RESUMO
Strong quantitative and functional antibody responses to the quadrivalent human papillomavirus (HPV) vaccine were reported in mid-adult aged men, but there are limited data on the avidity of the antibody response and the memory B-cell response following vaccination. Although circulating antibodies induced by vaccination are believed to be the main mediators of protection against infection, evaluation of avidity of antibodies and memory B cell responses are critical for a better understanding of the vaccine immunogenicity mechanisms. Both the modified enzyme-linked immunosorbent assay (ELISA) and the enzyme-linked immunosorbent spot (ELISpot) assay are tools to measure the humoral and cellular immune responses post vaccination to characterize vaccine immunogenicity. The avidity of HPV-16 and HPV-18 specific IgG in the serum of mid-adult aged men (N = 126) who received three quadrivalent HPV vaccine doses was examined using a modified ELISA. HPV-16 memory B-cell responses were assessed via ELISpot at month 0 (prior to vaccination) and 1-month post-dose three of the vaccine (month 7). The quadrivalent vaccine induced an increase in HPV-16 and HPV-18 antibody avidity at month 7. HPV-18 avidity levels moderately correlated with anti-HPV-18 antibody titers, but no association was observed for HPV-16 antibody titers and avidity levels. The HPV-16-specific memory B-cell response was induced following three vaccine doses, however, no association with anti-HPV-16 antibody avidity was observed. Three doses of quadrivalent HPV vaccine increased antibody affinity maturation for HPV-16/18 and increased the frequency of anti-HPV-16 memory B-cells in mid-adult aged men.
Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adulto , Idoso , Anticorpos Antivirais , Afinidade de Anticorpos , Linfócitos B , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Masculino , Infecções por Papillomavirus/prevenção & controleRESUMO
BACKGROUND: HPV-16 and HPV-18 cause most oropharyngeal cancers, which are increasing in incidence among males. Although HPV vaccines are highly effective against a number of HPV-associated cancers, efficacy for oropharyngeal cancers has not yet been demonstrated. In addition, the level of antibodies required for protection against oral HPV infection is unknown. METHODS: 150 men ages 27-45â¯years from Tampa, FL, USA, and Cuernavaca, Mexico, received Gardasil at Day 1, Months 2, and 6. Then, sera and oral gargles were collected one month, 12â¯months, and 24â¯months after completion of the three doses (Month 7, 18 and 30 of the study) and tested for anti-HPV-16 and HPV-18 IgG antibody levels by a L1 VLP ELISA. RESULTS: All participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies and most had detectable antibodies in oral gargles at Month 7 (HPV-16: 93.2%; HPV-18: 72.1%). By months 18 and 30, oral antibodies were detectable in a lower number of participants (HPV-16, 39.8% and 29.6%; HPV-18, 10.7% and 4.6% of individuals, respectively). Overall, oral HPV-16- and 18-specific antibody levels, normalized to total IgG at months 7, 18, and 30, correlated with serum levels (HPV-16, R2â¯=â¯0.93; HPV-18, R2â¯=â¯0.91). CONCLUSIONS: Reduced detectability of oral and serum HPV-16 and HPV-18 antibodies was observed at months 18 and 30 after initiation of the quadrivalent vaccination. However, when detectable, serum and oral HPV-16 and HPV-18 antibody levels were strongly correlated.
Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra Papillomavirus/imunologia , Vacinação , Ensaio de Imunoadsorção Enzimática , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Masculino , Saliva/virologiaRESUMO
Duration and functional aspects of the oral and systemic antibody responses following HPV vaccination in HIV-negative (HIV-) and HIV-positive (HIV+) men are not well characterized. Oral and systemic HPV-16 and HPV-18-specific antibody levels were evaluated over 18-months of follow-up, in HIV+ and HIV- men. Sera and oral gargles from 147 HIV- men, ages 27-45 and 75 HIV+ men, ages 22-61, who received 3-doses of quadrivalent HPV vaccine were tested for HPV-16 and HPV-18 antibodies at Day 1, Month 7 (1â¯month post-dose 3), and Month 18 (12â¯months post-dose 3) and HPV avidity (Day 1, and Month 7) using L1-VLP ELISA. All individuals seroconverted, regardless of HIV-status, following 3-doses of vaccine for HPV-16 and HPV-18. Serum HPV-16 and HPV-18 antibody geometric mean levels were >2-fold lower in HIV+ compared to HIV- men at Month 7 (HPV-16: 808.5 versus 2119.8â¯EU/mL, and HPV-18: 285.8 versus 611.6â¯EU/mL, pâ¯<â¯0.001) but not significantly different at Month 18 (HPV-16: 281.8 versus 359.7â¯EU/mL, pâ¯=â¯0.145, and HPV-18: 120.2 versus 93.4â¯EU/mL, pâ¯=â¯0.372). Post-vaccination, only oral HPV-16 antibody levels at Month 7 were significantly different between HIV+ and HIV- men (127.7 versus 177.1â¯EU/mg of IgG, pâ¯=â¯0.008). Among baseline HPV-seronegative men, circulating levels of HPV-16 and HPV-18 antibodies were up to >3 fold lower in HIV+ men, at Months 7 and 18. In contrast, levels of HPV-16 and HPV-18 antibodies after vaccination were not inferior in baseline HPV-seropositive, HIV+ men. HPV-16 and HPV-18 avidity was lower among HIV+ compared to HIV- men at Month 7 (HPV-16: 1.95â¯M versus 2.12â¯M, pâ¯=â¯0.027; HPV-18: 1.50â¯M versus 1.72â¯M, pâ¯<â¯0.001). Although differences in peak antibody levels were observed between HIV+ and HIV- men following 3 doses of vaccine, plateau antibody levels were overall comparable, and avidity was relatively high for both groups. These data indicate that the vaccine induced antibody affinity maturation in both HIV+ and HIV- men and will likely result in long-term protective immune responses.
Assuntos
Alphapapillomavirus/imunologia , Anticorpos Antivirais/sangue , Infecções por HIV/complicações , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Boca/imunologia , Infecções por Papillomavirus/prevenção & controle , Adulto , Anticorpos Neutralizantes/sangue , Afinidade de Anticorpos , Infecções por HIV/epidemiologia , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/administração & dosagem , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/imunologia , Vacinação , Adulto JovemRESUMO
BACKGROUND: Current Human papillomavirus (HPV) L1 VLP vaccines protect against HPV-16 and HPV-18-associated cancers, in females and males. Although correlates of protection have not been identified, HPV-specific antibodies at sites of infection are thought to be the main mechanism of protection afforded by vaccination. Oral sampling has gained increased attention as a potential alternative to serum in monitoring immunity to vaccination and understanding local immunity in oral cancers. METHODS: Serum was collected via venipuncture, and saliva was collected via oral rinses and Merocel® sponges from healthy volunteers: 16 unvaccinated females, 6 females (ages 24-41) and 6 mid-adult aged males (ages 27-45) recipients of three doses of the HPV-16/18/6/11 vaccine (Gardasil®). Mid-adult male vaccine trial participants were compared to female participants. Samples were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay (ELISA). RESULTS: All vaccinated participants had detectable serum anti-HPV-16 and anti-HPV-18 antibodies. Optimal standard concentration range and sample serial dilutions for oral rinses were determined. The standard curve was not affected by the type of solution examined. Reproducibility of HPV-16 and HPV-18 antibody titers in mouthwash (overall CVâ¯<â¯10%) or in Merocel® extraction buffer was robust (CVâ¯<â¯13%). Excellent assay linearity (R2â¯>â¯0.9) was observed for sera spiked controls in both solutions. HPV-16 and HPV-18 specific antibodies were detectable in saliva from vaccine recipients, both in mouthwash and in Merocel® sponges but levels were several logs lower than those in serum. CONCLUSIONS: This study confirms the application of HPV-16 and HPV-18 ELISAs currently used in sero-epidemiological studies of immunogenicity of HPV vaccines for use with oral samples. Oral samples may be a useful resource for the detection of HPV-16 and HPV-18-specific antibodies in saliva following vaccination.
Assuntos
Anticorpos Antivirais/análise , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Saliva/virologia , Manejo de Espécimes/métodos , Adulto , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/normas , Feminino , Formaldeído , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Vacinas contra Papillomavirus/uso terapêutico , Álcool de Polivinil , Valores de Referência , Reprodutibilidade dos Testes , Manejo de Espécimes/instrumentaçãoRESUMO
Background: Previously, we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonrandomized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine. Here we extend data to seven years following initial vaccination. Methods: We evaluated HPV16/18-vaccinated women who received one (n = 134), two (n 0/1 = 193, n 0/6 = 79), or three doses (n = 2043) to a median of 6.9 years postvaccination. Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system; HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays (n = 486). Infection and immunological measures were compared across vaccine dose groups. Prevalent HPV infection at year 7 was also compared with an unvaccinated control group (UCG). All statistical tests were two-sided. Results: Among women in the three-dose, two-dose 0/6 , two-dose 0/1 , and one-dose groups, cumulative incident HPV16/18 infection rates (No. of events/No. of individuals) were 4.3% (88/2036, 95% confidence interval [CI] = 3.5% to 5.3%), 3.8% (3/78, 95% CI = 1.0% to 10.1%), 3.6% (7/192, 95% CI = 1.6% to 7.1%), and 1.5% (2/133, 95% CI = 0.3% to 4.9%; P = 1.00, .85, .17 comparing the two-dose 0/6 , two-dose 0/1 , and one-dose groups to the three-dose group, respectively). The prevalence of other carcinogenic and noncarcinogenic HPV types, excluding HPV16/18/31/33/45, were high and not statistically different among all dose groups, indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure. At seven years, 100% of participants in all dose groups remained HPV16 and HPV18 seropositive. A non-statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group: -10.8% (95% CI = -25.3% to 6.6%); two-dose (0/6 months) group: -17.3% (95% CI = -39.3% to 12.8%), two-dose (0/1 month) group: -6.9% (95% CI = -22.1% to 11.2%), and one-dose group: -5.5% (95% CI = -29.7% to 27.0%); results were similar for HPV18. Conclusions: At an average of seven years of follow-up, we observed similar low rates of HPV16/18 infections and slight, if any, decreases in HPV16/18 antibody levels by dose group.
Assuntos
Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Colo do Útero/virologia , DNA Viral/genética , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Doenças do Colo do Útero/imunologia , Doenças do Colo do Útero/prevenção & controle , Doenças do Colo do Útero/virologia , Adulto JovemRESUMO
BACKGROUND: Human papillomavirus virus type 16 (HPV-16) and HPV-18 cause a large proportion of oropharyngeal cancers, which are increasing in incidence among males, and vaccine efficacy against oral HPV infections in men has not been previously evaluated. METHODS: Sera and saliva collected in mouthwash and Merocel sponges at day 1 and month 7 were obtained from 150 men aged 27-45 years from Tampa, Florida, and Cuernavaca, Mexico, who received Gardasil at day 1 and months 2 and 6. Specimens were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G (IgG) levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay. RESULTS: All participants developed detectable serum anti-HPV-16 and anti-HPV-18 antibodies, and most had detectable antibodies in both oral specimen types at month 7 (HPV-16 was detected in 93.2% of mouthwash specimens and 95.7% of sponge specimens; HPV-18 was detected in 72.1% and 65.5%, respectively). Antibody concentrations in saliva were approximately 3 logs lower than in serum. HPV-16- and HPV-18-specific antibody levels, normalized to total IgG levels, in both oral specimen types at month 7 were significantly correlated with serum levels (for HPV-16, ρ was 0.90 for mouthwash specimens and 0.92 for sponge specimens; for HPV-18, ρ was 0.89 and 0.86, respectively). CONCLUSIONS: This is the first study demonstrating that vaccination of males with Gardasil induces HPV antibody levels at the oral cavity that correlate with circulating levels.
Assuntos
Anticorpos Antivirais/imunologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Boca/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Florida , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , México , Pessoa de Meia-Idade , Saliva/imunologia , Vacinação/métodosRESUMO
Immunization with Human Papillomavirus (HPV) L1 virus-like particles or L2 capsid protein elicits neutralizing antibodies that mediate protection. A high-throughput and sensitive in vitro neutralization assay is therefore valuable for prophylactic HPV vaccine studies. Over several hours during infection of the genital tract, virions take on a distinct intermediate conformation, including a required furin cleavage of L2 at its N-terminus. This intermediate is an important target for neutralization by L2-specific antibody, but it is very transiently exposed during in vitro infection of most cell lines resulting in insensitive measurement for L2, but not L1-specific neutralizing antibodies. To model this intermediate, we describe a protocol to generate furin-cleaved HPV pseudovirions (fc-PsV), which deliver an encapsidated reporter plasmid to facilitate infectivity measurements. We also describe a protocol for use of fc-PsV in a high-throughput in vitro neutralization assay for the sensitive measurement of both L1 and L2-specific neutralizing antibodies.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Furina/metabolismo , Testes de Neutralização/métodos , Papillomaviridae/imunologia , Virossomos/imunologia , Ensaios de Triagem em Larga Escala , Humanos , Papillomaviridae/genética , Virossomos/genéticaRESUMO
Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype.
Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Doenças da Medula Óssea/diagnóstico , Disceratose Congênita/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Anemia de Fanconi/diagnóstico , Hemoglobinúria Paroxística/diagnóstico , Lipomatose/diagnóstico , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Anemia Aplástica , Anemia de Diamond-Blackfan/tratamento farmacológico , Anemia de Diamond-Blackfan/imunologia , Anemia de Diamond-Blackfan/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Doenças da Medula Óssea/congênito , Doenças da Medula Óssea/tratamento farmacológico , Doenças da Medula Óssea/imunologia , Transtornos da Insuficiência da Medula Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/biossíntese , Citocinas/imunologia , Disceratose Congênita/tratamento farmacológico , Disceratose Congênita/imunologia , Disceratose Congênita/patologia , Insuficiência Pancreática Exócrina/congênito , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/imunologia , Família , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/imunologia , Anemia de Fanconi/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos/biossíntese , Fator Estimulador de Colônias de Granulócitos/imunologia , Hemoglobinúria Paroxística/congênito , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/imunologia , Humanos , Imunoglobulinas/biossíntese , Lactente , Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Lipomatose/congênito , Lipomatose/tratamento farmacológico , Lipomatose/imunologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/imunologiaRESUMO
Two HPV virus-like particle (VLP) vaccines, HPV-16/18 (GlaxoSmithKline, Cervarix®) and HPV-6/11/16/18 (Merck, Gardasil®), are currently licensed in the United States. Given the similar antigenic content but different adjuvant formulations in the 2 vaccines, they provide an efficient method for evaluating adjuvants and comparing the kinetics of the innate and adaptive immune responses. We randomized women to receive either Cervarix® or Gardasil®, followed 6 month vaccination delivery schedules per manufacturer's recommendations, and analyzed the humoral immune response, T cell response, and circulating plasma cytokine levels in response to vaccination. Cervarix® recipients had higher anti-HPV-16 antibody and neutralization titers at month 7, and elevated anti-HPV-18 antibody and neutralization titers at months 7 and 12. Antibody avidity was similar for the 2 vaccines. HPV-31 was the only phylogenetically related non-vaccine HPV type, for which there is evidence of cross-protection, to be cross-neutralized and only in response to Cervarix®. Comparing CD4+ T cell cytokine responses at month 12, there was a trend of increased levels of IL-2 and TNF-α in the Cervarix® groups versus the Gardasil® groups that was consistent across all 4 tested HPV types (16/18/33/45). Elevated levels of circulating plasma cytokine/chemokines were observed post first vaccination in Gardasil® recipients and proinflammatory cytokines were elevated following 1st and 3rd Cervarix® vaccinations. Cervarix® and Gardasil® are both highly immunogenic vaccines. Higher antibody levels and CD4 T cell responses were achieved with Cervarix® after 3 doses, although similar affinity maturation was measured for the 2 vaccines. The clinical implications of the differences in immune responses are unknown.
Assuntos
Imunidade Adaptativa , Vacinas contra Papillomavirus/imunologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Quimiocinas/sangue , Citocinas/sangue , Feminino , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18 , Humanos , Imunidade Inata , Adulto JovemRESUMO
BACKGROUND: Investigations of vaccine efficacy and immunogenicity for adult females receiving fewer than three doses of human papillomavirus (HPV) vaccine have suggested protection against infection and precancerous lesions. We investigated the immunogenicity of bivalent HPV vaccines among adolescent girls from Uganda who received one, two, or three vaccine doses. METHODS: Young girls vaccinated through a government program in Uganda were invited to participate. HPV16- and HPV18-specific antibodies were measured at ≥24 months after the last vaccine dose using an enzyme linked immunoassay in girls who received one (n=36), two (n=145), or three (n=195) doses. RESULTS: Nearly all subjects (99%) were HPV16 and HPV18 seropositive at the time of blood-draw. Geometric mean antibody levels (GMTs) were: HPV161-dose=230 EU/mL, HPV162-dose=808 EU/mL, and HPV163-dose=1607 EU/mL; HPV181-dose=87 EU/mL, HPV182-dose=270 EU/mL, and HPV183-dose=296 EU/mL. The GMT ratio for 2:3 doses was 0.50 (HPV16) and 0.68 (HPV18) and did not meet the non-inferiority criteria (i.e., lower bound of 97.5% confidence interval of the GMT ratio greater than 0.50). The GMT ratio for 1:3 doses for HPV16 and HPV18 was inferior, but absolute GMTs for one dose were higher than adult women who received one dose (HPV16=124 EU/mL, HPV18=69 EU/mL) where efficacy has been demonstrated. CONCLUSIONS: Even though immunogenicity with less than three doses did not meet a priori non-inferiority thresholds, antibody levels measured ≥24 months after last dose were similar to those of adult women who have been followed for more than eight years for efficacy.
Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Criança , Estudos Transversais , Relação Dose-Resposta Imunológica , Feminino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Vacinas contra Papillomavirus/imunologia , Uganda , Neoplasias do Colo do Útero/prevenção & controleRESUMO
Patients with Fanconi anemia (FA) and other inherited bone marrow failure syndromes (IBMFS) have extremely high risks of squamous cell head and neck, and gynecologic carcinomas. In the general population, these sites are often associated with infection with human papillomaviruses (HPV), particularly HPV16 and HPV18. Our objectives were to measure the levels of HPV antibodies in unvaccinated patients, and to determine whether these patients developed and maintained similar levels of antibodies as those observed in healthy women, following vaccination with the currently licensed HPV L1 virus-like particles (VLP) vaccines. We measured anti-HPV IgG antibody levels in sera from patients using an HPV16 or HPV18 L1 VLP enzyme-linked immunoabsorbent assay. Most unvaccinated patients did not have detectable antibody levels, except for a few women above age 25. Both FA and other IBMFS patients developed antibody levels following vaccination that were similar to those previously described in healthy women, and those levels appeared to be sustained out to 5 years after immunization. Thus, antibody responses to the HPV L1 VLP vaccine in patients with FA and other IBMFS appeared to be similar to the responses reported in the general population, implying potential efficacy against future infections with the HPV types contained in the vaccine.
Assuntos
Formação de Anticorpos , Anemia de Fanconi/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Adolescente , Adulto , Anemia Aplástica , Anticorpos Antivirais/sangue , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Hemoglobinúria Paroxística/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection.
Assuntos
Anticorpos Antivirais/sangue , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/uso terapêutico , Vacinas de Partículas Semelhantes a Vírus/uso terapêutico , Anticorpos Antivirais/imunologia , Formação de Anticorpos , Costa Rica , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologiaRESUMO
BACKGROUND: We previously demonstrated that Cervarix(®) elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix(®)-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women. METHODS: A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory. RESULTS: In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p=0.009) and HPV-45 (month 12, p=0.003), but then persisted up to month 36 (HPV-31, p=0.01; HPV-45, p=0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p=0.04) and lower in HPV-16 infected women at month 12 (p=0.006) compared to the HPV negative women. CONCLUSIONS: The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in protection against infection.
Assuntos
Anticorpos Neutralizantes/imunologia , Infecções por Papillomavirus/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Vacinas contra Papillomavirus/uso terapêuticoRESUMO
Antibody responses against infectious agents are an important component in the prevention of disease. The avidity of antibodies for their antigens relates to their functional efficiency, and is a fundamental aspect in the investigation of humoral responses. Modified ELISAs are used to estimate avidity through the use of chaotropic agents and the measurement of the degree to which they disrupt the interaction between antibody and antigen. The theory behind the assay is the higher the avidity of an interaction the less susceptible it is to the effects of the chaotropic agent. The goal of this study was to generate a modified ELISA where a complex, multimeric coating-antigen, human papillomavirus (HPV) virus-like particles (VLP), was used to measure the avidity of anti-HPV antibodies generated following vaccination with HPV VLPs. A series of chaotropic agents were evaluated in the assay for their effectiveness in measuring avidity. Guanidine hydrochloride (GuHCl) was selected as a chaotropic reagent with the ability to disrupt antibody and antigen interactions, while not affecting the integrity of the plate-bound VLP. Two methods of determining the avidity index were assessed and shown to be comparable. This assay was then successfully applied to measure the avidity of anti-HPV VLP serum antibodies in samples from an HPV L1 VLP vaccine clinical trial. Overall, the assay was highly reproducible and captured a wide range of antibody avidities. Therefore, a GuHCl-modified ELISA is an acceptable method that can be used to determine HPV-specific antibody avidity indices within a clinical trial setting.
Assuntos
Anticorpos Antivirais/química , Afinidade de Anticorpos , Proteínas do Capsídeo/imunologia , Guanidina/química , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinação , Anticorpos Antivirais/sangue , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estatísticas não Paramétricas , Vacinas de Partículas Semelhantes a VírusRESUMO
Human papillomavirus (HPV) L1 VLP-based vaccines are protective against HPV vaccine-related types; however, the correlates of protection have not been defined. We observed that vaccination with Cervarix™ induced cross-neutralizing antibodies for HPV types for which evidence of vaccine efficacy has been demonstrated (HPV31/45) but not for other types (HPV52/58). In addition, HPV31/45 cross-neutralizing titers showed a significant increase with number of doses (HPV31, p<0.001; HPV45, p<0.001) and correlated with HPV16/18 neutralizing titers, respectively. These findings raise the possibility that cross-neutralizing antibodies are effectors of cross-protection observed for the HPV16/18 vaccine.
Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Proteção Cruzada , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Formação de Anticorpos , Feminino , Humanos , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologiaRESUMO
Human papillomavirus (HPV)-specific antibodies are proposed to be the correlate of protection afforded by HPV L1 virus-like particle (VLP) vaccines. Previous studies have characterized the systemic antibody response to immunization in terms of both the quantity and the ability to neutralize HPV. Here, we have adapted a generalized memory B cell ELISPOT to the HPV16 system and expanded the analysis of the systemic antibody response to include an avidity measurement of HPV L1 VLP-specific antibodies. We show the results of the memory B cell ELISPOT significantly correlated with IgG and neutralizing antibody titers, but not with the avidity measurement. This is the first comprehensive study to correlate a variety of humoral aspects potentially associated with protective immunity following vaccination with a HPV16 L1 VLP vaccine.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Papillomavirus Humano 16/imunologia , Memória Imunológica/efeitos dos fármacos , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinação , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , Método Duplo-Cego , Feminino , Humanos , Memória Imunológica/imunologia , Infecções por Papillomavirus/sangue , Vacinas contra Papillomavirus/imunologiaRESUMO
Depriving cells of iron likely stresses them and can result in cell death. To examine the potential relationship between this form of stress and cell death, Jurkat T-lymphocytes were made iron-deficient by exposing them to the iron chelator, deferoxamine (DFO). Such treatment produced evidence of apoptosis, including cell shrinkage, membrane blebbing, chromatin condensation and fragmentation, and also formation of apoptotic bodies. Additionally, proteolytic cleavage of poly(ADP-ribose)polymerase was detected, suggesting involvement of caspases in initiating apoptosis. Indeed, a selective caspase-3 inhibitor prevented the effects of DFO. During the early induction period of apoptosis, GRP78 and HSP70 mRNA expression was not affected. In contrast, there was mainly increased mRNA expression of Growth Arrest and DNA Damage-inducible gene 153 (GADD153), which seemed to be at the level of transcription rather than mRNA stability. Furthermore, fortifying cells with antioxidants did not prevent the increased GADD153 mRNA expression, and no evidence of single-strand breaks in DNA was found, suggesting that neither reactive oxygen species nor DNA damage was involved in triggering GADD153 gene activation. DFO also caused GADD153 protein to be expressed. Because GADD153 is recognized as a pro-apoptotic gene, these findings generate the notion that GADD153 might help mediate apoptosis in iron-deficient cells.