RESUMO
RV144 correlates of risk analysis showed that IgG antibodies to gp70V1V2 scaffolds inversely correlated with risk of HIV acquisition. We investigated IgG antibody responses in RV135 and RV132, two ALVAC-HIV prime-boost vaccine trials conducted in Thailand prior to RV144. Both trials used ALVAC-HIV (vCP1521) at 0, 1, 3, and 6 months and HIV-1 gp120MNgD and gp120A244gD in alum (RV135) or gp120SF2 and gp120CM235 in MF59 (RV132) at 3 and 6 months. We assessed ELISA binding antibodies to the envelope proteins (Env) 92TH023, A244gD and MNgD, cyclicV2, and gp70V1V2 CaseA2 (subtype B) and 92TH023 (subtype CRF01_AE), and Env-specific IgG1 and IgG3. Antibody responses to gp120 A244gD, MNgD, and gp70V1V2 92TH023 scaffold were significantly higher in RV135 than in RV132. Antibodies to gp70V1V2 CaseA2 were detected only in RV135 vaccine recipients and IgG1 and IgG3 antibody responses to A244gD were significantly higher in RV135. IgG binding to gp70V1V2 CaseA2 and CRF01_AE scaffolds was higher with the AIDSVAX(®)B/E boost but both trials showed similar rates of antibody decline post-vaccination. MF59 did not result in higher IgG antibody responses compared to alum with the antigens tested. However, notable differences in the structure of the recombinant proteins and dosage used for immunizations may have contributed to the magnitude and specificity of IgG induced by the two trials.
Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/sangue , Antígenos HIV/imunologia , HIV-1/imunologia , Esquemas de Imunização , Imunoglobulina G/sangue , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Adjuvantes Imunológicos/administração & dosagem , Formação de Anticorpos , Ensaio de Imunoadsorção Enzimática , Antígenos HIV/genética , HIV-1/genética , Humanos , Tailândia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. METHODS: In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. RESULTS: Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. CONCLUSIONS: Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. CLINICAL TRIALS REGISTRATION: NCT00270465.
Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Método Duplo-Cego , Mapeamento de Epitopos , Epitopos de Linfócito T/imunologia , Seguimentos , Infecções por HIV/terapia , Infecções por HIV/virologia , Humanos , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas Recombinantes , Linfócitos T Citotóxicos/imunologia , Vacinação , Carga Viral , Latência ViralRESUMO
Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
Assuntos
Adenoviridae , Linfócitos T CD8-Positivos/imunologia , Vetores Genéticos/farmacologia , Imunização/métodos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Administração Intranasal , Aerossóis , Animais , Furões , Imunidade Celular/imunologia , Virus da Influenza A Subtipo H5N1/genética , Pulmão , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologiaRESUMO
BACKGROUND: The severe acute respiratory syndrome (SARS) virus is a member of the Coronaviridae (CoV) family that first appeared in the Guangdong Province of China in 2002 and was recognized as an emerging infectious disease in March 2003. Over 8000 cases and 900 deaths occurred during the epidemic. We report the safety and immunogenicity of a SARS DNA vaccine in a Phase I human study. METHODS: A single-plasmid DNA vaccine encoding the Spike (S) glycoprotein was evaluated in 10 healthy adults. Nine subjects completed the 3 dose vaccination schedule and were evaluated for vaccine safety and immune responses. Immune response was assessed by intracellular cytokine staining (ICS), ELISpot, ELISA, and neutralization assays. RESULTS: The vaccine was well tolerated. SARS-CoV-specific antibody was detected by ELISA in 8 of 10 subjects and neutralizing antibody was detected in all subjects who received 3 doses of vaccine. SARS-CoV-specific CD4+ T-cell responses were detected in all vaccinees, and CD8+ T-cell responses in approximately 20% of individuals. CONCLUSIONS: The VRC SARS DNA vaccine was well tolerated and produced cellular immune responses and neutralizing antibody in healthy adults.
Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/imunologia , Vacinas de DNA , Vacinas Virais , Adolescente , Adulto , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Testes de Neutralização , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/imunologia , Glicoproteína da Espícula de Coronavírus , Resultado do Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Vacinas Virais/imunologia , Adulto JovemRESUMO
Needle-free delivery of a six-plasmid HIV-1 DNA vaccine encoding EnvA, EnvB, EnvC, and subtype B Gag, Pol, and Nef underwent open-label evaluation in 15 subjects; 14 completed the 0, 1, 2 month vaccination schedule. T cell responses to HIV-specific peptide pools were detected by intracellular cytokine staining of CD4(+) [13/14 (93%)] and CD8(+) [5/14 (36%)], and by ELISpot in 11/14 (79%). Ten of 14 (71%) had ELISA antibody responses to Env proteins. Compared to a four-plasmid product, Gag- and Nef-specific T cell responses were improved, while Env-specific responses were maintained. This candidate vaccine has now advanced to Phase II evaluation.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas de DNA/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene nef/imunologia , Anticorpos Anti-HIV/biossíntese , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Imunidade Celular/imunologia , Masculino , Plasmídeos/genética , Plasmídeos/imunologia , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/genética , Vacinas Combinadas/imunologia , Vacinas de DNA/efeitos adversos , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
OBJECTIVE: To evaluate the safety and immunogenicity of a candidate HIV DNA vaccine administered using a needle-free device. DESIGN: In this phase 1, dose escalation, double-blind, placebo-controlled clinical trial, 21 healthy adults were randomized to receive placebo or 0.5, 1.5, or 4 mg of a single plasmid expressing a Gag/Pol fusion protein. Each participant received repeat immunizations at days 28 and 56 after the first inoculation. Safety and immunogenicity data were collected. RESULTS: The vaccine was well tolerated, with most adverse events being mild injection site reactions, including pain, tenderness, and erythema. No dose-limiting toxicities occurred. HIV-specific antibody response was not detected in any vaccinee by enzyme-linked immunosorbent assay. HIV-specific T-cell responses to Gag or Pol as measured by enzyme-linked immunospot assay and intracellular cytokine staining were of low frequency and magnitude. CONCLUSIONS: This candidate HIV DNA vaccine was safe and well tolerated. No HIV-specific antibody responses were detected, and only low-magnitude HIV-specific T-cell responses were detected in 8 (53%) of 15 vaccinees. This initial product led to the development of a 4-plasmid multiclade HIV DNA Vaccine Research Center vaccine candidate in which envelope genes expressing Env from clades A, B, and C and a Nef gene from clade B have been added.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Soronegatividade para HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adulto , Método Duplo-Cego , Feminino , Genes gag , Genes pol , Anticorpos Anti-HIV/biossíntese , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/genética , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Segurança , Linfócitos T/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologiaRESUMO
BACKGROUND: West Nile virus (WNV) is a mosquito-borne flavivirus that can cause severe meningitis and encephalitis in infected individuals. We report the safety and immunogenicity of a WNV DNA vaccine in its first phase 1 human study. METHODS: A single-plasmid DNA vaccine encoding the premembrane and the envelope glycoproteins of the NY99 strain of WNV was evaluated in an open-label study in 15 healthy adults. Twelve subjects completed the 3-dose vaccination schedule, and all subjects completed 32 weeks of evaluation for safety and immunogenicity. The development of a vaccine-induced immune response was assessed by enzyme-linked immunosorbant assay, neutralization assays, intracelluar cytokine staining, and enzyme-linked immunospot assay. RESULTS: The vaccine was safe and well tolerated, with no significant adverse events. Vaccine-induced T cell and antibody responses were detected in the majority of subjects. Neutralizing antibody to WNV was detected in all subjects who completed the 3-dose vaccination schedule, at levels shown to be protective in studies of horses, an incidental natural host for WNV. CONCLUSIONS: Further assessment of this DNA platform for human immunization against WNV is warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00106769 .
Assuntos
Anticorpos Antivirais/biossíntese , Vacinas de DNA/uso terapêutico , Febre do Nilo Ocidental/prevenção & controle , Vacinas contra o Vírus do Nilo Ocidental/uso terapêutico , Vírus do Nilo Ocidental/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/virologia , Febre do Nilo Ocidental/virologia , Vacinas contra o Vírus do Nilo Ocidental/genética , Vacinas contra o Vírus do Nilo Ocidental/imunologia , Vírus do Nilo Ocidental/genéticaRESUMO
BACKGROUND: The development of an effective human immunodeficiency virus (HIV) vaccine is a high global priority. Here, we report the safety, tolerability, and immunogenicity of a replication-defective recombinant adenovirus serotype 5 (rAd5) vector HIV-1 candidate vaccine. METHODS: The vaccine is a mixture of 4 rAd5 vectors that express HIV-1 subtype B Gag-Pol fusion protein and envelope (Env) from subtypes A, B, and C. Healthy, uninfected adults were randomized to receive 1 intramuscular injection of placebo (n=6) or vaccine at dose levels of 10(9) (n=10), 10(10) (n=10), or 10(11) (n=10) particle units and were followed for 24 weeks to assess immunogenicity and safety. RESULTS: The vaccine was well tolerated but was associated with more reactogenicity at the highest dose. At week 4, vaccine antigen-specific T cell responses were detected in 28 (93.3%) and 18 (60%) of 30 vaccine recipients for CD4(+) and CD8(+) T cells, respectively, by intracellular cytokine staining assay and in 22 (73%) of 30 vaccine recipients by enzyme-linked immunospot assay. Env-specific antibody responses were detected in 15 (50%) of 30 vaccine recipients by enzyme-linked immunosorbant assay and in 28 (93.3%) of 30 vaccine recipients by immunoprecipitation followed by Western blotting. No neutralizing antibody was detected. CONCLUSIONS: A single injection induced HIV-1 antigen-specific CD4(+) T cell, CD8(+) T cell, and antibody responses in the majority of vaccine recipients. This multiclade rAd5 HIV-1 vaccine is now being evaluated in combination with a multiclade HIV-1 DNA plasmid vaccine.
Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Náusea/etiologia , Vacinação , Vacinas contra a AIDS/administração & dosagem , Adenovírus Humanos/genética , Adolescente , Adulto , Especificidade de Anticorpos , Western Blotting , Citocinas/análise , Citocinas/biossíntese , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Proteínas de Fusão gag-pol/imunologia , Produtos do Gene env/imunologia , Vetores Genéticos , Humanos , Injeções Intramusculares , Masculino , Recombinação Genética , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Produtos do Gene env do Vírus da Imunodeficiência HumanaRESUMO
BACKGROUND: Gene-based vaccine delivery is an important strategy in the development of a preventive vaccine for acquired immunodeficiency syndrome (AIDS). Vaccine Research Center (VRC) 004 is the first phase 1 dose-escalation study of a multiclade HIV-1 DNA vaccine. METHODS: VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n=10) or study vaccine at 2 mg (n=5), 4 mg (n=20), or 8 mg (n=15) by needle-free intramuscular injection. Humoral responses (measured by enzyme-linked immunosorbant assay, Western blotting, and neutralization assay) and T cell responses (measured by enzyme-linked immunospot assay and intracellular cytokine staining after stimulation with antigen-specific peptide pools) were measured. RESULTS: The vaccine was well tolerated and induced cellular and humoral responses. The maximal CD4(+) and CD8(+) T cell responses occurred after 3 injections and were in response to Env peptide pools. The pattern of cytokine expression by vaccine-induced HIV-specific T cells evolved over time, with a diminished frequency of interferon- gamma -producing T cells and an increased frequency of interleukin-2-producing T cells at 1 year. CONCLUSIONS: DNA vaccination induced antibody to and T cell responses against 3 major HIV-1 subtypes and will be further evaluated as a potential component of a preventive AIDS vaccine regimen.
Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Vetores Genéticos , Infecções por HIV/imunologia , HIV-1/imunologia , Esquemas de Imunização , Testes de Neutralização , Plasmídeos , Vacinação , Vacinas contra a AIDS/administração & dosagem , Adolescente , Adulto , Anticorpos Antivirais/sangue , Especificidade de Anticorpos , Western Blotting , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/análise , Citocinas/biossíntese , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Fusão gag-pol/genética , Proteínas de Fusão gag-pol/imunologia , Produtos do Gene nef/genética , Produtos do Gene nef/imunologia , Infecções por HIV/sangue , Humanos , Injeções Intramusculares , Masculino , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Vacinas de DNA/imunologia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
Ebola viruses represent a class of filoviruses that causes severe hemorrhagic fever with high mortality. Recognized first in 1976 in the Democratic Republic of Congo, outbreaks continue to occur in equatorial Africa. A safe and effective Ebola virus vaccine is needed because of its continued emergence and its potential for use for biodefense. We report the safety and immunogenicity of an Ebola virus vaccine in its first phase I human study. A three-plasmid DNA vaccine encoding the envelope glycoproteins (GP) from the Zaire and Sudan/Gulu species as well as the nucleoprotein was evaluated in a randomized, placebo-controlled, double-blinded, dose escalation study. Healthy adults, ages 18 to 44 years, were randomized to receive three injections of vaccine at 2 mg (n = 5), 4 mg (n = 8), or 8 mg (n = 8) or placebo (n = 6). Immunogenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoprecipitation-Western blotting, intracellular cytokine staining (ICS), and enzyme-linked immunospot assay. The vaccine was well-tolerated, with no significant adverse events or coagulation abnormalities. Specific antibody responses to at least one of the three antigens encoded by the vaccine as assessed by ELISA and CD4(+) T-cell GP-specific responses as assessed by ICS were detected in 20/20 vaccinees. CD8(+) T-cell GP-specific responses were detected by ICS assay in 6/20 vaccinees. This Ebola virus DNA vaccine was safe and immunogenic in humans. Further assessment of the DNA platform alone and in combination with replication-defective adenoviral vector vaccines, in concert with challenge and immune data from nonhuman primates, will facilitate evaluation and potential licensure of an Ebola virus vaccine under the Animal Rule.