RESUMEN
BACKGROUND: World Health Organization human papillomavirus (HPV) vaccination recommendations include a single- or two-dose schedule in individuals 9-20 years old and advice for generating data on single-dose efficacy or immunobridging. The ongoing Phase 3 trial of Innovax's bivalent (types 16 and 18) HPV vaccine (Cecolin®) assesses in low- and middle-income countries alternative dosing schedules and generates data following one dose in girls 9-14 years old. Interim data for the 6-month dosing groups are presented. METHODS: In Bangladesh and Ghana, 1,025 girls were randomized to receive either two doses of Cecolin at 6-, 12-, or 24-month intervals; one dose of Gardasil® followed by one dose of Cecolin at month 24; or two doses of Gardasil 6 months apart (referent). Serology was measured by enzyme-linked immunosorbent assay (ELISA) and, in a subset, by neutralization assays. Primary objectives include immunological non-inferiority of the Cecolin schedules to referent one month after the second dose. Safety endpoints include reactogenicity and unsolicited adverse events for 7 and 30 days post-vaccination, respectively, as well as serious adverse events throughout the study. RESULTS: Interim analyses included data from the two groups on a 0, 6-month schedule with 205 participants per group. One month after Dose 2, 100% of participants were seropositive by ELISA and had seroconverted for both antigens. Non-inferiority of Cecolin to Gardasil was demonstrated. Six months following one dose, over 96% of participants were seropositive by ELISA for both HPV antigens, with a trend for higher geometric mean concentration following Cecolin administration. Reactogenicity and safety were comparable between both vaccines. CONCLUSIONS: Cecolin in a 0, 6-month schedule elicits robust immunogenicity. Non-inferiority to Gardasil was demonstrated one month after a 0, 6-month schedule. Immunogenicity following one dose was comparable to Gardasil up to six months. Both vaccines were safe and well tolerated (ClinicalTrials.gov No. 04508309).
Asunto(s)
Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Femenino , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Infecciones por Papillomavirus/prevención & control , Anticuerpos Antivirales , Vacunación , Inmunogenicidad VacunalRESUMEN
BACKGROUND: To meet global cervical cancer elimination efforts, a wider range of affordable and accessible vaccines against human papillomavirus (HPV) are needed. We aimed to evaluate the immunogenicity and safety of a quadrivalent HPV vaccine (targeting HPV types 6, 11, 16, and 18), developed and manufactured by the Serum Institute of India (SIIPL). Here we report outcomes in the 9-14 years cohort. METHODS: This randomised, active-controlled, phase 2/3 trial was conducted at 12 tertiary care hospitals across India. Healthy participants aged 9-14 years or 15-26 years with no history of HPV vaccination were eligible for enrolment. Female participants were randomly assigned (1:1) with an interactive web response system, by use of a central computer-generated schedule and block randomisation (block sizes of 2, 4, 6, and 8), to receive the SIIPL quadrivalent HPV vaccine (Cervavac; SIIPL, Pune, India) or the comparator quadrivalent HPV vaccine (Gardasil; Merck Sharp & Dohme, Harleem, the Netherlands). Participants, investigators, laboratory technicians, and sponsors were masked to treatment allocation of female participants. Male participants were given the SIIPL quadrivalent HPV vaccine in an open-label manner. Study vaccines were administered intramuscularly with a two-dose schedule (at day 0 and 6 months) in the cohort aged 9-14 years, and with a three-dose schedule (at day 0, month 2, and month 6) in the cohort aged 15-26-years. Immunogenicity was assessed 30 days after the last dose by use of multiplexed ELISA. The primary outcome was the non-inferiority of immune response in terms of the geometric mean titre (GMT) of antibodies against HPV types 6, 11, 16, and 18 generated by the SIIPL quadrivalent HPV vaccine in girls and boys (aged 9-14 years) compared with the GMT generated by the comparator quadrivalent HPV vaccine in women aged 15-26 years at month 7 in the modified per-protocol population (ie, all participants who received all doses of study vaccines per assigned treatment group and had both day 0 and 1-month immunogenicity measurements after the last dose following protocol-defined window periods with no major protocol deviations). Non-inferiority was established if the lower bound of the 98·75% CI of the GMT ratio was 0·67 or higher. The co-primary outcome of occurrence of solicited adverse events (within 7 days of each dose) and unsolicited adverse events (up to 30 days after the last dose) was assessed in all participants who were enrolled and received at least one dose of study vaccine. The trial is registered with the Clinical Trials Registry - India (CTRI/2018/06/014601), and long-term follow-up is ongoing. FINDINGS: Between Sept 20, 2018, and Feb 9, 2021, 2341 individuals were screened, of whom 2307 eligible individuals were enrolled and vaccinated: 1107 (738 girls and 369 boys) in the cohort aged 9-14 years and 1200 (819 women and 381 men) in the cohort aged 15-26 years. No race or ethnicity data were collected. 350 girls and 349 boys in the SIIPL quadrivalent HPV vaccine group and 338 women in the comparator vaccine group were included in the modified per-protocol population for the primary endpoint analysis. The median follow-up for the analyses was 221 days (IQR 215-231) for girls and 222 days (217-230) for boys in the SIIPL quadrivalent HPV vaccine group, 223 days (216-232) for girls in the comparator vaccine group, and 222 days (216-230) for women in the comparator vaccine group. GMT ratios were non-inferior in girls and boys receiving the SIIPL quadrivalent HPV vaccine compared with women receiving the comparator vaccine: GMT ratios for girls were 1·97 (98·75% CI 1·67-2·32) for HPV type 6, 1·63 (1·38-1·91) for HPV type 11, 1·90 (1·60-2·25) for HPV type 16, and 2·16 (1·79-2·61) for HPV type 18. For boys the GMT ratios were 1·86 (1·57-2·21) for HPV type 6, 1·46 (1·23-1·73) for HPV type 11, 1·62 (1·36-1·94) for HPV type 16, and 1·80 (1·48-2·18) for HPV type 18. The safety population comprised all 1107 participants (369 girls and 369 boys in the SIIPL quadrivalent HPV vaccine group, and 369 girls in the comparator group). Solicited adverse events occurred in 176 (48%) of 369 girls and 124 (34%) of 369 boys in the SIIPL vaccine group and 179 (49%) of 369 girls in the comparator vaccine group. No grade 3-4 solicited adverse events occurred within 7 days of each dose. Unsolicited adverse events occurred in 143 (39%) girls and 147 (40%) boys in the SIIPL vaccine group, and 143 (39%) girls in the comparator vaccine group. The most common grade 3 unsolicited adverse event was dengue fever, in one (<1%) girl in the SIIPL vaccine group and three (1%) girls in the comparator group. There were no grade 4 or 5 adverse events. Serious adverse events occurred in three (1%) girls and three (1%) boys in the SIIPL vaccine group, and five (1%) girls in the comparator vaccine group. No vaccine-related serious adverse events were reported. There were no treatment-related deaths. INTERPRETATION: We observed a non-inferior immune response with the SIIPL quadrivalent HPV vaccine in girls and boys aged 9-14 years and an acceptable safety profile compared with the comparator vaccine. These findings support extrapolation of efficacy from the comparator vaccine to the SIIPL quadrivalent HPV vaccine in the younger population. The availability of the SIIPL quadrivalent HPV vaccine could help meet the global demand for HPV vaccines, and boost coverage for both girls and boys globally. FUNDING: Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.
Asunto(s)
Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Humanos , Masculino , Femenino , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/epidemiología , India , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Cuello del Útero , Papillomavirus Humano 6 , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Método Doble Ciego , Anticuerpos AntiviralesRESUMEN
Treatment of anogenital warts (AGWs) is challenging. Candida antigen immunotherapy has been proven to be a safe and relatively effective therapeutic modality; nevertheless, some patients may experience a partial or no response. Combining Candida antigen with other immunotherapies has been proposed to improve the cure rate. Immunotherapy with human papillomavirus (HPV) vaccines has been tried with conflicting outcomes. This study aimed to assess the efficacy and safety of intralesional Candida antigen, either alone or in combination with intralesional bivalent or quadrivalent HPV vaccines, for treating multiple AGWs. Eighty patients with multiple AGWs were included and randomly assigned to four equal groups: group A treated with intralesional Candida antigen only; group B treated with intralesional bivalent HPV vaccine (Cervarix) and Candida; group C treated with intralesional quadrivalent HPV vaccine (Gardasil) and Candida; and group D (control) treated with intralesional saline. Complete clearance of lesions was detected in 40%, 20%, and 60% of patients in Candida monotherapy, Cervarix/Candida, and Gardasil/Candida groups, respectively, whereas 40%, 60%, and 20% of patients in the three groups, respectively, showed partial response. Only 10% of the control group had a partial response. Therapeutic outcomes were significantly better in the three treatment groups compared to the control group, with no statistically significant difference between the Candida monotherapy group and the combination groups, but the response was significantly better in the Gardasil/Candida group than in the Cervarix/Candida group. No statistically significant difference was found between the studied groups regarding the development of side effects. Moreover, no recurrence was detected in any of the groups throughout the 3-month follow-up period. Based on our results, combining intralesional HPV vaccines with Candida antigen immunotherapy may have no significant benefit for treating multiple AGWs. Candida antigen may be recommended as a relatively effective and inexpensive therapeutic modality. The combination of Gardasil and Candida was also effective but very expensive. The results of the Cervarix/Candida combination were unsatisfactory. This clinical trial was registered and approved prospectively by the ethical review board at Faculty of Medicine, Zagazig University.
Asunto(s)
Condiloma Acuminado , Vacunas contra Papillomavirus , Verrugas , Humanos , Candida , Condiloma Acuminado/terapia , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Virus del Papiloma Humano , Inmunoterapia/métodos , Inyecciones Intralesiones , Vacunas contra Papillomavirus/efectos adversosRESUMEN
BACKGROUND: Solid-organ transplant recipients are at increased risk of developing human papillomavirus-related diseases. METHODS: To evaluate the immunogenicity of a quadrivalent vaccine, a prospective observational study included females aged 12-19 years who had received kidney or liver transplants, or were otherwise healthy volunteers. With the three-dose vaccination, serum antibodies were measured. RESULTS: The study included 17 transplant recipients (seven kidney and 10 liver) and 16 healthy participants. Six of seven kidney transplant recipients were on three immunosuppressive medications, whereas 9 of the 10 liver transplant recipients were on one. For the serology within 6 months from the last vaccine dose, the geometric mean titers of human papillomavirus types 6, 11, 16, and 18 were 26.7, 8.6, 35.7, and 42.4 (kidney transplant); 579.2, 569.3, 3097.3, and 835.7 (liver transplant); and 860.5, 638.8, 4391.6, and 902.6 milli-Merck Units/ml (healthy). The seropositivity rates of kidney transplant recipients for the four serotypes ranged from 50% to 75%, while all liver transplant recipients and healthy participants had 100% seropositivity rates for all four types. While there were no statistical differences of titers between liver transplant recipients and healthy participants, the titers of kidney transplant recipients were lower than those of healthy participants for type 6 (p = .034), type 11 (p = .032), and type 16 (p = .032). CONCLUSIONS: The results support the recommendation of human papillomavirus vaccination in pediatric transplant recipients given the significant risk of human papillomavirus-related diseases in this population, though immunogenicity was lower in kidney transplant recipients on multiple immunosuppressive medications.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18 , Trasplante de Riñón , Trasplante de Hígado , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Niño , Femenino , Humanos , Anticuerpos Antivirales , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Virus del Papiloma Humano , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Receptores de Trasplantes , Huésped InmunocomprometidoRESUMEN
BACKGROUND: Human papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent). METHODS: 1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20-26, 27-35, or 36-45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference > -10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio > 0.5. RESULTS: Among the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded -10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios > 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths. CONCLUSIONS: This study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Infecciones por Papillomavirus/prevención & control , Gammapapillomavirus , Anticuerpos Antivirales , Neoplasias del Cuello Uterino/prevención & control , Papillomaviridae , China , Inmunogenicidad VacunalRESUMEN
Erythema multiforme (EM) is a mucocutaneous condition of uncertain etiology, although the hypersensitivity reaction to a wide variety of agents may be related to the onset of the lesions. In about half of the affected patients it is possible to identify a previous infection. This article aims to report a case of EM in the oralmucosa after qHPV vaccine (Gardasil®), to highlight the diagnostic process and the proposed treatment. Female patient, 16 years old, after 10 days of receiving the first dose of the qHPV vaccine. On physical examination, she presented multiple ulcers and hemorrhagic crusts to the touch, based on the clinical picture and the history of the disease, a diagnostic hypothesis was EM. Low-level laser therapy (LLLT) was chosen as an alternative treatment, since the exercises applied were not successful. The patient was followed up, reported decreased pain and burn and, after one year of treatment, there was no recurrence of the lesions. Laser treatment showed an effective treatment alternative, in addition to the low cost and ease of application.
El eritema multiforme (EM) es una afección mucocutánea de etiología incierta, aunque la reacción de hipersensibilidad a una amplia variedad de agentes puede estar relacionada con la aparición de las lesiones. En aproximadamente la mitad de los pacientes afectados es posible identificar una infección previa. Este artículo tiene como objetivo informar un caso de EM en la mucosa oral después de la vacuna qHPV (Gardasil®), para resaltar el proceso de diagnóstico y el tratamiento propuesto. Paciente de 16 años, después de 10 días de recibir la primera dosis de la vacuna qHPV. En el examen físico, presentó múltiples úlceras y costras hemorrágicas al tacto, según el cuadro clínico y la historia de la enfermedad, una hipótesis diagnóstica fue EM. La terapia con láser de baja potencia (TLBP) se eligió como un tratamiento alternativo, ya que los ejercicios aplicados no tuvieron éxito. La paciente fue seguida, informó disminución del dolor y las quemaduras y, después de un año de tratamiento, no hubo recurrencia de las lesiones. El tratamiento con láser mostró una alternativa de tratamiento efectivo, además del bajo costo y la facilidad de aplicación.
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Humanos , Femenino , Adolescente , Eritema Multiforme/diagnóstico , Eritema Multiforme/radioterapia , Úlceras Bucales/diagnóstico , Terapia por Luz de Baja Intensidad , Resultado del Tratamiento , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversosRESUMEN
BACKGROUND: Human papillomavirus (HPV)-associated cervical cancer is a leading cause of death among Indian women. Indian women living with HIV (WLWH) may be at especially high risk. The quadrivalent HPV (qHPV) vaccine is effective in prevention of initial infection with HPV-6/11/16/18 in HIV-negative women. Little is known about previous exposure to HPV-6/11/16/18, safety, and immunogenicity of qHPV in Indian WLWH. METHODOLOGY: One hundred fifty WLWH with different CD4 levels and HIV viral load (VL) were vaccinated at 0/2/6 months at CART-CRS-IDMC, Chennai, India. Serology was performed at weeks 0, 28, and 52 for HPV-6/11/16/18 using a competitive Luminex immunoassay and for HPV-16/18 using a pseudovirion-based neutralization assay. RESULTS: Mean age was 30.8 years (range, 19-44 years). 71/87/73/81% of women were naive (sero-negative and DNA-negative) to HPV-6/11/16/18 at baseline, respectively. Among per-protocol women naive to HPV-6/11/16/18 at baseline, 100/99/99/90%, respectively, seroconverted at week 28 and 95/96/98/71% were sero-positive at week 52, respectively. Pseudovirion-based neutralization assay identified more seroconversion to HPV-18 than competitive Luminex immunoassay. There were no significant differences in the proportion seroconverting by baseline or nadir CD4 or HIV VL; however, there was a trend for increased proportion seroconverting to HPV-18 among women with higher baseline CD4 level (P = 0.052). There were no qHPV-related serious adverse events and no change in CD4 level or HIV VL among women on ART. CONCLUSIONS: qHPV vaccine was safe and immunogenic in Indian WLWH. A high proportion were naive to HPV-6/11/16/18 and may benefit from vaccination although many were married and several years post-initiation of sexual activity.
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Anticuerpos Antivirales/sangre , Infecciones por VIH/tratamiento farmacológico , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Infecciones por Papillomavirus/prevención & control , Adulto , Femenino , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 18/inmunología , Humanos , India , Infecciones por Papillomavirus/virología , Proyectos Piloto , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Vacunación , Carga Viral/inmunología , Adulto JovenRESUMEN
AIM: The quadrivalent human papillomavirus (4vHPV) vaccine has demonstrated efficacy and immunogenicity and was generally well tolerated in clinical trials conducted in Japan. We report a detailed safety analysis of injection-site reactions in female Japanese 4vHPV clinical trial participants. METHODS: This post-hoc analysis included data from 2 double-blind, placebo-controlled phase II clinical trials of a 3-dose (Day 1, Month 2, Month 6) regimen of 4vHPV vaccine in Japanese young women aged 18-26 years (N = 1021; NCT00378560) and girls aged 9-17 years (N = 107; NCT00411749). Injection-site and systemic adverse events (AEs) were monitored using vaccination report cards for 15 days after each vaccine dose; serious AEs were reported throughout the trials. Post-hoc analyses of data from these trials were performed to examine details of injection-site AEs, including day of onset, time from onset to resolution, and maximum intensity. RESULTS: Injection-site AEs were reported by 85.6% of 4vHPV vaccine recipients and 72.4% of placebo recipients, most commonly erythema, pain, pruritus, and swelling (each >5% of 4vHPV vaccine recipients). The majority of injection-site AEs had an onset within 3 days of vaccination and were mild to moderate in intensity; few 4vHPV vaccine recipients reported severe injection-site AEs (2.0% overall). All injection-site AEs resolved, and most (4vHPV: 87.5%; placebo: 92.7%) resolved within 5 days of onset. CONCLUSIONS: Most injection-site reactions are mild or moderate in intensity and of short duration. The 3-dose regimen of 4vHPV vaccine is well tolerated in Japanese female clinical trial participants based on this post-hoc analysis. These results will further support safety communication between healthcare providers and vaccine recipients regarding the HPV vaccine. TRIAL REGISTRATION: Clinicaltrials. gov: NCT00378560 and NCT00411749.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Reacción en el Punto de Inyección/etiología , Inyecciones Intramusculares/efectos adversos , Infecciones por Papillomavirus/prevención & control , Vacunación/efectos adversos , Adolescente , Adulto , Alphapapillomavirus/inmunología , Método Doble Ciego , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Humanos , Japón , Adulto JovenRESUMEN
Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14â¯years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Infecciones por Papillomavirus/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Infecciones por Papillomavirus/virología , Vigilancia de Productos Comercializados , Sistema de Registros , Países Escandinavos y Nórdicos , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
In March 2014, the Quadrivalent human papilloma virus vaccine (4vHPV) was introduced in the female adolescents vaccination schedule of the National Immunization Program (PNI). A school-based vaccination program was implemented. We conducted a retrospective, descriptive study of the adverse events that took place after HPV vaccination, reported to the Adverse Events Following Immunization (AEFI) Information System in Sao Paulo State, from March 2014 to December 2016. All reports that fit the definitions of the 2014 National Manual on AEFI surveillance were included. AEFI risk was estimated by dividing the number of reports by the number of vaccine doses administered in the period. In the three-year period, 3,390,376 HPV vaccine doses were administered and 465 AEFI reports were registered, with 1,378 signs and symptoms. The reporting rate was 13.72 per 100,000 vaccine doses administered. The reports peaked in the first year of the program. The most frequent AEFI was syncope, with 5.7 reports per 100,000 doses administered, followed by dizziness, malaise, headache and nausea. Overall, 39 AEFI cases (8.4%) were classified as severe , with a reporting rate of 1.15 per 100,000 vaccine doses administered. Most cases were classified as severe because of hospitalization. Among them, there were cases of Guillain-Barré Syndrome, deep vein thrombosis, seizures and miscarriage. All young women recovered without sequelae. We identified five clusters of AEFI reports in four cities; the larger AEFI cluster occurred in the city of Bertioga, in September 2014, involving 13 female adolescents. Our data are in accordance with those from other countries and corroborate the safety of HPV vaccines.
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Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Adolescente , Adulto , Sistemas de Registro de Reacción Adversa a Medicamentos , Brasil/epidemiología , Niño , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Esquemas de Inmunización , Infecciones por Papillomavirus/prevención & control , Vigilancia de la Población , Estudios Retrospectivos , Adulto JovenRESUMEN
Human papillomavirus (HPV)-associated disease is common among men with HPV infection. A quadrivalent HPV (qHPV) vaccine has demonstrated 85.9% efficacy against HPV6/11/16/18-related, persistent (≥ 6 month) infection in a study of Japanese men aged 16-26 years old. Here, we report the results of an open-label study of the immunogenicity and tolerability of the qHPV vaccine (NCT02576054), conducted to bridge findings from Japanese men to Japanese boys aged 9-15 years old. A total of 100 boys completed a three-vaccination regimen (Day 1, and Months 2 and 6), and 99 boys were included in the primary analysis population. The rate of seroconversion at one month after vaccine Dose 3 (Month 7) was high for each type of HPV (anti-HPV6/11/16/18 seroconversion rates [95% CI]: 94.9% [85.5%, 98.3%], 99.0% [94.4%, 100.0%], 99.0% [94.5%, 100.0%], and 99.0% [94.4%, 100.0%], respectively). Moreover, anti-HPV6/11/16/18 geometric mean titers were 482.9 mMU/mL, 1052.8 mMU/mL, 3878.3 mMU/mL, and 1114.5 mMU/mL, respectively. Immune responses to the qHPV vaccine were non-inferior among Japanese boys included in the current study and compared with young Japanese men from a separate study. Injection-site reactions were the most common adverse events, and administration of the vaccine was well tolerated in Japanese boys.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Infecciones por Papillomavirus/prevención & control , Adolescente , Anticuerpos Antivirales/sangre , Pueblo Asiatico , Niño , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Masculino , SeroconversiónRESUMEN
BACKGROUND: The quadrivalent (q) human papillomavirus (HPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, and 18. We report efficacy, immunogenicity, and safety of qHPV vaccine in a Phase 3 study in Japanese men. METHODS: In this randomized, double-blind trial (NCT01862874), Japanese men (aged 16-26â¯years) were randomized in a 1:1 ratio to receive three doses of qHPV vaccine or placebo (Day 1, Month 2, Month 6). The primary efficacy endpoint was the combined incidence of HPV6/11/16/18-related persistent anogenital infection (detected at ≥2 consecutive visits ≥6â¯months apart), assessed in the per-protocol population of men who received all three vaccinations, and were seronegative at Day 1 and PCR negative from Day 1 to Month 7 to the relevant HPV type. Results are from the interim and final analyses. RESULTS: In total, 1124 participants were randomized. The vaccine demonstrated 83.3% (95% confidence interval: 24.9, 98.2; pâ¯=â¯0.007) and 85.9% (95% confidence interval: 52.7, 97.3; pâ¯<â¯0.001) efficacy against HPV6/11/16/18-related persistent infection in the interim and final analyses, respectively. Two cases of HPV6/11/16/18-related external genital lesions (condyloma and PIN 1) were observed in the placebo group and none in the qHPV vaccine group at study end. At Month 7, >97% of participants who received qHPV vaccine seroconverted to each of the vaccine HPV types. Most participants remained seropositive at Month 36, although the seropositivity rate declined between Months 7 and 36. Vaccination-related adverse events were reported in 60.8% and 56.5% of participants in the qHPV vaccine and placebo groups, respectively; most commonly mild to moderate injection-site pain, erythema, and swelling. Injection-site pain and swelling were more common with qHPV vaccine than placebo (each pâ¯<â¯0.05). CONCLUSIONS: Results suggest qHPV vaccine is efficacious against HPV6/11/16/18-related persistent infections, immunogenic, and well-tolerated in Japanese men. Clinical trial registration identifier: NCT01862874.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Inmunogenicidad Vacunal , Infecciones por Papillomavirus/prevención & control , Adolescente , Adulto , Homosexualidad Masculina , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Humanos , Japón/epidemiología , Masculino , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/transmisión , Evaluación del Resultado de la Atención al Paciente , Factores de Riesgo , Factores Sexuales , Vacunación/métodos , Adulto JovenRESUMEN
BACKGROUND: Few studies have studied the association between unintended human papillomavirus (HPV) vaccination and adverse pregnancy outcomes. This study set out to determine the association between HPV vaccination during pregnancy and subsequent risk of spontaneous abortion, stillbirth, and one-year infant mortality. METHODS: Population-based study including all pregnancies in Denmark (October 2006-December 2014) among women born 1975-1992. From nationwide health registries using the personal identification numbers, we obtained information on HPV vaccination, pregnancy outcomes, and infant mortality. The exposure window went from four weeks before conception date until 22â¯weeks of gestation for the outcome spontaneous abortion, and until birth for stillbirth and infant mortality outcomes. In the analyses of spontaneous abortion, we used time to event models, for stillbirth logistic regression models, and for infant mortality Cox regression was applied. RESULTS: We included 522,705 pregnancies for the outcome spontaneous abortion (7487 exposed to at least one dose during pregnancy); 351,878 births (5262 exposed to at least one dose during pregnancy) for the stillbirth; and 350,739 live births (5245 exposed to at least one dose during pregnancy) for infant mortality. No significantly increased rate of spontaneous abortion among women vaccinated during pregnancy compared with unvaccinated women was found. In addition, we found no association between HPV vaccination during pregnancy and stillbirth (adjusted odds ratioâ¯=â¯0.96 [95% CI: 0.57-1.61]), or infant mortality (adjusted hazard ratioâ¯=â¯0.94 [95% CI: 0.53-1.67]). A secondary analysis showed no association between number of doses and timing of administration (i.e. vaccination before or during pregnancy) and an increased risk of spontaneous abortion. CONCLUSION: We found no increased risk of spontaneous abortion, stillbirth, or infant mortality following unintended HPV vaccination during pregnancy.
Asunto(s)
Aborto Espontáneo/etiología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Mortalidad Infantil , Infecciones por Papillomavirus/prevención & control , Resultado del Embarazo/epidemiología , Vacunación/efectos adversos , Adulto , Dinamarca/epidemiología , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Oportunidad Relativa , Embarazo , Sistema de Registros , Mortinato/epidemiología , Adulto JovenAsunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/economía , Vacunas contra Papillomavirus/economía , Neoplasias del Cuello Uterino/economía , Neoplasias del Cuello Uterino/prevención & control , Análisis Costo-Beneficio , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/uso terapéutico , Humanos , Vacunas contra Papillomavirus/efectos adversos , Vacunas contra Papillomavirus/uso terapéutico , Tailandia , Neoplasias del Cuello Uterino/inmunologíaRESUMEN
INTRODUCTION: In sub-Saharan Africa, a generation of HIV-1-infected children is approaching the age of sexual debut and becoming at risk for HPV infection and its sequelae. We assessed safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in HIV-1-infected adolescents. METHODS: In an open-label trial among Kenyan, HIV-1-infected adolescents aged 9-14â¯years, we administered the qHPV vaccine at 0, 2 and 6â¯months and measured antibody titers to HPV-16, 18, 6 and 11 at month 7 and 12 post-vaccination. Measures of immunogenic response from HIV-1-negative historical cohorts from Africa and HIV-1 positive adolescent cohorts from the USA were used for comparison. RESULTS: We enrolled 100 girls and 80 boys with a median age of 12â¯years and median baseline CD4 cell count of 684 (IQR 478, 935) cells/µL. One hundred and fifty four (86%) were receiving antiretroviral therapy for a median of 4.5 (IQR 2.3, 6.3) years; 110 (71%) had <400 copies of plasma HIV-1 RNA/mL. Of 189 enrolled children, 179 received all three doses. Two hundred and eighty five (64%) of 445 adverse events were injection site reactions; none were greater than grade 2. Of 6 Serious Adverse Events (SAEs), none were considered vaccine related. Seroconversion to HPV-18, 16, 11, 6 at month 7 occurred in 93.3%, 98.3%, 97.2% and 99.6% of vaccine recipients; similar rates have been reported in historical controls. The mean log10 HPV antibody titer measured at month 7 increased with each log10 increase in CD4 by 1.4 (95% CI: 1.1-1.7) for HPV-18; 1.2 (0.9-1.4) for HPV-16; 1.1 (0.8-1.3) for HPV-11; 0.7 (0.5-1.0) for HPV-6 (all pâ¯<â¯0.0001). CONCLUSION: Almost all Kenyan HIV-1-infected adolescents mounted an immune response comparable to other immunized populations. HPV antibody titers were higher in those with preserved CD4 cell counts. Longer term-follow up will determine sustainability of the immune response. ClinicalTrials.gov number, NCT00557245.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Infecciones por VIH/complicaciones , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Inmunogenicidad Vacunal , Infecciones por Papillomavirus/prevención & control , Adolescente , Anticuerpos Antivirales/sangre , Niño , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Esquemas de Inmunización , Kenia , Masculino , Estados UnidosRESUMEN
OBJECTIVE: To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. METHODS: Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. RESULTS: We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). CONCLUSION: Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.
Asunto(s)
Aborto Espontáneo/epidemiología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Exposición Materna/efectos adversos , Infecciones por Papillomavirus/prevención & control , Vacunación/efectos adversos , Aborto Espontáneo/inducido químicamente , Adolescente , Adulto , Niño , Bases de Datos Factuales , Femenino , Humanos , Papillomaviridae , Embarazo , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Mortinato/epidemiología , Factores de Tiempo , Adulto JovenAsunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacunas contra Papillomavirus/efectos adversos , Seudolinfoma/inducido químicamente , Enfermedades de la Piel/inducido químicamente , Adulto , Betametasona/análogos & derivados , Betametasona/uso terapéutico , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Inyecciones Intralesiones , Inyecciones Intramusculares , Imagen por Resonancia Magnética , Seudolinfoma/diagnóstico , Seudolinfoma/tratamiento farmacológico , Enfermedades Raras , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/tratamiento farmacológicoRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This paper is being retracted at the request of the authors. The authors report that there was an incorrect interpretation of the odds ratio meaning that instead of HPV vaccination potentially being protective, there may be an associated increased risk of preterm delivery. The authors believe that an increased risk of preterm delivery is unlikely and not consistent with the evidence to date. Further, the authors have not been able to access the original source data as per protocol to check the data validity. The authors wish to repeat the study to reassure themselves that there were no data processing or other errors in the databases in order to reach definitive conclusions. Lastly, it is of serious concern to the Editor-in-Chief that the Conflict of Interest statement was only added to the paper by the authors after acceptance and was not made visible to the editor or reviewers prior to acceptance. The authors state that there was no input to the methodology, implementation and results of this study by any commercial entity. The pharma distribution company CSL mentioned in the conflict of interest statement only knew about the study after publication.
Asunto(s)
Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vigilancia de la Población , Nacimiento Prematuro/etiología , Vacunación/efectos adversos , Estudios de Cohortes , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/administración & dosificación , Humanos , Recién Nacido , Edad Materna , Nueva Zelanda/epidemiología , Oportunidad Relativa , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Embarazo , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Mortinato/epidemiología , Neoplasias del Cuello Uterino/prevención & control , Adulto JovenRESUMEN
We evaluated quadrivalent human papillomavirus vaccine seroresponses among 35 girls living with HIV (9-13 years of ages) and compared with data on girls without HIV, as part of a subgroup analysis. The quadrivalent human papillomavirus vaccine was safe and well tolerated. However, antibody response was significantly lower in girls living with HIV relative to girls without HIV. HIV virologic suppression predicted better antibody response.
Asunto(s)
Infecciones por VIH/virología , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/inmunología , Inmunogenicidad Vacunal , Infecciones por Papillomavirus/prevención & control , Adolescente , Anticuerpos Antivirales/sangre , Recuento de Linfocito CD4 , Canadá , Niño , Femenino , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/efectos adversos , Vacuna Tetravalente Recombinante contra el Virus del Papiloma Humano Tipos 6, 11 , 16, 18/uso terapéutico , Humanos , Estudios Longitudinales , Estudios ProspectivosRESUMEN
It is well-established that immunocompromised people are at increased risk of HPV-related disease compared with those who are immunocompetent. Prophylactic HPV sub-unit vaccines are safe and immunogenic in immunocompromised people and it is strongly recommended that vaccination occur according to national guidelines. When delivered to immunocompromised populations, HPV vaccines should be given as a 3-dose regimen.