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1.
Contemp Clin Trials ; : 105856, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669449

RESUMO

Randomized controlled trials have traditionally been the gold standard for evaluating efficacy and safety of medical products and for regulatory decision-making. With the advancement of information technologies, vast amounts of data pertinent to patient health status and health care delivery are becoming available from a variety of real-world sources, including electronic health records, medical claims, patient registries, and patient-generated data. In 2016, the United States Congress passed the 21st Century Cures Act, mandating the U.S. FDA to establish a program to evaluate the potential use of real-world evidence (RWE) for regulatory purposes. In 2018, the FDA published the framework on its RWE program. One particular study type identified in the framework is the hybrid design - integration of a traditional randomized controlled trial with pragmatic design aspects to collect real-world data on patients. This design preserves the benefit of randomization, provides real-world outcome data while potentially accelerating product development and lowering the cost of data collection and patient follow-up. Here we focus on design considerations for hybrid trials to support regulatory decisions and provide a sponsor's perspective. While applicable to all medical products, we emphasize vaccine development where such hybrid designs are particularly useful given the low incidence rate of some vaccine-preventable clinical outcomes. We propose program strategies on how such hybrid designs may be integrated into a clinical development plan, illustrated by three examples. Major challenges are discussed and recommendations provided. Given the promise of hybrid designs and the challenges in implementation, we encourage proactive discussion with health authorities.

2.
Vaccine ; 37(13): 1876-1884, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30558818

RESUMO

BACKGROUND: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months. METHODS: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains. RESULTS: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo. CONCLUSIONS: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains. CLINICAL TRIAL REGISTRATION: EudraCT no. 2013-001231-51.

3.
N Engl J Med ; 379(2): 138-149, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29996082

RESUMO

BACKGROUND: Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette-Guérin (BCG) vaccination may offer partial protection against infection. METHODS: In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo. RESULTS: Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination. CONCLUSIONS: In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 ClinicalTrials.gov number, NCT02075203 .).


Assuntos
Vacina BCG , Imunização Secundária , Mycobacterium tuberculosis/imunologia , Soroconversão , Vacinas contra a Tuberculose , Tuberculose/prevenção & controle , Adolescente , Anticorpos Antibacterianos/sangue , Vacina BCG/efeitos adversos , Vacina BCG/imunologia , Criança , Feminino , Humanos , Masculino , Modelos de Riscos Proporcionais , Tuberculose/diagnóstico , Tuberculose/transmissão , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia
4.
N Engl J Med ; 379(4): 327-340, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29897841

RESUMO

BACKGROUND: In efficacy trials of a tetravalent dengue vaccine (CYD-TDV), excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age. Precise risk estimates according to observed dengue serostatus could not be ascertained because of the limited numbers of samples collected at baseline. We developed a dengue anti-nonstructural protein 1 (NS1) IgG enzyme-linked immunosorbent assay and used samples from month 13 to infer serostatus for a post hoc analysis of safety and efficacy. METHODS: In a case-cohort study, we reanalyzed data from three efficacy trials. For the principal analyses, we used baseline serostatus determined on the basis of measured (when baseline values were available) or imputed (when baseline values were missing) titers from a 50% plaque-reduction neutralization test (PRNT50), with imputation conducted with the use of covariates that included the month 13 anti-NS1 assay results. The risk of hospitalization for virologically confirmed dengue (VCD), of severe VCD, and of symptomatic VCD according to dengue serostatus was estimated by weighted Cox regression and targeted minimum loss-based estimation. RESULTS: Among dengue-seronegative participants 2 to 16 years of age, the cumulative 5-year incidence of hospitalization for VCD was 3.06% among vaccine recipients and 1.87% among controls, with a hazard ratio (vaccine vs. control) through data cutoff of 1.75 (95% confidence interval [CI], 1.14 to 2.70). Among dengue-seronegative participants 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 1.57% among vaccine recipients and 1.09% among controls, with a hazard ratio of 1.41 (95% CI, 0.74 to 2.68). Similar trends toward a higher risk among seronegative vaccine recipients than among seronegative controls were also found for severe VCD. Among dengue-seropositive participants 2 to 16 years of age and those 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 0.75% and 0.38%, respectively, among vaccine recipients and 2.47% and 1.88% among controls, with hazard ratios of 0.32 (95% CI, 0.23 to 0.45) and 0.21 (95% CI, 0.14 to 0.31). The risk of severe VCD was also lower among seropositive vaccine recipients than among seropositive controls. CONCLUSIONS: CYD-TDV protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 .).


Assuntos
Vacinas contra Dengue/efeitos adversos , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Hospitalização/estatística & dados numéricos , Proteínas não Estruturais Virais/sangue , Adolescente , Anticorpos Antivirais/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Dengue/epidemiologia , Dengue/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Modelos de Riscos Proporcionais , Resultado do Tratamento
5.
Hum Vaccin Immunother ; 11(7): 1836-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25912273

RESUMO

Currently marketed Streptococcus pneumoniae vaccines are based on polysaccharide capsular antigens from the most common strains. Pneumococcal histidine triad protein D (PhtD) is a conserved surface protein that is being evaluated as a candidate for a vaccine with improved serotype coverage. Here, we measured the functional activity of human anti-PhtD antibodies in a passive protection model wherein mice were challenged with a lethal dose of S. pneumoniae by intravenous injection. This functional activity was compared with anti-PhtD antibody concentrations measured by enzyme-linked immunosorbent assay (ELISA) to estimate the 50% protective dose (ED50). Anti-PhtD antibodies affinity purified from pooled normal human sera passively protected mice with an ED50 of 1679 ELISA units/ml (95% confidence interval, 1420-1946). Sera from subjects injected with aluminum-adjuvanted PhtD in a phase I trial had similar activity per unit of antibody (ED50 = 1331 ELISA units/ml [95% confidence interval, 762-2038]). Vaccine-induced activity in the passive protection model was blocked by pre-incubation with recombinant PhtD but not by a control S. pneumoniae antigen (LytB). These results show that human anti-PhtD antibodies, whether naturally acquired or induced by the PhtD candidate vaccine, are functional. This supports the development of the PhtD candidate as part of a broadly protective pneumococcal vaccine.


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Imunização Passiva/métodos , Proteínas de Membrana/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/uso terapêutico , Streptococcus pneumoniae/imunologia , Adulto , Idoso , Animais , Anticorpos Antibacterianos/análise , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/uso terapêutico , Especificidade de Anticorpos , Antígenos de Bactérias/imunologia , Ensaios Clínicos Fase I como Assunto , Humanos , Camundongos , Pessoa de Meia-Idade , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/imunologia , Análise de Sobrevida
6.
N Engl J Med ; 371(7): 635-45, 2014 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-25119609

RESUMO

BACKGROUND: As compared with a standard-dose vaccine, a high-dose, trivalent, inactivated influenza vaccine (IIV3-HD) improves antibody responses to influenza among adults 65 years of age or older. This study evaluated whether IIV3-HD also improves protection against laboratory-confirmed influenza illness. METHODS: We conducted a phase IIIb-IV, multicenter, randomized, double-blind, active-controlled trial to compare IIV3-HD (60 µg of hemagglutinin per strain) with standard-dose trivalent, inactivated influenza vaccine (IIV3-SD [15 µg of hemagglutinin per strain]) in adults 65 years of age or older. Assessments of relative efficacy, effectiveness, safety (serious adverse events), and immunogenicity (hemagglutination-inhibition [HAI] titers) were performed during the 2011-2012 (year 1) and the 2012-2013 (year 2) northern-hemisphere influenza seasons. RESULTS: A total of 31,989 participants were enrolled from 126 research centers in the United States and Canada (15,991 were randomly assigned to receive IIV3-HD, and 15,998 to receive IIV3-SD). In the intention-to-treat analysis, 228 participants in the IIV3-HD group (1.4%) and 301 participants in the IIV3-SD group (1.9%) had laboratory-confirmed influenza caused by any viral type or subtype associated with a protocol-defined influenza-like illness (relative efficacy, 24.2%; 95% confidence interval [CI], 9.7 to 36.5). At least one serious adverse event during the safety surveillance period was reported by 1323 (8.3%) of the participants in the IIV3-HD group, as compared with 1442 (9.0%) of the participants in the IIV3-SD group (relative risk, 0.92; 95% CI, 0.85 to 0.99). After vaccination, HAI titers and seroprotection rates (the percentage of participants with HAI titers ≥ 1:40) were significantly higher in the IIV3-HD group. Conclusions: Among persons 65 years of age or older, IIV3-HD induced significantly higher antibody responses and provided better protection against laboratory-confirmed influenza illness than did IIV3-SD. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01427309.).


Assuntos
Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Idoso , Anticorpos Antivirais/sangue , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Análise de Intenção de Tratamento , Masculino , Orthomyxoviridae/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/imunologia
7.
Vaccine ; 31(2): 327-33, 2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23153437

RESUMO

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: This study examined the safety and immunogenicity in adults of three doses of a pneumococcal single-antigen protein vaccine candidate formulated with aluminum hydroxide adjuvant and recombinantly derived, highly detoxified, genetically mutated pneumolysin protein (PlyD1). METHODS: This phase I, randomized, placebo-controlled, observer-blinded, dose-escalating study enrolled adults (18-50 years). In a pilot safety study, participants received a single injection of 10 µg PlyD1 and were observed for 24 h. Following review of the pilot safety data, participants were randomized (2:1) to receive two injections of PlyD1 at one of three doses or placebo 30 days apart. Assignment of second injection and successive dose cohorts was made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site reactions, solicited systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included geometric mean concentrations of anti-PlyD1 IgG as determined by ELISA and functional assessment in an in vitro toxin neutralization assay. RESULTS: The study included a total of 100 participants, including 10 in the pilot study and 90 in the randomized study. None of the participants in the pilot study had SAEs, allergic reactions, or other safety concerns. Ninety participants received two doses of or placebo (n=30) or active vaccine candidate at 10 (n=20), 25 (n=20), or 50 µg (n=20). No vaccine-related SAE or discontinuation due to an AE occurred. Most solicited reactions were mild and transient. The most frequently reported solicited reactions were pain at the injection site and myalgia. Antigen-specific IgG levels and functional activity showed dose-related increases. When comparing the three dose levels, a plateau effect was observed at the 25 µg dose. CONCLUSIONS: All dose levels were safe and immunogenic. Repeat vaccination significantly increased the level of anti-PlyD1 antibodies. Functional antibody activity was demonstrated in sera from vaccinated individuals (ClinicalTrials.gov no. NCT01444352).


Assuntos
Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Estreptolisinas/imunologia , Adjuvantes Imunológicos , Adulto , Hidróxido de Alumínio/imunologia , Formação de Anticorpos , Proteínas de Bactérias/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização/métodos , Projetos Piloto , Adulto Jovem
8.
J Acquir Immune Defic Syndr ; 63(1): 1-8, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23221981

RESUMO

BACKGROUND: The development of a safe and effective vaccine against HIV type 1 for the prevention of mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from phase 1, randomized, double-blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV type 1-infected women in Uganda are reported. METHODS: HIV-exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8, and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination and days 1 and 2 postvaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA polymerase chain reaction. RESULTS: From October 2006 to May 2007, 60 infants (48 vaccine and 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by diphtheria, polio, hepatitis B, haemophilus influenzae type B, and measles vaccination were similar in the 2 arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine and 1 placebo) and 1 in vaccine arm at 2 weeks of age]. CONCLUSION: The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high-quality infant HIV vaccine trials is achievable in Africa.


Assuntos
Vacinas contra a AIDS , Proteína gp120 do Envelope de HIV , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adolescente , Adulto , Aleitamento Materno , Pré-Escolar , Método Duplo-Cego , Feminino , Proteína gp120 do Envelope de HIV/administração & dosagem , Proteína gp120 do Envelope de HIV/efeitos adversos , Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1 , Humanos , Lactente , Recém-Nascido , Leite Humano , Resultado do Tratamento , Uganda , Vacinação , Adulto Jovem
9.
AIDS Res Hum Retroviruses ; 29(2): 266-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22908887

RESUMO

Although there is discordance between human immunodeficiency virus (HIV) blood plasma and seminal plasma viral loads (VL), little is known about the dynamics of VL rebound in these compartments upon discontinuation of highly active antiretroviral therapy (HAART). Therefore, we sought to examine the relationship between blood and semen VL rebound after discontinuation of HAART. Participants in this substudy were men enrolled from two centers of a multicenter, placebo-controlled randomized trial of HIV therapeutic vaccination using ALVAC with or without Remune. With at least 2 years of sustained virologic suppression and following a 20-week vaccination course, subjects underwent structured HAART interruption. Fourteen men provided semen samples. Seven to 12 weeks after HAART interruption, all 14 men had detectable blood VLs whereas 8 of 14 had detectable seminal VLs. There was a significant correlation between blood and seminal VLs (Spearman r=0.58, p=0.03) at the time of semen collection. An earlier time to detectable blood VL after HAART interruption was associated with higher seminal VL (Spearman r=-0.64, p=0.02). These findings support the compartmentalization of HIV and underscore the importance of understanding the genital tract as an HIV reservoir in the quest to minimize HIV transmission.


Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV/isolamento & purificação , Plasma/virologia , Sêmen/virologia , Carga Viral , Vacinas contra a AIDS/administração & dosagem , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem
10.
J Infect Dis ; 207(8): 1195-205, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22837492

RESUMO

BACKGROUND: The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection. METHODS: CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VEP) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models. RESULTS: There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VEP (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04). CONCLUSIONS: Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Vacinas Virais/imunologia , Vacinas contra a AIDS/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Seguimentos , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/prevenção & controle , HIV-1/patogenicidade , Humanos , Modelos Lineares , Masculino , Estudos Prospectivos , Assunção de Riscos , Sêmen/virologia , Tailândia , Fatores de Tempo , Vacinação , Vagina/virologia , Carga Viral , Vacinas Virais/administração & dosagem , Adulto Jovem
11.
Vaccine ; 30(52): 7455-60, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23131206

RESUMO

BACKGROUND: Pneumococcal vaccines based on conserved protein antigens have the potential to offer expanded protection against Streptococcus pneumoniae. OBJECTIVE: To explore safety and immunogenicity of a recombinant protein vaccine candidate against S. pneumoniae composed of adjuvanted pneumococcal histidine triad protein D (PhtD). METHODS: This phase I, exploratory, open-label, single-center clinical study enrolled adults (18-50 years). Participants in a pilot safety cohort received a single intramuscular injection of 6 µg. Following safety review, 3 dose cohorts were enrolled (6, 25, and 100 µg); participants received 2 injections administered approximately 30 days apart. Assignment of the second injection and successive dose cohorts were made after blinded safety reviews after each injection at each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events, serious adverse events, and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD antibodies as measured by ELISA. RESULTS: Sixty-three participants were enrolled and received the pilot safety dose (n=3) or at least 1 dose of PhtD vaccine candidate at 6 µg (n=20), 25 µg (n=20), or 100 µg (n=20). No safety concerns were identified. No vaccine-related serious adverse event was reported. The most common solicited injection site reaction was pain and most common solicited systemic reactions were myalgia and headache; most reactions were mild and transient. Observed geometric mean concentrations (95% CI) were 200.99 ELISA units (148.46, 272.10), 352.07 (193.49, 640.63), and 699.15 (405.49, 1205.48) post-injection 1 in the 6, 25, and 100 µg dose cohorts, respectively, and 378.25 (275.56, 519.21), 837.32 (539.29, 1300.04), and 1568.62 (1082.92, 2272.16) post-injection 2. CONCLUSIONS: All dose levels were safe and immunogenic. The frequency of solicited reactions was highest at the 100 µg dose. Administration of a second injection significantly increased the levels of anti-PhtD antibodies (ClinicalTrials.gov registry no. NCT01444001).


Assuntos
Proteínas de Bactérias/imunologia , Hidrolases/imunologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Hidrolases/genética , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Streptococcus pneumoniae/genética , Vacinação/métodos , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Adulto Jovem
12.
Vaccine ; 30(52): 7461-8, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23123106

RESUMO

BACKGROUND: Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. OBJECTIVE: To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. METHODS: This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 µg) or PhtD-PcpA (10 µg each), participants in the main study received AH-adjuvanted PcpA (25 µg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 µg each), unadjuvanted PhtD-PcpA (25 µg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). RESULTS: Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 µg dose was observed as measured by geometric mean concentrations and by fold increases. CONCLUSIONS: Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339).


Assuntos
Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Hidrolases/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Adolescente , Adulto , Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Hidrolases/genética , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos/administração & dosagem , Vacinas Pneumocócicas/efeitos adversos , Vacinas Pneumocócicas/genética , Método Simples-Cego , Streptococcus pneumoniae/genética , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos , Vacinas de Subunidades/genética , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Adulto Jovem
13.
AIDS Res Hum Retroviruses ; 28(11): 1444-57, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23035746

RESUMO

The Thai Phase III clinical trial (RV144) showed modest efficacy in preventing HIV-1 acquisition. Plasma collected from HIV-1-uninfected trial participants completing all injections with ALVAC-HIV (vCP1521) prime and AIDSVAX B/E boost were tested for antibody responses against HIV-1 gp120 envelope (Env). Peptide microarray analysis from six HIV-1 subtypes and group M consensus showed that vaccination induced antibody responses to the second variable (V2) loop of gp120 of multiple subtypes. We further evaluated V2 responses by ELISA and surface plasmon resonance using cyclic (Cyc) and linear V2 loop peptides. Thirty-one of 32 vaccine recipients tested (97%) had antibody responses against Cyc V2 at 2 weeks postimmunization with a reciprocal geometric mean titer (GMT) of 1100 (range: 200-3200). The frequency of detecting plasma V2 antibodies declined to 19% at 28 weeks post-last injection (GMT: 110, range: 100-200). Antibody responses targeted the mid-region of the V2 loop that contains conserved epitopes and has the amino acid sequence KQKVHALFYKLDIVPI (HXB2 Numbering sequence 169-184). Valine at position 172 was critical for antibody binding. The frequency of V3 responses at 2 weeks postimmunization was modest (18/32, 56%) with a GMT of 185 (range: 100-800). In contrast, naturally infected HIV-1 individuals had a lower frequency of antibody responses to V2 (10/20, 50%; p=0.003) and a higher frequency of responses to V3 (19/20, 95%), with GMTs of 400 (range: 100-3200) and 3570 (range: 200-12,800), respectively. RV144 vaccination induced antibodies that targeted a region of the V2 loop that contains conserved epitopes. Early HIV-1 transmission events involve V2 loop interactions, raising the possibility that anti-V2 antibodies in RV144 may have contributed to viral inhibition.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Sequência de Aminoácidos , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito T , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Análise Serial de Proteínas
14.
Lancet Infect Dis ; 12(7): 531-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22652344

RESUMO

BACKGROUND: The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination. METHODS: RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18-30 years were recruited from the community. In this post-hoc analysis of the modified intention-to-treat population (16,395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classified participants' behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. FINDINGS: Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early--cumulative vaccine efficacy was estimated to be 60·5% (95% CI 22-80) through the 12 months after initial vaccination--and declined quickly. Vaccination did not seem to affect viral load in either early or late infections. INTERPRETATION: Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules. FUNDING: US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Infecções por HIV/prevenção & controle , Assunção de Riscos , Adolescente , Adulto , Feminino , Infecções por HIV/epidemiologia , Homossexualidade Masculina , Humanos , Estimativa de Kaplan-Meier , Masculino , Estatísticas não Paramétricas , Abuso de Substâncias por Via Intravenosa/epidemiologia , Inquéritos e Questionários , Tailândia/epidemiologia , Fatores de Tempo , Carga Viral , Adulto Jovem
15.
Vaccine ; 30(5): 832-6, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22085554

RESUMO

Immune responses to vaccines may be influenced or associated with allelic variants of host genes such as those encoding human leucocyte antigens (HLA). We have molecularly determined the HLA class II DR and DQ gene, allele and haploype profiles in HIV-1 negative ethnic Thai recipients of an HIV-1 prime boost vaccine regimen, designed to induce neutralizing antibody (NAb) responses to HIV-1 CRF01_AE. Non-response to vaccine associated with DRB1*11 (3/32 responders vs. 7/13 non-responders, p(c)=0.027) and DRB1*16:02 (0/32 responders vs. 4/13 non-responders, p(c)=0.078) alleles. Furthermore, vaccine recipients with HLA-DQ heterodimers encoded by DQA1*05:01 and DQB1*03:01 alleles, were much less likely to produce NAb (p=0.009). These data suggest that the lack of response to a vaccine designed to induce clade-specific NAb to HIV-1 is associated with the presence of certain HLA class II alleles and heterodimers in some Southeast Asians.


Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Anti-HIV/sangue , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Vacinas contra a AIDS/administração & dosagem , Alelos , Genótipo , Experimentação Humana , Humanos , Tailândia
16.
PLoS One ; 6(12): e27837, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22205930

RESUMO

BACKGROUND: A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand. METHODOLOGY/PRINCIPAL FINDINGS: Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days. CONCLUSIONS/SIGNIFICANCE: The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand. TRIAL REGISTRATION: ClinicalTrials.govNCT00223080.


Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Imunização Secundária/efeitos adversos , Segurança , Vacinação/efeitos adversos , Adolescente , Adulto , Feminino , Proteína gp120 do Envelope de HIV/efeitos adversos , Humanos , Masculino , Gravidez , Resultado da Gravidez , Tailândia , Adulto Jovem
17.
AIDS ; 25(6): 731-9, 2011 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-21330911

RESUMO

OBJECTIVES: Therapeutic HIV vaccination during the time of virologic suppression may delay or blunt viral load rebound after interruption of antiretroviral therapy (ART). The use of ALVAC, to enhance cytotoxic T-lymphocyte responses, with Remune, which provides CD4 T-cell help, may induce anti-HIV responses capable of controlling viral replication. METHODS: CTN173 was a randomized, placebo-controlled double-blind study in which effectively treated HIV-infected individuals (viral load <50 copies/ml for more than 2 years) with CD4 nadir more than 250 cells/µl and current CD4 cell counts more than 500 cells/µl were randomized to receive: ALVAC with Remune, ALVAC alone or matching placebos over 20 weeks. At week 24, participants interrupted ART with intensive clinical, virologic and immunologic monitoring to week 48. RESULTS: Baseline characteristics of the 52 randomized participants were balanced between arms. Forty-eight participants who received all vaccinations interrupted ART at week 24. Median time to viral load more than 50 copies/ml tended to be greater in the two vaccine arms (24.5, 23.0 vs. 13.5 days in the placebo arm, P = 0.097 for combined vaccine groups vs. placebo), but subsequent viral load set-point was not different between groups. Significantly fewer participants in the two vaccine arms restarted ART or met CD4 criteria to do so (P = 0.024). CONCLUSION: Although ALVAC with or without Remune did not lower the viral load set-point, it tended to delay viral load rebound and was associated with a greater time to meet preset criteria to restart ART. Further investigations of those individuals who derived benefit from vaccination could provide important insights into HIV therapeutic vaccine development.


Assuntos
Vacinas contra a AIDS/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas Virais/uso terapêutico , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Masculino , Placebos , Linfócitos T Citotóxicos/efeitos dos fármacos , Carga Viral
18.
Vaccine ; 28(50): 7881-9, 2010 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-20937317

RESUMO

Following the disappointing outcome of the phase IIb test-of-concept step study in which Merck's adenovirus type 5 (Ad5) HIV-1 clade B gag/pol/nef vaccine failed to demonstrate efficacy in HIV high-risk individuals, an extensive review of the trial and preclinical studies which supported the trial is ongoing. One point of interest is how well preclinical nonhuman primate immunogenicity studies predicted what was observed in humans. Here we compare the HIV-1-specific cellular immune responses elicited in nonhuman primates and human clinical trial subjects to several HIV-1 vaccine candidates. We find that although rhesus macaques are immunologically more responsive to vaccination than humans, the hierarchy in potency of single-modality prime-boost regimens using several vector approaches (adenovirus, DNA, and pox vectors) was well predicted. Vaccine approaches using complex formulations such as novel adjuvants (DNA+CRL1005) or mixed-modality prime-boost (DNA/Ad5; Ad5/ALVAC) did not correlate as well between rhesus macaques and humans. Although the immunogenicity of the vaccines and vaccine regimens evaluated were not all accurately predicted, testing in rhesus macaques generally offers an indispensable tool for ranking the immunological potential of HIV-1 vaccine candidates.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , Imunidade Celular , Linfócitos T/imunologia , Adenoviridae/imunologia , Animais , Ensaios Clínicos Fase I como Assunto , Genes gag , Infecções por HIV/imunologia , Humanos , Imunização Secundária , Interferon gama/imunologia , Macaca mulatta/imunologia , Modelos Animais , Vacinas de DNA/imunologia
19.
N Engl J Med ; 361(23): 2209-20, 2009 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-19843557

RESUMO

BACKGROUND: The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. METHODS: In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. RESULTS: In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. CONCLUSIONS: This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)


Assuntos
Vacinas contra a AIDS , Infecções por HIV/prevenção & controle , HIV-1 , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adulto , Contagem de Linfócito CD4 , Método Duplo-Cego , Feminino , Seguimentos , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Tailândia , Resultado do Tratamento , Carga Viral , Adulto Jovem
20.
J Acquir Immune Defic Syndr ; 46(1): 48-55, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17909315

RESUMO

BACKGROUND: The development of an effective HIV-1 vaccine is critical to control the pandemic. A prime-boost HIV-1 vaccine trial assessing safety and immunogenicity was conducted in Thailand as part of an evaluation of candidate regimens for a phase 3 efficacy trial. METHODS: ALVAC-HIV (vCP1521), expressing circulating recombinant form 01_AE (CRF01_AE) gp120/subtype B LAI and subtype B Gag/Protease boosted with recombinant envelope oligomeric CRF01_AE gp160 (ogp160) or bivalent CRF01_AE/subtype B gp120 CM235/SF2, was evaluated in a phase 1/II trial of 130 HIV-negative Thai adults. RESULTS: One hundred forty volunteers were enrolled, and 130 completed all safety and immunogenicity visits. Reactogenicity was common but generally mild, and there was no significant difference in the adverse event rate between vaccine and placebo recipients (P = 0.26). There were 7 serious adverse events during the follow-up period, none of which were vaccine related. Cumulative HIV-specific, CD8-mediated, cytotoxic T-lymphocyte responses were observed in 11 (25%) of 44 subjects who received ALVAC boosted by bivalent gp120 and in 5 (11%) of 45 subjects who received ALVAC boosted by ogp160, but these differences were not statistically significant compared with those in placebo recipients (P = 0.62 and P = 0.37, respectively). HIV-specific lymphoproliferative responses were detected in 84% of subunit-boosted vaccine recipients and in 10% of placebo recipients. Neutralizing antibody responses to CRF01_AE and subtype B laboratory strains were seen in 95% of ogp160-boosted and 100% of gp120 B/E-boosted vaccinees, respectively. CONCLUSIONS: These 2 different prime-boost regimens seem to be safe and displayed cell-mediated immune responses consistent with those in other trials of canarypox vectors.


Assuntos
Vacinas contra a AIDS/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp160 do Envelope de HIV/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adulto , Proliferação de Células , Método Duplo-Cego , Feminino , Anticorpos Anti-HIV/imunologia , Antígenos HIV/administração & dosagem , Antígenos HIV/efeitos adversos , Antígenos HIV/imunologia , Proteína gp120 do Envelope de HIV/administração & dosagem , Proteína gp120 do Envelope de HIV/efeitos adversos , Proteína gp160 do Envelope de HIV/administração & dosagem , Proteína gp160 do Envelope de HIV/efeitos adversos , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Vacinação
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