RESUMO
BACKGROUND: Human papillomavirus type 16 (HPV-16) infection is strongly associated with considerable parts of cervical, neck, and head cancers. Performed investigations have had moderate clinical success, so research to reach an efficient vaccine has been of great interest. In the present study, the immunization potential of a newly designed HPV-16 construct was evaluated in a mouse model. RESULTS: Initially, a construct containing HPV-16 mutant (m) E6/E7 fusion gene was designed and antigen produced in two platforms (i.e., DNA vaccine and recombinant protein). Subsequently, the immunogenicity of these platforms was investigated in five mice) C57BL/6 (groups based on several administration strategies. Three mice groups were immunized recombinant protein, DNA vaccine, and a combination of them, and two other groups were negative controls. The peripheral blood mononuclear cells (PBMCs) proliferation, Interleukin-5 (IL-5) and interferon-γ (IFN-γ) cytokines, IgG1 and IgG2a antibody levels were measured. After two weeks, TC-1 tumor cells were injected into all mice groups, and subsequently further analysis of tumor growth and metastasis and mice survival were performed according to the schedule. Overall, the results obtained from in vitro immunology and tumor cells challenging assays indicated the potential of the mE6/E7 construct as an HPV16 therapeutic vaccine candidate. The results demonstrated a significant increase in IFN-γ cytokine (P value < 0.05) in the Protein/Protein (D) and DNA/Protein (E) groups. This finding was in agreement with in vivo assays. Control groups show a 10.5-fold increase (P value < 0.001) and (C) DNA/DNA group shows a 2.5-fold increase (P value < 0.01) in tumor growth compared to D and E groups. Also, a significant increase in survival of D and E (P value < 0.001) and C (P value < 0.01) groups were observed. CONCLUSIONS: So, according to the findings, the recombinant protein could induce stronger protection compared to the DNA vaccine form. Protein/Protein and DNA/Protein are promising administration strategies for presenting this construct to develop an HPV-16 therapeutic vaccine candidate.
Assuntos
Papillomavirus Humano 16 , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas Virais , Proteínas E7 de Papillomavirus , Vacinas contra Papillomavirus , Proteínas Repressoras , Vacinas de DNA , Animais , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/imunologia , Camundongos , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Vacinas de DNA/imunologia , Vacinas de DNA/genética , Vacinas de DNA/administração & dosagem , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Vacinas contra Papillomavirus/imunologia , Vacinas contra Papillomavirus/genética , Vacinas contra Papillomavirus/administração & dosagem , Feminino , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/imunologia , Modelos Animais de Doenças , Humanos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologiaRESUMO
Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Memória Imunológica , Neoplasias Pulmonares , Células T de Memória , Animais , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/patologia , Camundongos , Células T de Memória/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Camundongos Endogâmicos C57BL , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Imunização Secundária/métodos , Vacinação/métodos , Feminino , Humanos , Administração Intranasal , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Pulmão/imunologia , Pulmão/patologiaRESUMO
BACKGROUND: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor. METHODS: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model. RESULTS: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination. CONCLUSIONS: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.
Assuntos
Vacinas Anticâncer , Eletroporação , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Eletroporação/métodos , Camundongos , Vacinas Anticâncer/imunologia , Camundongos Endogâmicos C57BL , Imunoterapia Adotiva/métodos , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Modelos Animais de Doenças , Linhagem Celular Tumoral , Células Alógenas/imunologia , Receptores ErbB/imunologiaRESUMO
Herpes simplex virus (HSV) has coevolved with Homo sapiens for over 100,000 years, maintaining a tenacious presence by establishing lifelong, incurable infections in over half the human population. As of 2024, an effective prophylactic or therapeutic vaccine for HSV remains elusive. In this review, we independently screened PubMed, EMBASE, Medline, and Google Scholar for clinically relevant articles on HSV vaccines. We identified 12 vaccines from our literature review and found promising candidates across various classes, including subunit vaccines, live vaccines, DNA vaccines, and mRNA vaccines. Notably, several vaccines-SL-V20, HF10, VC2, and mRNA-1608-have shown promising preclinical results, suggesting that an effective HSV vaccine may be within reach. Additionally, several other vaccines such as GEN-003 (a subunit vaccine from Genocea), HerpV (a subunit vaccine from Agenus), 0ΔNLS/RVx201 (a live-attenuated replication-competent vaccine from Rational Vaccines), HSV 529 (a replication-defective vaccine from Sanofi Pasteur), and COR-1 (a DNA-based vaccine from Anteris Technologies) have demonstrated potential in clinical trials. However, GEN-003 and HerpV have not advanced further despite promising results. Continued progress with these candidates brings us closer to a significant breakthrough in preventing and treating HSV infections.
Assuntos
Vacinas contra o Vírus do Herpes Simples , Herpes Simples , Simplexvirus , Vacinação , Humanos , Herpes Simples/prevenção & controle , Herpes Simples/imunologia , Herpes Simples/virologia , Vacinas contra o Vírus do Herpes Simples/imunologia , Vacinas contra o Vírus do Herpes Simples/administração & dosagem , Vacinas contra o Vírus do Herpes Simples/genética , Animais , Simplexvirus/genética , Simplexvirus/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de DNA/imunologia , Vacinas Atenuadas/imunologia , Erradicação de DoençasRESUMO
Introduction: Epstein-Barr virus (EBV) is an oncogenic human herpesvirus associated with ~350,000 cases of lymphoid and epithelial malignancies every year, and is etiologically linked to infectious mononucleosis and multiple sclerosis. Despite four decades of research, no EBV vaccine candidate has yet reached licensure. Most previous vaccine attempts focused on a single viral entry glycoprotein, gp350, but recent data from clinical and pre-clinical studies, and the elucidation of viral entry mechanisms, support the inclusion of multiple entry glycoproteins in EBV vaccine design. Methods: Here we generated a modified vaccinia Ankara (MVA)-vectored EBV vaccine, MVA-EBV5-2, that targets five EBV entry glycoproteins, gp350, gB, and the gp42gHgL complex. We characterized the genetic and translational stability of the vaccine, followed by immunogenicity assessment in BALB/c mice and rhesus lymphocryptovirus-negative rhesus macaques as compared to a gp350-based MVA vaccine. Finally, we assessed the efficacy of MVA-EBV5-2-immune rhesus serum at preventing EBV infection in human CD34+ hematopoietic stem cell-reconstituted NSG mice, under two EBV challenge doses. Results: The MVA-EBV5-2 vaccine was genetically and translationally stable over 10 viral passages as shown by genetic and protein expression analysis, and when administered to female and male BALB/c mice, elicited serum EBV-specific IgG of both IgG1 and IgG2a subtypes with neutralizing activity in vitro. In Raji B cells, this neutralizing activity outperformed that of serum from mice immunized with a monovalent MVA-vectored gp350 vaccine. Similarly, MVA-EBV5-2 elicited EBV-specific IgG in rhesus macaques that were detected in both serum and saliva of immunized animals, with serum antibodies demonstrating neutralizing activity in vitro that outperformed serum from MVA-gp350-immunized macaques. Finally, pre-treatment with serum from MVA-EBV5-2-immunized macaques resulted in fewer EBV-infected mice in the two challenge experiments than pretreatment with serum from pre-immune macaques or macaques immunized with the monovalent gp350-based vaccine. Discussion: These results support the inclusion of multiple entry glycoproteins in EBV vaccine design and position our vaccine as a strong candidate for clinical translation.
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Macaca mulatta , Animais , Humanos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Camundongos , Herpesvirus Humano 4/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Camundongos Endogâmicos BALB C , Vacinas de DNA/imunologia , Feminino , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Vetores Genéticos/genética , Vaccinia virus/imunologia , Vaccinia virus/genéticaRESUMO
Infections caused by the influenza virus lead to both epidemic and pandemic outbreaks in humans and animals. Owing to their rapid production, safety, and stability, DNA vaccines represent a promising avenue for eliciting immunity and thwarting viral infections. While DNA vaccines have demonstrated substantial efficacy in murine models, their effectiveness in larger animals remains subdued. This limitation may be addressed by augmenting the immunogenicity of DNA-based vaccines. In the investigation here, protein expression was enhanced via codon optimization and then mouse cytotoxic T-lymphocyte antigen 4 (CTLA-4) was harnessed as a modulatory adjunct to bind directly to antigen-presenting cells. Further, the study evaluated the immunogenicity of two variants of the hemagglutinin (HA) antigen, i.e. the full-length and the C-terminal deletion versions. The study findings revealed that the codon-optimized HA gene (pcHA) led to increased protein synthesis, as evidenced by elevated mRNA levels. Codon optimization also significantly bolstered both cellular and humoral immune responses. In cytokine assays, all plasmid constructs, particularly pCTLA4-cHA, induced robust interferon (IFN)-γ production, while interleukin (IL)-4 levels remained uniformly non-significant. Mice immunized with pcHA displayed an augmented presence of IFNγ+ T-cells, underscoring the enhanced potency of the codon-optimized HA vaccine. Contrarily, CTLA-4-fused DNA vaccines did not significantly amplify the immune response.
Assuntos
Antígeno CTLA-4 , Códon , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Vacinas de DNA/genética , Camundongos , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Códon/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Humanos , Feminino , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Vírus da Influenza A Subtipo H1N1/imunologiaRESUMO
Despite the decrease in mortality and morbidity due to SARS-CoV-2 infection, the incidence of infections due to Omicron subvariants of SARS-CoV-2 remains high. The mutations acquired by these subvariants, mainly concentrated in the receptor-binding domain (RBD), have caused a shift in infectivity and transmissibility, leading to a loss of effectiveness of the first authorized COVID-19 vaccines, among other reasons, by neutralizing antibody evasion. Hence, the generation of new vaccine candidates adapted to Omicron subvariants is of special interest in an effort to overcome this immune evasion. Here, an optimized COVID-19 vaccine candidate, termed MVA-S(3P_BA.1), was developed using a modified vaccinia virus Ankara (MVA) vector expressing a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein from the Omicron BA.1 variant. The immunogenicity and efficacy induced by MVA-S(3P_BA.1) were evaluated in mice in a head-to-head comparison with the previously generated vaccine candidates MVA-S(3P) and MVA-S(3Pbeta), which express prefusion-stabilized S proteins from Wuhan strain and Beta variant, respectively, and with a bivalent vaccine candidate composed of a combination of MVA-S(3P) and MVA-S(3P_BA.1). The results showed that all four vaccine candidates elicited, after a single intramuscular dose, protection of transgenic K18-hACE2 mice challenged with SARS-CoV-2 Omicron BA.1, reducing viral loads, histopathological lesions, and levels of proinflammatory cytokines in the lungs. They also elicited anti-S IgG and neutralizing antibodies against various Omicron subvariants, with MVA-S(3P_BA.1) and the bivalent vaccine candidate inducing higher titers. Additionally, an intranasal immunization in C57BL/6 mice with all four vaccine candidates induced systemic and mucosal S-specific CD4+ and CD8+ T-cell and humoral immune responses, and the bivalent vaccine candidate induced broader immune responses, eliciting antibodies against the ancestral Wuhan strain and different Omicron subvariants. These results highlight the use of MVA as a potent and adaptable vaccine vector against new emerging SARS-CoV-2 variants, as well as the promising feature of combining multivalent MVA vaccine candidates.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunidade Celular , Imunidade Humoral , Camundongos Transgênicos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/imunologia , Camundongos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Humanos , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Feminino , Vacinas de DNA/imunologia , Vaccinia virus/imunologia , Vaccinia virus/genética , Imunogenicidade da VacinaRESUMO
Vaccine manufacturing fosters the prevention, control, and eradication of infectious diseases. Recombinant DNA and in vitro (IVT) mRNA vaccine manufacturing technologies were enforced to combat the recent pandemic. Despite the impact of these technologies, there exists no scientific announcement that compares them. Digital Shadows are employed in this study to simulate each technology, investigating root cause deviations, technical merits, and liabilities, evaluating cost scenarios. Under this lens we provide an unbiased, advanced comparative technoeconomic study, one that determines which of these manufacturing platforms are suited for the two types of vaccines considered (monoclonal antibodies or antigens). We find recombinant DNA technology to exhibit higher Profitability Index due to lower capital and starting material requirements, pertaining to lower Minimum Selling Price per Dose values, delivering products of established quality. However, the potency of the mRNA, the streamlined and scalable synthetic processes involved and the raw material availability, facilitate faster market penetration and product flexibility, constituting these vaccines preferable whenever short product development cycles become a necessity.
Assuntos
RNA Mensageiro , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Humanos , DNA Recombinante/genética , Vacinas/imunologia , Vacinas de DNA/imunologia , Vacinas de DNA/genética , Anticorpos Monoclonais/imunologia , Desenvolvimento de VacinasRESUMO
Introduction: Various COVID-19 vaccine trials have shown that vaccines can successfully prevent symptomatic cases of COVID-19 and death. Head-to-head comparisons help to better understand the immune response characteristics of different COVID-19 vaccines in humans. Methods: We randomly selected 20 participants from each of five ongoing Phase II trials of COVID-19 vaccines. Here, SARS-CoV 2-specific immune responses to DNA vaccine (INO-4800), mRNA vaccine (BNT162b2), Adenovirus-vectored vaccine (CONVIDECIA), Protein subunit vaccine (Recombinant COVID- 19 Vaccine (Sf9 Cells)), Inactivated Vaccine (KCONVAC) were examined longitudinally in healthy adults between Jan 15, 2021 and July 5, 2021 for 6 months. RBD-IgG titres were detected by ELISA, neutralising antibody titer were detected by pseudoviral neutralization and immune cell response were detected by flow cytometry. Results: At the first visit (V1), 100% of individuals who received the BNT162b2, CONVIDECIA, or KCONVAC vaccines experienced seroconversion of neutralizing and binding antibodies in the serum. Except for the Recombinant COVID-19 Vaccine (Sf9 Cells) vaccine having the highest neutralizing antibody GMT at the second visit (although there was no statistically significant difference in geometric mean titers between V1 and V2), the rest of the vaccines had the highest levels of binding antibodies and neutralizing antibodies at V1. The neutralizing antibodies GMT of all vaccines showed a significant decrease at V3 compared to V1. The neutralizing antibody GMT against the omicron variant of all vaccines at V1 showed a significant decrease compared to the wild strain. We observed statistically significant differences in Tcm cells and RBD-specific memory B cells among various vaccines. Discussion: BNT162b2 (mRNA vaccine) exhibits the highest antibody levels among the five vaccines evaluated, regardless of whether the target is the wild-type virus or its variants. However, its cellular immune response may be weaker compared to CONVIDECIA (adenovirus type 5 vector vaccine).
Assuntos
Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Imunidade Celular , Imunidade Humoral , SARS-CoV-2 , Humanos , Vacinas contra COVID-19/imunologia , Adulto , COVID-19/imunologia , COVID-19/prevenção & controle , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Masculino , Feminino , China , Pessoa de Meia-Idade , Adulto Jovem , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de DNA/imunologia , Vacina BNT162/imunologia , Imunogenicidade da Vacina , Vacinas de Produtos Inativados/imunologiaRESUMO
Largemouth bass virus (LMBV) infections has resulted in high mortality and economic losses to the global largemouth bass industry and has seriously restricted the healthy development of the bass aquaculture industry. There are currently no antiviral therapies available for the control of this disease. In this study, we developed three types of vaccine against LMBV; whole virus inactivated vaccine (I), a subunit vaccine composed of the major viral capsid protein MCP (S) as well as an MCP DNA vaccine(D), These were employed using differing immunization and booster strategies spaced 2 weeks apart as follows: II, SS, DD and DS. We found that all vaccine groups induced humoral and cellular immune responses and protected largemouth bass from a lethal LMBV challenge to varying degrees and DD produced the best overall effect. Specifically, the levels of specific IgM in serum in all immunized groups were elevated and significantly higher than those in the control group. Moreover, the expression of humoral immunity (CD4 and IgM) and cellular immunity (MHCI-α) as well as cytokines (IL-1ß) was increased, and the activity of immunity-related enzymes ACP, AKP, LZM, and T-SOD in the serum was significantly enhanced. In addition, the relative percent survival of fish following an LMBV lethal challenge 4 weeks after the initial immunizations were high for each group: DD(89.5 %),DS(63.2 %),SS(50 %) and II (44.7 %). These results indicated that the MCP DNA vaccine is the most suitable and promising vaccine candidate for the effective control of LMBV disease.
Assuntos
Bass , Infecções por Vírus de DNA , Doenças dos Peixes , Vacinas de DNA , Vacinas Virais , Animais , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Doenças dos Peixes/prevenção & controle , Doenças dos Peixes/imunologia , Bass/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Infecções por Vírus de DNA/veterinária , Infecções por Vírus de DNA/prevenção & controle , Infecções por Vírus de DNA/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Imunidade Humoral , Ranavirus/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Imunidade CelularRESUMO
We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients. Specifically, 22 patients with non-metastatic, castration-sensitive PCa (nmCSPC) were treated with pTVG-HP, 100-1500 µg, administered over 12 weeks and followed for 15 y. 17 patients with non-metastatic castration-resistant PCa (nmCRPC) were treated with 100 µg pTVG-HP with different schedules of administration over 1 y and followed for 5 y. No adverse events were detected in long-term follow-up from either trial that were deemed possibly related to vaccination. Patients with nmCSPC had a median overall survival of 12.3 y, with 5/22 (23%) alive at 15 y. 8/22 (36%) died due to prostate cancer with a median survival of 11.0 y, and 9/22 (41%) died of other causes. Patients with nmCRPC had a median overall survival of 4.5 y, with 8/17 (47%) alive at 5 y. The presence of T-cells specific for the PAP target antigen was detectable in 6/10 (60%) individuals with nmCSPC, and 3/5 (60%) individuals with nmCRPC, many years after immunization. The detection of immune responses to the vaccine target years after immunization suggests durable immunity can be elicited in patients using a DNA vaccine encoding a tumor-associated antigen.Trial Registration: NCT00582140 and NCT00849121.
Assuntos
Vacinas Anticâncer , Antígeno Prostático Específico , Neoplasias da Próstata , Vacinas de DNA , Humanos , Masculino , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Antígeno Prostático Específico/imunologia , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Idoso , Seguimentos , Neoplasias da Próstata/imunologia , Pessoa de Meia-Idade , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Resultado do Tratamento , Idoso de 80 Anos ou mais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Recidiva Local de Neoplasia , Análise de Sobrevida , Fosfatase Ácida , Proteínas Tirosina Fosfatases/imunologiaRESUMO
Aim: To develop a trivalent DNA vaccine candidate encapsulated in Chitosan-TPP nanoparticles against hand foot and mouth disease (HFMD) and assess its immunogenicity in mice.Materials & methods: Trivalent plasmid carrying the VP1 and VP2 genes of EV-A71, VP1 gene of CV-A16 was encapsulated in Chitosan-TPP nanoparticles through ionic gelation. In vitro characterization and in vivo immunization studies of the CS-TPP-NPs (pIRES-VP121) were performed.Results: Mice administered with CS-TPP NPs (pIRES-VP121) intramuscularly were observed to have the highest IFN-γ response. Sera from mice immunized with the naked pDNA and CS-TPP-NPs (pIRES-VP121) demonstrated good viral clearance against wild-type EV-A71 and CV-A16 in RD cells.Conclusion: CS-TPP-NPs (pIRES-VP121) could serve as a prototype for future development of multivalent HFMD DNA vaccine candidates.
[Box: see text].
Assuntos
Quitosana , Enterovirus Humano A , Doença de Mão, Pé e Boca , Nanopartículas , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Quitosana/química , Nanopartículas/química , Camundongos , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Doença de Mão, Pé e Boca/imunologia , Camundongos Endogâmicos BALB C , Feminino , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Humanos , Plasmídeos , Interferon gama/metabolismo , Proteínas do Capsídeo/imunologia , Proteínas do Capsídeo/química , PolifosfatosRESUMO
In 2009, a novel swine-origin H1N1 virus emerged, causing a pandemic. The virus, known as H1N1pdm09, quickly displaced the circulating H1 lineage and became the dominant seasonal influenza A virus subtype infecting humans. Human-to-swine spillovers of the H1N1pdm09 have occurred frequently, and each occurrence has led to sustained transmission of the human-origin H1N1pdm09 within swine populations. In the present study, we developed a lipid nanoparticle-based DNA vaccine (LNP-DNA) containing the hemagglutinin gene of a swine-origin H1N1pdm09. In pigs, this LNP-DNA vaccine induced a robust antibody response after a single intramuscular immunization and protected the pigs against challenge infection with the homologous swine-origin H1N1pdm09 virus. In a mouse model, the LNP-DNA vaccine induced antibody and T-cell responses and protected mice against lethal challenge with a mouse-adapted human-origin H1N1pdm09 virus. These findings demonstrate the potential of the LNP-DNA vaccine to protect against both swine- and human-origin H1N1pdm09 viruses. IMPORTANCE: Swine influenza A virus (IAV) is widespread and causes significant economic losses to the swine industry. Moreover, bidirectional transmission of IAV between swine and humans commonly occurs. Once introduced into the swine population, human-origin IAV often reassorts with endemic swine IAV, resulting in reassortant viruses. Thus, it is imperative to develop a vaccine that is not only effective against IAV strains endemic in swine but also capable of preventing the spillover of human-origin IAV. In this study, we developed a lipid nanoparticle-encapsulated DNA plasmid vaccine (LNP-DNA) that demonstrates efficacy against both swine- and human-origin H1N1 viruses. The LNP-DNA vaccines are non-infectious and non-viable, meeting the criteria to serve as a vaccine platform for rapidly updating vaccines. Collectively, this LNP-DNA vaccine approach holds great potential for alleviating the impact of IAV on the swine industry and preventing the emergence of reassortant IAV strains.
Assuntos
Anticorpos Antivirais , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Nanopartículas , Infecções por Orthomyxoviridae , Doenças dos Suínos , Vacinas de DNA , Animais , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/genética , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Suínos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/genética , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/veterinária , Nanopartículas/administração & dosagem , Humanos , Camundongos , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/virologia , Doenças dos Suínos/imunologia , Anticorpos Antivirais/sangue , Influenza Humana/prevenção & controle , Influenza Humana/imunologia , Influenza Humana/virologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Feminino , Camundongos Endogâmicos BALB C , Lipossomos/administração & dosagemRESUMO
BACKGROUND: Influenza viruses pose a persistent threat to global public health, necessitating the development of innovative and broadly effective vaccines. METHODS: This study focuses on a multiepitope vaccine (MEV) designed to provide broad-spectrum protection against different influenza viruses. The MEV, containing 19 B-cell linear epitopes, 7 CD4+ T cells, and 11 CD8+ T cells epitopes identified through enzyme-linked immunospot assay (ELISPOT) in influenza viruses infected mice, was administered through a regimen of two doses of DNA vaccine followed by one dose of a protein vaccine in C57BL/6 female mice. FINDINGS: Upon lethal challenge with both seasonal circulating strains (H1N1, H3N2, BV, and BY) and historical strains (H1N1-PR8 and H3N2-X31), MEV demonstrated substantial protection against different influenza seasonal strains, with partial efficacy against historical strains. Notably, the increased germinal centre B cells and antibody-secreting cells, along with robust T cell immune responses, highlighted the comprehensive immune defence elicited by MEV. Elevated hemagglutinin inhibition antibody was also observed against seasonal circulating and historical strains. Additionally, mice vaccinated with MEV exhibited significantly lower counts of inflammatory cells in the lungs compared to negative control groups. INTERPRETATION: Our results demonstrated the efficacy of a broad-spectrum MEV against influenza viruses in mice. Conducting long-term studies to evaluate the durability of MEV-induced immune responses and explore its potential application in diverse populations will offer valuable insights for the continued advancement of this promising vaccine. FUNDING: Funding bodies are described in the Acknowledgments section.
Assuntos
Epitopos de Linfócito B , Vírus da Influenza B , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Animais , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Camundongos , Vírus da Influenza B/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/imunologia , Feminino , Epitopos de Linfócito B/imunologia , Vírus da Influenza A/imunologia , Anticorpos Antivirais/imunologia , Epitopos de Linfócito T/imunologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Estações do Ano , Vírus da Influenza A Subtipo H3N2/imunologia , HumanosRESUMO
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Assuntos
Vacinas Anticâncer , Macroglobulinemia de Waldenstrom , Humanos , Masculino , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Pessoa de Meia-Idade , Feminino , Macroglobulinemia de Waldenstrom/imunologia , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/genética , Idoso , Microambiente Tumoral/imunologia , Medicina de Precisão/métodos , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologiaRESUMO
Trypanosomes are the extracellular protozoan parasites that cause human African trypanosomiasis disease in humans and nagana disease in animals. Tsetse flies act as a vector for the transmission of the disease in African countries. Animals infected with these parasites become useless or workless, and if not treated, disease can be fatal. There are many side effects associated with old treatments and some of them result in death in 5% of cases. There is a major surface glycoprotein in the parasite known as variant surface glycoprotein. The immune system of the host develops antibodies against this antigen but due to antigenic variation, parasites evade the immune response. Currently, no vaccine is available that provides complete protection. In murine models, only partial protection was observed using certain antigens. In order to develop vaccines against trypanosomes, molecular biology and immunology tools have been used. Immunization is the sole method for the control of disease because the eradication of the vector from endemic areas is an impossible task. Genetic vaccines can carry multiple genes encoding different antigens of the same parasite or different parasites. DNA immunization induces the activation of both cellular immune response and humoral immune response along with the generation of memory. This review highlights the importance of DNA vaccines and advances in the development of DNA vaccines against T. brucei.
Assuntos
Vacinas Protozoárias , Trypanosoma brucei brucei , Tripanossomíase Africana , Vacinas de DNA , Animais , Vacinas de DNA/imunologia , Humanos , Tripanossomíase Africana/prevenção & controle , Tripanossomíase Africana/imunologia , Trypanosoma brucei brucei/imunologia , Trypanosoma brucei brucei/genética , Vacinas Protozoárias/imunologia , Desenvolvimento de Vacinas , Antígenos de Protozoários/imunologiaRESUMO
The H9N2 avian influenza virus (AIV) is spreading worldwide. Presence of H9N2 virus tends to increase the chances of infection with other pathogens which can lead to more serious economic losses. In a previous study, a regulated delayed lysis Salmonella vector was used to deliver a DNA vaccine named pYL233 encoding M1 protein, mosaic HA protein and chicken GM-CSF adjuvant. To further increase its efficiency, chitosan as a natural adjuvant was applied in this study. The purified plasmid pYL233 was coated with chitosan to form a DNA containing nanoparticles (named CS233) by ionic gel method and immunized by intranasal boost immunization in birds primed by oral administration with Salmonella strain. The CS233 DNA nanoparticle has a particle size of about 150 nm, with an encapsulation efficiency of 93.2 ± 0.12 % which protected the DNA plasmid from DNase I digestion and could be stable for a period of time at 37°. After intranasal boost immunization, the CS233 immunized chickens elicited higher antibody response, elevated CD4+ T cells and CD8+ T cells activation and increased T-lymphocyte proliferation, as well as increased productions of IL-4 and IFN-γ. After challenge, chickens immunized with CS233 resulted in the lowest levels of pulmonary virus titer and viral shedding as compared to the other challenge groups. The results showed that the combination of intranasal immunization with chitosan-coated DNA vaccine and oral immunization with regulatory delayed lytic Salmonella strain could enhance the immune response and able to provide protection against H9N2 challenge.
Assuntos
Administração Intranasal , Anticorpos Antivirais , Galinhas , Quitosana , Imunidade Celular , Vírus da Influenza A Subtipo H9N2 , Vacinas contra Influenza , Influenza Aviária , Plasmídeos , Vacinas de DNA , Eliminação de Partículas Virais , Animais , Vírus da Influenza A Subtipo H9N2/imunologia , Vírus da Influenza A Subtipo H9N2/genética , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , Influenza Aviária/prevenção & controle , Influenza Aviária/imunologia , Galinhas/imunologia , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/administração & dosagem , Anticorpos Antivirais/sangue , Plasmídeos/genética , Nanopartículas , Imunização Secundária , Linfócitos T CD8-Positivos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Interferon gama , Interleucina-4 , Adjuvantes de Vacinas , Doenças das Aves Domésticas/prevenção & controle , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/virologia , Linfócitos T CD4-Positivos/imunologia , Salmonella/imunologia , Salmonella/genéticaRESUMO
DNA vaccines are prospective for their efficient manufacturing process, but their immunogenicity is limited as they cannot efficiently induce CD8+ T cell responses. A promising approach is to induce cross-presentation by targeting antigens to DCs. Flt3L can expand the number of type 1 conventional DCs and thereby improve cross-presentation. In this study, we first constructed a DNA vaccine expressing soluble PD1 and found that the therapeutic effect of targeting DCs with only the sPD1 vaccine was limited. When combined the vaccine with Flt3L, the anti-tumor effect was significantly enhanced. Considering the complexity of tumors and that a single method may not be able to activate a large number of effective CD8+ T cells, we combined different drugs and the vaccine with Flt3L based on the characteristics of different tumors. In 4T1 model, we reduced Tregs through cyclophosphamide. In Panc02 model, we increased activated DCs by using aCD40. Both strategies triggered strong CD8+ T cell responses and significantly improved the therapeutic effect. Our study provides important support for the clinical exploration of DC-targeted DNA vaccines in combination with Flt3L.
Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Células Dendríticas , Proteínas de Membrana , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1 , Vacinas de DNA , Vacinas de DNA/imunologia , Animais , Células Dendríticas/imunologia , Receptor de Morte Celular Programada 1/imunologia , Vacinas Anticâncer/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/genética , Feminino , Camundongos , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUNDAn HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55Gag boost was compared with p55Gag.METHODSTwo groups (n = 25) received 4 DNA vaccinations (CE/CE+p55Gag or p55Gag) by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n = 6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses.RESULTSBoth regimens were safe and generally well tolerated. The p24CE vaccine was immunogenic and significantly boosted by CE+p55Gag (64% CD4+, P = 0.037; 42% CD8+, P = 0.004). CE+p55Gag induced responses to 5 of 7 CE, compared with only 2 CE by p55Gag DNA, with a higher response to CE5 in 30% of individuals (P = 0.006). CE+p55Gag induced significantly higher CD4+ CE T cell breadth (0.68 vs. 0.22 CE; P = 0.029) and a strong trend for overall T cell breadth (1.14 vs. 0.52 CE; P = 0.051). Both groups developed high cellular and humoral responses. p24CE vaccine-induced CD4+ CE T cell responses correlated (P = 0.007) with p24Gag antibody responses.CONCLUSIONThe CE/CE+p55Gag DNA vaccine induced T cell responses to conserved regions in p24Gag, increasing breadth and epitope recognition throughout p55Gag compared with p55Gag DNA. Vaccines focusing immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.TRIAL REGISTRATIONClinical Trials.gov NCT03181789FUNDINGHVTN, NIAID/NIH.
Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Vacinas de DNA , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Humanos , Vacinas de DNA/imunologia , Vacinas de DNA/administração & dosagem , HIV-1/imunologia , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem , Feminino , Adulto , Masculino , Método Duplo-Cego , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Pessoa de Meia-Idade , Adulto Jovem , Linfócitos T/imunologia , Anticorpos Anti-HIV/imunologia , Vacinação/métodos , Imunogenicidade da Vacina , Linfócitos T CD4-Positivos/imunologiaRESUMO
Seasonal influenza is an annually severe crisis for global public health, and an ideal influenza vaccine is expected to provide broad protection against constantly drifted strains. Compared to highly flexible hemagglutinin (HA), increasing data have demonstrated that neuraminidase (NA) might be a potential target against influenza variants. In the present study, a series of genetic algorithm-based mosaic NA were designed, and then cloned into recombinant DNA and replication-defective Vesicular Stomatitis Virus (VSV) vector as a novel influenza vaccine candidate. Our Results showed that DNA prime/VSV boost strategy elicited a robust NA-specific Th1-dominated immune response, but the traditional inactivated influenza vaccine elicited a Th2-dominated immune response. More importantly, the superior NA-specific immunity induced by our strategy could confer both a full protection against lethal homologous influenza challenge and a partial protection against heterologous influenza infection. These findings will provide insights on designing NA-based universal vaccine strategy against influenza variants.