RESUMEN
Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination. Epitope spread to non-vaccinating neoantigens, including responses to KRAS G12C and G12V mutations, were detected post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination revealed effector and cytotoxic phenotypes with increased CD4+ T cell infiltration in the post-vaccine tumor biopsy. Collectively, these data support the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.
Asunto(s)
Vacunas contra el Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antígenos de Neoplasias , Linfocitos T CD8-positivos , Vacunas contra el Cáncer/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genéticaRESUMEN
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
Asunto(s)
Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Medicina de Precisión/métodos , Anciano , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Persona de Mediana Edad , Mutación , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
PURPOSE: Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. PATIENTS AND METHODS: In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. RESULTS: Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. CONCLUSION: PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Poxviridae/inmunología , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata/terapia , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Vectores Genéticos/inmunología , Humanos , Inmunización , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Orquiectomía , Antígeno Prostático Específico/antagonistas & inhibidores , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Vacunas Sintéticas/inmunologíaRESUMEN
PURPOSE: An open-label Phase 1 study of recombinant prime-boost poxviruses targeting CEA and MUC-1 in patients with advanced pancreatic cancer was conducted to determine safety, tolerability and obtain preliminary data on immune response and survival. PATIENTS AND METHODS: Ten patients with advanced pancreatic cancer were treated on a Phase I clinical trial. The vaccination regimen consisted of vaccinia virus expressing tumor antigens carcinoembryonic antigen (CEA) and mucin-1 (MUC-1) with three costimulatory molecules B7.1, ICAM-1 and LFA-3 (TRICOM) (PANVAC-V) and fowlpox virus expressing the same antigens and costimulatory molecules (PANVAC-F). Patients were primed with PANVAC-V followed by three booster vaccinations using PANVAC-F. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used as a local adjuvant after each vaccination and for 3 consecutive days thereafter. Monthly booster vaccinations for up to 12 months were provided for patients without progressive disease. Peripheral blood was collected before, during and after vaccinations for immune analysis. RESULTS: The most common treatment-related adverse events were mild injection-site reactions. Antibody responses against vaccinia virus was observed in all 10 patients and antigen-specific T cell responses were observed in 5 out of 8 evaluable patients (62.5%). Median overall survival was 6.3 months and a significant increase in overall survival was noted in patients who generated anti CEA- and/or MUC-1-specific immune responses compared with those who did not (15.1 vs 3.9 months, respectively; P = .002). CONCLUSION: Poxvirus vaccination is safe, well tolerated, and capable of generating antigen-specific immune responses in patients with advanced pancreatic cancer.
Asunto(s)
Vacunas contra el Cáncer/administración & dosificación , Neoplasias Pancreáticas/terapia , Virus Vaccinia/genética , Adulto , Anciano , Anticuerpos Antineoplásicos/biosíntesis , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/inmunología , Antígeno Carcinoembrionario/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucina-1/inmunología , Linfocitos T/inmunologíaRESUMEN
As the diversity of potential immunogens increases within certain classes of vectors, the possibility has arisen of employing heterologous prime/boost immunizations using diverse members of the same family of vectors. The present study was initiated to explore the use of divergent pox vectors in a prime/boost regimen to elicit high-frequency cellular immune responses to human immunodeficiency virus type 1 envelope and simian immunodeficiency virus gag in rhesus monkeys. We demonstrated that monkeys vaccinated with a recombinant modified vaccinia virus Ankara (rMVA) prime/recombinant fowlpox virus (rFPV) boost regimen and monkeys vaccinated with a recombinant vaccinia virus prime/rFPV boost regimen developed comparable cellular immune responses that were greater in magnitude than those elicited by a homologous prime/boost with rMVA. Nevertheless, comparable magnitude recall cellular immune responses were observed in monkeys vaccinated with heterologous and homologous recombinant poxvirus following challenge with the CXCR4-tropic SHIV-89.6P. Consistent with this finding, comparable levels of containment of viral replication and CD4(+) T-lymphocyte preservation were seen in these groups of recombinant poxvirus-vaccinated monkeys. This study supports further exploration of combining recombinant vectors of the same family in prime/boost immunization strategies to optimize vaccine-elicited cellular immune responses.
Asunto(s)
Vectores Genéticos/inmunología , Inmunización Secundaria/métodos , Poxviridae/inmunología , Vacunación/métodos , Virus Vaccinia/inmunología , Animales , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Vectores Genéticos/genética , Inmunidad Celular , Macaca mulatta , Poxviridae/genética , ARN Viral/sangre , Virus Vaccinia/genética , Replicación ViralRESUMEN
Although live attenuated vaccines can provide potent protection against simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus challenges, the specific immune responses that confer this protection have not been determined. To test whether cellular immune responses mediated by CD8+ lymphocytes contribute to this vaccine-induced protection, we depleted rhesus macaques vaccinated with the live attenuated virus SIVmac239Delta3 of CD8+ lymphocytes and then challenged them with SIVmac251 by the intravenous route. While vaccination did not prevent infection with the pathogenic challenge virus, the postchallenge levels of virus in the plasmas of vaccinated control animals were significantly lower than those for unvaccinated animals. The depletion of CD8+ lymphocytes at the time of challenge resulted in virus levels in the plasma that were intermediate between those of the vaccinated and unvaccinated controls, suggesting that CD8+ cell-mediated immune responses contributed to protection. Interestingly, at the time of challenge, animals expressing the Mamu-A*01 major histocompatibility complex class I allele showed significantly higher frequencies of SIV-specific CD8+ T-cell responses and lower neutralizing antibody titers than those in Mamu-A*01- animals. Consistent with these findings, the depletion of CD8+ lymphocytes abrogated vaccine-induced protection, as judged by the peak postchallenge viremia, to a greater extent in Mamu-A*01+ than in Mamu-A*01- animals. The partial control of postchallenge viremia after CD8+ lymphocyte depletion suggests that both humoral and cellular immune responses induced by live attenuated SIV vaccines can contribute to protection against a pathogenic challenge and that the relative contribution of each of these responses to protection may be genetically determined.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Productos del Gen env/inmunología , Depleción Linfocítica , Proteínas Oncogénicas de Retroviridae/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas Virales de Fusión/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Antivirales/sangre , Inmunofenotipificación , Macaca mulatta , Eliminación de Secuencia , Virus de la Inmunodeficiencia de los Simios/fisiología , Vacunas Virales , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiologíaRESUMEN
Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CD8 and IFN-gamma. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.
Asunto(s)
Antígeno B7-1/genética , Terapia Genética , Inmunoterapia , Melanoma/terapia , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Adulto , Anciano , Antígenos de Neoplasias , Antígeno B7-1/uso terapéutico , Antígenos CD8/genética , Femenino , Expresión Génica , Antígenos HLA-A , Antígeno HLA-A2 , Humanos , Inyecciones Intralesiones , Interferón gamma/genética , Interleucina-10/genética , Antígeno MART-1 , Masculino , Melanoma/genética , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana Edad , Proteínas de Neoplasias/inmunología , Linfocitos T/inmunologíaRESUMEN
Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.
Asunto(s)
Vacunas contra el SIDA/inmunología , Vectores Genéticos/genética , Infecciones por VIH/inmunología , Virus Vaccinia/genética , Virus Vaccinia/patogenicidad , Animales , Femenino , Eliminación de Gen , Anticuerpos Anti-VIH/sangre , Proteína gp120 de Envoltorio del VIH/genética , Inmunización , Inmunización Secundaria , Dosificación Letal Mediana , Ratones , Ratones Endogámicos BALB C , Vacunas Sintéticas/inmunología , VirulenciaRESUMEN
Production of IL-2 and IFN-gamma by CD4+ T lymphocytes is important for the maintenance of a functional immune system in infected individuals. In the present study, we assessed the cytokine production profiles of functionally distinct subsets of CD4+ T lymphocytes in rhesus monkeys infected with pathogenic or attenuated SIV/simian human immunodeficiency virus (SHIV) isolates, and these responses were compared with those in vaccinated monkeys that were protected from immunodeficiency following pathogenic SHIV challenge. We observed that preserved central memory CD4+ T lymphocyte production of SIV/SHIV-induced IL-2 was associated with disease protection following primate lentivirus infection. Persisting clinical protection in vaccinated and challenged monkeys is thus correlated with a preserved capacity of the peripheral blood central memory CD4+ T cells to express this important immunomodulatory cytokine.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , VIH/inmunología , Interleucina-2/biosíntesis , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/farmacología , Animales , Antígenos CD28/metabolismo , Productos del Gen gag , VIH/patogenicidad , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Memoria Inmunológica , Técnicas In Vitro , Interferón gamma/biosíntesis , Macaca mulatta , ARN Viral/sangre , Vacunas contra el SIDAS/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Subgrupos de Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Receptor fas/metabolismoRESUMEN
The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01+ monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01- monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination.
Asunto(s)
Vacunas contra el SIDA/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , VIH/fisiología , Antígenos de Histocompatibilidad Clase I/inmunología , Memoria Inmunológica , Virus de la Inmunodeficiencia de los Simios/fisiología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virología , Animales , Cartilla de ADN , Humanos , Macaca mulatta , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Replicación ViralRESUMEN
PURPOSE: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the construction and characterization of two viral vector vaccines to address these issues. EXPERIMENTAL DESIGN: The two viral vectors analyzed are the replication-competent recombinant vaccinia virus (rV-) and the avipox vector, fowlpox (rF-), which is replication incompetent in mammalian cells. Each vector encodes the transgenes for three human costimulatory molecules (B7-1, ICAM-1, and LFA-3, designated TRICOM) and the CEA and MUC-1 transgenes (which also contain agonist epitopes). The vectors are designated rV-CEA/MUC/TRICOM and rF-CEA/MUC/TRICOM. RESULTS: Each of the vectors is shown to be capable of faithfully expressing all five transgenes in human dendritic cells (DC). DCs infected with either vector are shown to activate both CEA- and MUC-1-specific T-cell lines to the same level as DCs infected with CEA-TRICOM or MUC-1-TRICOM vectors. Thus, no evidence of antigenic competition between CEA and MUC-1 was observed. Human DCs infected with rV-CEA/MUC/TRICOM or rF-CEA/MUC/TRICOM are also shown to be capable of generating both MUC-1- and CEA-specific T-cell lines; these T-cell lines are in turn shown to be capable of lysing targets pulsed with MUC-1 or CEA peptides as well as human tumor cells endogenously expressing MUC-1 and/or CEA. CONCLUSION: These studies provide the rationale for the clinical evaluation of these multigene vectors in patients with a range of carcinomas expressing MUC-1 and/or CEA.
Asunto(s)
Vacunas contra el Cáncer/genética , Vectores Genéticos/genética , Transgenes/genética , Animales , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígenos CD58/genética , Antígenos CD58/inmunología , Vacunas contra el Cáncer/inmunología , Antígeno Carcinoembrionario/genética , Antígeno Carcinoembrionario/inmunología , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Citotoxicidad Inmunológica/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Virus de la Viruela de las Aves de Corral/genética , Humanos , Immunoblotting , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Interferón gamma/biosíntesis , Mucina-1/genética , Mucina-1/inmunología , Recombinación Genética , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transfección , Transgenes/inmunología , Virus Vaccinia/genéticaRESUMEN
The ability of memory T cells to mount a recall response plays a key role in the ability of vaccinated animals to contain viral challenge. In this study, we intensively monitored the expansion of SIV Gag-specific CD8+ T cells in peripheral blood and tissues of rhesus macaques vaccinated with the attenuated strain SIVmac239Delta3 and challenged with the pathogenic viruses SIVmac239 or SIVsmE660. Although all vaccinated animals were infected with challenge virus, peak levels of plasma viremia in vaccinees were decreased by 1.5 to 2 logs as compared with naive controls. Decreased levels of plasma viremia in vaccinated animals were evident as early as 7 days post-challenge, well before the expansion of SIV-specific CD8+ T cells. Expansion of SIV-specific CD8+ T cells was not observed in peripheral blood or tissues until at least 14 days after infection and did not occur in most animals until after the initial peak of viral replication. The observation that expansion of SIV-specific CD8+ T cells is delayed until 7 days or more after initial detection of viremia highlights fundamental limitations in the ability of lentivirus-specific CD8+ T cells to mediate protection against challenge.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Productos del Gen gag/inmunología , Vacunas contra el SIDAS/administración & dosificación , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Antivirales/sangre , Citotoxicidad Inmunológica , Cinética , Ganglios Linfáticos/inmunología , Macaca mulatta , ARN Viral/sangre , Recto/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Viremia/inmunologíaRESUMEN
Whole killed human immunodeficiency virus type 1 (HIV-1) immunogens contain the more conserved epitopes of HIV-1 and therefore may provide some utility as potential HIV-1 vaccine candidates. Previous studies have shown that synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-guanine (CpG) dinucleotides trigger rapid stimulation of both CD4+ and CD8+ T cells. Here, we investigated whether immunization of rhesus macaques with an inactivated gp120-depleted HIV-1 immunogen, emulsified in incomplete Freund's adjuvant (IFA) together with immunostimulatory CpG-containing ODN (ODN 2006), would elicit HIV-specific cellular and humoral immune responses. High titer anti-p24 antibody levels were induced in all four immunized animals that were sustained 6 weeks after the fifth and final boost at 23 months. These anti-gag antibodies mapped to linear B-cell epitopes within the matrix (MA), capsid (CA), p2, nucleocapsid (NC) and p6 proteins of HIV-1 gag. HIV-specific interferon-gamma-producing CD4+ and CD8+ T-cell responses were measured before and after the fourth and fifth immunizations by both intracellular cytokine (ICC) and ELISPOT techniques; responses were detected in three of the four immunized animals. CD4+ T-cell epitopes appear to map within amino acids 261-290 and 291-320 of p24 CA protein. Immunizations were well tolerated both locally and systemically. Based on these results, further studies of this approach are warranted.
Asunto(s)
Vacunas contra el SIDA/inmunología , Islas de CpG/inmunología , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/administración & dosificación , Animales , Formación de Anticuerpos , Adyuvante de Freund/inmunología , Anticuerpos Anti-VIH/biosíntesis , Infecciones por VIH/prevención & control , VIH-1/genética , Inmunidad Celular , Interferón gamma/inmunología , Macaca mulatta , VacunaciónRESUMEN
We explored the use of a simian-human immunodeficiency virus (SHIV) DNA vaccine as an effective mucosal priming agent to stimulate a protective immune response for AIDS prevention. Rhesus macaques were vaccinated rectally with a DNA construct producing replication-defective SHIV particles, and boosted with either the same DNA construct or recombinant modified vaccinia virus Ankara (MVA) expressing SIV Gag, SIV Pol, and HIV Env (MVA-SHIV). Virus-specific mucosal and systemic humoral and cell-mediated immune responses could be stimulated by this approach but were present inconsistently among the vaccinated animals. Rectal vaccination with either SHIV DNA alone or SHIV DNA followed by MVA-SHIV induced SIV Gag/Pol- or HIV gp120-specific IgA in rectal secretions of four of seven animals. However, the gp120-specific rectal IgA antibody responses were not durable and had become undetectable in all but one animal shortly before rectal challenge with pathogenic SHIV 89.6P. Only the macaques primed with SHIV DNA and boosted with MVA-SHIV demonstrated SHIV-specific IgG in plasma. In addition, these animals developed more consistent antiviral cell-mediated responses and had better preservation of CD4 T cells following challenge with SHIV 89.6P. Our study demonstrates the utility of a rectal DNA/MVA vaccination protocol for the induction of diverse responses in different immunological compartments. In addition, the immunity achieved with this mucosal vaccination regimen is sufficient to delay progression to AIDS.
Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas contra el SIDA/genética , Administración Rectal , Animales , Proteínas de Fusión gag-pol/genética , Proteínas de Fusión gag-pol/inmunología , Inmunidad Mucosa , Macaca mulatta , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Virus de la Estomatitis Vesicular Indiana/genética , Virus de la Estomatitis Vesicular Indiana/inmunologíaRESUMEN
Although a consensus has emerged that an HIV vaccine should elicit a cytotoxic T lymphocyte (CTL) response, the characteristics of an effective vaccine-induced T lymphocyte response remain unclear. We explored this issue in the simian human immunodeficiency virus/rhesus monkey model in the course of assessing the relative immunogenicity of vaccine regimens that included a cytokine-augmented plasmid DNA prime and a boost with DNA or recombinant pox vectors. Recombinant vaccinia virus, recombinant modified vaccinia Ankara (MVA), and recombinant fowlpox were comparable in their immunogenicity. Moreover, whereas the magnitude of the peak vaccine-elicited T lymphocyte responses in the recombinant pox virus-boosted monkeys was substantially greater than that seen in the monkeys immunized with plasmid DNA alone, the magnitudes of recombinant pox boosted CTL responses decayed rapidly and were comparable to those of the DNA-alone-vaccinated monkeys by the time of viral challenge. Consistent with these comparable memory T cell responses, the clinical protection seen in all groups of experimentally vaccinated monkeys was similar. This study, therefore, indicates that the steady-state memory, rather than the peak effector vaccine-elicited T lymphocyte responses, may be the critical immune correlate of protection for a CTL-based HIV vaccine.
Asunto(s)
Memoria Inmunológica , Poxviridae/genética , Linfocitos T Citotóxicos/inmunología , Linfocitos T/inmunología , Animales , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/inmunología , Ensayo de Inmunoadsorción Enzimática , Recuento de Linfocitos , Macaca mulatta , Reacción en Cadena de la Polimerasa/métodos , ARN Viral/inmunología , Mapeo Restrictivo , Virus Vaccinia/genética , Vacunas Virales/inmunologíaRESUMEN
DNA vaccines are an important vaccine approach for many infectious diseases including human immunodeficiency virus (HIV). Recently, there have been exciting results reported for plasmid vaccination in pathogenic SHIV model systems. In these studies, plasmid vaccines supplemented by IL-2 Ig cytokine gene adjuvants or boosted by recombinant MVA vectors expressing relevant SIV and HIV antigens prevented CD4(+) T-cell loss and lowered viral loads following pathogenic challenge. However, similar results have not been reported in a direct pathogenic macaque challenge model. Here we report on a study of the ability of a multiplasmid SIV DNA vaccine in a pathogenic SIV251 rhesus mucosal challenge study. We observed that pGag/Pol+pEnv/Rev plasmid vaccines could not prevent SIV infection; however, vaccinated animals exhibited significant improvement in control of viral challenge compared to control animals. Furthermore, vaccinated animals exhibited protection against CD4(+) T-cell loss.
Asunto(s)
Vacunas contra el SIDAS , Vacunas de ADN , Animales , Recuento de Linfocito CD4 , Proteínas de Fusión gag-pol/genética , Proteínas de Fusión gag-pol/inmunología , Productos del Gen env/genética , Productos del Gen env/inmunología , Productos del Gen rev/genética , Productos del Gen rev/inmunología , Macaca mulatta , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Vacunación , Vacunas de ADN/inmunología , Carga ViralRESUMEN
Recombinant protein subunit AIDS vaccines have been based predominantly on the virus envelope protein. Such vaccines elicit neutralizing antibody responses that can provide type-specific sterilizing immunity, but in most cases do not confer protection against divergent viruses. In this report we demonstrate that a multiantigen subunit protein vaccine was able to prevent the development of disease induced in rhesus monkeys by a partially heterologous AIDS virus. The vaccine was composed of recombinant human immunodeficiency virus type 1 (HIV-1) gp120, NefTat fusion protein, and simian immunodeficiency virus (SIV) Nef formulated in the clinically tested adjuvant AS02A. Upon challenge of genetically unselected rhesus monkeys with the highly pathogenic and partially heterologous SIV/HIV strain SHIV(89.6p) the vaccine was able to reduce virus load and protect the animals from a decline in CD4-positive cells. Furthermore, vaccination prevented the development of AIDS for more than 2.5 years. The combination of the regulatory proteins Nef and Tat together with the structural protein gp120 was required for vaccine efficacy.