RESUMO
BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti-pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13.
Assuntos
Anemia Falciforme/imunologia , Anticorpos Antibacterianos/sangue , Vacinas Pneumocócicas/imunologia , Vacinas Conjugadas/imunologia , Adolescente , Anticorpos Antibacterianos/imunologia , Criança , Feminino , Humanos , Imunização Secundária , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Fagocitose/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Streptococcus pneumoniae/imunologiaRESUMO
BACKGROUND: Persons with human immunodeficiency virus (HIV) infection are at increased risk of pneumococcal disease. We evaluated the safety and immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) in this population. METHODS: HIV-infected persons ≥ 18 years of age who were previously vaccinated with ≥ 1 dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and had CD4 cell counts ≥ 200 cells/mm(3) and HIV viral loads <50 000 copies/mL were enrolled in this 3-dose PCV13 open-label study. RESULTS: A total of 329 subjects received ≥ 1 dose, and 279 received 3 doses administered at 6-month intervals. Increases in anticapsular polysaccharide immunoglobulin G concentrations and opsonophagocytic antibody titers were demonstrated 1 month after each of the 3 doses of PCV13. Antibody levels were generally similar after each dose. The responses were similar whether subjects had previously received 1 or ≥ 2 doses of PPSV23. Pain at the injection-site was the most common local reaction. Severe injection site or systemic events were uncommon. CONCLUSIONS: Vaccination with PCV13 induces anticapsular immunoglobulin G and opsonophagocytic antibody responses in HIV-infected adults with prior PPSV23 vaccination and CD4 cell counts ≥ 200 cells/mm(3). The observations support the use of PCV13 in this population. CLINICAL TRIALS REGISTRATION: NCT00963235.
Assuntos
Infecções por HIV/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Atividade Bactericida do Sangue , Contagem de Linfócito CD4 , Feminino , HIV/isolamento & purificação , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Proteínas Opsonizantes/sangue , Fagocitose , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/administração & dosagem , Carga Viral , Adulto JovemRESUMO
This randomized open-label trial was designed to provide preliminary immunogenicity and safety data to support development of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) for adults. The aims were to: identify an age-appropriate PCV13 formulation, i.e., with (n = 309) or without (n = 304) aluminum phosphate (AlPO 4); compare the selected PCV13 formulation (n = 309) with 23-valent pneumococcal polysaccharide vaccine (PPSV23; n = 301); and, together with an extension study, assess sequential use of pneumococcal vaccines at 1-year intervals in adults aged ≥65 years (n = 105) not pre-vaccinated with PPSV23. Immune responses were measured by ELISA and opsonophagocytic activity assays 1 month postvaccination. Immunoglobulin G responses elicited by PCV13 with AlPO 4 and PCV13 without AlPO 4 were similar for the majority, and noninferior for all PCV13 serotypes. PCV13 with AlPO 4 was generally more reactogenic, with reactions mainly mild or moderate. Thus, PCV13 with AlPO 4 (hereafter PCV13) became the selected formulation. Immune responses to PCV13 were noninferior for all but one serotype and for most PCV13 serotypes superior to PPSV23. Vaccine sequence assessments showed that for PCV13/PPSV23, the initial PCV13 dose generally enhanced responses to a subsequent PPSV23 dose, compared with PPSV23 alone. For PCV13/PCV13, a second dose did not enhance the first dose response when given after 1 year. For PCV13/PPSV23/PCV13, priming with PCV13 (vaccination 1) did not protect against lower responses induced by PPSV23 to subsequent PCV13 (vaccination 3). In conclusion, the pediatric PCV13 formulation with AlPO 4 is well tolerated and immunogenic in adults, is generally more immunogenic than PPSV23, and subsequent vaccination with PPSV23 is possible if required.
Assuntos
Compostos de Alumínio/imunologia , Fenômenos Imunogenéticos/imunologia , Fosfatos/imunologia , Vacinas Pneumocócicas/imunologia , Vacinas Conjugadas/imunologia , Idoso , Idoso de 80 Anos ou mais , Compostos de Alumínio/efeitos adversos , Química Farmacêutica , Método Duplo-Cego , Fadiga/induzido quimicamente , Fadiga/imunologia , Feminino , Humanos , Fenômenos Imunogenéticos/efeitos dos fármacos , Masculino , Dor/induzido quimicamente , Dor/imunologia , Fosfatos/efeitos adversos , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/efeitos adversos , África do Sul/epidemiologia , Vacinas Conjugadas/efeitos adversosRESUMO
OBJECTIVE: To assess the safety and immune responses induced by a 13-valent pneumococcal conjugate vaccine (PCV13) after immunization of infants in Mexico. METHODS: PCV13 was given with other routine childhood vaccinations to 225 infants in Mexico at ages 2, 4, 6, and 12 months. RESULTS: The proportions of subjects achieving immunoglobulin G (IgG) concentrations ≥0.35 µg/mL after the infant series and toddler dose were ≥93.1% and ≥96.7%, respectively, for all 13 serotypes. The serotype-specific pneumococcal IgG geometric mean concentrations after the infant series and toddler dose ranged from 1.18 to 9.13 µg/mL and from 1.62 to 15.41 µg/mL, respectively. The most common local reaction and systemic event after each dose were tenderness and irritability, respectively. Most fever was mild; no fever >40.0°C (i.e., severe) was reported. One subject withdrew because of Kawasaki disease 5 days after the first dose of vaccines, but this condition was not considered related to PCV13. CONCLUSIONS: Overall, PCV13 administered with routine pediatric vaccines was immunogenic and safe in healthy infants in Mexico.
OBJETIVO: Evaluar la seguridad y la respuesta inmunitaria inducida por una vacuna antineumocócica conjugada 13 valente (PCV13) tras la vacunación de lactantes en México. MÉTODOS: Se administró la PCV13, junto con otras vacunas habituales de la niñez, a 225 lactantes a los 2, 4, 6 y 12 meses de edad en México. RESULTADOS: Las proporciones de lactantes que alcanzaron concentraciones de inmunoglobulina G (IgG) iguales o superiores a 0,35 µg/ml después de las tres primeras dosis (serie del lactante) y tras la cuarta (dosis del inicio de la deambulación) fueron de ≥ 93,1% y ≥ 96,7%, respectivamente, para los 13 serotipos. Las medias geométricas de las concentraciones de IgG antineumocócica específica de serotipo después de las tres primeras dosis y tras la cuarta variaron de 1,18 a 9,13 µg/ml, y de 1,62 a 15,41 µg/ml, respectivamente. Las reacciones local y sistémica más frecuentes después de cada dosis fueron respectivamente el dolor en el punto de inyección y la irritabilidad. En la mayor parte de los casos, la fiebre fue de carácter leve; no se notificó ningún caso de fiebre de más de 40,0 °C (fiebre grave). Un lactante fue excluido del estudio como consecuencia de la aparición de una enfermedad de Kawasaki cinco días después de la primera dosis de la vacuna, aunque se consideró que este proceso no estaba relacionado con la PCV13. CONCLUSIONES: En términos generales, la PCV13, administrada conjuntamente con las vacunas pediátricas habituales, se mostró inmunógena e inocua en lactantes sanos de México.
Assuntos
Humanos , Masculino , Feminino , Lactente , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , MéxicoRESUMO
The importance of host cellular immune responses, particularly CD8(+) cytotoxic T-lymphocyte (CTL) responses, in control of human immunodeficiency virus type 1 (HIV-1) infection has been demonstrated in many clinical studies. These studies, along with vaccination challenge studies in rhesus macaques, indicate the importance of cellular immune responses against HIV-1. Toward this end, we evaluated anti-HIV-1 cellular immune responses in a cohort of 54 subjects who were chronically infected with HIV-1. By validation of IFN-gamma ELISpot assay, we established a dual cut-off criterion for scoring a positive response. The magnitude and frequency of cellular immune responses were measured against HIV-1 antigens (Gag, Pol, Nef, Rev, and Tat), using synthetic peptides as antigens in ELISpot assay. Here we showed that HIV-1 Gag, Pol, and Nef were frequent targets of T cell responses in these subjects, whereas Tat and Rev were less frequently recognized. We further evaluated the possible association between host cellular immune responses and corresponding plasma viral loads in this cohort. By performing ranking correlation analysis, we demonstrated a positive correlation between host viral loads and ELISpot responses of HIV Gag and Pol in untreated subjects. For the subjects under antiviral regimens, however, we did not find any significant association. Our findings suggest that the high levels of ELISpot responses in chronically infected subjects were reflective of their persistent viral infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Contagem de Linfócito CD4 , Doença Crônica , Estudos de Coortes , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Produtos do Gene gag/imunologia , Produtos do Gene nef/imunologia , Produtos do Gene pol/imunologia , Produtos do Gene tat/imunologia , Infecções por HIV/virologia , Hispânico ou Latino/estatística & dados numéricos , Humanos , Imunidade Celular , Interferon gama/imunologia , Masculino , RNA Viral/sangue , Carga Viral , População Branca/estatística & dados numéricos , Produtos do Gene nef do Vírus da Imunodeficiência Humana , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
Lack of virus specific antibody response is commonly observed in both HIV-1-infected humans and SIV-infected monkeys with rapid disease progression. However, the mechanisms underlying this important observation still remain unclear. In a titration study of a SIVmac239 viral stock, three out of six animals with viral inoculation rapidly progressed to AIDS within 5 months. Unexpectedly, there was no obvious depletion of CD4(+) T cells in both peripheral and lymph node (LN) compartments in these animals. Instead, progressive depletion of proliferating B cells and disruption of the follicular dendritic cell (FDC) network in germinal centers (GC) was evident in the samples collected at as early as 20 days after viral challenge. This coincided with undetectable, or weak and transient, virus-specific antibody responses over the course of infection. In situ hybridization of SIV RNA in the LN samples revealed a high frequency of SIV productively infected cells and large amounts of accumulated viral RNA in the GCs in these animals. Early severe depletion of GC proliferating B cells and disruption of the FDC network may thus result in an inability to mount a virus-specific antibody response in rapid progressors, which has been shown to contribute to accelerated disease progression of SIV infection.
Assuntos
Linfonodos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia , Animais , Anticorpos Antivirais/sangue , Linfócitos B/citologia , Biópsia , Contagem de Células , Progressão da Doença , Centro Germinativo/imunologia , Centro Germinativo/virologia , Hiperplasia/patologia , Linfonodos/patologia , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/diagnóstico , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/imunologia , Carga ViralRESUMO
The prophylactic efficacy of DNA and replication-incompetent adenovirus serotype 5 (Ad5) vaccine vectors expressing simian immunodeficiency virus (SIV) Gag was examined in rhesus macaques using an SIVmac239 challenge. Cohorts of either Mamu-A*01(+) or Mamu-A*01(-) macaques were immunized with a DNA prime-Ad5 boost regimen; for comparison, a third cohort consisting of Mamu-A*01(+) monkeys was immunized using the Ad5 vector alone for both prime and boost. All animals, along with unvaccinated control cohorts of Mamu-A*01(+) and Mamu-A*01(-) macaques, were challenged intrarectally with SIVmac239. Viral loads were measured in both peripheral and lymphoid compartments. Only the DNA prime-Ad5-boosted Mamu-A*01(+) cohort exhibited a notable reduction in peak plasma viral load (sevenfold) as well as in early set-point viral burdens in both plasma and lymphoid tissues (10-fold) relative to those observed in the control monkeys sharing the same Mamu-A*01 allele. The degree of control in each animal correlated with the levels of Gag-specific immunity before virus challenge. However, virus control was short-lived, and indications of viral escape were evident as early as 6 months postinfection. The implications of these results in vaccine design and clinical testing are discussed.
Assuntos
Produtos do Gene gag/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vacinas de DNA/administração & dosagem , Adenoviridae/genética , Animais , Anticorpos Antivirais/sangue , Produtos do Gene gag/administração & dosagem , Produtos do Gene gag/genética , Vetores Genéticos , Imunização , Macaca mulatta , Recombinação Genética , Vacinas de DNA/imunologia , Carga ViralRESUMO
Simian-human immunodeficiency virus (SHIV) challenge studies in rhesus macaques were conducted to evaluate the efficacy of adenovirus-based vaccines in the context of different major histocompatibility complex class I genetic backgrounds and different vaccine compositions. Mamu-A*01 allele-negative rhesus monkeys were immunized with one of the following vaccine constructs: (i) replication-defective recombinant adenovirus type 5 (Ad5) expressing human immunodeficiency virus type 1 (HIV-1) Tat (Ad5/HIVTat); (ii) Ad5 vector expressing simian immunodeficiency virus (SIV) Gag (Ad5/SIVGag); (iii) Ad5 vector expressing the truncated HIV-1(jrfl) Env, gp140 (Ad5/gp140_jrfl); (iv) Ad5 vector expressing the SHIV-89.6P gp140 (Ad5/gp140_89.6P); or (v) the combination of Ad5/SIVGag and Ad5/gp140_jrfl. Following intravenous challenge with SHIV-89.6P, only those cohorts that received vaccines expressing Gag or Env exhibited an attenuation of the acute viremia and associated CD4-cell lymphopenia. While no prechallenge neutralizing antibody titers were detectable in either Ad5/gp140-vaccinated group, an accelerated neutralizing antibody response was observed in the Ad5/gp140_89.6P-vaccinated group upon viral challenge. The set-point viral loads in the Ad5/SIVGag- and Ad5/gp140_jrfl-vaccinated groups were associated with the overall strength of the induced cellular immune responses. To examine the contribution of Mamu-A*01 allele in vaccine efficacy against SHIV-89.6P challenge, Mamu-A*01-positive monkeys were immunized with Ad5/SIVGag. Vaccine-mediated protection was significantly more pronounced in the Mamu-A*01-positive monkeys than in Mamu-A*01-negative monkeys, suggesting the strong contributions of T-cell epitopes restricted by the Mamu-A*01 molecule. The implications of these results in the development of an HIV-1 vaccine will be discussed.
Assuntos
Vacinas contra a AIDS/imunologia , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene tat/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Adenoviridae/genética , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Antígenos Virais/imunologia , Contagem de Linfócito CD4 , Modelos Animais de Doenças , Produtos do Gene env/genética , Produtos do Gene tat/genética , Vetores Genéticos , HIV/genética , HIV/imunologia , Imunidade Celular , Macaca mulatta , Testes de Neutralização , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Carga Viral , Viremia , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
Conventional influenza vaccines can prevent infection, but their efficacy depends on the degree of antigenic "match" between the strains used for vaccine preparation and those circulating in the population. A universal influenza vaccine based on invariant regions of the virus, able to provide broadly cross-reactive protection, without requiring continuous manufacturing update, would solve a major medical need. Since the temporal and geographical dominance of the influenza virus type and/or subtype (A/H3, A/H1, or B) cannot yet be predicted, a universal vaccine, like the vaccines currently in use, should include both type A and type B influenza virus components. However, while encouraging preclinical data are available for influenza A virus, no candidate universal vaccine is available for influenza B virus. We show here that a peptide conjugate vaccine, based on the highly conserved maturational cleavage site of the HA(0) precursor of the influenza B virus hemagglutinin, can elicit a protective immune response against lethal challenge with viruses belonging to either one of the representative, non-antigenically cross-reactive influenza B virus lineages. We demonstrate that protection by the HA(0) vaccine is mediated by antibodies, probably through effector mechanisms, and that a major part of the protective response targets the most conserved region of HA(0), the P1 residue of the scissile bond and the fusion peptide domain. In addition, we present preliminary evidence that the approach can be extended to influenza A virus, although the equivalent HA(0) conjugate is not as efficacious as for influenza B virus.
Assuntos
Desenho de Fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza B/imunologia , Vacinas contra Influenza , Influenza Humana/prevenção & controle , Precursores de Proteínas , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza B/patogenicidade , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/genética , Peptídeos/imunologia , Precursores de Proteínas/química , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/química , Vacinas Conjugadas/imunologiaRESUMO
We compared the human immunodeficiency virus type 1 (HIV-1)-specific cellular immune responses elicited in nonhuman primates by HIV-1 gag-expressing replication-defective adenovirus serotype 5 (Ad5) or poxvirus vectors, used either alone or in combination with each other. The responses arising from a heterologous Ad5 priming-poxvirus boosting regimen were significantly greater than those elicited by homologous regimens with the individual vectors or by a heterologous poxvirus priming-Ad5 boosting regimen. The heterologous Ad5 priming-poxvirus boosting approach may have potential utility in humans as a means of inducing high levels of cellular immunity.
Assuntos
Vacinas contra a AIDS/imunologia , Adenoviridae/genética , Produtos do Gene gag/imunologia , Imunização , Poxviridae/genética , Linfócitos T/imunologia , Vacinas contra a AIDS/administração & dosagem , Adenoviridae/imunologia , Animais , Vetores Genéticos , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Humanos , Imunização Secundária , Interferon gama/metabolismo , Macaca mulatta , Poxviridae/imunologia , Replicação ViralRESUMO
HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.
Assuntos
Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Oxidiazóis/química , Linhagem Celular Tumoral , Farmacorresistência Viral Múltipla , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/enzimologia , HIV-1/isolamento & purificação , Humanos , Indinavir/análogos & derivados , Indinavir/síntese química , Indinavir/química , Indinavir/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Piridinas/química , EstereoisomerismoRESUMO
An increasing body of evidence suggests that a vaccine that elicits anti-HIV-1 cellular immunity could provide the basis for an effective AIDS vaccine. Comparative immunization experiments testing a variety of vaccine approaches have demonstrated that replication-incompetent adenovirus vectors are an effective means for eliciting cytotoxic T-lymphocyte (CTL) immune responses against HIV-1 antigens. These immune responses effectively control viremia in nonhuman primates following challenge with simian AIDS viruses. Such data, coupled with epidemiology studies that identify HIV-1 gag, pol, and nef as the best antigens for broadly directed cellular immune responses, provide guidance for the development of a potential AIDS vaccine.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Adenoviridae/fisiologia , Vetores Genéticos/uso terapêutico , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Replicação Viral , Vacinas contra a AIDS/genética , Animais , Vetores Genéticos/genética , HumanosRESUMO
First-generation adenovectors have been developed for gene therapy and vaccine applications. The construction of these adenovectors has entailed the use of numerous types of expression cassettes. It has long been known that first-generation adenovectors can be rescued more easily and to higher titers with some transgenes than with others. This study has systematically shown that there can be marked differences in growth properties of recombinant adenovectors attributable to the use of promoters, the orientation of the transgene within the E1A/E1B-deleted region, and the inclusion of the E3 region. In addition, we had demonstrated the benefit of extending the packaging signal region to include elements V, VI, and VII. The effects of the complete packaging region were studied by plasmid competition studies between original and modified adenovectors. Similar competition studies between E3(+) and E3(-) adenovectors were performed and showed that the E3(+) vector had a growth advantage over its E3(-) counterpart. By making various changes, we have enhanced the growth capacity of our recombinant adenovector by more than 3-fold under serum-free and cell suspension growth conditions. Along with this enhanced growth, our adenovectors have maintained their genetic stability after 21 successive passages in cell culture. This increased robustness will be critical when adapting first-generation recombinant adenovectors to commercial production.
Assuntos
Adenoviridae/genética , Regulação Viral da Expressão Gênica , Vetores Genéticos/genética , Adenoviridae/crescimento & desenvolvimento , Proteínas E1A de Adenovirus/biossíntese , Proteínas E3 de Adenovirus/genética , Animais , Proteínas do Capsídeo/biossíntese , Proteínas do Capsídeo/genética , Citomegalovirus/genética , Elementos Facilitadores Genéticos , Genes gag , Genoma Viral , Proteínas Imediatamente Precoces/genética , Proteínas de Membrana , Camundongos , Plasmídeos , Regiões Promotoras Genéticas , Sinais de Poliadenilação na Ponta 3' do RNA , Transgenes , Montagem de VírusRESUMO
The cellular immunogenicity of formulated plasmid DNA and replication-defective human adenovirus serotype 5 (Ad5) vaccine vectors expressing a codon-optimized human immunodeficiency virus type 1 gag gene was examined in baboons. The Ad5 vaccine was capable of inducing consistently strong, long-lived CD8(+)-biased T-cell responses and in vitro cytotoxic activities. The DNA vaccine-elicited immune responses were weaker than those elicited by the Ad5 vaccine and highly variable; formulation with chemical adjuvants led to moderate increases in the levels of Gag-specific T cells. Increasing the DNA-primed responses with booster doses of either Ad5 or modified vaccinia virus Ankara vaccines suggests a difference in the relative levels of cytotoxic and helper responses. The implications of these results are discussed.
Assuntos
Vacinas contra a AIDS/imunologia , Adenoviridae/genética , Vírus Defeituosos/genética , Genes gag , HIV-1/genética , Vacinas contra a AIDS/administração & dosagem , Adenoviridae/imunologia , Animais , Vírus Defeituosos/imunologia , Relação Dose-Resposta Imunológica , Papio , Linfócitos T/imunologiaRESUMO
Cellular immune responses, particularly those associated with CD3(+) CD8(+) cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1). Accordingly, recent HIV-1 vaccine research efforts have focused on establishing the optimal means of eliciting such antiviral CTL immune responses. We evaluated several DNA vaccine formulations, a modified vaccinia virus Ankara vector, and a replication-defective adenovirus serotype 5 (Ad5) vector, each expressing the same codon-optimized HIV-1 gag gene for immunogenicity in rhesus monkeys. The DNA vaccines were formulated with and without one of two chemical adjuvants (aluminum phosphate and CRL1005). The Ad5-gag vector was the most effective in eliciting anti-Gag CTL. The vaccine produced both CD4(+) and CD8(+) T-cell responses, with the latter consistently being the dominant component. To determine the effect of existing antiadenovirus immunity on Ad5-gag-induced immune responses, monkeys were exposed to adenovirus subtype 5 that did not encode antigen prior to immunization with Ad5-gag. The resulting anti-Gag T-cell responses were attenuated but not abolished. Regimens that involved priming with different DNA vaccine formulations followed by boosting with the adenovirus vector were also compared. Of the formulations tested, the DNA-CRL1005 vaccine primed T-cell responses most effectively and provided the best overall immune responses after boosting with Ad5-gag. These results are suggestive of an immunization strategy for humans that are centered on use of the adenovirus vector and in which existing adenovirus immunity may be overcome by combined immunization with adjuvanted DNA and adenovirus vector boosting.
Assuntos
Vacinas contra a AIDS/imunologia , Genes gag/imunologia , Vetores Genéticos/imunologia , Infecções por HIV/prevenção & controle , Vacinas de DNA/imunologia , Vacinas contra a AIDS/administração & dosagem , Adenovírus Humanos/genética , Adenovírus Humanos/imunologia , Adjuvantes Imunológicos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Genes gag/genética , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Imunização , Macaca mulatta , Plasmídeos , Recombinação Genética , Vaccinia virus/genética , Vaccinia virus/imunologia , Replicação ViralRESUMO
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Pirrolidinas/farmacocinética , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Cães , Meia-Vida , Humanos , Leucócitos Mononucleares , Macaca mulatta , Taxa de Depuração Metabólica , Piperidinas/química , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Expression of several major histocompatibility complex (MHC) class I alleles is associated with a protective effect against disease progression in both human immunodeficiency virus type 1 and simian immunodeficiency virus infection. To understand the mechanism underlying this effect, we investigated the expression of the MHC class I allele Mamu-A*01 in simian-human immunodeficiency virus (SHIV) infection, one of the major models for evaluation of AIDS vaccine candidates. We found that disease progression was significantly delayed in Mamu-A*01-positive rhesus monkeys infected with the highly pathogenic SHIV 89.6P. The delay corresponded not only to a noted Mamu-A*01-restricted dominant cytotoxic T-lymphocyte (CTL) response but also to a lower viral load in lymph nodes (LN) and, importantly, to minimal destruction of LN structure during early infection. In contrast, Mamu-A*01-negative monkeys exhibited massive destruction of LN structure with accompanying rapid disease progression. These data indicate that MHC class I allele-restricted CTL responses may play an important role in preservation of lymphoid tissue structure, thereby resulting in attenuation of disease progression in immunodeficiency virus infection.
Assuntos
Síndrome da Imunodeficiência Adquirida/imunologia , Genes MHC Classe I/fisiologia , Antígenos de Histocompatibilidade Classe I/genética , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vacinas contra a AIDS/imunologia , Alelos , Animais , Contagem de Linfócito CD4 , Células Dendríticas Foliculares/patologia , Progressão da Doença , Produtos do Gene gag/análise , Centro Germinativo/patologia , Linfonodos/virologia , Macaca mulatta , Carga ViralRESUMO
We examined the influence of dose and method of antigen delivery on the dynamics and durability of T-cell responses to candidate human immunodeficiency virus (HIV) vaccines. Codon-optimized sequences from the HIV gag gene were inserted into alternative DNA vaccine vectors to express the coding sequence with or without the tissue plasminogen activator leader sequence. We delivered the vaccines by intramuscular injection as plasmid DNA without adjuvant or as plasmid DNA formulated with a novel block copolymer adjuvant (CRL8623) and then monitored the ensuing T-cell responses by using a gamma interferon enzyme-linked immunospot assay. We demonstrated persistence of the cell-mediated immune (CMI) response in rhesus macaques for at least 18 months following a four-dose vaccination regimen. The plasmid vaccine, with or without CRL8623, was immunogenic in macaques; however, the form coadministered with adjuvant exhibited improved T-cell responses, with a bias toward more antigen-specific CD8(+) T cells. Finally, we examined the fine specificity of the T-cell response to the gag vaccines by testing the response of 23 vaccinated macaques to individual Gag 20-mer peptides. Collectively, the monkeys responded to 25 epitopes, and, on average, each monkey recognized a minimum of 2.7 epitopes. The results indicate that a broad and durable CMI response to HIV DNA vaccines can be induced in a relevant nonhuman primate model.
Assuntos
Vacinas contra a AIDS/imunologia , Produtos do Gene gag/imunologia , Interferon gama/biossíntese , Linfócitos T/imunologia , Vacinas de DNA/imunologia , Animais , Imunização , Macaca mulattaRESUMO
Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.
Assuntos
Inibidores da Protease de HIV/síntese química , HIV/efeitos dos fármacos , Indinavir/análogos & derivados , Animais , Área Sob a Curva , Cães , Resistência a Medicamentos , Protease de HIV/efeitos dos fármacos , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/metabolismo , Indinavir/farmacocinética , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.