Search

Melanoma is known to be the most hazardous and life‐threatening type of skin cancer. Although numerous treatments have been authorized in recent years, they often result in severe side effects and may not fully cure the disease. To combat this issue, immunotherapy has emerged as a promising approach for the prevention and treatment of melanoma. Specifically, the use of epitope melanoma vaccine, a subset of immunotherapy, has recently gained attention. The aim of this study was to create a multi‐epitope melanoma vaccine using immunoinformatic methods. Two well‐known antigens, NYESO‐1 and MAGE‐C2, were selected due to their strong immunogenicity and high expression in melanoma. To enhance the immunogenicity of the peptide vaccine, Brucella cell‐surface protein 31 (BCSP31), the G5 domain of resuscitation‐promoting factor B (RpfB) adjuvants, and the helper epitope of pan HLADR‐binding epitope (PADRE) were incorporated to vaccine construct. These different segments were connected with suitable linkers and the resulting vaccine structure was evaluated for its physicochemical, structural, and immunological properties using computational tools. The designed vaccine was found to have satisfactory allergenicity, antigenicity, and physicochemical parameters. Additionally, a high‐quality tertiary structure of the vaccine was achieved through modeling, refinement, and validation. Docking and molecular dynamics studies showed that the vaccine had a stable and appropriate interaction with the cognate TLR2 and TLR4 receptors during the simulation period. Finally, in silico immune simulation analysis revealed a significant increase in the levels of helper and cytotoxic T cells, as well as the cytokines interferon‐gamma and interleukin‐2, after repeated exposure to the melanoma vaccine. These results suggest that the designed vaccine has the potential to be an effective therapeutic option for melanoma. However, additional in vitro and in vivo validations are crucial to assess real‐world efficacy and safety. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is the highest‐ranked fungal pathogen in the Fungal Priority Pathogens List (FPPL) released by the World Health Organization (WHO). In this study, through in silico simulations, a multi‐epitope vaccine against Cryptococcus neoformans was developed using the mannoprotein antigen (MP88) as a vaccine candidate. Following the retrieval of the MP88 protein sequences, these were used to predict antigenic B‐cell and T‐cell epitopes via the bepipred tool and the artificial neural network, respectively. Conserved B‐cell epitopes AYSTPA, AYSTPAS, PASSNCK, and DSAYPP were identified as the most promising B‐cell epitopes. While YMAADQFCL, VSYEEWMNY, and FQQRYTGTF were identified as the best candidates for CD8+ T‐cell epitopes; and YARLLSLNA, ISYGTAMAV, and INQTSYARL were identified as the most promising CD4+ T‐cell epitopes. The vaccine construct was modeled along with adjuvant and peptide linkers and the expasy protparam tool was used to predict the physiochemical properties. According to this, the construct vaccine was predicted to be antigenic, nontoxic, nonallergenic, soluble, stable, hydrophilic, and thermostable. Furthermore, the three‐dimensional structure was also used in docking analyses with Toll‐like receptor (TLR4). Finally, the cDNA of vaccine was successfully cloned into the E. coli pET‐28a (+) expression vector. The results presented here could contribute towards the design of an effective vaccine against Cryptococcus neoformans. [ABSTRACT FROM AUTHOR]

In the landscape of infectious diseases, human coronaviruses such as SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 pose significant threats, characterized by severe respiratory illnesses and notable resistance to conventional treatments due to their rapid evolution and the emergence of diverse variants, particularly within SARS‐CoV‐2. This study investigated the development of broad‐spectrum coronavirus vaccines using heterodimeric RBD‐Fc proteins engineered through the "Knob‐into‐Hole" technique. We constructed various recombinant proteins incorporating the receptor‐binding domains (RBDs) of different coronaviruses. Heterodimers combining RBDs from SARS‐CoV‐2 with those of SARS‐CoV or MERS‐CoV elicited superior neutralizing responses compared to homodimeric proteins in murine models. Additionally, heterotetrameric proteins, specifically D614G_Delta/BA.1_XBB.1.5‐RBD and MERS_D614G/BA.1_XBB.1.5‐RBD, elicited remarkable breadth and potency in neutralizing all known SARS‐CoV‐2 variants, SARS‐CoV, related sarbecoviruses like GD‐Pangolin and WIV1, and even MERS‐CoV pseudoviruses. Furthermore, these heterotetrameric proteins also demonstrated enhanced cellular immune responses. These findings underscore the potential of recombinant hetero proteins as a universal vaccine strategy against current and future coronavirus threats. [ABSTRACT FROM AUTHOR]

The Toll‐like receptor 9 (TLR9) stimulator, CpG oligodeoxynucleotide, has emerged as a potent enhancer of protein subunit vaccines. Incorporating the protein antigen directly with the CpG adjuvant presents a novel strategy to significantly reduce the required dosage of CpG compared to traditional methods that use separate components. In contrast to existing chemical conjugation methods, this study introduces an enzymatic approach for antigen‐adjuvant coupling using a recombinant endonuclease DCV fused with SpyTag. This fusion protein catalyzes the covalent linkage between itself and the CpG adjuvant under mild conditions. These conjugates can be further linked with target protein antigens containing the SpyCatcher sequence, yielding stable, covalently‐linked antigen‐adjuvant complexes. The corresponding complex utilizing the receptor‐binding domain (RBD) of SARS‐CoV‐2 spike protein as the model antigen, elicits high‐titer, specific antibody production in mice via both subcutaneous administration and intratracheal inoculation. Notably, the tumor vaccine candidate fabricated by this method has also shown significant inhibition of cancer progression after intratracheal administration. The technique ensures precise, site‐specific coupling and preserves the antigen's structural integrity due to the post‐purification coupling strategy that simplifies manufacturing and aids in developing inhalable vaccines. [ABSTRACT FROM AUTHOR]

The emergence or reemergence of monkeypox (Mpox) and Ebola virus (EBOV) agents causing zoonotic diseases remains a huge threat to human health. Our study aimed at designing a multi‐epitope vaccine (MEV) candidate to target both the Mpox and EBOV agents using immunoinformatics tools. Viral protein sequences were retrieved, and potential nonallergenic, nontoxic, and antigenic epitopes were obtained. Next, cytotoxic and helper T‐cell (CTL and HTL, respectively) and B‐cell (BCL) epitopes were predicted, and those potential epitopes were fused utilizing proper linkers. The in silico cloning and expression processes were implemented using Escherichia coli K12. The immune responses were prognosticated using the C‐ImmSim server. The MEV construct (29.53 kDa) included four BCL, two CTL, and four HTL epitopes and adjuvant. The MEV traits were pertinent in terms of antigenicity, non‐allergenicity, nontoxicity, physicochemical characters, and stability. The MEV candidate was also highly expressed in E. coli K12. The strong affinity of MEV‐TLR3 was confirmed using molecular docking and molecular dynamics simulation analyses. Immune simulation analyses unraveled durable activation and responses of cellular and humoral arms alongside innate immune responses. The designed MEV candidate demonstrated appropriate traits and was promising in the prediction of immune responses against both Mpox and EBOV agents. Further experimental assessments of the MEV are required to verify its efficacy. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) is a foodborne virus transmitted through the faecal–oral route that causes viral hepatitis in humans worldwide. Ever since its discovery as a zoonotic agent, HEV was isolated from several species with an expanding range of hosts. HEV possesses several features of other RNA viruses but also has certain HEV‐specific traits that make its viral–host interactions inimitable. HEV leads to severe morbidity and mortality in immunocompromised people and pregnant women across the world. The situation in underdeveloped countries is even more alarming. Even after creating a menace across the world, we still lack an effective vaccine against HEV. Till date, there is only one licensed vaccine for HEV available only in China. The development of an anti‐HEV vaccine that can reduce HEV‐induced morbidity and mortality is required. Live attenuated and killed vaccines against HEV are not accessible due to the lack of a tolerant cell culture system, slow viral replication kinetics and varying growth conditions. Thus, the main focus for anti‐HEV vaccine development is now on the molecular approaches. In the current study, we have designed a multi‐epitope vaccine against HEV through a reverse vaccinology approach. For the first time, we have used viral ORF3, capsid protein and polyprotein altogether for epitope prediction. These are crucial for viral replication and persistence and are major vaccine targets against HEV. The proposed in silico vaccine construct comprises of highly immunogenic and antigenic T‐cell and B‐cell epitopes of HEV proteins. The construct is capable of inducing an effective and long‐lasting host immune response as evident from the simulation results. In addition, the construct is stable, non‐allergic and antigenic for the host. Altogether, our findings suggest that the in silico vaccine construct may be useful as a vaccine candidate for preventing HEV infections. [ABSTRACT FROM AUTHOR]

Background: The identification of epitope peptides from tumor‐associated antigens (TAAs) is informative for developing tumor‐specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC). Methods: Novel mouse c‐Met‐derived T‐cell epitopes were predicted by computer‐based algorithms. Mouse HNSCC cell line‐bearing mice were treated with a c‐Met peptide vaccine. The effects of CD8 and/or CD4 T‐cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re‐inoculation was performed to assess T‐cell memory. Results: We identified c‐Met‐derived short and long epitopes that elicited c‐Met‐reactive antitumor CD8 and/or CD4 T‐cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c‐Met peptide‐vaccinated mice rejected the re‐inoculated tumors. Conclusions: We demonstrated that novel c‐Met peptide vaccines can induce antitumor T‐cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model. [ABSTRACT FROM AUTHOR]

This article discusses the immunotherapeutic effects of specific and nonspecific mRNA-lipid nanoparticles (LNPs) in a mouse model of house dust mite (HDM)-induced airway inflammation. The study found that the mRNA-LNP vaccines were able to reduce key allergic parameters such as IL-5, specific IgE, and eosinophilia. However, the mRNA-LNP vaccines also switched HDM-specific airway eosinophilia into airway neutrophilia. The authors speculate that this may be due to the development of allergen-specific Th17 cells induced by the mRNA-LNP vaccines. Further research is needed to understand the distinct immunological pathways mediated by HDM-specific and nonspecific mRNA-LNP vaccines. [Extracted from the article]

Various vaccine platforms were developed and deployed against the COVID‐19 disease. The Fc‐mediated functions of IgG antibodies are essential in the adaptive immune response elicited by vaccines. However, the long‐term changes of protein subunit vaccines and their combinations with messenger RNA (mRNA) vaccines are unknown. A total of 272 serum and plasma samples were collected from individuals who received first to third doses of the protein subunit Medigen, the mRNA (BNT, Moderna), or the adenovector AstraZeneca vaccines. The IgG subclass level was measured using enzyme‐linked immunosorbent assay, and Fc‐N glycosylation was measured using liquid chromatography coupled to tandem mass spectrometry. Antibody‐dependent‐cellular‐phagocytosis (ADCP) and complement deposition (ADCD) of anti‐spike (S) IgG antibodies were measured by flow cytometry. IgG1 and 3 reached the highest anti‐S IgG subclass level. IgG1, 2, and 4 subclass levels significantly increased in mRNA‐ and Medigen‐vaccinated individuals. Fc‐glycosylation was stable, except in female BNT vaccinees, who showed increased bisection and decreased galactosylation. Female BNT vaccinees had a higher anti‐S IgG titer than that of males. ADCP declined in all groups. ADCD was significantly lower in AstraZeneca‐vaccinated individuals. Each vaccine produced specific long‐term changes in Fc structure and function. This finding is critical when selecting a vaccine platform or combination to achieve the desired immune response. [ABSTRACT FROM AUTHOR]

With the continued transmission of SARS‐CoV‐2 across widely vaccinated populations, it remains important to develop new vaccines and vaccination strategies capable of providing protective immunity and limiting the spread of disease. Heterologous prime‐boost vaccination based on the selection of different vaccine formulations and administration routes for priming and booster doses presents a promising strategy for inducing broader immune responses in key systemic and respiratory mucosal compartments. Intranasal vaccination can induce mucosal immune responses at the site of SARS‐CoV‐2 infection; however, the lack of clinically approved mucosal adjuvants makes it difficult to induce robust immune responses with protein subunit vaccines. Herein, we evaluated the immunogenicity of heterologous prime‐boost regimens in mice and hamsters based on a parenteral vaccination of the antigen in combination with sulfated lactosylarchaeol (SLA) archaeosomes, a liposome adjuvant comprised of a single semisynthetic archaeal lipid, followed by an intranasally administered unadjuvanted SARS‐CoV‐2 spike antigen. Intranasal administration of unadjuvanted spike to mice and hamsters increased serum spike‐specific IgG titers and spike‐neutralizing activity compared with nonboosted animals. Spike‐specific IgA responses were also detected in the bronchoalveolar lavage fluid in the lungs of mice that received an intranasal boost. In hamsters, the intranasal boost showed high efficacy against SARS‐CoV‐2 infection by protecting from body weight loss and reducing viral titers in the lungs and nasal turbinate. Overall, our heterologous intramuscular prime‐intranasal boost with SLA‐adjuvanted and unadjuvanted spike, respectively, demonstrated the potential of protein subunit formulations to promote antigen‐specific systemic and mucosal immune responses. [ABSTRACT FROM AUTHOR]

Chagas disease (CD), or American trypanosomiasis, caused by the parasitic protozoa Trypanosoma cruzi, is a substantial global health burden. This comprehensive review explored the multifaceted landscape of CD treatment, providing a historical perspective on the development and discontinuation of benznidazole (BNZ) and nifurtimox (NF), the primary medications. Efforts towards a pediatric version of BZN in Brazil address demographic‐specific treatments, while concerns over drug resistance prompt the exploration of alternative medications like Amiodarone, Allopurinol, Posaconazole, Ravuconazole, and Fexinidazole, which were clinically tested as antichagasic drugs. In recent years, some of the synthesized derivative (1,3‐thiazoles, 4‐thiazolidinones, 2‐styrylquinolines, imidazole‐containing nitrophthalazine, and some others) were found to better activity as compared to standard drug. Traditional herbal alternatives (Resveratrol, curcumin, 1,8‐cineole, β‐pinene, and some others) rooted in traditional practices show promise, with various plant extracts exhibiting anti‐parasitic properties. The frontier of nanomedicine unfolds with studies on solid nanomedicines, PLA‐nanoparticles, ZIF‐8, BNZ carriers, and PLGA nanoparticles, showcasing improved drug delivery systems and controlled release mechanisms. The absence of a definitive vaccine accentuates ongoing research in recombinant antigens, peptide‐based vaccines, and nanoparticle formulations, with notable candidates like TcG1, TcG2, TcG4, MASPpep‐KLH, adenovirus vectors, Tc24 protein, and integrin activators. A novel strategy combining a recombinant protein vaccine with low dose BZN treatment presents promising results in a mouse model, emphasizing the urgency for further research and potential advancements in CD therapeutics. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the safety and efficacy of vascular endothelial growth factor receptor (VEGFR)‐targeted peptide vaccines for the immunization of patients with unresectable hepatocellular carcinoma (HCC) who had responded to transarterial chemoembolization. Methods: Twenty‐two patients were randomized 1:1 to receive VEGFR‐targeted peptides or placebo. The primary end‐point was the safety assessment of the immunization. The secondary end‐points were evaluation of immunological responses and clinical outcomes. Results: No severe adverse events were induced by the study agents. Among the 12 patients in the vaccine group, a VEGFR1‐specific cytotoxic T lymphocyte (CTL) response was induced in eight (66.7%) patients and a VEGFR2‐specific CTL response was induced in 10 (83.3%). The median progression‐free survival (PFS) and overall survival (OS) rates were 4.8 and 52.0 months, respectively, in the vaccine group, and 2.7 and 21.8 months, respectively, in the placebo group. No statistically significant differences were found between the two groups (PFS p = 0.925, OS p = 0.190). When divided into two groups according to immunoreactivity, the median PFS of patients with and without a strong immune response to VEGFR1 were 7.4 and 2.7 months, and that to VEGFR2 were 10.6 and 2.7 months, respectively; there were significant differences according to the immune response. Conclusions: Immunotherapy with peptide vaccines targeting VEGFR1 and VEGFR2 was well tolerated with no serious adverse events. It also effectively induced peptide‐specific CTLs in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Ovarian cancer continues to be a difficult medical issue that affects millions of individuals worldwide. Important platforms for cancer immunotherapy include checkpoint inhibitors, chimeric antigen receptor T cells, bispecific antibodies, cancer vaccines, and other cell‐based treatments. To avoid numerous infectious illnesses, conventional vaccinations based on synthetic peptides, recombinant subunit vaccines, and live attenuated and inactivated pathogens are frequently utilized. Vaccine manufacturing processes, however, are not entirely safe and carry a significant danger of contaminating living microorganisms. As a result, the creation of substitute vaccinations is required for both viral and noninfectious illnesses, including cancer. Recently, there has been testing of nucleic acid vaccines, or NAVs, as a cancer therapeutic. Tumor antigens (TAs) are genetically encoded by DNA and mRNA vaccines, which the host uses to trigger immune responses against ovarian cancer cells that exhibit the TAs. Despite being straightforward, safe, and easy to produce, NAVs are not currently thought to be an ideal replacement for peptide vaccines. Some obstacles to this strategy include selecting the appropriate therapeutic agents (TAs), inadequate immunogenicity, and the immunosuppressive characteristic of ovarian cancer. We focus on strategies that have been employed to increase NAVs' effectiveness in the fight against ovarian cancer in this review. [ABSTRACT FROM AUTHOR]

Toxoplasmosis is one of the most dangerous zoonotic diseases, causing serious economic losses worldwide due to abortion and reproductive problems. Vaccination is the best way to prevent disease; thus, it is imperative to develop a candidate vaccine for toxoplasmosis. BAG1 and ROP8 have the potential to become vaccine candidates. In this study, rTgBAG1, rTgROP8, and rTgBAG1‐rTgROP8 were used to evaluate the immune effect of vaccines in each group by detecting the humoral and cellular immune response levels of BABL/c mice after immunization and the ability to resist acute and chronic infection with Toxoplasma gondii (T. gondii). We divided the mice into vaccine groups with different proteins, and the mice were immunized on days 0, 14, and 28. The protective effects of different proteins against T. gondii were analysed by measuring the cytokines, serum antibodies, splenocyte proliferation assay results, survival time, and number and diameter of brain cysts of mice after infection. The vaccine groups exhibited substantially higher IgG, IgG1, and IgG2a levels and effectively stimulated lymphocyte proliferation. The levels of IFN‐γ and IL‐2 in the vaccine group were significantly increased. The survival time of the mice in each vaccine group was prolonged and the diameter of the cysts in the vaccine group was smaller; rTgBAG1‐rTgROP8 had a better protection. Our study showed that the rTgBAG1, rTgROP8, and rTgBAG1‐rTgROP8 recombinant protein vaccines are partial but effective approaches against acute or chronic T. gondii infection. They are potential candidates for a toxoplasmosis vaccine. [ABSTRACT FROM AUTHOR]

Vaccines have demonstrated remarkable effectiveness in protecting against COVID‐19; however, concerns regarding vaccine‐associated enhanced respiratory diseases (VAERD) following breakthrough infections have emerged. Spike protein subunit vaccines for SARS‐CoV‐2 induce VAERD in hamsters, where aluminum adjuvants promote a Th2‐biased immune response, leading to increased type 2 pulmonary inflammation in animals with breakthrough infections. To gain a deeper understanding of the potential risks and the underlying mechanisms of VAERD, we immunized ACE2‐humanized mice with SARS‐CoV‐2 Spike protein adjuvanted with aluminum and CpG‐ODN. Subsequently, we exposed them to increasing doses of SARS‐CoV‐2 to establish a breakthrough infection. The vaccine elicited robust neutralizing antibody responses, reduced viral titers, and enhanced host survival. However, following a breakthrough infection, vaccinated animals exhibited severe pulmonary immunopathology, characterized by a significant perivascular infiltration of eosinophils and CD4+ T cells, along with increased expression of Th2/Th17 cytokines. Intracellular flow cytometric analysis revealed a systemic Th17 inflammatory response, particularly pronounced in the lungs. Our data demonstrate that aluminum/CpG adjuvants induce strong antibody and Th1‐associated immunity against COVID‐19 but also prime a robust Th2/Th17 inflammatory response, which may contribute to the rapid onset of T cell‐mediated pulmonary immunopathology following a breakthrough infection. These findings underscore the necessity for further research to unravel the complexities of VAERD in COVID‐19 and to enhance vaccine formulations for broad protection and maximum safety. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 48-year-old male with recurrent squamous cell carcinoma in situ (SCCIS) of the penis. The patient had undergone multiple surgeries over 13 years but experienced a recurrence of the SCCIS. Instead of further surgery or imiquimod treatment, the patient opted for a combined systemic and intralesional 9-valent human papillomavirus (HPV) vaccine. The treatment resulted in clinical and histologic resolution of the SCCIS, and the patient has not had a clinical recurrence in 20 months. The article suggests that the 9-valent HPV vaccine may have therapeutic properties and could be an effective alternative treatment for poor surgical candidates with SCCIS of the penis. Further research is needed to understand the specific types of HPV present in these patients and the mechanism underlying the therapeutic benefit of the vaccine. [Extracted from the article]

This article provides a concise summary of the life and contributions of Otto Scheiner, an Austrian scientist in the field of allergy and immunology. Scheiner studied chemistry, physics, and philosophy at the University of Vienna and later joined the Allergy and Immunology Research Group. He conducted research on receptors for complement system proteins and established cooperation with the Institute of Specific Prophylaxis and Tropical Medicine. Scheiner played a significant role in the development of recombinant allergens and the identification of important pathogenic antigens. He also contributed to the field of cancer vaccines through the use of phage display technology. Scheiner's work is documented in over 300 scientific publications, and he had a lasting influence on the field. [Extracted from the article]

COVID‐19 pandemic has been the deadliest infectious disease outbreak since Spanish flu. The emerging variant lineages, decay of neutralizing antibodies, and occur of reinfections require the development of highly protective and safe vaccines. As currently approved COVID‐19 vaccines that utilize virus‐related genetic material are less than ideal, other vaccine types have been also widely investigated. Among them, peptide‐based vaccines hold great promise in countering COVID‐19 as they may overcome most of the shortcomings of RNA/DNA and protein vaccines. Two basic types of potential peptide vaccines can be developed. The first type are those which rely on cytotoxic T‐cell (CTL) responses to kill infected host cells and stop the replication via employing CTL‐epitopes as vaccine antigens. The second type of peptide vaccines are those that rely on B‐cell peptide epitopes to trigger humoral response via generating SARS‐CoV‐2‐specific antibodies to neutralize and/or opsonize the virus. We propose that combining both cellular and humoral immune responses would be highly protective. Here we discuss opportunities and challenges in the development of an effective and safe peptide‐based vaccine against COVID‐19. [ABSTRACT FROM AUTHOR]

Retraction: "Safety and immunogenicity of a recombinant receptor‐binding domain‐based protein subunit vaccine (Noora vaccine™) against COVID‐19 in adults: A randomized, double‐blind, placebo‐controlled, Phase 1 trial," by Salimian J, Ahmadi A, Amani J, et al. J Med Virol. 2022;95:e28097. The above article, published online on August 27, 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jmv.28097) has been retracted by agreement between the journal's Editor in Chief, Shou‐Jiang (SJ) Gao, and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties regarding issues with the data presented in the article.1 Several inconsistencies concerning the information provided about the analyzed subjects were additionally identified. Furthermore, the authors failed to disclose the presence of potential conflicts of interest that may have affected the interpretation of the results presented. Accordingly, the editors consider the conclusions of this manuscript to be invalid. The authors have been informed of the decision to retract but did not agree with it. REFERENCE 1. Forthal DN. Comment on the immunogenicity of the Noora vaccine against SARS‐CoV‐2. J Med Virol. 2023;95:e28731. doi:10.1002/jmv.28731 [ABSTRACT FROM AUTHOR]

Background & Aims: Immunotherapy is a promising treatment option for cholangiocarcinoma. We compared cytotoxic T lymphocyte (CTL) responses against several tumour‐associated antigen (TAA)‐derived epitopes in cholangiocarcinoma patients to identify candidate epitopes for immunotherapy. Methods: Twenty‐six TAAs were selected, and the expression of TAAs in 6 cholangiocarcinoma cell lines and 9 specimens were measured using real‐time polymerase chain reaction (PCR). CTL responses against 38 TAA‐derived epitopes were measured using samples from 26 cholangiocarcinoma patients by interferon‐γ enzyme linked immunospot (ELISPOT)‐assay. Results: Most TAAs were expressed in cholangiocarcinoma cell lines and specimens in PCR. Epitopes that stimulated a specific immune response were defined as those that elicited a CTL response in more than 3 patients and little response in healthy volunteers, as measured by ELISPOT‐assay. Based on these criteria, there were 18 epitopes that stimulated specific immune responses: squamous cell carcinoma antigen recognized by T cells (SART)1690, P53161, multidrug resistance‐associated protein (MRP)3503, Survivin2B80, melanoma‐associated antigen (MAGE)‐A4143, receptor tyrosine kinase ErbB‐2/neu (Her2/neu)63, Wilms tumour (WT1)235, WT1417, β‐catenin29, carcinoembryonic antigen (CEA)268, CEA652, epithelial cell adhesion molecule (EpCAM)173, enhancer of zeste homolog (EZH)2291, mucin 5AC (MUC5AC)716, glypican‐3 (GPC3)298 and kinesin family member 20A (KIF20A)66. Furthermore, the absolute number of lymphocytes in peripheral blood was significantly correlated with the TAA‐specific response. Lastly, the overall survival was significantly prolonged in patients with 2 or more TAA‐specific CTL responses compared with none to one. Conclusions: These results demonstrated several TAAs may be promising for immunotherapy for cholangiocarcinoma, and patients with high lymphocyte counts may benefit more from immunotherapy. [ABSTRACT FROM AUTHOR]

To develop a peptide vaccine for cancer patients with the HLA-A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA-A26+/A26+ cancer patients to four different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide-specific IgG responses in pre-vaccination plasma were selected from the four peptide candidates applicable for HLA-A26+/A26+ cancer patients and administered s.c. Peptide-specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLA-A26 genotypes were HLA-A26:01 ( n = 24), HLA-A26:03 ( n = 10), and HLA-A26:02 ( n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide-specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide-specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA-A26+ advanced cancer patients because of their safety and higher rates of immunological responses. [ABSTRACT FROM AUTHOR]

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area. [ABSTRACT FROM AUTHOR]

The application of the fields of pharmacogenomics and pharmacogenetics to vaccine design has been recently labeled 'vaccinomics'. This newly named area of vaccine research, heavily intertwined with bioinformatics, seems to be leading the charge in developing novel vaccines for currently unmet medical needs against hypervariable viruses such as human immunodeficiency virus (HIV), hepatitis C and emerging avian and swine influenza. Some of the more recent bioinformatic approaches in the area of vaccine research include the use of epitope determination and prediction algorithms for exploring the use of peptide epitopes as vaccine immunogens. This paper briefly discusses and explores some current uses of bioinformatics in vaccine design toward the pursuit of peptide vaccines for hypervariable viruses. The various informatics and vaccine design strategies attempted by other groups toward hypervariable viruses will also be briefly examined, along with the strategy used by our group in the design and synthesis of peptide immunogens for candidate HIV and influenza vaccines. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are increasingly exploited for cell-based immunotherapy. However, limitations in ex vivo DC growth and DC functional heterogeneity have motivated development of complementary antigen-presenting cell sources. Here, the ability of CD40 ligand (CD40L)-activated B cells to fulfil that role was investigated. We demonstrate for the first time that non-specific or antigen-specific murine B cells can be grown for extended periods of time by stimulation with CD40L. These cells rapidly up-regulate and maintain high levels of co-stimulatory molecules. In a head-to-head comparison with DC, CD40L-expanded B cells were comparable to DC in the presentation of peptides to CD4+ and CD8+ T cells. While DC were superior to antigen non-specific CD40L-activated B cells with regard to whole protein (NP-BSA) processing and presentation, CD40L-expanded B cells from NP-BSA-immunized mice were comparable to DC when presenting BSA or NP-BSA to primed primary T cells or when presenting NP linked to an unrelated carrier, CGG, to naïve T cells. Thus, the combination of CD40L activation, which supports B-cell growth and augments intracellular protein processing, and antigen uptake via the B-cell receptor, allows for efficient uptake, processing, and presentation of whole protein antigens in a fashion comparable to that observed with mature DC. Like DC, CD40L-activated B cells efficiently home to secondary lymphoid organs in vivo. This system represents a unique tool for studying primary antigen-specific B cells and the results suggest that the outgrowth of large numbers of highly activated B cells represents a viable and practical complement to DC for cell-based immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Several cytotoxic T lymphocyte peptide-based vaccines against hepatitis B, human immunodeficiency virus and melanoma were recently studied in clinical trials. One interesting melanoma vaccine candidate alone or in combination with other tumor antigens, is the decapeptide ELA. This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog, with an N-terminal glutamic acid. It has been reported that the amino group and γ-carboxylic group of glutamic acids, as well as the amino group and γ-carboxamide group of glutamines, condense easily to form pyroglutamic derivatives. To overcome this stability problem, several peptides of pharmaceutical interest have been developed with a pyroglutamic acid instead of N-terminal glutamine or glutamic acid, without loss of pharmacological properties. Unfortunately compared with ELA, the pyroglutamic acid derivative (PyrELA) and also the N-terminal acetyl-capped derivative (AcELA) failed to elicit cytotoxic T lymphocyte (CTL) activity. Despite the apparent minor modifications introduced in PyrELA and AcELA, these two derivatives probably have lower affinity than ELA for the specific class I major histocompatibility complex. Consequently, in order to conserve full activity of ELA, the formation of PyrELA must be avoided. Furthermore, this stability problem is worse in the case of clinical grade ELA, produced as an acetate salt, like most of the pharmaceutical grade peptides. We report here that the hydrochloride salt, shows higher stability than the acetate salt and may be suitable for use in man. Similar stability data were also obtained for MAGE-3, another N-terminal glutamic acid containing CTL peptide in clinical development, leading us to suggest that all N-terminal glutamic acid and probably glutamine-containing CTL peptide epitopes may be stabilized as hydrochloride salts. [ABSTRACT FROM AUTHOR]