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Microbiology Spectrum Oct 2022The yellow fever (YF) live attenuated vaccine strain 17D (termed 17D) has been widely used for the prevention and control of YF disease. However, 17D retains significant...
The yellow fever (YF) live attenuated vaccine strain 17D (termed 17D) has been widely used for the prevention and control of YF disease. However, 17D retains significant neurovirulence and viscerotropism in mice, which is probably linked to the increased occurrences of serious adverse events following 17D vaccination. Thus, the development of an updated version of the YF vaccine with an improved safety profile is of high priority. Here, we generated a viable bicistronic YF virus (YFV) by incorporating the internal ribosome entry site (IRES) from virus into an infectious clone of YFV 17D. The resulting recombinant virus, 17D-IRES, exhibited similar replication efficiency to its parental virus (17D) in mammalian cell lines, while it was highly restricted in mosquito cells. Serial passage of 17D-IRES in BHK-21 cells showed good genetic stability. More importantly, in comparison with the parental 17D, 17D-IRES displayed significantly decreased mouse neurovirulence and viscerotropism in type I interferon (IFN)-signaling-deficient and immunocompetent mouse models. Interestingly, 17D-IRES showed enhanced sensitivity to type I IFN compared with 17D. Moreover, immunization with 17D-IRES provided solid protection for mice against a lethal challenge with YFV. These preclinical data support further development of 17D-IRES as an updated version for the approved YF vaccine. This IRES-based attenuation strategy could be also applied to the design of live attenuated vaccines against other mosquito-borne flaviviruses. Yellow fever (YF) continually spreads and causes epidemics around the world, posing a great threat to human health. The YF live attenuated vaccine 17D is considered the most efficient vaccine available and helps to successfully control disease epidemics. However, side effects may occur after vaccination, such as viscerotropic disease (YEL-AVD) and neurotropic adverse disease (YEL-AND). Thus, there is an urgent need for a safer YF vaccine. Here, an IRES strategy was employed, and a bicistronic YFV was successfully developed (named 17D-IRES). 17D-IRES showed effective replication and genetic stability and high attenuation . Importantly, 17D-IRES induced humoral and cellular immune responses and conferred full protection against lethal YFV challenge. Our study provides data suggesting that 17D-IRES, with its prominent advantages, could be a vaccine candidate against YF. Moreover, this IRES-based bicistronic technology platform represents a promising strategy for developing other live attenuated vaccines against emerging viruses.
Topics: Mice; Humans; Animals; Yellow Fever; Vaccines, Attenuated; Internal Ribosome Entry Sites; Yellow Fever Vaccine; Yellow fever virus; Antigens, Viral; Interferon Type I; Mammals
PubMed: 35980184
DOI: 10.1128/spectrum.02246-22 -
Expert Review of Vaccines Oct 2019: Human respiratory syncytial virus (RSV) is a major health threat both for the very young and the elderly. With yearly 3.2 million hospital admissions and approximately... (Review)
Review
: Human respiratory syncytial virus (RSV) is a major health threat both for the very young and the elderly. With yearly 3.2 million hospital admissions and approximately 118,000 deaths due to RSV in children across the globe, the impact of this infectious disease is very high. Development of a safe RSV vaccine is of utmost importance but has proven to be challenging for several reasons. Researchers are faced with the history of a failed RSV vaccine trial, difficult target populations, a virus that naturally does not induce a long-lasting immune response and ambiguity concerning the optimal correlate of protection. Many different vaccine formats are being tested in preclinical models and about 30 candidate RSV vaccines are being evaluated in clinical trials.: In this review we focus on the difficulties concerning the development of an effective RSV vaccine and discuss vaccines that are currently in clinical trials and how they have dealt with these challenges. We review live-attenuated vaccines, vectored vaccines, subunit vaccines and particle-based vaccines.: It is clear that this field is progressing rapidly with several promising RSV vaccine candidates. A safe and effective RSV vaccine might be on the brink of clinical implementation soon.
Topics: Animals; Clinical Trials as Topic; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Vaccination; Vaccines, Attenuated; Vaccines, Subunit
PubMed: 31587585
DOI: 10.1080/14760584.2019.1675520 -
Virology Journal May 2023Pseudorabies (PR) (also called Aujeszky's disease, AD) is a serious infectious disease affecting pigs and other animals worldwide. The emergence of variant strains of...
BACKGROUND
Pseudorabies (PR) (also called Aujeszky's disease, AD) is a serious infectious disease affecting pigs and other animals worldwide. The emergence of variant strains of pseudorabies virus (PRV) since 2011 has led to PR outbreaks in China and a vaccine that antigenically more closely matches these PRV variants could represent an added value to control these infections.
METHODS
The objective of this study was to develop new live attenuated and subunit vaccines against PRV variant strains. Genomic alterations of vaccine strains were based on the highly virulent SD-2017 mutant strain and gene-deleted strains SD-2017ΔgE/gI and SD-2017ΔgE/gI/TK, which constructed using homologous recombination technology. PRV gB-DCpep (Dendritic cells targeting peptide) and PorB (the outer membrane pore proteins of N. meningitidis) proteins containing gp67 protein secretion signal peptide were expressed using the baculovirus system for the preparation of subunit vaccines. We used experimental animal rabbits to test immunogenicity to evaluate the effect of the newly constructed PR vaccines.
RESULTS
Compared with the PRV-gB subunit vaccine and SD-2017ΔgE/gI inactivated vaccines, rabbits (n = 10) that were intramuscularly vaccinated with SD-2017ΔgE/gI/TK live attenuated vaccine and PRV-gB + PorB subunit vaccine showed significantly higher anti-PRV-specific antibodies as well as neutralizing antibodies and IFN-γ levels in serum. In addition, the SD-2017ΔgE/gI/TK live attenuated vaccine and PRV-gB + PorB subunit vaccine protected (90-100%) rabbits against homologous infection by the PRV variant strain. No obvious pathological damage was observed in these vaccinated rabbits.
CONCLUSIONS
The SD-2017ΔgE/gI/TK live attenuated vaccine provided 100% protection against PRV variant challenge. Interestingly, the subunit vaccines with gB protein linked to DCpep and PorB protein as adjuvant may also be a promising and effective PRV variant vaccine candidate.
Topics: Rabbits; Animals; Swine; Herpesvirus 1, Suid; Vaccines, Attenuated; Vaccines, Subunit; Pseudorabies; Adjuvants, Immunologic; GB virus C
PubMed: 37221518
DOI: 10.1186/s12985-023-02051-w -
Journal of Virology Jun 2021Live-attenuated virus vaccines are highly effective in preventing viral disease but carry intrinsic risks of residual virulence and reversion to pathogenicity. The...
Live-attenuated virus vaccines are highly effective in preventing viral disease but carry intrinsic risks of residual virulence and reversion to pathogenicity. The classically derived Candid#1 virus protects seasonal field workers in Argentina against zoonotic infection by Junín virus (JUNV) but is not approved in the United States, in part due to the potential for reversion at the attenuating locus, a phenylalanine-to-isoleucine substitution at position 427 in the GP2 subunit of the GPC envelope glycoprotein. Previously, we demonstrated facile reversion of recombinant Candid#1 (rCan) in cell culture and identified an epistatic interaction between the attenuating I427 and a secondary K33S mutation in the stable signal peptide (SSP) subunit of GPC that imposes an evolutionary barrier to reversion. The magnitude of this genetic barrier is manifest in our repeated failures to rescue the hypothetical revertant virus. In this study, we show that K33S rCan is safe and attenuated in guinea pigs and capable of eliciting potent virus-neutralizing antibodies. Immunized animals are fully protected against lethal challenge with virulent JUNV. In addition, we employed a more permissive model of infection in neonatal mice to investigate genetic reversion. RNA sequence analysis of the recovered virus identified revertant viruses in pups inoculated with the parental rCan virus and none in mice receiving K33S rCan ( < 0.0001). Taken together, our findings support the further development of K33S rCan as a safe second-generation JUNV vaccine. Our most successful vaccines comprise weakened strains of virus that initiate a limited and benign infection in immunized persons. The live-attenuated Candid#1 strain of Junín virus (JUNV) was developed to protect field workers in Argentina from rodent-borne hemorrhagic fever but is not licensed in the United States, in part due to the likelihood of genetic reversion to virulence. A single-amino-acid change in the GPC envelope glycoprotein of the virus is responsible for attenuation, and a single nucleotide change may regenerate the pathogenic virus. Here, we take advantage of a unique genetic interaction between GPC subunits to design a mutant Candid#1 virus that establishes an evolutionary barrier to reversion. The mutant virus (K33S rCan) is fully attenuated and protects immunized guinea pigs against lethal JUNV infection. We find no instances of reversion in mice inoculated with K33S rCan. This work supports the further development of K33S rCan as a second-generation JUNV vaccine.
Topics: Animals; Antibodies, Viral; Chlorocebus aethiops; Guinea Pigs; Hemorrhagic Fever, American; Immunogenicity, Vaccine; Junin virus; Male; Vaccines, Attenuated; Vaccines, Synthetic; Vero Cells; Viral Vaccines; Virulence
PubMed: 33952638
DOI: 10.1128/JVI.00397-21 -
The Lancet. Rheumatology Apr 2024The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations on herpes zoster vaccination for adult patients with rheumatic immune-mediated... (Review)
Review
The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations on herpes zoster vaccination for adult patients with rheumatic immune-mediated inflammatory diseases stated that these patients are at increased risk of herpes zoster compared with the general population. However, these recommendations lack clarity and specificity and are cautiously phrased, which might cause physicians to underestimate the importance of herpes zoster vaccination for these patients, potentially resulting in suboptimal protection. Since the formulation of the 2019 EULAR guidelines, new data on herpes zoster in patients with immune-mediated inflammatory diseases have been published. Moreover, a recombinant herpes zoster vaccine (Shingrix) has become available that can be given to these patients in a more accessible manner than the original live-attenuated vaccine (Zostavax). Here, we evaluate existing evidence on risk factors for herpes zoster and the safety and efficacy of the recombinant vaccine in patients with rheumatic immune-mediated inflammatory diseases and discuss the necessity of herpes zoster vaccination for these patients.
Topics: Humans; Herpes Zoster Vaccine; Herpes Zoster; Herpesvirus 3, Human; Vaccination; Vaccines, Attenuated; Rheumatic Diseases
PubMed: 38373432
DOI: 10.1016/S2665-9913(24)00019-5 -
Frontiers in Immunology 2022Live vaccines use attenuated microbes to acquire immunity against pathogens in a safe way. As live attenuated vaccines (LAVs) still maintain infectivity, the vaccination... (Review)
Review
Live vaccines use attenuated microbes to acquire immunity against pathogens in a safe way. As live attenuated vaccines (LAVs) still maintain infectivity, the vaccination stimulates diverse immune responses by mimicking natural infection. Induction of pathogen-specific antibodies or cell-mediated cytotoxicity provides means of specific protection, but LAV can also elicit unintended off-target effects, termed non-specific effects. Such mechanisms as short-lived genetic interference and non-specific innate immune response or long-lasting trained immunity and heterologous immunity allow LAVs to develop resistance to subsequent microbial infections. Based on their safety and potential for interference, LAVs may be considered as an alternative for immediate mitigation and control of unexpected pandemic outbreaks before pathogen-specific therapeutic and prophylactic measures are deployed.
Topics: Immunity; Immunity, Heterologous; Vaccination; Vaccines, Attenuated
PubMed: 35651619
DOI: 10.3389/fimmu.2022.877845 -
Journal of Virology Dec 2023Coronaviruses are important pathogens of humans and animals, and vaccine developments against them are imperative. Due to the ability to induce broad and prolonged...
Coronaviruses are important pathogens of humans and animals, and vaccine developments against them are imperative. Due to the ability to induce broad and prolonged protective immunity and the convenient administration routes, live attenuated vaccines (LAVs) are promising arms for controlling the deadly coronavirus infections. However, potential recombination events between vaccine and field strains raise a safety concern for LAVs. The porcine epidemic diarrhea virus (PEDV) remodeled TRS (RMT) mutant generated in this study replicated efficiently in both cell culture and in pigs and retained protective immunogenicity against PEDV challenge in pigs. Furthermore, the RMT PEDV was resistant to recombination and genetically stable. Therefore, RMT PEDV can be further optimized as a backbone for the development of safe LAVs.
Topics: Animals; Coronavirus Infections; Porcine epidemic diarrhea virus; Recombination, Genetic; Swine; Swine Diseases; Vaccines, Attenuated; Viral Vaccines; Virus Replication; Cells, Cultured; Mutation
PubMed: 37971221
DOI: 10.1128/jvi.01193-23 -
Viruses Jun 2022From 2017 to 2019, several vaccine-like recombinant strains of lumpy skin disease virus (LSDV) were discovered in Kazakhstan and neighbouring regions of Russia and...
From 2017 to 2019, several vaccine-like recombinant strains of lumpy skin disease virus (LSDV) were discovered in Kazakhstan and neighbouring regions of Russia and China. Shortly before their emergence, the authorities in Kazakhstan launched a mass vaccination campaign with the Neethling-based Lumpivax vaccine. Since none of the other countries in the affected region had used a homologous LSDV vaccine, it was soon suspected that the Lumpivax vaccine was the cause of these unusual LSDV strains. In this study, we performed a genome-wide molecular analysis to investigate the composition of two Lumpivax vaccine batches and to establish a possible link between the vaccine and the recent outbreaks. Although labelled as a pure Neethling-based LSDV vaccine, the Lumpivax vaccine appears to be a complex mixture of multiple CaPVs. Using an iterative enrichment/assembly strategy, we obtained the complete genomes of a Neethling-like LSDV vaccine strain, a KSGP-like LSDV vaccine strain and a Sudan-like GTPV strain. The same analysis also revealed the presence of several recombinant LSDV strains that were (almost) identical to the recently described vaccine-like LSDV strains. Based on their InDel/SNP signatures, the vaccine-like recombinant strains can be divided into four groups. Each group has a distinct breakpoint pattern resulting from multiple recombination events, with the number of genetic exchanges ranging from 126 to 146. The enormous divergence of the recombinant strains suggests that they arose during seed production. The recent emergence of vaccine-like LSDV strains in large parts of Asia is, therefore, most likely the result of a spillover from animals vaccinated with the Lumpivax vaccine.
Topics: Animals; Asia; Cattle; Lumpy Skin Disease; Lumpy skin disease virus; Vaccines, Attenuated; Viral Vaccines
PubMed: 35891412
DOI: 10.3390/v14071429 -
Applied Microbiology and Biotechnology Jan 2022Inactivated and live attenuated vaccines have improved human life and significantly reduced morbidity and mortality of several human infectious diseases. However, these... (Review)
Review
Inactivated and live attenuated vaccines have improved human life and significantly reduced morbidity and mortality of several human infectious diseases. However, these vaccines have faults, such as reactivity or suboptimal efficacy and expensive and time-consuming development and production. Additionally, despite the enormous efforts to develop vaccines against some infectious diseases, the traditional technologies have not been successful in achieving this. At the same time, the concerns about emerging and re-emerging diseases urge the need to develop technologies that can be rapidly applied to combat the new challenges. Within the last two decades, the research of vaccine technologies has taken several directions to achieve safe, efficient, and economic platforms or technologies for novel vaccines. This review will give a brief overview of the current state of the novel vaccine technologies, new vaccine candidates in clinical trial phases 1-3 (listed by European Medicines Agency (EMA) and Food and Drug Administration (FDA)), and vaccines based on the novel technologies which have already been commercially available (approved by EMA and FDA) with the special reference to pandemic COVID-19 vaccines. KEY POINTS: • Vaccines of the new generation follow the minimalist strategy. • Some infectious diseases remain a challenge for the vaccine development. • The number of new vaccine candidates in the late phase clinical trials remains low.
Topics: COVID-19; COVID-19 Vaccines; Communicable Diseases; Humans; SARS-CoV-2; Vaccine Development; Vaccines, Attenuated
PubMed: 34889981
DOI: 10.1007/s00253-021-11713-0 -
Emerging Microbes & Infections Dec 2021Human adenovirus types 4 (HAdV4) and 7 (HAdV7) often lead to severe respiratory diseases and occur epidemically in children, adults, immune deficiency patients, and...
Human adenovirus types 4 (HAdV4) and 7 (HAdV7) often lead to severe respiratory diseases and occur epidemically in children, adults, immune deficiency patients, and other groups, leading to mild or severe symptoms and even death. However, no licensed adenovirus vaccine has been approved in the market for general use. E3 genes of adenovirus are generally considered nonessential for virulence and replication; however, a few studies have demonstrated that the products of these genes are also functional. In this study, most of the E3 genes were deleted, and two E3-deleted recombinant adenoviruses (ΔE3-rAdVs) were constructed as components of the vaccine. After E3 deletion, the replication efficiencies and cytopathogenicity of ΔE3-rAdVs were reduced, indicating that ΔE3-rAdVs were attenuated after E3 genes deletion. Furthermore, single immunization with live-attenuated bivalent vaccine candidate protects mice against challenge with wild-type human adenovirus types 4 and 7, respectively. Vaccinated mice demonstrated remarkably decreased viral loads in the lungs and less lung pathology compared to the control animals. Taken together, our study confirms the possibility of the two live-attenuated viruses as a vaccine for clinic use and illustrates a novel strategy for the construction of an adenovirus vaccine.
Topics: A549 Cells; Adenovirus E3 Proteins; Adenovirus Infections, Human; Adenovirus Vaccines; Adenoviruses, Human; Animals; Cell Line; Female; Gene Deletion; HEK293 Cells; Humans; Mice; Mice, Inbred BALB C; Vaccines, Attenuated; Viral Load
PubMed: 34520320
DOI: 10.1080/22221751.2021.1981157