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European Journal of Immunology May 2024Live-attenuated yellow fever vaccine (YF17D) was developed in the 1930s as the first ever empirically derived human vaccine. Ninety years later, it is still a benchmark... (Review)
Review
Live-attenuated yellow fever vaccine (YF17D) was developed in the 1930s as the first ever empirically derived human vaccine. Ninety years later, it is still a benchmark for vaccines made today. YF17D triggers a particularly broad and polyfunctional response engaging multiple arms of innate, humoral and cellular immunity. This unique immunogenicity translates into an extraordinary vaccine efficacy and outstanding longevity of protection, possibly by single-dose immunization. More recently, progress in molecular virology and synthetic biology allowed engineering of YF17D as a powerful vector and promising platform for the development of novel recombinant live vaccines, including two licensed vaccines against Japanese encephalitis and dengue, even in paediatric use. Likewise, numerous chimeric and transgenic preclinical candidates have been described. These include prophylactic vaccines against emerging viral infections (e.g. Lassa, Zika and SARS-CoV-2) and parasitic diseases (e.g. malaria), as well as therapeutic applications targeting persistent infections (e.g. HIV and chronic hepatitis), and cancer. Efforts to overcome historical safety concerns and manufacturing challenges are ongoing and pave the way for wider use of YF17D-based vaccines. In this review, we summarize recent insights regarding YF17D as vaccine platform, and how YF17D-based vaccines may complement as well as differentiate from other emerging modalities in response to unmet medical needs and for pandemic preparedness.
Topics: Humans; Yellow Fever Vaccine; Yellow fever virus; Vaccines, Attenuated; Animals; Yellow Fever; Vaccination
PubMed: 38571392
DOI: 10.1002/eji.202250133 -
Journal of Virology Sep 2023African swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease in domestic pigs and wild boars. Domestic pigs infected with virulent African swine...
African swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease in domestic pigs and wild boars. Domestic pigs infected with virulent African swine fever virus (ASFV) isolates have a high mortality, approaching 100%. Identification of ASFV genes related to virulence/pathogenicity and deletion of them are considered to be key steps in the development of live attenuated vaccines, because the ability of ASFV to escape host innate immune responses is related to viral pathogenicity. However, the relationship between the host antiviral innate immune responses and the pathogenic genes of ASFV has not been fully understood. In this study, the ASFV H240R protein (pH240R), a capsid protein of ASFV, was found to inhibit type I interferon (IFN) production. Mechanistically, pH240R interacted with the N-terminal transmembrane domain of stimulator of interferon genes (STING) and inhibited its oligomerization and translocation from the endoplasmic reticulum to the Golgi apparatus. Additionally, pH240R inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and TANK binding kinase 1 (TBK1), leading to reduced production of type I IFN. Consistent with these results, infection with -deficient ASFV (ASFV-ΔH240R) induced more type I IFN than infection with its parental strain, ASFV HLJ/18. We also found that pH240R may enhance viral replication via inhibition of type I IFN production and the antiviral effect of interferon alpha (IFN-α). Taken together, our findings provide a new explanation for the reduction of ASFV's replication ability by knockout of the gene and a clue for the development of live attenuated ASFV vaccines. African swine fever (ASF), caused by African swine fever virus (ASFV), is a highly contagious and acute hemorrhagic viral disease with a high mortality, approaching 100% in domestic pigs. However, the relationship between viral pathogenicity and immune evasion of ASFV is not fully understood, which limits the development of safe and effective ASF vaccines, specifically, live attenuated vaccines. In this study, we found that pH240R, as a potent antagonist, inhibited type I IFN production by targeting STING and inhibiting its oligomerization and translocation from the endoplasmic reticulum to the Golgi apparatus. Furthermore, we also found that deletion of the gene reduced viral pathogenicity by enhancing type I IFN production, which decreases ASFV replication. Taken together, our findings provide a clue for the development of an ASFV live attenuated vaccine via deleting the gene.
Topics: Animals; African Swine Fever; African Swine Fever Virus; Interferon Type I; Sus scrofa; Swine; Vaccines, Attenuated; Viral Proteins
PubMed: 37199611
DOI: 10.1128/jvi.00577-23 -
Methods in Molecular Biology (Clifton,... 2024Creating a safe and effective vaccine against infection by the fungal pathogen Cryptococcus neoformans is an appealing option that complements the discovery of new small...
Creating a safe and effective vaccine against infection by the fungal pathogen Cryptococcus neoformans is an appealing option that complements the discovery of new small molecule antifungals. Recent animal studies have yielded promising results for a variety of vaccines that include live-attenuated and heat-killed whole-cell vaccines, as well as subunit vaccines formulated around recombinant proteins. Some of the recombinantly engineered cryptococcal mutants in the chitosan biosynthesis pathway are avirulent and very effective at conferring protective immunity. Mice vaccinated with these avirulent chitosan-deficient strains are protected from a lethal pulmonary infection with C. neoformans strain KN99. Heat-killed derivatives of the vaccination strains are likewise effective in a murine model of infection. The efficacy of these whole-cell vaccines, however, is dependent on a number of factors, including the inoculation dose, route of vaccination, frequency of vaccination, and the specific mouse strain used in the study. Here, we present detailed methods for identifying and optimizing various factors influencing vaccine potency and efficacy in various inbred mouse strains using a chitosan-deficient cda1Δcda2Δcda3Δ strain as a whole-cell vaccine candidate. This chapter describes the protocols for immunizing three different laboratory mouse strains with vaccination regimens that use intranasal, orotracheal, and subcutaneous vaccination routes after the animals were sedated using two different types of anesthesia.
Topics: Animals; Chitosan; Mice; Fungal Vaccines; Cryptococcosis; Cryptococcus neoformans; Disease Models, Animal; Vaccination; Female; Vaccines, Attenuated
PubMed: 38758333
DOI: 10.1007/978-1-0716-3722-7_27 -
Brazilian Journal of Microbiology :... Mar 2024The swine industry across the globe is recently facing a devastating situation imparted by a highly contagious and deadly viral disease, African swine fever. The disease... (Review)
Review
The swine industry across the globe is recently facing a devastating situation imparted by a highly contagious and deadly viral disease, African swine fever. The disease is caused by a DNA virus, the African swine fever virus (ASFV) of the genus Asfivirus. ASFV affects both wild boars and domestic pigs resulting in an acute form of hemorrhagic fever. Since the first report in 1921, the disease remains endemic in some of the African countries. However, the recent occurrence of ASF outbreaks in Asia led to a fresh and formidable challenge to the global swine production industry. Culling of the infected animals along with the implementation of strict sanitary measures remains the only options to control this devastating disease. Efforts to develop an effective and safe vaccine against ASF began as early as in the mid-1960s. Different approaches have been employed for the development of effective ASF vaccines including inactivated vaccines, subunit vaccines, DNA vaccines, virus-vectored vaccines, and live attenuated vaccines (LAVs). Inactivated vaccines are a non-feasible strategy against ASF due to their inability to generate a complete cellular immune response. However genetically engineered vaccines, such as subunit vaccines, DNA vaccines, and virus vector vaccines, represent tailored approaches with minimal adverse effects and enhanced safety profiles. As per the available data, gene deleted LAVs appear to be the most potential vaccine candidates. Currently, a gene deleted LAV (ASFV-G-∆I177L), developed in Vietnam, stands as the sole commercially available vaccine against ASF. The major barrier to the goal of developing an effective vaccine is the critical gaps in the knowledge of ASFV biology and the immune response induced by ASFV infection. The precise contribution of various hosts, vectors, and environmental factors in the virus transmission must also be investigated in depth to unravel the disease epidemiology. In this review, we mainly focus on the recent progress in vaccine development against ASF and the major gaps associated with it.
Topics: Swine; Animals; African Swine Fever; African Swine Fever Virus; Vaccines, DNA; Sus scrofa; Viral Vaccines; Vaccines, Attenuated; Vaccine Development; Vaccines, Inactivated; Vaccines, Subunit
PubMed: 38311710
DOI: 10.1007/s42770-024-01264-7 -
Vaccines Oct 2023, along with several non-albicans species, comprise a prominent fungal pathogen in humans, leading to candidiasis in various organs. The global impact of candidiasis in... (Review)
Review
, along with several non-albicans species, comprise a prominent fungal pathogen in humans, leading to candidiasis in various organs. The global impact of candidiasis in terms of disease burden, suffering, and fatalities is alarmingly high, making it a pressing global healthcare concern. Current treatment options rely on antifungal drugs such as azoles, polyenes, and echinocandins but are delimited due to the emergence of drug-resistant strains and associated adverse effects. The current review highlights the striking absence of a licensed antifungal vaccine for human use and the urgent need to shift our focus toward developing an anti-Candida vaccine. A number of factors affect the development of vaccines against fungal infections, including the host, intraspecies and interspecies antigenic variations, and hence, a lack of commercial interest. In addition, individuals with a high risk of fungal infection tend to be immunocompromised, so they are less likely to respond to inactivated or subunit whole organisms. Therefore, it is pertinent to discover newer and novel alternative strategies to develop safe and effective vaccines against fungal infections. This review article provides an overview of current vaccination strategies (live attenuated, whole-cell killed, subunit, conjugate, and oral vaccine), including their preclinical and clinical data on efficacy and safety. We also discuss the mechanisms of immune protection against candidiasis, including the role of innate and adaptive immunity and potential biomarkers of protection. Challenges, solutions, and future directions in vaccine development, namely, exploring novel adjuvants, harnessing the trained immunity, and utilizing immunoinformatics approaches for vaccine design and development, are also discussed. This review concludes with a summary of key findings, their implications for clinical practice and public health, and a call to action for continued investment in candidiasis vaccine research.
PubMed: 38005990
DOI: 10.3390/vaccines11111658 -
Microbial Biotechnology Oct 2023Toxoplasma gondii is a ubiquitous pathogen that infects all warm-blooded animals, including humans, causing substantial socioeconomic and healthcare burdens. However,...
Toxoplasma gondii is a ubiquitous pathogen that infects all warm-blooded animals, including humans, causing substantial socioeconomic and healthcare burdens. However, there is no ideal vaccine for toxoplasmosis. As metabolism is important in the growth and virulence of Toxoplasma, some key pathways are promising antiparasitic targets. Here, we identified 6-phosphogluconate dehydrogenase 1 (Tg6PGDH1) in the oxidative pentose phosphate pathway as a cytoplasmic protein that is dispensable for tachyzoite growth of T. gondii in vitro but critical for virulence and cyst formation in vivo. The depletion of Tg6PGDH1 causes decreased gene transcription involved in signal transduction, transcriptional regulation and virulence. Furthermore, we analysed the protective effect of the ME49Δ6pgdh1 mutant as an attenuated vaccine and found that ME49Δ6pgdh1 immunization stimulated strong protective immunity against lethal challenges and blocked cyst formation caused by reinfection. Furthermore, we showed that ME49Δ6pgdh1 immunization stimulated increased levels of interferon-gamma, tumour necrosis factor-alpha and Toxoplasma-specific IgG antibodies. These data highlight the role of Tg6PGDH1 in the growth and virulence of T. gondii and its potential as a target for the development of a live-attenuated vaccine.
PubMed: 37556171
DOI: 10.1111/1751-7915.14324 -
Human Vaccines & Immunotherapeutics Dec 2023Co-administration of vaccines can facilitate the introduction of new vaccines in immunization schedules. This study aimed to evaluate the immunogenicity and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunogenicity and safety of a live attenuated varicella vaccine co-administered with inactive hepatitis A vaccine: A phase 4, single-center, randomized, controlled trial.
Co-administration of vaccines can facilitate the introduction of new vaccines in immunization schedules. This study aimed to evaluate the immunogenicity and safety of co-administration with live attenuated varicella vaccine (VarV) and inactivated hepatitis A vaccine (HepA) among children aged 12 ~ 15 months. In this phase 4 clinical trial, 450 children were randomized with a ratio of 1:1 to receive VarV and Hep A simultaneously (Group A) or separately (Group B). The primary endpoints were the seroconversion rate of anti-varicella-zoster virus (VZV) antibodies 42 days after vaccination of VarV and the seroconversion rate of anti-Hepatitis A virus (HAV) antibodies 30 days after two-dose vaccination of HepA. After full immunization, the seroconversion rates of anti-VZV antibodies were 91.79% in Group A and 92.15% in Group B; the geometric mean titers (GMTs) were 11.80 and 12.19, respectively. The seroconversion rates of anti-HAV antibodies were 99.48% in Group A and 100.0% in Group B; the geometric mean concentrations (GMCs) reached 9499.11 and 9528.36 mIU/ml, respectively. The lower limits of the 95% CI for the seroconversion difference of anti-VZV antibodies and anti-HAV antibodies were -5.86% and -2.90%, which greater than the predefined non-inferiority margin (-10%). The incidence rate of adverse reactions in Group A was lower than Group B (9.33% vs 16.22%), and only one serious adverse event was reported in Group B, which was unrelated to the study vaccine. In conclusion, the co-administration of VarV with HepA has non-inferior immunogenicity and safety profiles were quite comparable with the separate administration of both vaccines.: NCT05526820 (ClinicalTrials.gov).
Topics: Child; Humans; Hepatitis A Vaccines; Hepatitis A Antibodies; Chickenpox Vaccine; Herpes Zoster Vaccine; Vaccines, Inactivated; Antibodies, Viral; Vaccines, Attenuated; Viral Vaccines; Immunogenicity, Vaccine
PubMed: 36593652
DOI: 10.1080/21645515.2022.2161789 -
Viruses Jan 2024SFTSV is an emerging tick-borne virus causing hemorrhagic fever with a case fatality rate (CFR) that can reach up to 27%. With endemic infection in East Asia and the... (Review)
Review
SFTSV is an emerging tick-borne virus causing hemorrhagic fever with a case fatality rate (CFR) that can reach up to 27%. With endemic infection in East Asia and the recent spread of the vector tick to more than 20 states in the United States, the SFTSV outbreak is a globally growing public health concern. However, there is currently no targeted antiviral therapy or licensed vaccine against SFTSV. Considering the age-dependent SFTS pathogenesis and disease outcome, a sophisticated vaccine development approach is required to safeguard the elderly population from lethal SFTSV infection. Given the recent emergence of SFTSV, the establishment of animal models to study immunogenicity and protection from SFTS symptoms has only occurred recently. The latest research efforts have applied diverse vaccine development approaches-including live-attenuated vaccine, DNA vaccine, whole inactivated virus vaccine, viral vector vaccine, protein subunit vaccine, and mRNA vaccine-in the quest to develop a safe and effective vaccine against SFTSV. This review aims to outline the current progress in SFTSV vaccine development and suggest future directions to enhance the safety and efficacy of these vaccines, ensuring their suitability for clinical application.
Topics: Aged; Animals; Humans; Severe Fever with Thrombocytopenia Syndrome; Vaccines, Attenuated; Disease Outbreaks; Models, Animal; Vaccine Development; Viral Vaccines
PubMed: 38257828
DOI: 10.3390/v16010128 -
Frontiers in Immunology 2023Porcine reproductive and respiratory syndrome virus (PRRSV) remains a leading cause of economic loss in pig farming worldwide. Existing commercial vaccines, all based on...
An attenuated herpesvirus vectored vaccine candidate induces T-cell responses against highly conserved porcine reproductive and respiratory syndrome virus M and NSP5 proteins that are unable to control infection.
Porcine reproductive and respiratory syndrome virus (PRRSV) remains a leading cause of economic loss in pig farming worldwide. Existing commercial vaccines, all based on modified live or inactivated PRRSV, fail to provide effective immunity against the highly diverse circulating strains of both PRRSV-1 and PRRSV-2. Therefore, there is an urgent need to develop more effective and broadly active PRRSV vaccines. In the absence of neutralizing antibodies, T cells are thought to play a central role in controlling PRRSV infection. Herpesvirus-based vectors are novel vaccine platforms capable of inducing high levels of T cells against encoded heterologous antigens. Therefore, the aim of this study was to assess the immunogenicity and efficacy of an attenuated herpesvirus-based vector (bovine herpesvirus-4; BoHV-4) expressing a fusion protein comprising two well-characterized PRRSV-1 T-cell antigens (M and NSP5). Prime-boost immunization of pigs with BoHV-4 expressing the M and NSP5 fusion protein (vector designated BoHV-4-M-NSP5) induced strong IFN-γ responses, as assessed by ELISpot assays of peripheral blood mononuclear cells (PBMC) stimulated with a pool of peptides representing PRRSV-1 M and NSP5. The responses were closely mirrored by spontaneous IFN-γ release from unstimulated cells, albeit at lower levels. A lower frequency of M and NSP5 specific IFN-γ responding cells was induced following a single dose of BoHV-4-M-NSP5 vector. Restimulation using M and NSP5 peptides from PRRSV-2 demonstrated a high level of cross-reactivity. Vaccination with BoHV-4-M-NSP5 did not affect viral loads in either the blood or lungs following challenge with the two heterologous PRRSV-1 strains. However, the BoHV-4-M-NSP5 prime-boost vaccination showed a marked trend toward reduced lung pathology following PRRSV-1 challenge. The limited effect of T cells on PRRSV-1 viral load was further examined by analyzing local and circulating T-cell responses using intracellular cytokine staining and proliferation assays. The results from this study suggest that vaccine-primed T-cell responses may have helped in the control of PRRSV-1 associated tissue damage, but had a minimal, if any, effect on controlling PRRSV-1 viral loads. Together, these results indicate that future efforts to develop effective PRRSV vaccines should focus on achieving a balanced T-cell and antibody response.
Topics: Herpesvirus Vaccines; Vaccines, Attenuated; T-Lymphocytes; Immunogenicity, Vaccine; Porcine respiratory and reproductive syndrome virus; Viral Nonstructural Proteins; Genetic Vectors; Porcine Reproductive and Respiratory Syndrome; Animals; Swine; Viral Matrix Proteins
PubMed: 37600784
DOI: 10.3389/fimmu.2023.1201973 -
Cureus Oct 2023Vaccination, for centuries, has been a potent preventive technique to treat morbidities. The messenger RNA (mRNA) vaccine technology is an innovative biomedical approach... (Review)
Review
Vaccination, for centuries, has been a potent preventive technique to treat morbidities. The messenger RNA (mRNA) vaccine technology is an innovative biomedical approach utilized in developing antigen-specific vaccines that can generate adaptive immune responses, triggering both humoral and cellular immunity to enhance the body's defense against specific infections. This review provides a comprehensive, comparative analysis of mRNA vaccine technology and conventional vaccines by focusing on the structures, components, and classifications. An exploratory analysis of the similarities and differences between mRNA vaccine technology and live-attenuated vaccines highlights the mechanisms by which mRNA vaccines elicit immune responses. This review extensively discusses the production, stability, synthesis, and delivery processes associated with mRNA vaccines, showcasing the advancements and technological superiority of this approach over conventional vaccine technologies. Additionally, the potential of mRNA vaccine technology as a potent alternative for the development of vaccine candidates targeting HIV and cancer is examined.
PubMed: 37920621
DOI: 10.7759/cureus.46354