n = 1,149, control + altruism: n = 1,142, control + altruism + individualism: n = 1,140). Within-group results showed that participants transitioned significantly in all three groups in the direction of higher intentions for receiving additional COVID-19 vaccine doses. The between-group differences in post intervention vaccine intentions were not significant. We found that psychosocial factors that include, collectivism, intellectual humility, intolerance to uncertainty, religiosity, identifying as gender diverse, and being indigenous were associated with higher vaccine intentions, whereas pandemic fatigue was associated with lower vaccine intentions. Our study highlighted that a short video that includes altruism and individualism messaging or general COVID-19 information can increase intentions to vaccine among young adults. Furthermore, we gained a comprehensive understanding of various psychosocial factors that influence ongoing COVID-19 vaccination. Our findings can be used to influence public health messaging around COVID-19 vaccination.

Three doses of Sars-CoV-2 mRNA vaccine in older adults result in similar antibody responses but reduced cellular cytokine responses relative to younger adults.

Objectives: Booster COVID-19 vaccinations are used to protect the elderly, a group vulnerable to severe disease. We compared humoral and cellular immunity in older versus younger adults up to eight months after administering a BNT16b2 booster vaccine dose. Next, we analyzed the plasma levels of soluble T cell activation/exhaustion markers. Methods: Home-dwelling older adults (n = 68, median age 86) and younger healthcare workers (n = 35, median age 39), previously vaccinated with two doses of BNT162b2, were given a booster dose at ten months after the initial dose. Our analysis consisted of spike-specific IgG, neutralizing antibodies, memory B cells, IFN-γ and IL-2 secreting T cells and soluble T cell exhaustion/activation markers. Results: Following the initial two doses, the elderly cohort exhibited lower humoral and IFN-γ responses compared to younger adults. The booster dose increased the humoral responses in both older and younger adults. At two months after the booster dose, older and younger vaccinees had comparable levels of antibodies and the responses were maintained up to 18 months. The younger cohort elicited an increase in the cellular response, while no increase was detected in the elderly. The elderly had higher plasma levels of soluble forms of the T cell activation/exhaustion markers CD25 and TIM-3, which inversely correlated with age and T-cell cytokine responses. This suggests that these markers may be related to the observed dysfunctional cellular cytokine response in older adults. However, both elderly and younger adults who experienced breakthrough infections after booster vaccination, elicited more robust humoral and IFN-γ responses. Conclusions: The booster dose elicited neutralizing and spike-specific antibody responses in the elderly that were comparable with that of the younger cohort. However, the lack of a strong cellular cytokine response to the third dose in the elderly may explain their vulnerability to severe infection and may be a consequence of exhausted or senescent T cell responses. (https://clinicaltrials.gov/study/NCT04706390).

Lipid-based Non-viral Vector: Promising Approach for Gene Delivery.

OBJECTIVES: The present review aims to discuss various strategies to overcome intracellular and extracellular barriers involved in gene delivery as well as the advantages, challenges, and mechanisms of gene delivery using non-viral vectors. Additionally, patents, clinical studies, and various formulation approaches related to lipid-based carrier systems are discussed. METHODS: Data were searched and collected from Google Scholar, ScienceDirect, Pubmed, and Springer. RESULTS: In this review, we have investigated the advantages of non-viral vectors over viral vectors. The advantage of using non-viral vectors are that they seek more attention in different fields. They play an important role in delivering the genetic materials. However, few nonviral vector-based carrier systems have been found in clinical settings. Challenges are developing more stable, site-specific gene delivery and conducting thorough safety assessments to minimize the undesired effects. CONCLUSION: In comparison to viral vectors, nonviral vector-based lipid nanocarriers have more advantages for gene delivery. Gene therapy research shows promise in addressing health concerns. Lipid-based nanocarriers can overcome intracellular and extracellular barriers, allowing efficient delivery of genetic materials. Non-viral vectors are more attractive due to their biocompatibility, ease of synthesis, and cost-effectiveness. They can deliver various nucleic acids and have improved gene delivery efficacy by avoiding degradation steps. Despite limited clinical use, many patents have been filed for mRNA vaccine delivery using non-viral vectors.

Effectiveness and Safety of mRNA Vaccines in the Therapy of Glioblastoma.

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy.

Molecular Dynamics Simulation of Lipid Nanoparticles Encapsulating mRNA.

mRNA vaccines have shown great potential in responding to emerging infectious diseases, with their efficacy and stability largely dependent on the delivery vehicles-lipid nanoparticles (LNPs). This study aims to explore the mechanisms by which LNPs encapsulate mRNA, as well as the effects of different N/P ratios and acid types in nucleic acid solutions on the structure and properties of LNPs, using the ethanol solvent injection method as the encapsulation technique. Six systems were designed, based on the composition and proportions of the existing mRNA vaccine mRNA-1273, and molecular dynamics (MD) simulations were employed to investigate the self-assembly process of LNPs. Ethanol was used as a solvent instead of pure water to better mimic experimental conditions. The results indicate that lipid components self-assemble into nanoparticles under neutral conditions, with the ionizable lipid SM-102 predominantly concentrating in the core of the particles. Upon mixing with nucleic acids in acidic conditions, LNPs undergo disassembly, during which protonated SM-102 encapsulates mRNA through electrostatic interactions, forming stable hydrogen bonds. Cluster structure analysis revealed that the four lipid components of LNPs are distributed sequentially from the outside inwards as DMG-PEG 2000, DSPC, cholesterol, and protonated SM-102. Moreover, LNPs constructed under low pH or low N/P ratios using citric acid exhibited larger volumes and more uniform distribution. These findings provide a scientific basis for further designing and optimizing LNP components to enhance the efficacy of mRNA vaccine encapsulation.

Current status of nucleic acid therapy and its new progress in cancer treatment.

Nucleic acid is an essential biopolymer in all living cells, performing the functions of storing and transmitting genetic information and synthesizing protein. In recent decades, with the progress of science and biotechnology and the continuous exploration of the functions performed by nucleic acid, more and more studies have confirmed that nucleic acid therapy for living organisms has great medical therapeutic potential. Nucleic acid drugs began to become independent therapeutic agents. As a new therapeutic method, nucleic acid therapy plays an important role in the treatment of genetic diseases, viral infections and cancers. There are currently 19 nucleic acid drugs approved by the Food and Drug Administration (FDA). In the following review, we start from principles and advantages of nucleic acid therapy, and briefly describe development history of nucleic acid drugs. And then we give examples of various RNA therapeutic drugs, including antisense oligonucleotides (ASO), mRNA vaccines, small interfering RNA (siRNA) and microRNA (miRNA), aptamers, and small activating RNA (saRNA). In addition, we also focused on the current status of nucleic acid drugs used in cancer therapy and the breakthrough in recent years. Clinical trials of nucleic acid drugs for cancer treatment are under way, conventional radiotherapy and chemotherapy combined with the immunotherapies such as checkpoint inhibitors and nucleic acid drugs may be the main prospects for successful cancer treatment.

Is there still hope for the prophylactic hepatitis C vaccine? A review of different approaches.

Despite remarkable progress in the treatment of hepatitis C virus (HCV) infection, it remains a significant global health burden, necessitating the development of an effective prophylactic vaccine. This review paper presents the current landscape of HCV vaccine candidates and approaches, including more traditional, based on inactivated virus, and more modern, such as subunit protein, vectored, based on nucleic acids (DNA and mRNA) and virus-like particles. The concept of the HCV vaccine is first put in the context of viral genetic diversity and adaptive responses to HCV infection, an understanding of which is crucial in guiding the development of an effective vaccine against such a complex virus. Because ethical dimensions are also significant in vaccine research, development, and potential deployment, we also address them in this paper. The road to a safe and effective vaccine to prevent HCV infection remains bumpy due to the genetic variation of HCV and its ability to evade immune responses. The progress in cell-culture systems allowed for the production of an inactivated HCV vaccine candidate, which can induce cross-neutralizing antibodies in vitro, but whether this could prevent infection in humans is unknown. Subunit protein vaccine candidates that entered clinical trials elicited HCV-specific humoral and cellular responses, though it remains to be shown whether they translate into effective prevention of HCV infection or progression of infection to a chronic state. Such responses were also induced by a clinically tested vector-based vaccine candidate, which decreased the viral HCV load but did not prevent chronic HCV infection. These disappointments were not readily predicted from preclinical animal studies. The vaccine platforms employing virus-like particles, DNA, and mRNA provide opportunities for the HCV vaccine, but their potential in this context has yet to be shown. Ensuring the designed vaccine is based on conserved epitope(s) and elicits broadly neutralizing immune responses is also essential. Given failures in developing a prophylactic HCV vaccine, it is crucial to continue supporting national strategies, including funding for screening and treatment programs. However, these actions are likely insufficient to permanently control the HCV burden, encouraging further mobilization of significant resources for HCV vaccine research as a missing element in the elimination of viral hepatitis as a global public health.

The Impact of Vaccination on the Likelihood of COVID-19 Infection.

The current study investigates COVID-19 infection likelihood using data from 5,819 respondents in Vietnam and Indonesia (December 10, 2022, to March 27, 2023) through binary logistic regressions. Descriptive statistics highlight the significance of vaccination status, with almost half of unvaccinated respondents contracting the infection. The second vaccine dose showed the lowest infection percentages, suggesting a potential dose-dependent effect. Those receiving mRNA vaccines consistently had reduced infection likelihood across the first four doses, with an unexpected reversal for the fifth dose. Vaccinated individuals, especially with mRNA vaccines, had faster recovery times, and variability in recovery times and milder symptoms were observed in mRNA vaccine recipients. Regression results from Model 1 reveal a substantial impact of vaccination, with vaccinated respondents having ∼48.1% lower odds than the unvaccinated. Model 2 underscores a dose-dependent protective effect, with each additional dose associated with a notable 6.6% reduction in infection likelihood. Beyond vaccination, gender, family size, marital status, employment, urban residence, and nationality influenced infection likelihood. Males, larger families, single marital status, unemployment, rural residence, and Indonesian nationality increased the likelihood of infection. Surprisingly, respondents with infected family members exhibited a lower infection likelihood, suggesting potential protective measures within households. These findings highlight COVID-19 dynamics, and ongoing research refines comprehension.