RESUMEN
BACKGROUND: The burden of human papillomavirus (HPV) diseases is high in Latin America. HPV vaccines licensed from 2006 onwards offer protection against most HPV-related cancers, especially when introduced into national immunization programs. Barriers to optimal vaccine uptake are, however, lowering the impact of adolescent HPV vaccination programs. Immunization of children might overcome these barriers and be a strategy of choice for some countries. METHODS: This multicenter phase III randomized, controlled, single-blind study (NCT01627561) was conducted in Colombia, Mexico and Panama to assess safety and immunogenicity of 2-dose vaccination with AS04-adjuvanted HPV-16/18 vaccine in girls 4-6 years of age. We report safety outcomes and anti-HPV-16/18 antibody titers measured by enzyme-linked immunosorbent assay in HPV-vaccinated girls that were followed over a 36-month period. RESULTS: Over 36 months (ie, 30 months after the second vaccine dose), among 74 girls included in the HPV group, 1 serious adverse event unrelated to vaccination has been reported. No withdrawal because of (serious) adverse events has been reported. At month 36, all girls in the per-protocol-cohort were still seropositive for anti-HPV-16 and anti-HPV-18 with geometric mean concentrations of 1680.6 and 536.4 enzyme-linked immunosorbent assay units/mL, respectively. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 vaccine administered according to a 2-dose schedule to girls 4-6 years of age induced a high and sustained immunologic response with an acceptable safety profile during the 30 months following vaccination.
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Hidróxido de Aluminio/efectos adversos , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Lípido A/análogos & derivados , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/inmunología , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antivirales/sangre , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Colombia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Estudios de Seguimiento , Humanos , Lípido A/administración & dosificación , Lípido A/efectos adversos , México , Panamá , Vacunas contra Papillomavirus/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Método Simple CiegoRESUMEN
Campylobacter jejuni is among the most common causes of diarrheal disease worldwide and efforts to develop protective measures against the pathogen are ongoing. One of the few defined virulence factors targeted for vaccine development is the capsule polysaccharide (CPS). We have developed a capsule conjugate vaccine against C. jejuni strain 81-176 (CPS-CRM) that is immunogenic in mice and nonhuman primates (NHPs) but only moderately immunogenic in humans when delivered alone or with aluminum hydroxide. To enhance immunogenicity, two novel liposome-based adjuvant systems, the Army Liposome Formulation (ALF), containing synthetic monophosphoryl lipid A, and ALF plus QS-21 (ALFQ), were evaluated with CPS-CRM in this study. In mice, ALF and ALFQ induced similar amounts of CPS-specific IgG that was significantly higher than levels induced by CPS-CRM alone. Qualitative differences in antibody responses were observed where CPS-CRM alone induced Th2-biased IgG1, whereas ALF and ALFQ enhanced Th1-mediated anti-CPS IgG2b and IgG2c and generated functional bactericidal antibody titers. CPS-CRM + ALFQ was superior to vaccine alone or CPS-CRM + ALF in augmenting antigen-specific Th1, Th2, and Th17 cytokine responses and a significantly higher proportion of CD4+ IFN-γ+ IL-2+ TNF-α+ and CD4+ IL-4+ IL-10+ T cells. ALFQ also significantly enhanced anti-CPS responses in NHPs when delivered with CPS-CRM compared to alum- or ALF-adjuvanted groups and showed the highest protective efficacy against diarrhea following orogastric challenge with C. jejuni This study provides evidence that the ALF adjuvants may provide enhanced immunogenicity of this and other novel C. jejuni capsule conjugate vaccines in humans.IMPORTANCECampylobacter jejuni is a leading cause of diarrheal disease worldwide, and currently no preventative interventions are available. C. jejuni is an invasive mucosal pathogen that has a variety of polysaccharide structures on its surface, including a capsule. In phase 1 studies, a C. jejuni capsule conjugate vaccine was safe but poorly immunogenic when delivered alone or with aluminum hydroxide. Here, we report enhanced immunogenicity of the conjugate vaccine delivered with liposome adjuvants containing monophosphoryl lipid A without or with QS-21, known as ALF and ALFQ, respectively, in preclinical studies. Both liposome adjuvants significantly enhanced immunity in mice and nonhuman primates and improved protective efficacy of the vaccine compared to alum in a nonhuman primate C. jejuni diarrhea model, providing promising evidence that these potent adjuvant formulations may enhance immunogenicity in upcoming human studies with this C. jejuni conjugate and other malaria and HIV vaccine platforms.
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Vacunas Bacterianas/inmunología , Infecciones por Campylobacter/prevención & control , Inmunogenicidad Vacunal , Lípido A/análogos & derivados , Saponinas/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Antibacterianos/sangre , Infecciones por Campylobacter/inmunología , Campylobacter jejuni/inmunología , Citocinas/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Lípido A/administración & dosificación , Liposomas/administración & dosificación , Liposomas/química , Masculino , Ratones , Ratones Endogámicos BALB C , Primates , Células TH1/inmunología , Células Th2/inmunología , Vacunas Conjugadas/administración & dosificaciónRESUMEN
BACKGROUND: The burden of cervical cancer caused by human papillomavirus (HPV) is high in Latin America. The suboptimal HPV vaccination coverage in adolescents could be improved by pediatric immunization. HPV vaccination has not yet been reported in girls <9 years of age. METHODS: This ongoing phase III, controlled, randomized, single-blind, multicenter study conducted in Colombia, Mexico and Panama (NCT01627561) evaluated the safety and immunogenicity of AS04-HPV-16/18 vaccine in 4-6-year-old girls. Healthy girls (randomized 1:1) received either 2 doses of AS04-HPV-16/18 vaccine (HPV group, N=74) or 1 dose of each measles-mumps-rubella and diphtheria-tetanus-acellular-pertussis vaccines (control group, N=74) 6 months apart. We report the safety and serum anti-HPV-16 and anti-HPV-18 antibodies (measured by enzyme-linked immunosorbent assay) up to 6 months postvaccination, that is, month (M) 12. RESULTS: Injection site pain was the most frequently reported solicited local symptom in HPV vaccinees. The incidence of other solicited and unsolicited symptoms after each vaccination was similar between the HPV and control group. Until M12, 1 girl in the HPV group and 2 in the control group reported serious adverse events; all serious adverse events were assessed as unrelated to study vaccines. No potential immune-mediated diseases were identified. All girls seroconverted for both antigens after 2 doses of AS04-HPV-16/18. In initially seronegative girls, anti-HPV-16 geometric mean concentrations were 20080.0 enzyme-linked immunosorbent assay units (EU)/mL at M7 and 3246.5 EU/mL at M12; anti-HPV-18 geometric mean concentrations were 10621.8 EU/mL at M7 and 1216.6 EU/mL at M12. CONCLUSIONS: Two-dose vaccination with AS04-HPV-16/18 was well tolerated and induced adequate antibody responses in 4-6-year-old girls.
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Hidróxido de Aluminio/efectos adversos , Hidróxido de Aluminio/inmunología , Lípido A/análogos & derivados , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/inmunología , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antivirales/sangre , Niño , Preescolar , Colombia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Voluntarios Sanos , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Humanos , Esquemas de Inmunización , Incidencia , Lípido A/administración & dosificación , Lípido A/efectos adversos , Lípido A/inmunología , México , Panamá , Vacunas contra Papillomavirus/administración & dosificación , Método Simple CiegoRESUMEN
Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 µg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01261130 for the Brazil trial and NCT01385189 for the US trial).
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Ancylostomatoidea/inmunología , Antígenos Helmínticos/inmunología , Glutatión Transferasa/inmunología , Infecciones por Uncinaria/prevención & control , Vacunas Sintéticas/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Hidróxido de Aluminio/administración & dosificación , Animales , Anticuerpos Antihelmínticos/sangre , Brasil , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Glucósidos/administración & dosificación , Voluntarios Sanos , Vacunas contra Hepatitis B/administración & dosificación , Infecciones por Uncinaria/inmunología , Humanos , Inmunoglobulina G/sangre , Inyecciones Intramusculares , Lípido A/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Estados Unidos , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Adulto JovenRESUMEN
The lack of antifungals with low toxicity and short-term therapy for patients with paracoccidioidomycosis (PCM) led us to evaluate adjuvants in immunotherapeutic intervention. We have previously shown complete Freund's adjuvant (CFA) to be therapeutic on experimental PCM. Owing to CFA toxicity, here we tested adjuvants approved for clinical use or in preclinical phase in experimental mouse PCM. Of all, only monophosporyl lipid A (MPLA) demonstrates a beneficial effect, by reducing the fungal burden and increasing the concentrations of IFN-γ and TNF-α, which are immunoprotective in PCM. These results suggest that MPLA might improve intervention in PCM.
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Factores Inmunológicos/administración & dosificación , Lípido A/análogos & derivados , Paracoccidioidomicosis/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Lípido A/administración & dosificación , Masculino , Ratones Endogámicos BALB C , Usos Terapéuticos , Resultado del TratamientoRESUMEN
The Tc24 calcium binding protein from the flagellar pocket of Trypanosoma cruzi is under evaluation as a candidate vaccine antigen against Chagas disease. Previously, a DNA vaccine encoding Tc24 was shown to be an effective vaccine (both as a preventive and therapeutic intervention) in mice and dogs, as evidenced by reductions in T. cruzi parasitemia and cardiac amastigotes, as well as reduced cardiac inflammation and increased host survival. Here we developed a suitable platform for the large scale production of recombinant Tc24 (rTc24) and show that when rTc24 is combined with a monophosphoryl-lipid A (MPLA) adjuvant, the formulated vaccine induces a Th1-biased immune response in mice, comprised of elevated IgG2a antibody levels and interferon-gamma levels from splenocytes, compared to controls. These immune responses also resulted in statistically significant decreased T. cruzi parasitemia and cardiac amastigotes, as well as increased survival following T. cruzi challenge infections, compared to controls. Partial protective efficacy was shown regardless of whether the antigen was expressed in Escherichia coli or in yeast (Pichia pastoris). While mouse vaccinations will require further modifications in order to optimize protective efficacy, such studies provide a basis for further evaluations of vaccines comprised of rTc24, together with alternative adjuvants and additional recombinant antigens.
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Antígenos de Protozoos/inmunología , Enfermedad de Chagas/prevención & control , Vacunas Antiprotozoos/inmunología , Trypanosoma cruzi/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/genética , Enfermedad de Chagas/inmunología , Clonación Molecular , Modelos Animales de Enfermedad , Escherichia coli/genética , Femenino , Expresión Génica , Interferón gamma/metabolismo , Leucocitos Mononucleares/inmunología , Lípido A/administración & dosificación , Ratones Endogámicos BALB C , Carga de Parásitos , Parasitemia/prevención & control , Pichia/genética , Vacunas Antiprotozoos/administración & dosificación , Vacunas Antiprotozoos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/aislamiento & purificación , Bazo/inmunología , Análisis de Supervivencia , Células TH1/inmunología , Trypanosoma cruzi/genética , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunologíaRESUMEN
A broad coverage influenza vaccine against multiple viral strains based on the viral nucleoprotein (NP) is a goal pursued by many laboratories. If the goal is to formulate the vaccine with recombinant NP it is essential to count on adjuvants capable of inducing cellular immunity. This work have studied the effect of the monophosphoryl lipid A and trehalose dimycolate, known as the Ribi Adjuvant System (RAS), in the immune response induced in mice immunized with recombinant NP. The NP was formulated with RAS and used to immunize BALB/c mice. Immunizations with NP-RAS increased the humoral and cellular immune responses compared to unadjuvanted NP. The predominant antibody isotype was IgG2a, suggesting the development of a Th1 response. Analysis of the cytokines from mice immunized with NP-RAS showed a significant increase in the production of IFN-g and a decreased production of IL-10 and IL-4 compared to controls without RAS. These results are similar to those usually obtained using Freund's adjuvant, known to induce Th1 and CTL responses when co-administered with purified proteins, and suggest that a similar approach may be possible to enhance the performance of a T-cell vaccine containing NP.
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Esqueleto de la Pared Celular/administración & dosificación , Factores Cordón/administración & dosificación , Gripe Humana/inmunología , Lípido A/análogos & derivados , Proteínas de Unión al ARN/inmunología , Células TH1/inmunología , Proteínas del Núcleo Viral/inmunología , Animales , Anticuerpos Antivirales/inmunología , Esqueleto de la Pared Celular/inmunología , Factores Cordón/inmunología , Femenino , Humanos , Inmunidad Celular , Inmunización , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Gripe Humana/virología , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-4/inmunología , Lípido A/administración & dosificación , Lípido A/inmunología , Ratones , Ratones Endogámicos BALB C , Proteínas de la Nucleocápside , Proteínas de Unión al ARN/administración & dosificación , Proteínas de Unión al ARN/genética , Linfocitos T Citotóxicos/inmunología , Proteínas del Núcleo Viral/administración & dosificación , Proteínas del Núcleo Viral/genéticaRESUMEN
In this study, we report on the safety and skin delayed-type hypersensitivity (DTH), responses of the Leishmania donovani whole cell sonicate antigen delivered in conjunction with alum-BCG (AlBCG), Montanide ISA 720 (MISA) or Monophosphoryl lipid A (MPLA) in groups of vervet monkeys. Following three intradermal injections of the inoculums on days 0, 28 and 42, safety and DTH responses were assessed. Preliminary tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were also measured and these were compared with DTH. Only those animals immunized with alum-BCG reacted adversely to the inoculum by producing ulcerative erythematous skin indurations. Non-parametric analysis of variance followed by a post-test showed significantly higher DTH responses in the MISA+Ag group compared with other immunized groups (p < 0.001). The MPLA+Ag group indicated significantly lower DTH responses to the sonicate antigen compared with the AlBCG+Ag group. There was a significant correlation between the DTH and cytokine responses (p < 0.0001). Based on this study we conclude that Leishmania donovani sonicate antigen containing MISA 720 is safe and is associated with a strong DTH reaction following immunization.
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Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Protozoos/administración & dosificación , Hipersensibilidad Tardía/inmunología , Leishmania donovani/inmunología , Leishmaniasis Visceral/inmunología , Lípido A/análogos & derivados , Adyuvantes Inmunológicos/efectos adversos , Animales , Chlorocebus aethiops , Ensayo de Inmunoadsorción Enzimática , Femenino , Interferón gamma/sangre , Lípido A/administración & dosificación , Lípido A/efectos adversos , Masculino , Factor de Necrosis Tumoral alfa/sangreRESUMEN
In this study, we report on the safety and skin delayed-type hypersensitivity (DTH), responses of the Leishmania donovani whole cell sonicate antigen delivered in conjunction with alum-BCG (AlBCG), Montanide ISA 720 (MISA) or Monophosphoryl lipid A (MPLA) in groups of vervet monkeys. Following three intradermal injections of the inoculums on days 0, 28 and 42, safety and DTH responses were assessed. Preliminary tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were also measured and these were compared with DTH. Only those animals immunized with alum-BCG reacted adversely to the inoculum by producing ulcerative erythematous skin indurations. Non-parametric analysis of variance followed by a post-test showed significantly higher DTH responses in the MISA+Ag group compared with other immunized groups (p < 0.001). The MPLA+Ag group indicated significantly lower DTH responses to the sonicate antigen compared with the AlBCG+Ag group. There was a significant correlation between the DTH and cytokine responses (p < 0.0001). Based on this study we conclude that Leishmania donovani sonicate antigen containing MISA 720 is safe and is associated with a strong DTH reaction following immunization.
Neste estudo reportamos segurança e resposta de hipersensibilidade tardia (DTH) do antígeno sonicado de células totais de Leishmania donovani introduzidos juntamente com alume-BCG (AIBCG) Montanide ISA 720 (MISA) ou lípide A monofosforilado (MPLA) em grupos de macacos vervet. Depois de três injeções intradérmicas do inóculo nos dias 0, 28 e 42 segurança e resposta DTH foram avaliados. Preliminarmente níveis de fator de necrose tumoral alfa (TNF-α) e interferon gama (IFN-γ) foram também medidos e comparados com o DTH. Somente os animais imunizados com alume-BCG reagiram de maneira diversa ao inóculo produzindo indurações ulceradas e eritematosas na pele. Análise não paramétrica de variação seguida por um teste posterior mostraram resposta significantemente mais alta do DTH no grupo MISA + Ag quando comparado com outros grupos imunizados (p < 0.001). O grupo MPLA + Ag demonstrou resposta DTH significantemente menor do antígeno sonicado comparado com o grupo AIBCG + Ag. Houve correlação significante entre o DTH e a resposta às citocinas (p < 0.0001). Baseados neste estudo concluímos que o antígeno sonicado de Leishmania donovani contendo MISA 720 é seguro e está associado com forte reação DTH após imunização.
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Animales , Femenino , Masculino , Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Protozoos/administración & dosificación , Hipersensibilidad Tardía/inmunología , Leishmania donovani/inmunología , Leishmaniasis Visceral/inmunología , Lípido A/análogos & derivados , Adyuvantes Inmunológicos/efectos adversos , Chlorocebus aethiops , Ensayo de Inmunoadsorción Enzimática , Interferón gamma/sangre , Lípido A/administración & dosificación , Lípido A/efectos adversos , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. INTERPRETATION: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. FUNDING: GlaxoSmithKline Biologicals.
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Adenocarcinoma/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Lípido A/análogos & derivados , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/virología , Adolescente , Adulto , Factores de Edad , Asia , Australia , ADN Viral/análisis , Método Doble Ciego , Europa (Continente) , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Lípido A/administración & dosificación , Clasificación del Tumor , América del Norte , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , América del Sur , Factores de Tiempo , Resultado del Tratamiento , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
BACKGROUND: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). INTERPRETATION: Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. FUNDING: GlaxoSmithKline Biologicals.
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Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Lípido A/análogos & derivados , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Lesiones Precancerosas/prevención & control , Displasia del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Antígenos Virales/inmunología , Asia , Australia , Reacciones Cruzadas , ADN Viral/análisis , Método Doble Ciego , Europa (Continente) , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Lípido A/administración & dosificación , Clasificación del Tumor , América del Norte , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/patología , Lesiones Precancerosas/virología , América del Sur , Factores de Tiempo , Resultado del Tratamiento , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
METHODS: We conducted a phase I, multicenter, randomized, double-blind, placebo-controlled, multi-arm (10) parallel study involving healthy adults to evaluate the safety and immunogenicity of influenza A (H1N1) 2009 non-adjuvanted and adjuvanted candidate vaccines. Subjects received two intramuscular injections of one of the candidate vaccines administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay before and 21 days after each vaccination. The three co-primary immunogenicity end points were the proportion of seroprotection >70%, seroconversion >40%, and the factor increase in the geometric mean titer >2.5. RESULTS: A total of 266 participants were enrolled into the study. No deaths or serious adverse events were reported. The most commonly solicited local and systemic adverse events were injection-site pain and headache, respectively. Only three subjects (1.1%) reported severe injection-site pain. Four 2009 influenza A (H1N1) inactivated monovalent candidate vaccines that met the three requirements to evaluate influenza protection, after a single dose, were identified: 15 µg of hemagglutinin antigen without adjuvant; 7.5 µg of hemagglutinin antigen with aluminum hydroxide, MPL and squalene; 3.75 µg of hemagglutinin antigen with aluminum hydroxide and MPL; and 3.75 µg of hemagglutinin antigen with aluminum hydroxide and squalene. CONCLUSIONS: Adjuvant systems can be safely used in influenza vaccines, including the adjuvant monophosphoryl lipid A (MPL) derived from Bordetella pertussis with squalene and aluminum hydroxide, MPL with aluminum hydroxide, and squalene and aluminum hydroxide.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Adulto , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Método Doble Ciego , Femenino , Pruebas de Inhibición de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/inmunología , Inyecciones Intramusculares , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Masculino , Escualeno/administración & dosificación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/efectos adversos , Vacunas de Productos Inactivados/inmunología , Adulto JovenRESUMEN
BACKGROUND: Anal cancer remains rare (incidence of about 1·5 per 100,000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18). METHODS: Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18-25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661. FINDINGS: All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1-73·1) compared with the cervix (76·4%, 67·0-83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7-92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4-94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article. INTERPRETATION: The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. FUNDING: National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.
Asunto(s)
Neoplasias del Ano/prevención & control , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Lesiones Precancerosas/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Adolescente , Adulto , Hidróxido de Aluminio/administración & dosificación , Neoplasias del Ano/epidemiología , Neoplasias del Ano/virología , Distribución de Chi-Cuadrado , Costa Rica/epidemiología , Método Doble Ciego , Femenino , Humanos , Esquemas de Inmunización , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Lesiones Precancerosas/epidemiología , Lesiones Precancerosas/virología , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
Consecutive lots of H5N1 (A/Vietnam/1194/2004 - NIBRG-14) split virion and whole virus vaccines were produced in a pilot-scale laboratory. The average yields of vaccine doses (15 microg HA) per egg were 0.57 doses for H5N1 split virion vaccine and 1.12 for H5N1 whole virus vaccine, compared to 2.09 doses for the seasonal H3N2 split virion vaccine. H5N1 split virion vaccine lots complied with WHO protein content criteria, while some lots of the H5N1 whole virus vaccine showed protein content per dose higher than the limit established. All lots of both vaccines showed ovalbumin (OVA) concentration below the recommended limit. Dose sparing strategies using adjuvant formulations using aluminum hydroxide (Al(OH)(3)) and monophosphoryl lipid A (MPLA) from Bordetella pertussis were tested in mice. Both 3.75 microg HA and 7.5 microg HA of H5N1 split virion vaccine with Al(OH)(3) or Al(OH)(3) plus MPLA in aqueous suspension showed higher hemagglutination-inhibition (HAI) titers when compared to the same vaccine dose without any adjuvant. Immunization with the H5N1 inactivated whole virus vaccine was also performed using 3.75 microg HA and HAI titers were higher than those induced by the split virion vaccine. Moreover, the use of Al(OH)(3) with MPLA as an emulsion induced a further increase in HAI titers.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Subtipo H5N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Hidróxido de Aluminio/administración & dosificación , Animales , Anticuerpos Antivirales/sangre , Antígenos Virales/análisis , Bordetella pertussis/química , Femenino , Pruebas de Inhibición de Hemaglutinación , Vacunas contra la Influenza/química , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Lípido A/aislamiento & purificación , Ratones , Ratones Endogámicos BALB C , Ovalbúmina/análisis , Vacunas de Productos Inactivados/química , Vacunas de Productos Inactivados/inmunología , Vacunas de Subunidad/química , Vacunas de Subunidad/inmunologíaRESUMEN
Bacterial lipopolysaccharide given intravenously at 30 mg/kg to anesthetized rats results in rapid systemic hypotension and hypovolemia, elaboration of cytokines, increased proteolysis and vascular endothelial dysfunction. When a monoclonal antibody SdJ5-1.17.15 (SdJ5) directed against the lipid A moiety of lipopolysaccharide was administered at (1.25 or 5.0 mg/kg) 5 min prior to the endotoxin, significant protection was afforded to rats. This protection was manifested by a significant reduction in the early hypotension, as well as attenuation of hypovolemia and proteolysis. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats 4 h after endotoxic challenge. Lipopolysaccharide (LPS) significantly reduced superior mesenteric artery vasorelaxation to acetylcholine and A23187, two endothelium-dependent vasodilators, but not to NaNO2, an endothelium-independent vasodilator. SdJ5 significantly preserved vasorelaxation responses to both acetylcholine and A23187, indicating a marked degree of endothelial preservation by this anti-lipid A monoclonal antibody. The protection was dose-dependent since 0.3 mg/kg of SdJ5 did not provide significant protection in any variable measured. Moreover, there was no significant difference between the 1.25 mg/kg and 5.0 mg/kg dose of SdJ5. Furthermore, plasma concentrations of TNF-alpha, a cytokine involved in mediating many of the effects associated with endotoxemia, was significantly reduced in SdJ5-treated animals. Thus, SdJ5 appears to be capable of counteracting many of the in vivo sequelae of endotoxemia in rats.