Compounds from Natural Products Candidates to Drug for Chikungunya Virus Infection: A Systematic Review.

INTRODUCTION: Chikungunya fever is a disease caused by infection with the Chikungunya virus, transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Despite its self-limited character, more than 60% of patients have chronic recurrent arthralgia with debilitating pain that lasts for years. AIM: The objective of this review was to gather and analyze evidence from the literature on potential therapeutic strategies with molecules from natural products for the treatment of Chikungunya fever. METHODS: A search was performed for clinical trials, observational studies, in vitro or in vivo, without restriction of the year of publication or language in electronic databases (Medline/PubMed, EMBASE, Google Scholar, The Cochrane Library, LILACS (BVS), clinical trial registries (Clinical Trials.gov), digital libraries from CAPES theses and dissertations (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil) and conference abstracts. A quality assessment of the selected studies was performed using the SYRCLE, RoB2 and SciRAP tools. RESULTS: 42 studies were included, which showed molecules with potential antiviral pharmacological activity or with activity in reducing the joint complications caused by CHIKV infection. CONCLUSIONS: Among the molecules found in the survey of references, regarding the class of secondary metabolites, flavonoids stood out and for this reason, the molecules may be promising candidates for future clinical trials. Overall, evidence from in vitro studies was of acceptable quality; in vivo and intervention studies showed a high risk of bias, which is a limitation of these studies.

Optimization of benzenesulfonyl derivatives as anti-Trypanosomatidae agents: Structural design, synthesis, and pharmacological assessment against Trypanosoma cruzi and Leishmania infantum.

Leishmaniasis and Chagas disease are neglected tropical diseases caused by Trypanosomatidae parasites. Given the numerous limitations associated with current treatments, such as extended treatment duration, variable efficacy, and severe side effects, there is an urgent imperative to explore novel therapeutic options. This study details the early stages of hit-to-lead optimization for a benzenesulfonyl derivative, denoted as initial hit, against Trypanossoma cruzi (T. cruzi), Leishmania infantum (L. infantum) and Leishmania braziliensis (L. braziliensis). We investigated structure - activity relationships using a series of 26 newly designed derivatives, ultimately yielding potential lead candidates with potent low-micromolar and sub-micromolar activities against T. cruzi and Leishmania spp, respectively, and low in vitro cytotoxicity against mammalian cells. These discoveries emphasize the significant promise of this chemical class in the fight against Chagas disease and leishmaniasis.

Strongyloides infection screening in transplant candidates: What is the best strategy?

BACKGROUND: The potential that Strongyloides stercoralis infection has to cause major morbidity and high mortality when the disseminated form occurs in transplant patients is of particular concern. METHODS: In this study, the objective was to observe S. stercoralis infection in patients who are candidates for transplantation by using parasitological, serological, and molecular techniques and to propose an algorithm for the detection of that infection in transplant candidates. RESULTS: By parasitological techniques, 10% of fecal samples were positive. Anti-Strongyloides antibodies immunoglobulin G were detected in 19.3% and 20.7% of patients by immunofluorescence assay and enzyme-linked immunosorbent assay, respectively. S. stercoralis DNA was observed in 17.3% of samples by conventional polymerase chain reaction and 32.7% of samples by quantitative polymerase chain reaction (qPCR). CONCLUSION: The set of results allows us to reinforce that a positive result by parasitological techniques and/or qPCR indicates that the specific treatment should be applied. However, the improvement of diagnostic techniques may suggest changes in the screening for strongyloidiasis in these patients.

Antitrypanosomal Activity of 1,2,3-Triazole-Based Hybrids Evaluated Using In Vitro Preclinical Translational Models.

Chagas disease therapy still relies on two nitroderivatives, nifurtimox and benznidazole (Bz), which have important limitations and serious adverse effects. New therapeutic alternatives for this silent disease, which has become a worldwide public health problem, are essential for its control and elimination. In this study, 1,2,3-triazole analogues were evaluated for efficacy against T. cruzi. Three triazole derivatives, 1d (0.21 µM), 1f (1.23 µM), and 1g (2.28 µM), showed potent activity against trypomastigotes, reaching IC50 values 10 to 100 times greater than Bz (22.79 µM). Promising candidates are active against intracellular amastigotes (IC50 ≤ 6.20 µM). Treatment of 3D cardiac spheroids, a translational in vitro model, significantly reduced parasite load, indicating good drug diffusion and efficacy. Oral bioavailability was predicted for triazole derivatives. Although infection was significantly reduced without drug pressure in a washout assay, the triazole derivatives did not inhibit parasite resurgence. An isobologram analysis revealed an additive interaction when 1,2,3-triazole analogs and Bz were combined in vitro. These data indicate a strengthened potential of the triazole scaffold and encourage optimization based on an analysis of the structure-activity relationship aimed at identifying new compounds potentially active against T. cruzi.

What Do We Know about Surface Proteins of Chicken Parasites Eimeria?

Poultry is the first source of animal protein for human consumption. In a changing world, this sector is facing new challenges, such as a projected increase in demand, higher standards of food quality and safety, and reduction of environmental impact. Chicken coccidiosis is a highly widespread enteric disease caused by Eimeria spp. which causes significant economic losses to the poultry industry worldwide; however, the impact on family poultry holders or backyard production-which plays a key role in food security in small communities and involves mainly rural women-has been little explored. Coccidiosis disease is controlled by good husbandry measures, chemoprophylaxis, and/or live vaccination. The first live vaccines against chicken coccidiosis were developed in the 1950s; however, after more than seven decades, none has reached the market. Current limitations on their use have led to research in next-generation vaccines based on recombinant or live-vectored vaccines. Next-generation vaccines are required to control this complex parasitic disease, and for this purpose, protective antigens need to be identified. In this review, we have scrutinised surface proteins identified so far in Eimeria spp. affecting chickens. Most of these surface proteins are anchored to the parasite membrane by a glycosylphosphatidylinositol (GPI) molecule. The biosynthesis of GPIs, as well as the role of currently identified surface proteins and interest as vaccine candidates has been summarised. The potential role of surface proteins in drug resistance and immune escape and how these could limit the efficacy of control strategies was also discussed.

Traditional herbal compounds as candidates to inhibit the SARS-CoV-2 main protease: an in silico study.

COVID-19, a disease caused by the SARS-CoV-2 virus, is responsible for a pandemic since March 2020 and it has no cure. Therefore, herein, different theoretical methods were used to obtain potential candidates from herbal compounds to inhibit the SARS-CoV-2 main protease (Mpro). Initially, the 16 best-scored compounds were selected from a library containing 4066 ligands using virtual screening by molecular docking. Among them, six molecules (physalin B 5,6-epoxide (PHY), methyl amentoflavone (MAM), withaphysalin C (WPC), daphnoline or trilobamine (TRI), cepharanoline (CEP) and tetrandrine (TET)) were selected based on Lipinski's rule and ADMET analysis as criteria. These compounds complexed with the Mpro were submitted to triplicate 100 ns molecular dynamics simulations. RMSD, RMSF, and radius of gyration results show that the overall protein structure is preserved along the simulation time. The average ΔGbinding values, calculated by the MM/PBSA method, were -41.7, -55.8, -45.2, -38.7, -49.3, and -57.9 kcal/mol for the PHY-Mpro, MAM-Mpro, WPC-Mpro, CEP-Mpro, TRI-Mpro, and TET-Mpro complexes, respectively. Pairwise decomposition analyses revealed that the binding pocket is formed by His41-Val42, Met165-Glu166-Leu167, Asp187, and Gln189. The PLS regression model generated by QSPR analysis indicated that non-polar and polar groups with the presence of hydrogen bond acceptors play an important role in the herbal compounds-Mpro interactions. Overall, we found six potential candidates to inhibit the SARS-CoV-2 Mpro and highlighted key residues from the binding pocket that can be used for future drug design. Communicated by Ramaswamy H. Sarma.

Identification of inhibitors as drug candidates against Chagas disease.

Chagas disease, after more than a century after its discovery, is still a major public health problem. It is estimated that approximately 10 million people worldwide are infected with T. cruzi. However, the situation is more critical in Latin America and other regions where the disease is endemic. The largest number of cases occurs in Brazil, Argentina, and Mexico as more than 100 million people in these regions are located in areas with a high risk of contamination by the vector. The need for new therapeutic alternatives is urgent, as the available drugs have severe limitations such as low efficacy and high toxicity. From this scenario, in this work, we employed the virtual screening technique using cruzain and BDF2 as key biological targets for the survival of the parasite. Our objective was to identify potential inhibitors of T. cruzi trypomastigotes, which could be considered drug candidates against Chagas disease. For this, we employed different in silico methodologies and the obtained results were corroborated using in vitro biological assays. For the VS studies, a database containing synthetic compounds was simulated at the binding site of cruzain and BDF2. In addition, pharmacophoric models were constructed in the initial phases of VS, as well as other advanced analyses (molecular dynamics simulations, calculations of binding free energy, and ADME prediction) were carried out and the results allowed the selection of potential inhibitors of T. cruzi. Based on the obtained data, 32 different compounds commercially available were subjected to biological tests against the trypomastigote form of T. cruzi. As result, 11 of those compounds displayed significant activity against T. cruzi and can be considered potential candidates for the treatment of Chagas disease.

Nonparametric cognitive diagnosis of profiles of mathematical knowledge of teacher education candidates.

Traditionally, the selection process of teacher candidates has emphasized the assessment of subject matter and pedagogical knowledge using psychometric methodologies, which simply organize candidates in continuous scales and require a large number of samples. However, these methods do not allow for the identification of candidates' knowledge profiles and learning paths, which would help develop programs tailored to support students in their training process. In this study, an evaluation instrument was developed by using the nonparametric approach to model diagnostic classifications and was then validated on a sample of 119 participants. This instrument allows for disaggregating candidates' initial knowledge and establishing relationships between its components. The results showed that candidates present a variety of profiles, which may consider more than one attribute. Not only does it provide a score that can be used for selection processes, it also provides useful information for initial teacher training methods.

Blood donor candidates and blood donations performed between 2005 and 2019 in Minas Gerais, Brazil: A time series analysis

ABSTRACT Introduction: Time series studies related to blood donor candidates and blood donations are rare in Brazil. Population aging suggests a better understanding of the context related to blood donor candidates and blood donations performed. Objective: The monthly series of candidates eligible to donate blood and actual donations between 2005 and 2019 at the Hemominas Foundation, Minas Gerais, Brazil, were described and analyzed. Methods: Ten time series were constructed of blood donor candidates and blood donations. Each series covered the period from January 2005 to December 2019. The stationarity of the series was verified by the unit root test; the data distribution, by the Shapiro-Wilk test; the trend, by the Cox-Stuart test, and; the seasonality, by the Fisher's test (significance levels of 10% for the first test and 5% for the last three). Results: All series were identified as non-stationary and presented trend and seasonality components. The rate of blood donor candidates and the rate of blood donations performed evidenced a positive upward trend until the last two-year analysis, when a drop occurred, from 1.75% and 1.42% in 2017 to 1.64% and 1.35% in 2019, respectively. The rate of blood donations trended downward, from 0.054% in 2005 to 0.046% in 2019. The proportion of unsuitable or unretained candidates reduced. Conclusion: The study emphasized the need to stimulate blood donation by specific groups and increase ways to reduce the demand for blood components through the implementation of programs that expand alternatives to blood transfusions.

The effects of a 6-month mandatory military police academy training on recruits' physical fitness.

BACKGROUND: Physical fitness for health and professional performance play important roles in police workforce considering that policing is a dangerous job, associated with high physical demands. OBJECTIVES: (1) To evaluate the effects of a 6-month course of police academy training on health-related physical fitness (HRPF) of military police recruits. (2) To investigate whether recruits' HRPF still met the academy entry standards after an unsupervised 7-month period prior to academy. METHODS: We conducted an observational and longitudinal study with 219 male police recruits (aged 25.5±3.6 years; BMI of 24.4±2.5 kg/m2). HRPF parameters included the Cooper 12-min running test for cardiorespiratory fitness (CRF), curl-ups, pull-ups and push-ups for muscle strength/endurance which were evaluated 3 times: 7 months prior to academy course and pre- and post-academy training period. RESULTS: Participants maintained optimal age-related HRPF during the unsupervised period prior to academy. After academy training upon graduation, all HRPF parameters further increased an average of 7.7 to 69.0% (p < 0.001; calculated Cohen's d effect size ≥0.95). CRF was the only HRPF that improved less than 10% after the academy course. CONCLUSIONS: Police recruits that had passed the application fitness standards maintained their HRPF prior to academy, and all their HRPF parameters increased after a 6-month academy training period which was not primarily focused on exercise training. Among all components of HRPF, CRF appears to be the most challenging one to improve among police recruits. Our findings suggest that regular training with minimum physical standards could be potentially beneficial to police officers' health and career longevity.

Replication and transmission features of two experimental vaccine candidates against bovine tuberculosis subcutaneously administrated in a murine model.

Cattle vaccination is an attractive approach in compliance with control and eradication programs against Bovine Tuberculosis (bTB). Today, there is no anti bTB vaccine licensed. Two vaccine candidates, MbΔmce2 and MbΔmce2-phoP previously designed were evaluated in BALB/c mice, including the parental M. bovis NCTC10772 and a M. bovis hypervirulent Mb04-303 strains as controls. Sentinel mice (non-inoculated) cohoused with subcutaneous inoculated mice. Persistence, visible tuberculosis lesions (VTL) in lungs and spleens and bacillary load were investigated subcutaneously delivered at 60 and 90 days after inoculation (dpi) as well as their potential transmission to naïve mice. While a 100% survival was observed at 90 dpi without VTL in all groups, transmission was not evidenced in the sentinels mice. Vaccine candidates and control strains were isolated from the spleen of all inoculated mice, while Mb04-303 was isolated from the lungs of one inoculated mouse. Vaccine candidate's attenuation considering survival, lung bacillary load and VTL was confirmed, administrated by the subcutaneous route. Future experiments are necessary to demonstrate whether the persistence of both mutants in the spleen, with low CFU, remains over time to increase the potential increasing risk of dissemination to organs and subsequent transmission to other animals by airborne or other routes.

Immune complexes as a tool for strongyloidiasis immunodiagnosis in kidney and liver transplant candidate.

Strongyloidiasis is a chronic and asymptomatic infection in immunocompetent patients. Immunocompromised patients, such as organ transplant candidates, can develop severe forms of this disease, and the best way to prevent progression to these forms is early diagnosis. Serological techniques using specific IgG and immune complexes (IC) detection can help in the diagnosis of these patients. This study aimed to detect specific anti-Strongyloides IC and IgG antibodies in kidney transplant (KT) and liver transplant (LT) candidates. A total of 100 blood samples was collected from transplant candidates (50 blood samples each from KT and LT candidates). Serum was obtained and analysed using enzyme-linked immunosorbent assay for IC and IgG detections. The IC levels showed frequencies of 18% and 2% in the KT and LT groups, respectively, whereas anti-Strongyloides IgG was detected in 34% and 12% of KT and LT candidates, respectively. The correlation between IC and IgG detection is poor in KT candidates, while in LT candidates, there is a significant positive correlation. The detection of IC can be an additional tool for the diagnosis of strongyloidiasis, especially when associated with the detection of specific IgG anti-Strongyloides antibodies.

Blood donor candidates and blood donations performed between 2005 and 2019 in Minas Gerais, Brazil: A time series analysis.

INTRODUCTION: Time series studies related to blood donor candidates and blood donations are rare in Brazil. Population aging suggests a better understanding of the context related to blood donor candidates and blood donations performed. OBJECTIVE: The monthly series of candidates eligible to donate blood and actual donations between 2005 and 2019 at the Hemominas Foundation, Minas Gerais, Brazil, were described and analyzed. METHODS: Ten time series were constructed of blood donor candidates and blood donations. Each series covered the period from January 2005 to December 2019. The stationarity of the series was verified by the unit root test; the data distribution, by the Shapiro-Wilk test; the trend, by the Cox-Stuart test, and; the seasonality, by the Fisher's test (significance levels of 10% for the first test and 5% for the last three). RESULTS: All series were identified as non-stationary and presented trend and seasonality components. The rate of blood donor candidates and the rate of blood donations performed evidenced a positive upward trend until the last two-year analysis, when a drop occurred, from 1.75% and 1.42% in 2017 to 1.64% and 1.35% in 2019, respectively. The rate of blood donations trended downward, from 0.054% in 2005 to 0.046% in 2019. The proportion of unsuitable or unretained candidates reduced. CONCLUSION: The study emphasized the need to stimulate blood donation by specific groups and increase ways to reduce the demand for blood components through the implementation of programs that expand alternatives to blood transfusions.

Plasmodium vivax vaccine: What is the best way to go?

Malaria is one of the most devastating human infectious diseases caused by Plasmodium spp. parasites. A search for an effective and safe vaccine is the main challenge for its eradication. Plasmodium vivax is the second most prevalent Plasmodium species and the most geographically distributed parasite and has been neglected for decades. This has a massive gap in knowledge and consequently in the development of vaccines. The most significant difficulties in obtaining a vaccine against P. vivax are the high genetic diversity and the extremely complex life cycle. Due to its complexity, studies have evaluated P. vivax antigens from different stages as potential targets for an effective vaccine. Therefore, the main vaccine candidates are grouped into preerythrocytic stage vaccines, blood-stage vaccines, and transmission-blocking vaccines. This review aims to support future investigations by presenting the main findings of vivax malaria vaccines to date. There are only a few P. vivax vaccines in clinical trials, and thus far, the best protective efficacy was a vaccine formulated with synthetic peptide from a circumsporozoite protein and Montanide ISA-51 as an adjuvant with 54.5% efficacy in a phase IIa study. In addition, the majority of P. vivax antigen candidates are polymorphic, induce strain-specific and heterogeneous immunity and provide only partial protection. Nevertheless, immunization with recombinant proteins and multiantigen vaccines have shown promising results and have emerged as excellent strategies. However, more studies are necessary to assess the ideal vaccine combination and test it in clinical trials. Developing a safe and effective vaccine against vivax malaria is essential for controlling and eliminating the disease. Therefore, it is necessary to determine what is already known to propose and identify new candidates.

New putative therapeutic targets against Serratia marcescens using reverse vaccinology and subtractive genomics.

The Gram-negative bacillus Serratia marcescens, a member of Enterobacteriaceae family, is an opportunistic nosocomial pathogen commonly found in hospital outbreaks that can cause infections in the urinary tract, bloodstream, central nervous system and pneumonia. Because S. marcescens strains are resistant to several antibiotics, it is critical the need for effective treatments, including new drugs and vaccines. Here, we applied reverse vaccinology and subtractive genomic approaches for the in silico prediction of potential vaccine and drug targets against 59 strains of S. marcescens. We found 759 core non-host homologous proteins, of which 87 are putative surface-exposed proteins, 183 secreted proteins, and 80 membrane proteins. From these proteins, we predicted seven candidates vaccine targets: a sn-glycerol-3-phosphate-binding periplasmic protein UgpB, a vitamin B12 TonB-dependent receptor, a ferrichrome porin FhuA, a divisome-associated lipoprotein YraP, a membrane-bound lytic murein transglycosylase A, a peptidoglycan lytic exotransglycosylase, and a DUF481 domain-containing protein. We also predicted two drug targets: a N(4)-acetylcytidine amidohydrolase, and a DUF1428 family protein. Using the molecular docking approach for each drug target, we identified and selected ZINC04259491 and ZINC04235390 molecules as the most favorable interactions with the target active site residues. Our findings may contribute to the development of vaccines and new drug targets against S. marcescens. Communicated by Ramaswamy H. Sarma.

Perspectives for a new drug candidate for Chagas disease therapy

Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.

O mal-estar na formação psicanalítica: ameaças à função generativa dos Institutos e Sociedades em que ocorre a formação psicanalítica / Processes of infantilization in psychoanalytic training: threats to the generative function of the institutes/societies in which psychoanalytic training takes place / El malestar en la formación psicoanalítica: amenazas a la función generativa de los Institutos y Sociedades en los que se desarrolla la formación psicoanalítica / Le malaise au sein de la formation psychanalytique: des menaces à la fonction générative des instituts et des sociétés où se passe la formation psychanalytique

Neste artigo, a autora focaliza a transmissão da psicanálise através da formação das próximas gerações. Destaca a tensão entre a necessidade dos psicanalistas de trabalhar em conjunto em uma instituição e a de manter certa distância, que possibilite uma terceira perspectiva quanto à sua identificação com o Instituto. Nesse contexto, apresenta o novo mandato do Comitê de Educação Psicanalítica (pec) e o seu projeto Encontros de Sociedades sobre Educação. Discute a questão da participação de candidatos/analistas em formação dentro dos Institutos. Aborda especialmente o desafio da supervisão na formação e suas vicissitudes. Outro tópico considerado são os seminários teóricos e a exigência de que os professores não confundam a necessária transmissão da tradição com idealizações do passado psicanalítico, e aceitem a natureza finita da sua compreensão da psicanálise.

This paper focuses on the transmission of psychoanalysis in training to the next generation. The tension between the need for psychoanalysts to work together in an institution and still maintain a certain distance for a third perspective in their identification with their Institute is highlighted. In this context, the new mandate of the Psychoanalytic Education Committee and its project' Meetings of Societies on Education' is presented. The question of the participation of candidates/analysts in training in the Institutes is discussed. The particular challenge of supervision in training and its vicissitudes is a main focus. A further topic are the theoretical seminars and the need that teachers do not confuse the necessary transmission of tradition with dogmatic idealization of the psychoanalytical past and can accept the finite nature of their understanding of psychoanalysis.

Este artículo se centra en la transmisión del psicoanálisis a través de la formación las próximas generaciones. La tensión entre la necesidad de que los psicoanalistas tengan que trabajar juntos en una institución y la de mantener una cierta distancia que permita destacar una tercera perspectiva respecto a su identificación con su Instituto es relevante. En este contexto, se presenta el nuevo mandato del Comité de Educación Psicoanalítica y su proyecto Encuentros de Sociedades sobre Educación. Se discute la cuestión de la participación de candidatos/analistas en la capacitación dentro de los Institutos. Su enfoque principal es la supervisión en la formación y sus vicisitudes. Otro asunto son los seminarios teóricos y la necesidad de que los maestros no confundan la necesaria transmisión de la tradición con las idealizaciones del pasado psicoanalítico, y acepten la naturaleza finita de su comprensión del psicoanálisis.

Cet article a son focus sur la transmission de la psychanalyse par l'intermédiaire de la formation des prochaines générations. On met en relief la tension entre le besoin des psychanalystes de travailler ensemble dans une institution et de garder une certaine distance, de façon à permettre une troisième perspective concernant son identification à son Institut. Dans ce contexte, on présente le nouveau mandat du Comité d'Education Psychanalytique et son projet Rencontres de Sociétés à Propos de l'Education. On discute encore de la question de la participation de candidats/analystes en formation dans les Instituts. L'un des points principaux, en particulier, c'est le défi de la supervision dans la formation et ses vicissitudes. Un autre point concerne les séminaires théoriques et le besoin des professeurs ne pas confondre la transmission nécessaire de la tradition et les idéalisations du passé psychanalytique, pouvant ainsi accepter la nature finie de leur compréhension de la psychanalyse.

In the era of rapid mRNA-based vaccines: Why is there no effective hepatitis C virus vaccine yet?

Hepatitis C virus (HCV) is responsible for no less than 71 million people chronically infected and is one of the most frequent indications for liver transplantation worldwide. Despite direct-acting antiviral therapies fuel optimism in controlling HCV infections, there are several obstacles regarding treatment accessibility and reinfection continues to remain a possibility. Indeed, the majority of new HCV infections in developed countries occur in people who inject drugs and are more plausible to get reinfected. To achieve global epidemic control of this virus the development of an effective prophylactic or therapeutic vaccine becomes a must. The coronavirus disease 19 (COVID-19) pandemic led to auspicious vaccine development against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which has renewed interest on fighting HCV epidemic with vaccination. The aim of this review is to highlight the current situation of HCV vaccine candidates designed to prevent and/or to reduce HCV infectious cases and their complications. We will emphasize on some of the crossroads encountered during vaccine development against this insidious virus, together with some key aspects of HCV immunology which have, so far, hampered the progress in this area. The main focus will be on nucleic acid-based as well as recombinant viral vector-based vaccine candidates as the most novel vaccine approaches, some of which have been recently and successfully employed for SARS-CoV-2 vaccines. Finally, some ideas will be presented on which methods to explore for the design of live-attenuated vaccines against HCV.