Special Issue "Genomic Medicine and Advances in Vaccine Technology and Development in the Developing and Developed World"

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (15 May 2020).

Special Issue Editor

Dr. Ian James Martins
Website
Guest Editor
Sarich Neuroscience Research Institute, Edith Cowan University, 8 Verdun Street, Nedlands 6009, Western Australia, Australia
Interests: Antiaging Research; Anti-Aging Genes; Appetite; Environment; Nutrition; Senescence
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The market for vaccines is expected to reach 50 billion dollars by the year 2020. The development process for vaccine development from research to marketing may take 10 years and cost approx 1 billion dollars but the success rate of vaccine development may be very low. Critical interest in research to maintain vaccines that enhance the immune response to prevent diseases has been the focus of vaccine development. WHO funded vaccine preventable conditions and disease projects may only be successful with effective low calorie nutrigenomic diets that activate anti-aging gene expression critical to maintain the primary and secondary immune response in man and other species. In the developing world increasing therapeutic anti-aging protein levels in the plasma and cells has become important to maintain the immune system with relevance to vaccine technology. Biotherapy, core body temperature and anti-aging gene activation with relevance to the chronic disease epidemic is critical to prevent mitophagy and autoimmune disease linked to the prevention of inactivation of vaccines and vaccine development. Articles for this special issue are required to assess the role of anti-aging genes and activation of the transcriptional co-activator relevant to the adaptive immune response that determines the success of old and new vaccine development.

Dr Ian James Martins
Guest Editor

Manuscript Submission Information

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Keywords

  • Genomic medicine
  • vaccine development
  • diet
  • anti-aging genes
  • transcriptional regulator
  • autoimmune disease
  • developing world
  • immune response
  • anti-aging protein
  • biotherapy
  • species

Published Papers (30 papers)

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Open AccessArticle
A Canine-Directed Chimeric Multi-Epitope Vaccine Induced Protective Immune Responses in BALB/c Mice Infected with Leishmania infantum
Vaccines 2020, 8(3), 350; https://doi.org/10.3390/vaccines8030350 - 30 Jun 2020
Abstract
Leishmaniases are complex vector-borne diseases caused by intracellular parasites of the genus Leishmania. The visceral form of the disease affects both humans and canids in tropical, subtropical, and Mediterranean regions. One health approach has suggested that controlling zoonotic visceral leishmaniasis (ZVL) could [...] Read more.
Leishmaniases are complex vector-borne diseases caused by intracellular parasites of the genus Leishmania. The visceral form of the disease affects both humans and canids in tropical, subtropical, and Mediterranean regions. One health approach has suggested that controlling zoonotic visceral leishmaniasis (ZVL) could have an impact on the reduction of the human incidence of visceral leishmaniasis (VL). Despite the fact that a preventive vaccination could help with leishmaniasis elimination, effective vaccines that are able to elicit protective immune responses are currently lacking. In the present study, we designed a chimeric multi-epitope protein composed of multiple CD8+ and CD4+ T cell epitopes which were obtained from six highly immunogenic proteins previously identified by an immunoproteomics approach, and the N-termini of the heparin-binding hemagglutinin (HBHA) of Mycobacterium tuberculosis served as an adjuvant. A preclinical evaluation of the candidate vaccine in BALB/c mice showed that when it was given along with the adjuvant Addavax it was able to induce strong immune responses. Cellular responses were dominated by the presence of central and effector multifunctional CD4+ and CD8+ T memory cells. Importantly, the vaccination reduced the parasite burden in both short-term and long-term vaccinated mice challenged with Leishmania infantum. Protection was characterized by the continuing presence of IFN-γ+TNFα+-producing CD8+ and CD4+ T cells and increased NO levels. The depletion of CD8+ T cells in short-term vaccinated mice conferred a significant loss of protection in both target organs of the parasite, indicating a significant involvement of this population in the protection against L. infantum challenge. Thus, the overall data could be considered to be a proof-of-concept that the design of efficacious T cell vaccines with the help of reverse vaccinology approaches is possible. Full article
Open AccessArticle
Establishing a Robust Manufacturing Platform for Recombinant Veterinary Vaccines: An Adenovirus-Vector Vaccine to Control Newcastle Disease Virus Infections of Poultry in Sub-Saharan Africa
Vaccines 2020, 8(2), 338; https://doi.org/10.3390/vaccines8020338 - 26 Jun 2020
Abstract
Developing vaccine technology platforms to respond to pandemic threats or zoonotic diseases is a worldwide high priority. The risk of infectious diseases transmitted from wildlife and domestic animals to humans makes veterinary vaccination and animal health monitoring highly relevant for the deployment of [...] Read more.
Developing vaccine technology platforms to respond to pandemic threats or zoonotic diseases is a worldwide high priority. The risk of infectious diseases transmitted from wildlife and domestic animals to humans makes veterinary vaccination and animal health monitoring highly relevant for the deployment of public health global policies in the context of “one world, one health” principles. Sub-Saharan Africa is frequently impacted by outbreaks of poultry diseases such as avian influenza and Newcastle Disease (ND). Here, an adenovirus-vectored vaccine technology platform is proposed for rapid adaptation to ND or other avian viral threats in the region. Ethiopian isolates of the Newcastle Disease virus (NDV) were subjected to sequence and phylogenetic analyses, enabling the construction of antigenically matched vaccine candidates expressing the fusion (F) and hemagglutinin-neuraminidase (HN) proteins. A cost-effective vaccine production process was developed using HEK293 cells in suspension and serum-free medium. Productive infection in bioreactors (1–3 L) at 2 × 106 cells/mL resulted in consistent infectious adenoviral vector titers of approximately 5–6 × 108 TCID50/mL (approximately 1011VP/mL) in the harvest lysates. Groups of chickens were twice immunized with 1 × 1010 TCID50 of the vectors, and full protection against a lethal NDV challenge was provided by the vector expressing the F antigen. These results consolidate the basis for a streamlined and scalable-vectored vaccine manufacturing process for deployment in low- and medium-income countries. Full article
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Open AccessArticle
Multiepitope-Based Subunit Vaccine Design and Evaluation against Respiratory Syncytial Virus Using Reverse Vaccinology Approach
Vaccines 2020, 8(2), 288; https://doi.org/10.3390/vaccines8020288 - 08 Jun 2020
Abstract
Respiratory syncytial virus (RSV) is primarily associated with respiratory disorders globally. Despite the availability of information, there is still no competitive vaccine available for RSV. Therefore, the present study has been designed to develop a multiepitope-based subunit vaccine (MEV) using a reverse vaccinology [...] Read more.
Respiratory syncytial virus (RSV) is primarily associated with respiratory disorders globally. Despite the availability of information, there is still no competitive vaccine available for RSV. Therefore, the present study has been designed to develop a multiepitope-based subunit vaccine (MEV) using a reverse vaccinology approach to curb RSV infections. Briefly, two highly antigenic and conserved proteins of RSV (glycoprotein and fusion protein) were selected and potential epitopes of different categories (B-cell and T-cell) were identified from them. Eminently antigenic and overlapping epitopes, which demonstrated strong associations with their respective human leukocyte antigen (HLA) alleles and depicted collective ~70% coverage of the world’s populace, were shortlisted. Finally, 282 amino acids long MEV construct was established by connecting 13 major histocompatibility complex (MHC) class-I with two MHC class-II epitopes with appropriate adjuvant and linkers. Adjuvant and linkers were added to increase the immunogenic stimulation of the MEV. Developed MEV was stable, soluble, non-allergenic, non-toxic, flexible and highly antigenic. Furthermore, molecular docking and molecular dynamics (MD) simulations analyses were carried out. Results have shown a firm and robust binding affinity of MEV with human pathogenic toll-like receptor three (TLR3). The computationally mediated immune response of MEV demonstrated increased interferon-γ production, a significant abundance of immunoglobulin and activation of macrophages which are essential for immune-response against RSV. Moreover, MEV codons were optimized and in silico cloning was performed, to ensure its increased expression. These outcomes proposed that the MEV developed in this study will be a significant candidate against RSV to control and prevent RSV-related disorders if further investigated experimentally. Full article
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Open AccessArticle
Protective Passive Immunity in Escherichia coli ETEC-Challenged Neonatal Mice Conferred by Orally Immunized Dams with Nanoparticles Containing Homologous Outer Membrane Vesicles
Vaccines 2020, 8(2), 286; https://doi.org/10.3390/vaccines8020286 - 08 Jun 2020
Abstract
Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of illness and death in mammals, including neonatal, recently weaned pigs and infant human beings. We have previously shown that outer membrane vesicles (OMV) obtained from ETEC serotypes encapsulated into zein nanoparticles, coated with [...] Read more.
Enterotoxigenic Escherichia coli (ETEC) strains are a major cause of illness and death in mammals, including neonatal, recently weaned pigs and infant human beings. We have previously shown that outer membrane vesicles (OMV) obtained from ETEC serotypes encapsulated into zein nanoparticles, coated with a Gantrez-mannosamine polymer conjugate (OMV-NP), were immunogenic in mice and sows. In the present study, we show that pups from vaccinated mice were protected against ETEC F4 serotype challenge through maternal passive immunization. OMV from F4 cultures were collected and characterized. Two-week-pregnant BALB/c mice were orally immunized with a single dose of vesicles (0.2 mg) either free (OMV) or encapsulated into nanoparticles (OMV-NP). Evaluation of the antibodies in serum (IgG1, Ig2a or IgA) and feces (IgA) of dams immunized with OMV-NP revealed an enhancement of specific immunogenicity. The antibody response conferred by the nanoparticle adjuvant was also correlated with IL-6 and IL-10 splenic levels. Each mother was allowed to feed her progeny for one week. Suckling pups presented specific IgA in feces demonstrating their passive immunization through colostrum intake. Two weeks after the pups were born, they were infected orally with a single dose of F4 E. coli (1.2 × 108 CFU/pup). Results showed that 70% of the pups from dams immunized with OMV-NP were protected. In contrast, 80% of the pups from dams immunized with free OMV died as a result of the experimental challenge. These findings support the use of zein nanoparticles coated with a Gantrez-mannosamine shield as adjuvant delivery system for the oral immunization during pregnancy to confer immunity to the offspring through maternal immunization Full article
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Open AccessArticle
Development of an Effective and Stable Genotype-Matched Live Attenuated Newcastle Disease Virus Vaccine Based on a Novel Naturally Recombinant Malaysian Isolate Using Reverse Genetics
Vaccines 2020, 8(2), 270; https://doi.org/10.3390/vaccines8020270 - 02 Jun 2020
Abstract
Genotype VII Newcastle disease viruses are associated with huge economic losses in the global poultry industry. Despite the intensive applications of vaccines, disease outbreaks caused by those viruses continue to occur frequently even among the vaccinated poultry farms. An important factor in the [...] Read more.
Genotype VII Newcastle disease viruses are associated with huge economic losses in the global poultry industry. Despite the intensive applications of vaccines, disease outbreaks caused by those viruses continue to occur frequently even among the vaccinated poultry farms. An important factor in the suboptimal protective efficacy of the current vaccines is the genetic mismatch between the prevalent strains and the vaccine strains. Therefore, in the present study, an effective and stable genotype-matched live attenuated Newcastle disease virus (NDV) vaccine was developed using reverse genetics, based on a recently isolated virulent naturally recombinant NDV IBS025/13 Malaysian strain. First of all, the sequence encoding the fusion protein (F) cleavage site of the virus was modified in silico from virulent polybasic (RRQKRF) to avirulent monobasic (GRQGRL) motif. The entire modified sequence was then chemically synthesized and inserted into pOLTV5 transcription vector for virus rescue. A recombinant virus termed mIBS025 was successfully recovered and shown to be highly attenuated based on OIE recommended pathogenicity assessment indices. Furthermore, the virus was shown to remain stably attenuated and retain the avirulent monobasic F cleavage site after 15 consecutive passages in specific-pathogen-free embryonated eggs and 12 passages in one-day-old chicks. More so, the recombinant virus induced a significantly higher hemagglutination inhibition antibody titre than LaSota although both vaccines fully protected chicken against genotype VII NDV induced mortality and morbidity. Finally, mIBS025 was shown to significantly reduce both the duration and quantity of cloacal and oropharyngeal shedding of the challenged genotype VII virus compared to the LaSota vaccine. These findings collectively indicate that mIBS025 provides a better protective efficacy than LaSota and therefore can be used as a promising vaccine candidate against genotype VII NDV strains. Full article
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Open AccessArticle
Chimeric Vaccines Designed by Immunoinformatics-Activated Polyfunctional and Memory T Cells That Trigger Protection against Experimental Visceral Leishmaniasis
Vaccines 2020, 8(2), 252; https://doi.org/10.3390/vaccines8020252 - 27 May 2020
Abstract
Many vaccine candidates against visceral leishmaniasis (VL) have been proposed; however, to date, none of them have been efficacious for the human or canine disease. On this basis, the design of leishmaniasis vaccines has been constantly changing, and the use of approaches to [...] Read more.
Many vaccine candidates against visceral leishmaniasis (VL) have been proposed; however, to date, none of them have been efficacious for the human or canine disease. On this basis, the design of leishmaniasis vaccines has been constantly changing, and the use of approaches to select specific epitopes seems to be crucial in this scenario. The ability to predict T cell-specific epitopes makes immunoinformatics an even more necessary approach, as in VL an efficient immune response against the parasite is triggered by T lymphocytes in response to Leishmania spp. immunogenic antigens. Moreover, the success of vaccines depends on the capacity to generate long-lasting memory and polyfunctional cells that are able to eliminate the parasite. In this sense, our study used a combination of different approaches to develop potential chimera candidate vaccines against VL. The first point was to identify the most immunogenic epitopes of Leishmania infantum proteins and construct chimeras composed of Major histocompatibility complex (MHC) class I and II epitopes. For this, we used immunoinformatics features. Following this, we validated these chimeras in a murine model in a thorough memory study and multifunctionality of T cells that contribute to a better elucidation of the immunological protective mechanisms of polyepitope vaccines (chimera A and B) using multicolor flow cytometry. Our results showed that in silico-designed chimeras can elicit polyfunctional T cells producing T helper (Th)1 cytokines, a strong immune response against Leishmania antigen, and the generation of central and effector memory T cells in the spleen cells of vaccinated animals that was able to reduce the parasite burden in this organ. These findings contribute two potential candidate vaccines against VL that can be used in further studies, and help in this complex field of vaccine development against this challenging parasite. Full article
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Open AccessArticle
N-Terminal Fatty Acids of NEFMUT Are Required for the CD8+ T-Cell Immunogenicity of In Vivo Engineered Extracellular Vesicles
Vaccines 2020, 8(2), 243; https://doi.org/10.3390/vaccines8020243 - 22 May 2020
Abstract
We recently described a cytotoxic CD8+ T lymphocyte (CTL) vaccine platform based on the intramuscular (i.m.) injection of DNA eukaryotic vectors expressing antigens of interest fused at the C-terminus of HIV-1 Nefmut, i.e., a functionally defective mutant that is incorporated [...] Read more.
We recently described a cytotoxic CD8+ T lymphocyte (CTL) vaccine platform based on the intramuscular (i.m.) injection of DNA eukaryotic vectors expressing antigens of interest fused at the C-terminus of HIV-1 Nefmut, i.e., a functionally defective mutant that is incorporated at quite high levels into exosomes/extracellular vesicles (EVs). This system has been proven to elicit strong CTL immunity against a plethora of both viral and tumor antigens, as well as inhibit both transplantable and orthotopic tumors in mice. However, a number of open issues remain regarding the underlying mechanism. Here we provide evidence that hindering the uploading into EVs of Nefmut-derived products by removing the Nefmut N-terminal fatty acids leads to a dramatic reduction of the downstream antigen-specific CD8+ T-cell activation after i.m. injection of DNA vectors in mice. This result formally demonstrates that the generation of engineered EVs is part of the mechanism underlying the in vivo induced CD8+ T-cell immunogenicity. Gaining new insights on the EV-based vaccine platform can be relevant in view of its possible translation into the clinic to counteract both chronic and acute infections as well as tumors. Full article
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Open AccessArticle
Zebrafish pten Genes Play Relevant but Distinct Roles in Antiviral Immunity
Vaccines 2020, 8(2), 199; https://doi.org/10.3390/vaccines8020199 - 26 Apr 2020
Abstract
The PTEN (phosphatase and TENsin homolog on chromosome 10) gene encodes a bifunctional phosphatase that acts as a tumor suppressor. However, PTEN has been implicated in different immune processes, including autophagy, inflammation, regulation of natural killer (NK) cell cytolytic activity and type I [...] Read more.
The PTEN (phosphatase and TENsin homolog on chromosome 10) gene encodes a bifunctional phosphatase that acts as a tumor suppressor. However, PTEN has been implicated in different immune processes, including autophagy, inflammation, regulation of natural killer (NK) cell cytolytic activity and type I interferon responses. Unlike mammals, zebrafish possess two pten genes (ptena and ptenb). This study explores the involvement of both zebrafish pten genes in antiviral defense. Although ptena−/− and ptenb−/− larvae were more susceptible to Spring viremia of carp virus (SVCV), the viral replication rate was lower in the mutant larvae than in the wild-type larvae. We observed that both mutant lines showed alterations in the transcription of numerous genes, including those related to the type I interferon (IFN) system, cytolytic activity, autophagy and inflammation, and some of these genes were regulated in opposite ways depending on which pten gene was mutated. Even though the lower replication rate of SVCV could be associated with impaired autophagy in the mutant lines, the higher mortality observed in the ptena−/− and ptenb−/− larvae does not seem to be associated with an uncontrolled inflammatory response. Full article
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Open AccessArticle
Disruption of the cpsE and endA Genes Attenuates Streptococcus pneumoniae Virulence: Towards the Development of a Live Attenuated Vaccine Candidate
Vaccines 2020, 8(2), 187; https://doi.org/10.3390/vaccines8020187 - 15 Apr 2020
Cited by 1
Abstract
The majority of deaths due to Streptococcus pneumoniae infections are in developing countries. Although polysaccharide-based pneumococcal vaccines are available, newer types of vaccines are needed to increase vaccine affordability, particularly in developing countries, and to provide broader protection across all pneumococcal serotypes. To [...] Read more.
The majority of deaths due to Streptococcus pneumoniae infections are in developing countries. Although polysaccharide-based pneumococcal vaccines are available, newer types of vaccines are needed to increase vaccine affordability, particularly in developing countries, and to provide broader protection across all pneumococcal serotypes. To attenuate pneumococcal virulence with the aim of engineering candidate live attenuated vaccines (LAVs), we constructed knockouts in S. pneumoniae D39 of one of the capsular biosynthetic genes, cpsE that encodes glycosyltransferase, and the endonuclease gene, endA, that had been implicated in the uptake of DNA from the environment as well as bacterial escape from neutrophil-mediated killing. The cpsE gene knockout significantly lowered peak bacterial density, BALB/c mice nasopharyngeal (NP) colonisation but increased biofilm formation when compared to the wild-type D39 strain as well as the endA gene knockout mutant. All constructed mutant strains were able to induce significantly high serum and mucosal antibody response in BALB/c mice. However, the cpsE-endA double mutant strain, designated SPEC, was able to protect mice from high dose mucosal challenge of the D39 wild-type. Furthermore, SPEC showed 23-fold attenuation of virulence compared to the wild-type. Thus, the cpsE-endA double-mutant strain could be a promising candidate for further development of a LAV for S. pneumoniae. Full article
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Open AccessArticle
The Design and Development of a Multi-HBV Antigen Encoded in Chimpanzee Adenoviral and Modified Vaccinia Ankara Viral Vectors; A Novel Therapeutic Vaccine Strategy against HBV
Vaccines 2020, 8(2), 184; https://doi.org/10.3390/vaccines8020184 - 14 Apr 2020
Abstract
Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to [...] Read more.
Chronic hepatitis B virus (HBV) infection affects 257 million people globally. Current therapies suppress HBV but viral rebound occurs on cessation of therapy; novel therapeutic strategies are urgently required. To develop a therapeutic HBV vaccine that can induce high magnitude T cells to all major HBV antigens, we have developed a novel HBV vaccine using chimpanzee adenovirus (ChAd) and modified vaccinia Ankara (MVA) viral vectors encoding multiple HBV antigens. ChAd vaccine alone generated very high magnitude HBV specific T cell responses to all HBV major antigens. The inclusion of a shark Invariant (SIi) chain genetic adjuvant significantly enhanced the magnitude of T-cells against HBV antigens. Compared to ChAd alone vaccination, ChAd-prime followed by MVA-boost vaccination further enhanced the magnitude and breadth of the vaccine induced T cell response. Intra-cellular cytokine staining study showed that HBV specific CD8+ and CD4+ T cells were polyfunctional, producing combinations of IFNγ, TNF-α, and IL-2. In summary, we have generated genetically adjuvanted ChAd and MVA vectored HBV vaccines with the potential to induce high-magnitude T cell responses through a prime-boost therapeutic vaccination approach. These pre-clinical studies pave the way for new studies of HBV therapeutic vaccination in humans with chronic hepatitis B infection. Full article
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Open AccessArticle
A Prime-Boost Immunization Strategy with Vaccinia Virus Expressing Novel gp120 Envelope Glycoprotein from a CRF02_AG Isolate Elicits Cross-Clade Tier 2 HIV-1 Neutralizing Antibodies
Vaccines 2020, 8(2), 171; https://doi.org/10.3390/vaccines8020171 - 07 Apr 2020
Abstract
Development of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a truncated version of gp120 [...] Read more.
Development of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a truncated version of gp120 (gp120t) from HIV-1 clades CRF02_AG, H, J, B, and C and examined their immunogenicity in mice and rabbits. Mice primed with the recombinant Vaccinia viruses and boosted with the homologous gp120t or C2V3C3 polypeptides developed antibodies that bind potently to homologous and heterologous envelope glycoproteins. Notably, a subset of mice immunized with the CRF02_AG-based envelope immunogens developed a cross-reactive neutralizing response against tier 2 HIV-1 Env-pseudoviruses and primary isolates. Rabbits vaccinated with the CRF02_AG-based envelope immunogens also generated potent binding antibodies, and one animal elicited antibodies that neutralized almost all (13 of 16, 81.3%) tier 2 HIV-1 isolates tested. Overall, the results suggest that the novel CRF02_AG-based envelope immunogens and prime-boost immunization strategy elicit the type of immune responses required for a preventive HIV-1 vaccine. Full article
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Open AccessCommunication
Immunization with the H5N1 Recombinant Vaccine Candidate Induces High Protection in Chickens against Vietnamese Highly Pathogenic Avian Influenza Virus Strains
Vaccines 2020, 8(2), 159; https://doi.org/10.3390/vaccines8020159 - 02 Apr 2020
Abstract
Vietnam is one of the countries most affected worldwide by the highly pathogenic avian influenza (HPAI) virus, which caused enormous economic loss and posed threats to public health. Over nearly two decades, with the antigenic changes in the diversified H5Ny viruses, the limited [...] Read more.
Vietnam is one of the countries most affected worldwide by the highly pathogenic avian influenza (HPAI) virus, which caused enormous economic loss and posed threats to public health. Over nearly two decades, with the antigenic changes in the diversified H5Ny viruses, the limited protective efficacy of the available vaccines was encountered. Therefore, it is necessary to approach a technology platform for the country to accelerate vaccine production that enables quick response to new influenza subtypes. This study utilized a powerful reverse genetics technique to successfully generate a recombinant H5N1 vaccine strain (designated as IBT-RG02) containing two surface proteins (haemagglutinin (HA) and neuraminidase (NA)) from the HPAI H5N1 (A/duck/Vietnam/HT2/2014(H5N1)) of the dominant clade 2.3.2.1c in Vietnam during 2012–2014. Importantly, the IBT-RG02 vaccine candidate has elicited high antibody titres in chickens (geometric mean titre (GMT) of 6.42 and 6.92, log2 on day 14 and day 28 p.i., respectively). To test the efficacy, immunized chickens were challenged with the circulating virulent strains. As results, there was a high protection rate of 91.6% chickens against the virulent A/DK/VN/Bacninh/NCVD-17A384/2017 of the same clade and a cross-protection of 83.3% against A/duck/TG/NAVET(3)/2013 virus of clade 1.1. Our promising results showed that we can independently master the reverse genetics technology for generation of highly immunogenic vaccine candidates, and henceforth, it is a timely manner to reformulate avian influenza virus vaccines against variable H5 clade HPAI viruses in Vietnam. Full article
Open AccessArticle
Identification of Toxoplasma Gondii Tyrosine Hydroxylase (TH) Activity and Molecular Immunoprotection against Toxoplasmosis
Vaccines 2020, 8(2), 158; https://doi.org/10.3390/vaccines8020158 - 01 Apr 2020
Cited by 1
Abstract
The neurotropic parasite Toxoplasma gondii (T. gondii) infection can change the behavior of rodents and cause neuropsychological symptoms in humans, which may be related to the change in neurotransmitter dopamine in the host brain caused by T. gondii infection. T. gondii [...] Read more.
The neurotropic parasite Toxoplasma gondii (T. gondii) infection can change the behavior of rodents and cause neuropsychological symptoms in humans, which may be related to the change in neurotransmitter dopamine in the host brain caused by T. gondii infection. T. gondii tyrosine hydroxylase (TgTH) is an important factor in increasing the neurotransmitter dopamine in the host brain. In this study, the enzyme activity of TgTH catalytic substrate for dopamine production and the molecular characteristics of TgTH were identified. In order to amplify the open reading frame (ORF), the designing of the specific primers for polymerase chain reaction (PCR) was on the basis of the TgTH sequence (GenBank Accession No. EU481510.1), which was inserted into pET-32a (+) for the expression of recombined TgTH (rTgTH). The sequence analysis indicated that the gene of TgTH directed the encoding of a 62.4-kDa protein consisting of 565 amino acid residues, which was predicted to have a high antigen index. The enzyme activity test showed that rTgTH and the soluble proteins extracted separately from T. gondii RH strain and PRU strain could catalyze the substrate to produce dopamine in a dose-dependent manner, and the optimum catalytic temperature was 37 °C. The result of the Western Blotting assay revealed that the rTgTH and the native TgTH extracted from somatic of T. gondii RH tachyzoite were successfully detected by the sera of mice infected with T. gondii and the rat serum after rTgTH immune, respectively. Immunofluorescence analysis using antibody against rTgTH demonstrated that the protein was expressed and located on the surface of T. gondii RH tachyzoite. Freund’s adjuvant was used to emulsify the rTgTH, which was subsequently applied to BALB/c mouse immune thrice on week 0, week 2, and week 4, respectively. The result of the animal challenge experiments showed an integral increase in IgG, IgG2a, IgG1, and IFN-γ, IL-4, and IL17 were as well significantly increased, and that the rTgTH vaccinated animals apparently had a prolonged survival time (14.30 ± 2.41) after infection with the RH strain of T. gondii compared with that of the non-vaccinated control animals, which died within 11 days. Additionally, in the rTgTH vaccination group, the number of brain cysts (1275 ± 224) significantly decreased (p < 0.05) compared to the blank control group (2375 ± 883), and the size of the brain cysts in the animals immunized with rTgTH vaccination was remarkably smaller than that of the control mice. All the findings prove that TgTH played an important role in increasing the neurotransmitter dopamine in the host brain and could be used as a vaccine candidate antigen to mediate cell-mediated and humoral immunity. Full article
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Open AccessArticle
Recombinant Rabies Virus Overexpressing OX40-Ligand Enhances Humoral Immune Responses by Increasing T Follicular Helper Cells and Germinal Center B Cells
Vaccines 2020, 8(1), 144; https://doi.org/10.3390/vaccines8010144 - 23 Mar 2020
Abstract
Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role [...] Read more.
Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role in the T cell-dependent humoral immune responses through T-B cell interaction. In this work, a recombinant RABV overexpressing mouse OX40L (LBNSE-OX40L) was constructed, and its effects on immunogenicity were evaluated in a mouse model. LBNSE-OX40L-immunized mice generated a larger number of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs) than the parent virus LBNSE-immunized mice. Furthermore, LBNSE-OX40L induced significantly higher levels of virus-neutralizing antibodies (VNA) as early as seven days post immunization (dpi), which lasted for eight weeks, resulting in better protection for mice than LBNSE (a live-attenuated rabies vaccine strain). Taken together, our data in this study suggest that OX40L can be a novel and potential adjuvant to improve the induction of protective antibody responses post RABV immunization by triggering T cell-dependent humoral immune responses, and that LBNSE-OX40L can be developed as an efficacious and nonpathogenic vaccine for animals. Full article
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Open AccessArticle
Stability of the HSV-2 US-6 Gene in the del II, del III, CP77, and I8R-G1L Sites in Modified Vaccinia Virus Ankara After Serial Passage of Recombinant Vectors in Cells
Vaccines 2020, 8(1), 137; https://doi.org/10.3390/vaccines8010137 - 19 Mar 2020
Abstract
The modified vaccinia virus Ankara (MVA), a severely attenuated strain of vaccinia virus, is a promising vector platform for viral-vectored vaccine development because of its attributes of efficient transgene expression and safety profile, among others. Thus, transgene stability in MVA is important to [...] Read more.
The modified vaccinia virus Ankara (MVA), a severely attenuated strain of vaccinia virus, is a promising vector platform for viral-vectored vaccine development because of its attributes of efficient transgene expression and safety profile, among others. Thus, transgene stability in MVA is important to assure immunogenicity and efficacy. The global GC content of the MVA genome is 33%, and GC-rich sequences containing runs of C or G nucleotides have been reported to be less stable with passage of MVA vectors in cells. The production of recombinant MVA vaccines requires a number of expansion steps in cell culture, depending on production scale. We assessed the effect of extensive passage of four recombinant MVA vectors on the stability of the GC-rich herpes simplex type 2 (HSV-2) US6 gene encoding viral glycoprotein D (gD2) inserted at four different genomic sites, including the deletion (del) II and del III sites, the CP77 gene locus (MVA_009–MVA_013) and the I8R-G1L intergenic region. Our data indicate that after 35 passages, there was a reduction in gD2 expression from del II, del III and CP77 sites. Sequencing analysis implicated US6 deletion and mutational events as responsible for the loss of gD2 expression. By contrast, 85.9% of recombinant plaques expressed gD2 from the I8R-G1L site, suggesting better accommodation of transgenes in this intergenic region. Thus, the I8R-G1L intergenic region may be more useful for transgene insertion for enhanced stability. Full article
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Open AccessArticle
Multiplex PCR-Based Neutralization (MPBN) Assay for Titers Determination of the Three Types of Anti-Poliovirus Neutralizing-Antibodies
Vaccines 2020, 8(1), 120; https://doi.org/10.3390/vaccines8010120 - 05 Mar 2020
Abstract
Determination of poliovirus-neutralizing antibodies is an important part of clinical studies of poliovirus vaccines, epidemiological surveillance and seroprevalence studies that are crucial for global polio eradication campaigns. The conventional neutralization test is based on inhibition of cytopathic effect caused by poliovirus by serial [...] Read more.
Determination of poliovirus-neutralizing antibodies is an important part of clinical studies of poliovirus vaccines, epidemiological surveillance and seroprevalence studies that are crucial for global polio eradication campaigns. The conventional neutralization test is based on inhibition of cytopathic effect caused by poliovirus by serial dilutions of test serum. It is laborious, time-consuming and not suitable for large scale analysis. To overcome these limitations, a multiplex PCR-based neutralization (MPBN) assay was developed to measure the neutralizing antibody titers of anti-poliovirus sera against three serotypes of the virus in the same reaction and in shorter time. All three anti-poliovirus sera types were analyzed in a single assay. The MPBN assay was reproducible, robust and sensitive. Its lower limits of titration for the three anti-poliovirus sera types were within range of 0.76–1.64 per mL. Different anti-poliovirus sera were tested with conventional and MPBN assays; the results obtained by both methods correlated well and generated similar results. The MPBN is the first neutralization assay that specifically titrates anti-poliovirus antibodies against the three serotypes of the virus in the same reaction; it can be completed in two to three days instead of ten days for the conventional assay and can be automated for high-throughput implementation. Full article
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Open AccessArticle
Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus
Vaccines 2020, 8(1), 116; https://doi.org/10.3390/vaccines8010116 - 02 Mar 2020
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory [...] Read more.
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These—originally β-cell secretory products—extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function. Full article
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Open AccessArticle
Advanced Safety and Genetic Stability in Mice of a Novel DNA-Launched Venezuelan Equine Encephalitis Virus Vaccine with Rearranged Structural Genes
Vaccines 2020, 8(1), 114; https://doi.org/10.3390/vaccines8010114 - 02 Mar 2020
Cited by 2
Abstract
The safety and genetic stability of V4020, a novel Venezuelan Equine Encephalitis Virus (VEEV) vaccine based on the investigational VEEV TC-83 strain, was evaluated in mice. V4020 was generated from infectious DNA, contains a stabilizing mutation in the E2-120 glycoprotein, and includes rearrangement [...] Read more.
The safety and genetic stability of V4020, a novel Venezuelan Equine Encephalitis Virus (VEEV) vaccine based on the investigational VEEV TC-83 strain, was evaluated in mice. V4020 was generated from infectious DNA, contains a stabilizing mutation in the E2-120 glycoprotein, and includes rearrangement of structural genes. After intracranial inoculation (IC), replication of V4020 was more attenuated than TC-83, as documented by low clinical scores, inflammation, viral load in brain, and earlier viral clearance. During the first 9 days post-inoculation (DPI), genes involved in inflammation, cytokine signaling, adaptive immune responses, and apoptosis were upregulated in both groups. However, the magnitude of upregulation was greater in TC-83 than V4020 mice, and this pattern persisted till 13 DPI, while V4020 gene expression profiles declined to mock-infected levels. In addition, genetic markers of macrophages, DCs, and microglia were strongly upregulated in TC-83 mice. During five serial passages in the brain, less severe clinical manifestations and a lower viral load were observed in V4020 mice and all animals survived. In contrast, 13.3% of mice met euthanasia criteria during the passages in TC-83 group. At 2 DPI, RNA-Seq analysis of brain tissues revealed that V4020 mice had lower rates of mutations throughout five passages. A higher synonymous mutation ratio was observed in the nsP4 (RdRP) gene of TC-83 compared to V4020 mice. At 2 DPI, both viruses induced different expression profiles of host genes involved in neuro-regeneration. Taken together, these results provide evidence for the improved safety and genetic stability of the experimental V4020 VEEV vaccine in a murine model. Full article
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Open AccessArticle
Generation of A Triple Insert Live Avian Herpesvirus Vectored Vaccine Using CRISPR/Cas9-Based Gene Editing
Vaccines 2020, 8(1), 97; https://doi.org/10.3390/vaccines8010097 - 21 Feb 2020
Cited by 1
Abstract
Herpesvirus of turkeys (HVT), used originally as a vaccine against Marek’s disease (MD), has recently been shown to be a highly effective viral vector for generation of recombinant vaccines that deliver protective antigens of other avian pathogens. Until the recent launch of commercial [...] Read more.
Herpesvirus of turkeys (HVT), used originally as a vaccine against Marek’s disease (MD), has recently been shown to be a highly effective viral vector for generation of recombinant vaccines that deliver protective antigens of other avian pathogens. Until the recent launch of commercial HVT-vectored dual insert vaccines, most of the HVT-vectored vaccines in the market carry a single foreign gene and are usually developed with slow and less efficient conventional recombination methods. There is immense value in developing multivalent HVT-vectored vaccines capable of inducing simultaneous protection against multiple avian pathogens, particularly to overcome the interference between individual recombinant HVT vaccines. Here we demonstrate the use of a previously developed CRISPR/Cas9 gene editing protocol for the insertion of ILTV gD-gI and the H9N2 AIV hemagglutinin expression cassettes into the distinct locations of the recombinant HVT-IBDV VP2 viral genome, to generate the triple insert HVT-VP2-gDgI-HA recombinant vaccine. The insertion, protein expression, and stability of each insert were then evaluated by PCR, immunostaining and Western blot analyses. The successful generation of the first triple insert recombinant HVT vaccine with the potential for the simultaneous protection against three major avian viral diseases in addition to MD is a major innovation in vaccination-based control of major poultry diseases. Full article
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Open AccessArticle
Development of an IL-17A DNA Vaccine to Treat Systemic Lupus Erythematosus in Mice
Vaccines 2020, 8(1), 83; https://doi.org/10.3390/vaccines8010083 - 12 Feb 2020
Abstract
The interleukin-17 (IL-17) family, especially IL-17A, plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). This study developed an IL-17A epitope vaccine to treat SLE in NZBWF1 and MRL/lpr mouse models. A plasmid vector encoding a hepatitis B core (HBc)-IL-17A [...] Read more.
The interleukin-17 (IL-17) family, especially IL-17A, plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). This study developed an IL-17A epitope vaccine to treat SLE in NZBWF1 and MRL/lpr mouse models. A plasmid vector encoding a hepatitis B core (HBc)-IL-17A epitope fusion protein was injected using electroporation into the skeletal muscle of NZBWF1(New Zealand Black mice x New Zealand White mice F1 hybrid strain) or MRL/lpr mice three times at 2-week intervals. As a result, anti-IL-17A antibodies were successfully produced in the HBc-IL-17A group. Accordingly, serum tumor necrosis factor alpha (TNF-α) concentrations were significantly reduced in the HBc-IL-17A group. According to pathological analysis, the IL-17A DNA vaccine significantly suppressed renal tissue damage and macrophage infiltration. Consequently, the survival rate was significantly improved in the HBc-IL-17A group. In addition, we evaluated the antigen reactivity of splenocytes from IL-17A-immunized mice using an enzyme-linked immune absorbent spot (ELISPot) assay for safety evaluation. Splenocytes from IL-17A-immunized mice were significantly stimulated by the HBc epitope peptide, but not by the IL-17A epitope or recombinant IL-17A. These results indicate that the IL-17A vaccine did not induce autoreactive T cells against endogenous IL-17A. This study demonstrates for the first time that an IL-17A DNA vaccine significantly reduced organ damage and extended survival time in lupus-prone mice. Full article
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Open AccessArticle
Plasmablast, Memory B Cell, CD4+ T Cell, and Circulating Follicular Helper T Cell Responses to a Non-Replicating Modified Vaccinia Ankara Vaccine
Vaccines 2020, 8(1), 69; https://doi.org/10.3390/vaccines8010069 - 06 Feb 2020
Abstract
Background: Vaccinia is known to induce antibody and cellular responses. Plasmablast, circulating follicular helper T (cTFH) cells, cytokine-expressing CD4 T cells, and memory B cells were compared between subcutaneous (SC) and needle-free jet injection (JI) recipients of non-replicating modified vaccinia Ankara [...] Read more.
Background: Vaccinia is known to induce antibody and cellular responses. Plasmablast, circulating follicular helper T (cTFH) cells, cytokine-expressing CD4 T cells, and memory B cells were compared between subcutaneous (SC) and needle-free jet injection (JI) recipients of non-replicating modified vaccinia Ankara (MVA) vaccine. Methods: Vaccinia-naïve adults received MVA SC or by JI on Days 1 and 29. Vaccinia-specific antibodies were quantified by plaque reduction neutralization test (PRNT) and enzyme-linked immunosorbent assay. Plasmablast, cTFH, and cytokine-expressing CD4 T cells were assessed on Days 1, 8, 15, 29, 36, 43 (cTFH and CD4+ only) and 57. Memory B cells were measured on Days 1 and 57. Results: Of the 36 enrolled subjects, only 22 received both vaccinations and had evaluable specimens after the second vaccine. Plasmablasts peaked one week after each vaccine. Day 15 plasmablasts correlated with peak PRNT titers. cTFH peaked on Days 8 and 36 and correlated with Day 36 plasmablasts. CD4+ peaked at Day 29 and one-third produced ≥2 cytokines. Day 57 memory B cells ranged from 0.1% to 0.17% of IgG-secreting B cells. Conclusions: This study provides insights into the cellular responses to non-replicating MVA, currently used as a vector for a variety of novel vaccines. Full article
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Open AccessArticle
Genetic Adjuvants in Replicating Single-Cycle Adenovirus Vectors Amplify Systemic and Mucosal Immune Responses against HIV-1 Envelope
Vaccines 2020, 8(1), 64; https://doi.org/10.3390/vaccines8010064 - 02 Feb 2020
Cited by 1
Abstract
Most infections occur at mucosal surfaces. Providing a barrier of protection at these surfaces may be a useful strategy to combat the earliest events in infection when there are relatively few pathogens to address. The majority of vaccines are delivered systemically by the [...] Read more.
Most infections occur at mucosal surfaces. Providing a barrier of protection at these surfaces may be a useful strategy to combat the earliest events in infection when there are relatively few pathogens to address. The majority of vaccines are delivered systemically by the intramuscular (IM) route. While IM vaccination can drive mucosal immune responses, mucosal immunization at intranasal (IN) or oral sites can lead to better immune responses at mucosal sites of viral entry. In macaques, IN immunization with replicating single-cycle adenovirus (SC-Ads) and protein boosts generated favorable mucosal immune responses. However, there was an apparent “distance effect” in generating mucosal immune responses. IN immunization generated antibodies against HIV envelope (env) nearby in the saliva, but weaker responses in samples collected from the distant vaginal samples. To improve on this, we tested here if SC-Ads expressing genetic adjuvants could be used to amplify antibody responses in distant vaginal samples when they are codelivered with SC-Ads expressing clade C HIV env immunogen. SC-Ads env 1157 was coadministered with SC-Ads expressing 4-1BBL, granulocyte macrophage colony-stimulating factor (GMCSF), IL-21, or Clostridoides difficile (C. diff.) toxin fragments by IN or IM routes. These data show that vaginal antibody responses were markedly amplified after a single immunization by the IN or IM routes, with SC-Ad expressing HIV env if this vaccine is complemented with SC-Ads expressing genetic adjuvants. Furthermore, the site and combination of adjuvants appear to “tune” these antibody responses towards an IgA or IgG isotype bias. Boosting these priming SC-Ad responses with another SC-Ad or with SOSIP native-like env proteins markedly amplifies env antibody levels in vaginal washes. Together, this data may be useful in informing the choice of route of delivery adenovirus and peptide vaccines against HIV-1. Full article
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Open AccessArticle
Hydrostatic Filtration Enables Large-Scale Production of Outer Membrane Vesicles That Effectively Protect Chickens against Gallibacterium anatis
Vaccines 2020, 8(1), 40; https://doi.org/10.3390/vaccines8010040 - 23 Jan 2020
Abstract
Gallibacterium anatis is a Gram-negative opportunistic avian pathogen representing an emerging threat to poultry meat and egg production worldwide. To date, no vaccine able to effectively prevent the morbidity associated with G. anatis infections has been developed yet. Our group previously reported that [...] Read more.
Gallibacterium anatis is a Gram-negative opportunistic avian pathogen representing an emerging threat to poultry meat and egg production worldwide. To date, no vaccine able to effectively prevent the morbidity associated with G. anatis infections has been developed yet. Our group previously reported that inoculation of different combinations of G. anatis outer membrane vesicles (OMVs), FlfA and GtxA-N proteins is effective in preventing lesions caused by G. anatis infections in layer chickens. Here we report the testing of the efficacy as vaccine prototypes of G. anatis OMVs isolated by hydrostatic filtration, a simple technique that allows the cost-effective isolation of high yields of OMVs. Layer chickens were immunized with OMVs alone or in combination with FlfA and/or GtxA-N proteins. Subsequent challenge with a heterologous G. anatis strain showed that immunization with OMVs alone could significantly reduce the lesions following a G. anatis infection. A second study was carried out to characterize the dose-response (0.25, 2.5 and 25 µg) relationship of G. anatis OMVs as immunogens, showing that 2.5 μg of OMVs represent the optimal dose to elicit protection in the immunized animals after a similar challenge. Additionally, administration of ≥2.5 μg of G. anatis OMVs induced specific IgY titers and possibly vertical transfer of immunity. Full article
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Open AccessArticle
Toxoplasma gondii ADSL Knockout Provides Excellent Immune Protection against a Variety of Strains
Vaccines 2020, 8(1), 16; https://doi.org/10.3390/vaccines8010016 - 06 Jan 2020
Abstract
Toxoplasma gondii is a protozoan parasite, occurring worldwide, endangers human health and causes enormous economic losses to the Ministry of Agriculture. A safe and effective vaccination is needed to handle these problems. In addition, ideal vaccine production is a challenge in the future. [...] Read more.
Toxoplasma gondii is a protozoan parasite, occurring worldwide, endangers human health and causes enormous economic losses to the Ministry of Agriculture. A safe and effective vaccination is needed to handle these problems. In addition, ideal vaccine production is a challenge in the future. In this study, we knocked out the adenylosuccinate lyase (ADSL) gene and found that the gene reduces the growth rate of T. gondii tachyzoites in vitro under standard growth conditions by plaque or replication experiments. Furthermore, mice that were immunized with tachyzoites of the ME49ΔADSL strain induced 100% protection efficacy against challenge with the type 1 strain RH, type 2 strain ME49 and type 3 strain VEG. All mice that were immunized with ME49ΔADSL had a survival rate of 100% when they were reinfected with wild-type strains, either 30 days or 70 days after immunization, and immunization was also protective against homologous infection with 50 T. gondii ME49 tissue cysts. In addition, the level of Toxoplasma-specific IgG was significantly elevated at 30 and 70 days after immunization. ME49ΔADSL induced high levels of Th1 cytokines (interferon gamma (IFN-γ), interleukin (IL)-12) at 4 weeks after immunization and spleen cell cultures from mice vaccinated for 150 days were able to produce robust INF-γ and IL-12 levels in the supernatant. The results of the present study showed that ΔADSL vaccination induced a T. gondii-specific cellular immune response against further infections. These results suggest that the ADSL-deficient vaccine can induce anti-Toxoplasma gondii humoral and cellular immune responses and has 100% immune protection against post-challenge by the type 1 strain RH, type 2 strain ME49 and type 3 strain VEG. It will be used as an excellent candidate for live vaccines and may contribute in a positive meaning to control human toxoplasmosis. Full article
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Open AccessArticle
Systems Vaccinology for a Live Attenuated Tularemia Vaccine Reveals Unique Transcriptional Signatures That Predict Humoral and Cellular Immune Responses
Vaccines 2020, 8(1), 4; https://doi.org/10.3390/vaccines8010004 - 24 Dec 2019
Cited by 2
Abstract
Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized [...] Read more.
Background: Tularemia is a potential biological weapon due to its high infectivity and ease of dissemination. This study aimed to characterize the innate and adaptive responses induced by two different lots of a live attenuated tularemia vaccine and compare them to other well-characterized viral vaccine immune responses. Methods: Microarray analyses were performed on human peripheral blood mononuclear cells (PBMCs) to determine changes in transcriptional activity that correlated with changes detected by cellular phenotyping, cytokine signaling, and serological assays. Transcriptional profiles after tularemia vaccination were compared with yellow fever [YF-17D], inactivated [TIV], and live attenuated [LAIV] influenza. Results: Tularemia vaccine lots produced strong innate immune responses by Day 2 after vaccination, with an increase in monocytes, NK cells, and cytokine signaling. T cell responses peaked at Day 14. Changes in gene expression, including upregulation of STAT1, GBP1, and IFIT2, predicted tularemia-specific antibody responses. Changes in CCL20 expression positively correlated with peak CD8+ T cell responses, but negatively correlated with peak CD4+ T cell activation. Tularemia vaccines elicited gene expression signatures similar to other replicating vaccines, inducing early upregulation of interferon-inducible genes. Conclusions: A systems vaccinology approach identified that tularemia vaccines induce a strong innate immune response early after vaccination, similar to the response seen after well-studied viral vaccines, and produce unique transcriptional signatures that are strongly correlated to the induction of T cell and antibody responses. Full article
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Open AccessArticle
Palm Tocotrienol-Adjuvanted Dendritic Cells Decrease Expression of the SATB1 Gene in Murine Breast Cancer Cells and Tissues
Vaccines 2019, 7(4), 198; https://doi.org/10.3390/vaccines7040198 - 27 Nov 2019
Abstract
The aim of this study was to evaluate the effectiveness of immunotherapy using dendritic cells (DC) pulsed with tumor lysate (a DC vaccine) in combination with daily supplementation of tocotrienol-rich fraction (TRF) to potentiate anti-tumor immune responses. We had previously reported that DC-vaccine [...] Read more.
The aim of this study was to evaluate the effectiveness of immunotherapy using dendritic cells (DC) pulsed with tumor lysate (a DC vaccine) in combination with daily supplementation of tocotrienol-rich fraction (TRF) to potentiate anti-tumor immune responses. We had previously reported that DC-vaccine immunotherapy together with TRF supplementation induced protective immunity to tumor challenge. Breast cancer was induced in female BALB/c mice. The mice were randomly assigned into the treatment groups. At autopsy, peripheral blood was collected in heparinized tube and the expression of cell surface molecules (CD40, CD80, CD83, and CD86) that are crucial for T-cell activation and survival were analyzed by flow cytometry. Tumor was excised from each animal and snap-frozen. Total RNA was extracted from each tumor tissue for microarray and gene expression analysis. Total protein was extracted from tumor tissue for protein expression studies using Western blotting. The results show that systemic administration of 1 mg TRF daily in combination with DC-vaccine immunotherapy (DC + TL + TRF) caused a marked reduction (p < 0.05) of tumor size and increased (p < 0.05) the survival rates of the tumor-inoculated mice. The expression of CD40, CD80, CD83, and CD86 were upregulated in peripheral blood from the DC + TL + TRF group compared to other groups. In addition, there was higher expression of FasL in tumor-excised mice from the DC + TL + TRF group compared to other groups. FasL plays an important role in maintaining immune privilege and is required for cytotoxic T-lymphocyte (CTL) activity. Microarray analysis identified several genes involved in the regulation of cancer. In this study, we focused on the special AT rich binding protein 1 (SATB1) gene, which was reported to have dual functions, one of which was to induce aggressive growth in breast cancer cells. Tumors from DC + TL + TRF mice showed lower (p < 0.05) expression of SATB1 gene. Further study will be conducted to investigate the molecular functions of and the role of SATB1 in 4T1 mammary cancer cells and DC. In conclusion, TRF supplementation can potentiate the effectiveness of DC-vaccine immunotherapy. Full article
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Review

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Open AccessReview
Technological Approaches for Improving Vaccination Compliance and Coverage
Vaccines 2020, 8(2), 304; https://doi.org/10.3390/vaccines8020304 - 16 Jun 2020
Abstract
Vaccination has been well recognised as a critically important tool in preventing infectious disease, yet incomplete immunisation coverage remains a major obstacle to achieving disease control and eradication. As medical products for global access, vaccines need to be safe, effective and inexpensive. In [...] Read more.
Vaccination has been well recognised as a critically important tool in preventing infectious disease, yet incomplete immunisation coverage remains a major obstacle to achieving disease control and eradication. As medical products for global access, vaccines need to be safe, effective and inexpensive. In line with these goals, continuous improvements of vaccine delivery strategies are necessary to achieve the full potential of immunisation. Novel technologies related to vaccine delivery and route of administration, use of advanced adjuvants and controlled antigen release (single-dose immunisation) approaches are expected to contribute to improved coverage and patient compliance. This review discusses the application of micro- and nano-technologies in the alternative routes of vaccine administration (mucosal and cutaneous vaccination), oral vaccine delivery as well as vaccine encapsulation with the aim of controlled antigen release for single-dose vaccination. Full article
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Open AccessReview
Vaccine Advances against Venezuelan, Eastern, and Western Equine Encephalitis Viruses
Vaccines 2020, 8(2), 273; https://doi.org/10.3390/vaccines8020273 - 03 Jun 2020
Abstract
Vaccinations are a crucial intervention in combating infectious diseases. The three neurotropic Alphaviruses, Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses, are pathogens of interest for animal health, public health, and biological defense. In both equines and humans, these viruses can [...] Read more.
Vaccinations are a crucial intervention in combating infectious diseases. The three neurotropic Alphaviruses, Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses, are pathogens of interest for animal health, public health, and biological defense. In both equines and humans, these viruses can cause febrile illness that may progress to encephalitis. Currently, there are no licensed treatments or vaccines available for these viruses in humans. Experimental vaccines have shown variable efficacy and may cause severe adverse effects. Here, we outline recent strategies used to generate vaccines against EEEV, VEEV, and WEEV with an emphasis on virus-vectored and plasmid DNA delivery. Despite candidate vaccines protecting against one of the three viruses, few studies have demonstrated an effective trivalent vaccine. We evaluated the potential of published vaccines to generate cross-reactive protective responses by comparing DNA vaccine sequences to a set of EEEV, VEEV, and WEEV genomes and determining the vaccine coverages of potential epitopes. Finally, we discuss future directions in the development of vaccines to combat EEEV, VEEV, and WEEV. Full article
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Open AccessReview
Human Cytomegalovirus Congenital (cCMV) Infection Following Primary and Nonprimary Maternal Infection: Perspectives of Prevention through Vaccine Development
Vaccines 2020, 8(2), 194; https://doi.org/10.3390/vaccines8020194 - 23 Apr 2020
Abstract
Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo [...] Read more.
Congenital cytomegalovirus (cCMV) might occur as a result of the human cytomegalovirus (HCMV) primary (PI) or nonprimary infection (NPI) in pregnant women. Immune correlates of protection against cCMV have been partly identified only for PI. Following either PI or NPI, HCMV strains undergo latency. From a diagnostic standpoint, while the serological criteria for the diagnosis of PI are well-established, those for the diagnosis of NPI are still incomplete. Thus far, a recombinant gB subunit vaccine has provided the best results in terms of partial protection. This partial efficacy was hypothetically attributed to the post-fusion instead of the pre-fusion conformation of the gB present in the vaccine. Future efforts should be addressed to verify whether a new recombinant gB pre-fusion vaccine would provide better results in terms of prevention of both PI and NPI. It is still a matter of debate whether human hyperimmune globulin are able to protect from HCMV vertical transmission. In conclusion, the development of an HCMV vaccine that would prevent a significant portion of PI would be a major step forward in the development of a vaccine for both PI and NPI. Full article
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Open AccessReview
Progress and Prospects on Vaccine Development against SARS-CoV-2
Vaccines 2020, 8(2), 153; https://doi.org/10.3390/vaccines8020153 - 29 Mar 2020
Cited by 13
Abstract
In December 2019, the outbreak of pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a serious pandemic in China and other countries worldwide. So far, more than 460,000 confirmed cases were diagnosed in nearly 190 [...] Read more.
In December 2019, the outbreak of pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a serious pandemic in China and other countries worldwide. So far, more than 460,000 confirmed cases were diagnosed in nearly 190 countries, causing globally over 20,000 deaths. Currently, the epidemic is still spreading and there is no effective means to prevent the infection. Vaccines are proved to be the most effective and economical means to prevent and control infectious diseases. Several countries, companies, and institutions announced their programs and progress on vaccine development against the virus. While most of the vaccines are under design and preparation, there are some that have entered efficacy evaluation in animals and initial clinical trials. This review mainly focused on the progress and our prospects on field of vaccine development against SARS-CoV-2. Full article
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