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Results for “Protein Subunit Vaccines”

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PubMed2002

Role of G protein beta3 subunit C825T and HLA class II polymorphisms in the immune response after HBV vaccination.

The G protein beta3 (GNB3) subunit and HLA are candidate genes predictive of immune response capacity. We therefore studied the influence of both gene systems on cellular and humoral immunity against hepatitis B virus (HBV) in 79 HBV booster-vaccinated healthy volunteers and an independent group of 77 probands after HBV basic immunization. Following booster vaccination, lymphocyte in vitro proliferation after stimulation with HBV surface antigen was 2.5-fold increased in GNB3 825T (TC + TT) vs CC allele carriers (P = 0.01) and was not influenced by HLA-DRB1 or DQB1 alleles. In addition, anti-HBs antibody titers in both groups were 2-fold increased in TC vs CC and decreased in TT vs CC allele carriers. However, antibody titers after HBV booster immunization were elevated in HLA-DQB1*0301 carriers (P corrected = 0.027). In summary, the GNB3 825T allele appears as a marker particularly predictive of cellular and HLA-DQB1*0301 of humoral immune responses following HBV vaccination.

Adult↗

PubMed1996

Isotype-specific antibody responses to rotavirus and virus proteins in cows inoculated with subunit vaccines composed of recombinant SA11 rotavirus core-like particles (CLP) or virus-like particles (VLP).

The isotype antibody responses to bovine IND P5, G6 and simian SA11 P2, G3 rotavirus and SA11 rotavirus proteins (VP4, VP6 and VP7) in serum, colostrum and milk were analysed by ELISA in three groups of vaccinated cows and nonvaccinated controls. Pregnant cows were vaccinated intramuscularly and intramammarily with recombinant baculovirus-expressed SA11 rotavirus VLP (triple-layered virus-like particles containing rotavirus VP2, VP4, VP6 and VP7); CLP (double-layered core-like particles containing rotavirus VP2 and VP6); or inactivated SA11 rotavirus, respectively. Rotavirus antigen titers were highest (30-200-fold) in ELISA in the VLP vaccine compared to the inactivated SA11 vaccine. The IgG1, IgG2 and IgM geometric mean antibody titers (GMT) to rotavirus (titers to bovine rotavirus vs SA11 rotavirus did not differ significantly for any isotype or group) and the IgG2 GMT to VP6 in serum at calving in the vaccinated groups were significantly (P < 0.05) higher than in the control group. In colostrum, IgG1 and IgA rotavirus antibody titers were significantly elevated for VLP (IgG1 GMT 832225; IgA GMT 16384), CLP (IgG1 GMT 660561; IgA GMT 10321) and SA11 (IgG1 GMT 131072; IgA GMT 1448) vaccinated cows compared to control cows (IgG1 GMT 11585; IgA GMT 45). The IgG1 and IgA GMT to rotavirus were significantly elevated (6-100-fold) in milk of VLP and CLP vaccinated cows compared to SA11 vaccinated or control cows. The isotype antibody responses to VP6 in serum, colostrum and milk paralleled the responses to rotavirus, but titers were approximately 2-10-fold lower. Only cows vaccinated with VLP had significantly enhanced serum, colostral and milk antibody titers to rotavirus VP4 and VP7. These results demonstrate that rotavirus antibody titers in serum, colostrum and milk are significantly enhanced by use of non-infectious VLP, CLP and inactivated SA11 rotavirus vaccines, but the VLP or CLP vaccines induced the highest antibody responses, corresponding to their higher rotavirus antigen titers measured by ELISA.

Animals↗

PubMed1989

Quality assessment of DNA vaccines: hepatitis-B vaccine.

Vaccines manufactured following "classical" methods contain inactivated or infectious but attenuated viruses or bacteria. In some instances, the inactivated agents are purified. In other cases, the vaccines contain protein subunits or practically pure polysaccharides. It is generally accepted that the final product cannot be completely characterised and that therefore extensive "in-process" controls are necessary to prove the consistent quality of such vaccines. Control tests are carried out on the substrate, the pooled bulk vaccine and on the final containers. Vaccines produced by recombinant DNA techniques consist of pure proteins. The production is carried out by the multiplication of the "working seed" under well-defined standardised conditions followed by clarification, extraction, purification, formulation. "In-process" controls are incorporated at each step and specifications for acceptance are formulated. The biological methods used for the classical vaccines are completed by physicochemical and immunological determinations of antigen content, identity and purity for the "new generation" products. The requirements for the manufacturers are based on the documents issued by the World Health Organisation and by the national control authorities. The marketing of vaccines is based on a lot by lot release procedure, whereby each lot is tested by the manufacturer and the national control authority before use. Hepatitis-B vaccine, derived from transformed yeast cells, is the first and sole vaccine which has obtained a world-wide license. The quality assessment of this vaccine has been achieved following the requirements for the new generation of biomolecules. It is an example for future vaccines.

Animals↗

PubMed2006

A proteomic-based approach for the identification of Candida albicans protein components present in a subunit vaccine that protects against disseminated candidiasis.

Candidiasis has become a prevalent infection in different types of immunocompromised patients. The cell wall of Candida albicans plays important functions during the host-fungus interactions. Cell wall (surface) proteins of C. albicans are major elicitors of host immune responses during candidiasis, and represent candidates for vaccine development. Groups of mice were vaccinated subcutaneously with a beta-mercaptoethanol (beta-ME) extract from C. albicans containing cell wall proteins. Vaccinated mice were then infected with a lethal dose of C. albicans. Increased survival and decreased fungal burden were observed in vaccinated mice as compared to a control group, and 75% of vaccinated mice with the beta-ME extract survived this otherwise lethal infection. We used a proteomic approach (2-DE followed by immunoblotting) to demonstrate a complex polypeptidic pattern associated with the beta-ME extract used in the vaccine formulation and to detect immunogenic components recognized by antibodies in immune sera from vaccinated animals. Reactive protein spots were identified by MALDI-TOF-MS and searches in genomic databases. As a conclusion, vaccination strategies using C. albicans cell wall proteins induce protective responses. These antigens can be identified by proteomic approaches and may be used as components of subcellular vaccines against candidiasis.

Animals↗

PubMedDate not supplied

Maternal immunization against viral disease.

The protective effect of maternal antibody against many viral diseases has been recognized. The use of maternal immunization has been considered as a means to augment this protection in the young infant against disease. Advantages of maternal immunization include the fact that young infants are most susceptible to infections but least responsive to vaccines, that pregnant women are accessible to medical care and respond well to vaccines, that IgG antibodies cross the placenta well during the third trimester, and that immunization of the pregnant woman has the potential to benefit both the mother and the infant. Disadvantages include the potential inhibition of an infant's response to active immunization or natural infection and liability issues with pharmaceutical companies and physicians. Immunization of pregnant women with viral vaccines for poliovirus, influenza viruses, and rubella has been described and maternal vaccination with these vaccines has been found to be safe for both the mother and the fetus. An open-label study of post-partum women immunized with the purified fusion protein of RSV (PFP-2, Wyeth-Lederle Pediatrics and Vaccines, Inc., Pearl River, NY) demonstrated that the vaccine was non-reactogenic and immunogenic; RSV-specific antibody was detected in breast milk. Immunization of pregnant women with purified protein or subunit vaccines could be considered against neonatal viral pathogens, such as respiratory syncytial virus, parainfluenza viruses, herpes group viruses, and human immunodeficiency virus. Further studies are needed to define the safety and efficacy of maternal immunization.

Female↗

PubMed1990

Isolation of recombinant fragments of the major outer-membrane protein of Chlamydia trachomatis: their potential as subunit vaccines.

Recombinant fragments of the major outer-membrane protein (MOMP) of Chlamydia trachomatis, expressed at high levels in Escherichia coli, were isolated and purified. Antisera to the recombinant proteins reacted preferentially with overlapping synthetic peptides covering the immunoaccessible variable segments of MOMP. These sera also reacted in a species-specific manner with the surface of intact infectious elementary bodies, and in a Chlamydia genus-specific manner in assays using denatured or bound chlamydial antigens. The ability of recombinant MOMP preparations to elicit antibody to the surface of chlamydial elementary bodies raises the possibility that these proteins may be useful for chlamydial vaccine development.

Animals↗

PubMed2026

Synthetic long peptide and DNA personalized cancer vaccines induce robust neoantigen-specific T cell responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to standard immunotherapies despite harboring cancer neoantigens capable of eliciting T cell responses. We completed two phase 1 clinical trials (NCT03956056 and NCT03122106) evaluating safety and immunogenicity of synthetic long peptide (SLP) and DNA personalized cancer vaccines (PCVs). PCVs were administered after resection and adjuvant chemotherapy. Tumor/normal whole-exome sequencing, RNA sequencing, and pVACtools were used to identify and prioritize candidate PCV neoantigens. PCVs were well tolerated without any grade ≥3 adverse events. Neoantigen-specific responses were demonstrated by interferon-γ enzyme-linked immunospot and intracellular cytokine staining. Expanded T cell receptor clonotypes were sequenced and transduced into autologous peripheral blood mononuclear cells to confirm neoantigen specificity. When compared with a contemporaneous institutional propensity-matched cohort, PCV patients demonstrated a trend toward prolonged median overall survival (4.4 versus 3.5 years, log-rank P = 0.23). Overall, PDAC PCVs are safe and feasible and elicit polyclonal T cell responses, linking prioritized cancer neoantigens to functional antitumor immunity.

Humans↗

PubMed1998

DNA-based and alphavirus-vectored immunisation with prM and E proteins elicits long-lived and protective immunity against the flavivirus, Murray Valley encephalitis virus.

The immunogenicity and protective efficacy of DNA-based vaccination with plasmids encoding the membrane proteins prM and E of the flavivirus Murray Valley encephalitis virus (MVE) were investigated. Gene gun-mediated intradermal delivery of DNA encoding the prM and E proteins elicited long-lived, virus-neutralising antibody responses in three inbred strains of mice and provided protection from challenge with a high titer inoculum of MVE. Intramuscular DNA vaccination by needle injection also induced MVE-specific antibodies that conferred resistance to challenge with live virus but failed to reduce virus infectivity in vitro. The two routes of DNA-based vaccination with prM and E encoding plasmids resulted in humoral immunty with distinct IgG subtypes. MVE-specific IgG1 antibodies were always prevalent after intradermal DNA vaccination via a gene gun but not detected when mice were immunised with DNA by the intramuscular route or infected with live virus. We also tested a Semliki Forest virus replicon as vector for a flavivirus prM and E protein-based subunit vaccine. Single-cycle infections in mice vaccinated with packaged recombinant replicon particles elicited durable, MVE-specific, and virus-neutralising antibody responses.

Animals↗

PubMed2026

Comparative Genomics-Guided Epitope Prioritization and in Silico Design of a Multi-Epitope DNA Vaccine Candidate Against Megalocytivirus pagrus 1.

Megalocytivirus pagrus 1 infection is a World Organisation for Animal Health-listed aquatic animal disease caused by a virus species comprising the RSIV, ISKNV, and TRBIV genogroups. Here, we integrated comparative genomics and immunoinformatics to prioritize a multi-epitope protein construct, pMEV, and to design a DNA vaccine candidate encoding it, with emphasis on RSIV-type infection relevant to rock bream aquaculture. Analysis of 61 complete genomes identified 28 core gene clusters, from which myristoylated membrane protein (MMP) and major capsid protein (MCP) were prioritized as source antigens for epitope screening. Four cytotoxic T-cell, five helper T-cell, and five linear B-cell epitope candidates were selected based on sequence-based screening and exploratory peptide-MHC docking. The selected epitopes were assembled with rock bream beta-defensin-3, PADRE, and peptide linkers to generate the 283-aa pMEV construct. Sequence-based physicochemical analyses indicated properties relevant to subsequent structural and expression-based evaluation, while computationally refined structural modeling identified nine putative conformational B-cell epitope regions. TLR3 docking, normal mode analysis, and a 200-ns molecular dynamics simulation characterized the structural behavior of the selected computational complex without inferring receptor activation. C-ImmSim further generated model-dependent generic humoral and helper T-cell-associated response patterns within a mammalian-based simulation framework. Finally, the pMEV coding sequence was codon-optimized and incorporated into an in silico pcDNA3.1(+)-based DNA vaccine design. Collectively, this study provides a comparative genomics-guided framework for prioritizing an experimentally testable multi-epitope DNA vaccine candidate against M. pagrus 1, while construct expression, immunogenicity, and protective efficacy remain to be evaluated experimentally.

Animals↗

PubMed2026

Computational prediction of a multi-epitope Human Metapneumovirus vaccine candidate through integrated reverse vaccinology and pan-genomic approaches.

Human metapneumovirus (HMPV) is a primary cause of global respiratory infections yet no approved vaccine currently exists. This study computationally predicts a multi-epitope vaccine candidate using a diverse dataset of 65 HMPV sequences spanning five continents. Following the screening of lead proteins for antigenicity and virulence, fifteen highly conserved MHC-I, MHC-II and B-cell epitopes were prioritized. These were integrated with a putative L7/L12 adjuvant using optimized AAY, GPGPG, and KK linkers to design three constructs (HMPV_V1-V3). Structural validation identified HMPV-V2 as the lead candidate that exhibits a Z-score of-5.24 and 87.7% of residues in favored Ramachandran regions indicating excellent stereochemical quality and structural stability. In silico docking indicated a strong predicted binding affinity between HMPV-V2 and the TLR4 receptor (energy: -969.2). Immune simulations predicted a robust adaptive response characterized by high IgG1 titers, memory B-cell maturation, and a Th1-dominant cytokine profile. Furthermore, molecular dynamics simulations suggested exceptional structural integrity for HMPV-V2, maintaining a low RMSD of 8.213 and RMSF of 0.737 throughout the simulation. Optimized in silico cloning into the pET28a (+) vector indicated a high potential for protein expression in E. coli systems. While these findings provide a theoretically grounded blueprint for vaccine development, this study is entirely computational and lacks experimental validation. Further in vitro and in vivo testing is required to confirm the actual safety and immunogenicity of the proposed candidate.

Metapneumovirus↗

PubMed2001

Identification of an immunodominant peptide in the parvovirus B19 VP1 unique region able to elicit a long-lasting immune response in humans.

The immune response against parvovirus B19 is mainly directed against the two structural proteins, VP1 and VP2. The amino terminal half of the VP1 unique region has been shown to elicit a dominant immune response in humans, more effective than other linear epitopes and also it has been seen to contain significant neutralizing linear epitopes. Three overlapping recombinant peptides corresponding to amino acids 2-40 (VP1-A), amino acids 32-71 (VP1-B), and amino acids 60-100 (VP1-C) of the VP1 unique region were produced by a procaryotic expression system. These peptides were used as antigens in a Western blot assay to detect specific immunoglobulin G (IgG) in serum samples from blood donors of different age groups with documented signs of a past B19 infection. Fragment VP1-C appeared significantly immunodominant over the other peptides, reacting with specific IgG in 86% of serum samples. The fragment VP1-C corresponds to a sequence with a known neutralizing activity and seems able to elicit a long-lasting immune response because specific IgG were present in blood donors of all age groups. VP1-C would therefore appear to be an attractive candidate as a component of a subunit vaccine.

Adult↗

PubMed2006

Immunogenicity of a receptor-binding domain of SARS coronavirus spike protein in mice: implications for a subunit vaccine.

We studied the immunogenicity of an anti-SARS subunit vaccine comprised of the fragment of the SARS coronavirus (SARS-CoV) spike protein amino acids 318-510 (S318-510) containing the receptor-binding domain. The S protein fragment was purified from the culture supernatant of stably transformed HEK293T cells secreting a tagged version of the protein. The vaccine was given subcutaneously to 129S6/SvEv mice in saline, with alum adjuvant or with alum plus CpG oligodeoxynucleotides (ODN). Mice immunized with the adjuvanted antigen elicited strong antibody and cellular immune responses; furthermore, adding the CpG ODN to the alum resulted in increased IgG2a antibody titers and a higher number of INF-gamma-secreting murine splenocytes. Mice vaccinated with S318-510 deglycosylated by PNGase F (dgS318-510) showed a lower neutralizing antibody response but had similar numbers of INF-gamma-producing cells in the spleen. This finding suggests that carbohydrate is important for the immunogenicity of the S318-510 protein fragment and provide useful information for designing an effective and safe SARS subunit vaccine.

Alum Compounds↗

PubMed2005

Vaccination equally enables both genetically susceptible and resistant mice to control infection with group A streptococci.

There is substantial evidence that host genetic factors are important in determining susceptibility to infection with group A streptococci (GAS). Several studies have revealed that, similarly to humans, a genetic component may be important in determining susceptibility to GAS infection in mice. Thus, C3H/HeN mice are much more susceptible to streptococcal infection than BALB/c mice. We have determined here whether vaccination makes genetically susceptible mice as capable as genetically resistant mice to control GAS infection. Resistant BALB/c and susceptible C3H/HeN mice were immunized either systemically with heat-killed GAS or through the mucosal route with an M protein-based subunit vaccine, and challenged with live bacteria. Vaccination elicited in both mouse strains similar levels of bactericidal anti-GAS IgG antibodies and also antigen-specific mucosal IgA. Vaccination provided mice of both strains with an increased and equal capacity to express immunity against GAS as indicated by the reduced level of bacteria in the organs and the ability of vaccinated mice to survive infection. Protection in vaccinated mice was dependent on the presence of T cell-dependent bactericidal antibodies as shown by the ability of serum elicited in immunocompetent mice but not of serum elicited in T cell-deficient nu/nu mice to passively transfer anti-GAS immunity. In conclusion, the results presented here demonstrated that the presence of anti-GAS specific, T cell-dependent bactericidal antibodies elicited after vaccination overcomes the innate genetic susceptibility of C3H/HeN mice and makes both resistant and susceptible mice equally capable of controlling GAS infection.

Animals↗

PubMed1999

Mycobacterial proteins--immune targets for antituberculous subunit vaccine.

Cellular and humoral immunity induced by Mycobacterium tuberculosis has led to identification of newer vaccine candidates, but despite this, many questions concerning the protection against tuberculosis remain unanswered. Recent progress in this field has centered on T cell subset responses and cytokines that these cells secrete. There has been a steady progress in identification and characterization of several classes of major mycobacterial proteins which includes secretory/export proteins, cell wall associated proteins, heat shock proteins and cytoplasmic proteins. The protein antigens are now believed to represent the key protective immunity inducing antigens in the bacillus. In this review, various mycobacterial protein antigens of vaccination potential are compared for their efficacy in light of current immunological knowledge.

Animals↗

PubMed1999

Is there an advantage to including the nucleoprotein in a rabies glycoprotein subunit vaccine?

The PV rabies (genotype 1) G and N proteins were produced by recombinant baculoviruses in insect cells. We tested the ability of recombinant antigens to synergistically induce an immune response and, particularly, to broaden the spectrum of Lyssavirus-neutralizing antibodies produced. Cell-free preparations of recombinant proteins caused an immune response. Recombinant rabies G protein (RRG) from infected cell extract or supernatant induced virus neutralizing antibodies (VNAb) against rabies (CVS virus (genotype 1) and in a less extent against European Bat Lyssavirus-1 (EBL-1:genotype 5) Recombinant rabies N protein (RRN) induced antibodies that reacted with the rabies virus ribonucleoprotein (RNP) and primed mice for both the production of VNAb induced by inactivated and purified rabies virus and the protection conferred by RNP. RRN also had an adjuvant effect on VNAb production induced by RRG when the two recombinant proteins were physically associated either encapsulated in liposomes or subjected to ultrasound treatment. However, there was no increase in production of VNAb directed against EBL-1 although classical vaccines (genotype 1) induce partial protection against this virus. thus, beside its adjuvant effect there is some doubt as to whether including rabies N protein in a rabies subunit vaccine containing the recombinant G protein would be advantageous.

Animals↗

PubMed1997

Fusions to the cholera toxin B subunit: influence on pentamerization and GM1 binding.

The cholera toxin B (CTB) subunit has been used extensively in vaccine research as a carrier for peptide immunogens due to its immunopotentiating properties, where coupling has been obtained either by genetic fusion or chemical conjugation. For genetically fused immunogens both N- and C-terminal fusions have been used. Only shorter extensions have previously been evaluated and in some reports these fusions have impaired the biological functions of CTB, such as the ability to form pentamers and to adhere to its cell receptor, the GM1 ganglioside. Here we report the first systematic study where the same fusion partner has been used for either C-terminal, N-terminal or dual fusions to CTB. The serum albumin binding region (BB, approximately 25 kDa) from streptococcal protein G, which is known to fold independently of N- or C-terminal fusions, was selected as fusion partner. The three fusion proteins CTB-BB, BB-CTB and BB-CTB-BB were expressed in Escherichia coli, where they were efficiently secreted to the periplasmic space, and could be purified by affinity chromatography on human serum albumin (HSA) columns. The CTB fusion proteins were compared for their ability to form pentamers, by gel electrophoresis and size-exclusion chromatography, and it was concluded that all three fusion proteins were able to pentamerize. Interestingly, the C-terminal fusion to CTB showed most efficient pentamerization, while the dual fusion was much less efficient. Purified pentamer fractions from all three fusions where found to react to a monoclonal antibody described to react only to pentameric forms of CTB. In addition, the purified pentamer fractions were analyzed in an enzyme-linked immunosorbent assay (ELISA) for their ability to bind GM1, and it was found that the C-terminal fusion (CTB-BB) showed significant GM1-binding, but that also the N-terminal and dual CTB fusion proteins bound GM1, although less efficiently. The implications of the results for the design and use of CTB fusion proteins as subunit vaccines are discussed.

Animals↗

PubMed2006

Plant-made subunit vaccine against pneumonic and bubonic plague is orally immunogenic in mice.

Yersinia pestis, the causative agent of plague, is an extremely virulent bacterium but there are no approved vaccines for protection against it. Our goal was to produce a vaccine that would address: ease of delivery, mucosal efficacy, safety, rapid scalability, and cost. We developed a novel production and delivery system for a plague vaccine of a Y. pestis F1-V antigen fusion protein expressed in tomato. Immunogenicity of the F1-V transgenic tomatoes was confirmed in mice that were primed subcutaneously with bacterially-produced F1-V and boosted orally with transgenic tomato fruit. Expression of the plague antigens in fruit allowed producing an oral vaccine candidate without protein purification and with minimal processing technology.

Administration, Oral↗

PubMed1996

Genetically engineered particulate virus-like structures and their use as vaccine delivery systems.

The Orbivirus genus within the family Reoviridae consists of nonenveloped architecturally complex viruses. The icosahedral viruses are 810 A diameter in size and are comprised of two protein shells containing seven proteins (VP1-VP7), surrounding a genome of ten double-stranded RNA segments. The prototype virus, bluetongue virus (BTV), is the etiological agent of a disease that can reach epidemic proportions among sheep and cattle. To develop highly protective virus-like particles, we have developed novel baculovirus multigene expression vector systems which have allowed us to coexpress three, four or five BTV genes from single recombinant vectors. The resultant particulate structures resemble BTV virus-like and subvirus-like particles which are structurally and immunologically indistinguishable from the BTV, and preliminary clinical trials have verified this vaccines safety and efficacy. Unlike live virus vaccines, VLPs are noninfectious and lack virus (or other) DNA/RNA required for replication. VLPs do not replicate in host cells. However, sheep trials have shown that VLPs are more immunogenic than subunit vaccines (viral proteins), or viruses killed by chemical inactivation. In addition, they are effective at eliciting humoral, cell-mediated and mucosal immunities. Virus-like particles (VLPs) are safe to produce and handle. The baculovirus vector and host cells used to make VLPs do not come from mammalian sources (hence they do not contain mammalian-derived pathogens). The multicomponent VLPs have also been utilized as vaccine delivery systems for multiple immunogens including B and T cell epitopes. The expression system described here is a tool which may have a range of applications in industries employing biotechnology to produce vaccines, insecticides, diagnostic and protein reagents.

Animals↗