RESUMO
BACKGROUND: Hepatitis B virus (HBV) infection remains a significant global burden, especially for patients with chronic kidney disease (CKD) receiving hemodialysis. Three doses of HepB-CpG (HEPLISAV-B® vaccine) induced a superior immune response compared with 4 double doses of HepB-Eng (Engerix-B®) in a phase 3 trial (HBV-17) in adults with CKD. Here we report the long-term immunogenicity and safety of HepB-CpG and HepB-Eng in eligible participants of HBV-17 who enrolled in this optional 34-month follow-up trial (HBV-19). METHODS: HBV-19 is a multicenter, open-label, phase 3b trial of adults with CKD who previously received a complete series of HepB-CpG or HepB-Eng in the HBV-17 trial. Participants were assigned to seroprotection categories at enrollment on the basis of their antibody response to hepatitis B surface antigen (anti-HBs) in HBV-17. The objective was to evaluate the durability of seroprotection (defined as an anti-HBs concentration ≥ 10mIU/mL) induced by HepB-CpG and HepB-Eng. Participants whose anti-HBs concentration was below 10mIU/mL received additional HepB-CpG or HepB-Eng doses. RESULTS: 147 participants were enrolled; 66.7 % were men, median age was 65.0 years, and 83.7 % were white. The durability of seroprotection in participants with CKD was similar in those who received HepB-CpG and those who received HepB-Eng. Antibody concentrations ≥ 100mIU/mL persisted for longer in HepB-CpG than HepB-Eng recipients, among those with anti-HBs ≥ 100mIU/mL post vaccination. The geometric mean anti-HBs concentration in the HepB-CpG group was significantly higher than in the HepB-Eng group over time (P ≤ 0.0001). The safety profiles were similar between the vaccine groups. CONCLUSIONS: Due to the higher antibody levels induced by HepB-CpG in participants with CKD, seroprotection against HBV may be expected to persist longer than that induced by HepB-Eng. CLINICALTRIALS: gov: NCT01282762.
Assuntos
Hepatite B , Insuficiência Renal Crônica , Masculino , Humanos , Adulto , Idoso , Feminino , Vacinas contra Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Hepatite B/prevenção & controle , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Anticorpos Anti-Hepatite B , EndoglinaRESUMO
BACKGROUND: Data from previous studies of the MVC-COV1901 vaccine, a subunit vaccine against SARS-CoV-2 based on the stable prefusion spike protein (S-2P) adjuvanted with CpG 1018 adjuvant and aluminum hydroxide, suggest that the vaccine is generally safe and elicits a good immune response in healthy adults and adolescents. By comparing with AZD1222, this study adds to the findings from previous trials and further evaluates the breadth of protection offered by MVC-COV1901. METHODS: In this phase 3, parallel group, randomized, double-blind, active-controlled trial conducted in 2 sites in Paraguay, we assigned adults aged 18-91 years in a 1:1 ratio to receive intramuscular doses of MVC-COV1901 or AZD1222 administered as scheduled in the clinical trial. Serum samples were collected on the day of vaccination and 14 days after the second dose. Primary and secondary safety and immunogenicity endpoints were assessed. In addition, other outcomes investigated were cross-reactive immunity against the Omicron strain and the induction of IgG subclasses. RESULTS: A total of 1,030 participants underwent randomization. Safety data was derived from this set while primary immunogenicity data involved a per-protocol immunogenicity (PPI) subset including 225 participants. Among the participants, 58% are seropositive at baseline. When compared against AZD1222, MVC-COV1901 exhibited superiority in terms of neutralizing antibody titers and non-inferiority in terms of seroconversion rates. Reactogenicity was generally mild and no serious adverse event was attributable to MVC-COV1901. Both vaccines have a Th1-biased response predominated by the production of IgG1 and IgG3 subclasses. Omicron-neutralizing titers were 44.5 times lower compared to wildtype-neutralizing titers among seronegative individuals at baseline. This fold-reduction was 3.0 times among the seropositive. CONCLUSION: Safety and immunogenicity data of MVC-COV1901 from the study in Paraguay confirm previous results. The previous infection coupled with vaccination of this vaccine may offer protection against the Omicron strain though its durability is still unknown.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Adolescente , Humanos , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , ChAdOx1 nCoV-19 , COVID-19/prevenção & controle , Paraguai , Método Duplo-Cego , Imunoglobulina G , Adjuvantes Imunológicos , Vacinas de Subunidades Antigênicas , Imunogenicidade da Vacina , Anticorpos Antivirais , Anticorpos NeutralizantesRESUMO
This study compared the immunogenicity and safety of a booster dose of HepB-CpG (HEPLISAV-B® vaccine) with HepB-Eng (Engerix-B®) and HepB-AS04 (Fendrix®) in patients receiving chronic hemodialysis. This was a multicenter, randomized, open-label, phase 3 study of adults receiving hemodialysis with antibodies to HBsAg (anti-HBs) <10 mIU/mL at study entry. The objective was to compare the seroprotection rate (SPR) induced by HepB-CpG with HepB-Eng or HepB-AS04. The SPR was defined as the percentage of patients with anti-HBs ≥10 mIU/mL post-vaccination. At 20 sites in Germany, 155 participants were randomized: HepB-CpG = 54; HepB-Eng = 50; and HepB-AS04 = 51. Of the 149 participants in the modified intention-to-treat population, 76.5% had not previously responded to at least one series of hepatitis B vaccine. Based on a post hoc analysis, the SPR in HepB-CpG recipients (52.8%; 95% confidence interval [CI]: 38.6%, 66.7%) was significantly higher than in HepB-Eng recipients (32.6%; 95% CI: 19.5%, 48.0%), and non-inferior to that in HepB-AS04 recipients (43.1%; 95% CI: 29.3%, 57.8%). Local post-injection reactions occurred in significantly fewer HepB-CpG (9.3%) than HepB-AS04 recipients (31.4%; p = .007) and at a similar rate to HepB-Eng recipients (8.2%). Systemic post-injection reactions in HepB-CpG recipients (18.5%) were similar to the HepB-AS04 group (19.6%) and higher than in the HepB-Eng group (12.2%). In this difficult-to-immunize population, a booster dose of HepB-CpG induced significantly higher levels of seroprotection than HepB-Eng with a similar safety profile. The higher levels of immunogenicity were not accompanied by higher levels of local post-injection reactions compared with HepB-AS04.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Humanos , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Anticorpos Anti-Hepatite B , Vacinação/efeitos adversos , Vacinação/métodos , EndoglinaRESUMO
INTRODUCTION: Older adults are subject to higher COVID-19 infection and mortality rates. Safety and immunogenicity of MVC-COV1901, a protein subunit vaccine have been demonstrated in phase 2 clinical trial for the general population, and negative correlations have been observed between immune responses and age, however, older adults were under-represented. METHODS: A double-blind, randomized, multi-center study compared safety and immunogenicity of high-dose (25 mcg) to mid-dose (15 mcg) of MVC-COV1901 administered 2 times 28 days apart in 420 participants of 65 years and older. The results have been stratified by the comorbidity status. RESULTS: Both high and mid-dose regimens elicited mostly mild adverse events and robust immune responses when measured as neutralizing and binding antibodies titers. High doses elicited better immune responses in the group without comorbidities. CONCLUSION: Given the general population-associated safety and immunogenicity of MVC-COV1901, we recommend high dose for immunization of elder adults with MVC-COV1901. The clinical trial was registered at https://clinicaltrials.gov/ (NCT04822025).
Assuntos
Vacinas contra COVID-19 , COVID-19 , Idoso , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Método Duplo-Cego , Vacinas contra COVID-19/efeitos adversosRESUMO
BACKGROUND: At least one-half of adults beginning an immunization series with a three-dose hepatitis B virus (HBV) vaccine (ENGERIX-B, RECOMBIVAX-B) have been reported not to receive the third dose. Use of a two-dose vaccine may improve adherence and lead to greater overall levels of seroprotection. OBJECTIVE: To examine expected levels of adherence and overall seroprotection at one year among adults in routine clinical settings beginning an immunization series with either ENGERIX-B or the two-dose HBV vaccine, HEPLISAV-B. METHODS: Decision-analytic model comparing expected levels of adherence and overall seroprotection at one year among a hypothetical cohort of one million previously unvaccinated adults aged ≥ 30 years receiving first doses of either ENGERIX-B or HEPLISAV-B in a routine clinical setting. We stratified the population by age (30-49 years vs ≥ 50 years) to allow for possible differences in adherence and seroprotection. We estimated our model using published adherence rates for HBV vaccines, and reported seroprotection rates by number of doses administered. We also compared total expected costs of HBV immunization with each vaccine. RESULTS: Use of a two-dose rather than three-dose HBV vaccine would increase the expected number of adults seroprotected at one year by 275,000 per one million persons beginning immunization series, largely reflecting a gain of 290,000 in the expected number of persons fully vaccinated. Results were similar for the two age groups. While the cost per dose of HEPLISAV-B exceeds that of ENGERIX-B, its estimated mean cost per person seroprotected at one year is $50-$70 (â¼15%) lower. CONCLUSIONS: Use of a two-dose HBV vaccine would increase the number of adults fully seroprotected at one year compared with the number expected with a three-dose vaccine. Notwithstanding its higher unit cost, mean expected cost per person seroprotected is substantially lower for HEPLISAV-B than ENGERIX-B as a result of much higher levels of seroprotection.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Estudos de Coortes , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Humanos , Imunização , Esquemas de ImunizaçãoRESUMO
Rapid development and deployment of vaccines is crucial to control the continuously evolving COVID-19 pandemic. The placebo-controlled phase 3 efficacy trial is still the standard for authorizing vaccines in the majority of the world. However, due to a lack of eligible participants in parts of the world, this has not always been feasible. Recently, the Taiwan Food and Drug Administration, following the consensus of the International Coalition of Medicines Regulatory Authorities (ICMRA), adopted the use of immunobridging studies as acceptable for authorizing COVID-19 vaccines in lieu of efficacy data. Here, we describe a study in which our candidate vaccine, MVC-COV1901, an adjuvanted protein subunit vaccine, has been granted emergency use authorization (EUA) in Taiwan based on a noninferiority immunobridging study. Immunogenicity results from the per protocol immunogenicity (PPI) subset (n = 903) from the MVC-COV1901 phase 2 trial were compared with results from 200 subjects who had received an adenovirus vector vaccine, AstraZeneca ChAdOx nCOV-19 (AZD1222), in a separate study. The lower bound of the 95% confidence interval (CI) of the geometric mean titer (GMT) ratio comparing MVC-COV1901 to AZD1222 was 3.4. The lower bound of the 95% CI of the sero-response rate was 95.5%. Both the GMT ratio and sero-response rate exceeded the criteria established by the Taiwan regulatory authority, leading to EUA approval of MVC-COV1901 in Taiwan.
RESUMO
BACKGROUND: There are currently no published data on the use of HepB-CpG (HEPLISAV-B®) during pregnancy or in women with documented pregnancies in the post-vaccination period. We aimed to evaluate data from the clinical development program of HepB-CpG in women who became pregnant during study participation and follow up. METHODS: We identified all study participants in the HepB-CpG pivotal pre-licensure clinical trials that had documented pregnancies during study follow up. We measured immunogenicity among study participants in the HepB-CpG (Heplisav-B®) arm compared to the HepB-alum (Engerix-B®) arm of the studies by comparing seroprotection rates (SPRs; anti-HBs ≥ 10 mIU/mL) and geometric mean concentrations (GMCs) of anti-HBs, obtained with FDA approved anti-HBsAg antibody assays at prespecified time points up to 28 weeks of follow up. Pregnancy outcomes were ascertained by chart review of extracted medical records of study participants. RESULTS: We identified 40 documented pregnancies in the HepB-CpG arm and 19 documented pregnancies in the HepB-alum arm. Among subjects with documentation of seroprotection rates, 97.2% (95% CI 85.5-99.9) were seroprotected in the HepB-CpG arm and 66.7% (95% CI 41.0-86.7) were seroprotected in the HepB-alum arm. In the HepB-CpG arm, thirty-six study participants from the pivotal trials had reported pregnancy outcomes, the majority, 21/36 (58%) had a healthy term delivery, with 3/36 (8%) with spontaneous abortions, 1/36 (3%) congenital anomaly, and 2/36 (6%) had preterm birth. In the HepB-alum arm, 10/17 (59%) had healthy term deliveries, with 2/17 (12%) had spontaneous abortions and 1/17 (6%) had congenital anomaly. CONCLUSIONS: These limited data suggest that HepB-CpG is immunogenic in women who become pregnant after vaccination, and pregnancy outcomes appear to be similar to women who received HepB-alum prior to pregnancy. These results need to be further verified with larger prospective studies with HBV vaccine administration during pregnancy.
Assuntos
Aborto Espontâneo , Nascimento Prematuro , Feminino , Antígenos de Superfície da Hepatite B , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Vacinação/efeitos adversosRESUMO
PURPOSE: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks. RESULTS: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1-11.1] months. The response rate was higher in human papillomavirus-positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1-31.7) and 64.7% (95% CI: 45.3-78.7), respectively. CONCLUSIONS: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity.
Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológicoRESUMO
BACKGROUND: In the absence of field efficacy studies, estimating the real-world effectiveness of vaccines may consider immunogenicity from randomized controlled clinical trials and real-world adherence. Combining seroprotection rates (SPRs) with regimen completion rates gives an estimate of an effective vaccine protection rate (eVPR), which can be leveraged to evaluate real-world cost-effectiveness by linking it with vaccine costs to estimate the cost-per-protected patient (CPP). METHODS: This study evaluated eVPR and CPP as estimates of vaccine clinical- and cost-effectiveness of two-dose (HepB-CpG) and three-dose (HepB-Alum) hepatitis B virus (HBV) vaccines in the general adult population and a subpopulation with diabetes mellitus. eVPR was calculated from head-to-head SPR data from phase 3 clinical trials directly comparing HepB-CpG and HepB-Alum vaccine regimens and real-world head-to-head adherence data. CPP was calculated as the average cost of each regimen divided by eVPR. RESULTS: Higher eVPR in the adult population was achieved with HepB-CpG (68.0%) versus HepB-Alum (41.6%), reflecting the combination of higher SPR and vaccine regimen completion. The CPP for HepB-CpG ($331.31) was $45.67 (95% CI: $36.66, $55.19) less than HepB-Alum ($377.09). Greater savings were observed among persons with diabetes, with CPP $149.60 (95% CI: $80.29, $195.63) lower with HepB-CpG ($367.57) than HepB-Alum ($517.37). CONCLUSIONS: Metrics estimating vaccine real-world effectiveness and value may guide informed decisions in vaccine selection. For example, using eVPR and CPP, HepB-CpG represents a more effective, value-advantaged approach than HepB-Alum toward reducing HBV infection.
Assuntos
Vírus da Hepatite B , Hepatite B , Adulto , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B , Humanos , VacinaçãoRESUMO
BACKGROUND: This was a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a SARS-CoV-2 S-2P protein vaccine adjuvanted with aluminum hydroxide and CpG 1018. METHODS: Between September 28 and November 13 2020, 77 participants were screened. Of these, 45 healthy adults from 20 to 49 years of age were to be administered two doses of MVC-COV1901 in doses of 5 µg, 15 µg, or 25 µg of spike protein at 28 days apart. There were 15 participants in each dose group; all were followed for 28 days after the second dose at the time of the interim analysis. Adverse events and laboratory data were recorded for the safety evaluation. Blood samples were collected for humoral, and cellular immune response at various time points. Trial Registration: ClinicalTrials.gov NCT04487210. FINDINGS: Solicited adverse events were mostly mild and similar. No subject experienced fever. After the second dose, the geometric mean titers (GMTs) for SARS-CoV-2 spike-specific immunoglobulin G were 7178.2, 7746.1, 11,220.6 in the 5 µg, 15 µg, and 25 µg dose groups, respectively. The neutralizing activity were detected in both methods. (Day 43 GMTs, 538.5, 993.1, and 1905.8 for pseudovirus; and 33.3, 76.3, and 167.4 for wild-type virus). The cellular immune response induced by MVC-COV1901 demonstrated substantially higher numbers of IFN-γ- producing cells, suggesting a Th1-skewed immune response. INTERPRETATION: The MVC-COV1901 vaccine was well tolerated and elicited robust immune responses and is suitable for further development. FUNDING: Medigen Vaccine Biologics Corporation.
RESUMO
PURPOSE: Although PD-(L)1 inhibitors have shown efficacy in advanced/metastatic non-small cell lung cancer (NSCLC), many patients do not respond to this treatment and more effective combinations with acceptable toxicities are needed. To assess the potential benefit of combining localized innate immune stimulation with checkpoint blockade, the TLR9 agonist DV281 was combined with nivolumab in a phase Ib study. PATIENTS AND METHODS: Patients after one or two prior lines of systemic therapy were enrolled in a dose-escalation study with a 3+3 design. DV281 was administered via inhalation in five dose cohorts at 1 to 25 mg; nivolumab 240 mg was administered intravenously every 2 weeks. Safety, tolerability, pharmacodynamics, and response to treatment were assessed. RESULTS: Twenty-six patients with advanced NSCLC enrolled. Baseline programmed death ligand 1 (PD-L1) expression was present in 16 patients (61.5%); 21 (80.7%) had received previous anti-PD-1/PD-L1. Thirteen patients (50%) had stable disease, nine (34.6%) had progressive disease, and four (15.4%) were not evaluable. Median duration of disease control was 124 days. Adverse events were seen in 16 patients (61.5%), mostly grade 1/2 chills, fatigue, flu-like symptoms, diarrhea, and rash; there was only one grade 3 adverse event (dyspnea). Pharmacodynamic assessment, measured by IFN- inducible gene expression, showed target engagement in all dose cohorts. Systemic pharmacodynamic responses plateaued in the 2 highest dose cohorts. CONCLUSIONS: DV281 with nivolumab was well tolerated with target engagement observed at every dose. Pharmacodynamic advantages at doses above 10 mg were unclear. The long duration of disease control in 50% of patients suggests clinically relevant activity in this population of heavily pretreated patients.
Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Nivolumabe , Receptor Toll-Like 9 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Administração por Inalação , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Combinação de Medicamentos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Receptor Toll-Like 9/agonistasRESUMO
BACKGROUND: Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and are poorly responsive to HBV vaccines. Current vaccine recommendations for hemodialysis patients utilize more than twice the amount of hepatitis B surface antigen (HBsAg) used for healthy adults and achieve lower immune responses. METHODS: An open-label, single-arm, multicenter trial was conducted among adults 18 years of age and older who were initiating or undergoing hemodialysis who had not previously received hepatitis B vaccine. Participants received four doses of HepB-CpG (HEPLISAV-B®) (20 mcg rHBsAg + 3000 mcg CpG 1018, a Toll-like receptor 9 agonist) administered at 0, 4, 8, and 16 weeks. Participants are being followed for 68 weeks. This paper reports the final immunogenicity analysis of the primary endpoint at study week 20 and an interim safety analysis. RESULTS: We enrolled 119 participants receiving hemodialysis who were followed for a median of 47.4 weeks. Of the 119 participants, 75 were in the per-protocol population. At week 20, the seroprotection rate (% with antibodies to hepatitis B surface antigen [anti-HBs] ≥ 10 mIU/mL) was 89.3% and the percentage of participants with anti-HBs ≥ 100 mIU/mL was 81.3%. The anti-HBs geometric mean concentration was 1061.8 mIU/mL. HepB-CpG was well tolerated with no observed safety concerns. CONCLUSION: In patients receiving hemodialysis, HepB-CpG given as four doses was well tolerated and induced very high anti-HBs concentrations and seroprotection in a very high proportion of recipients.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adolescente , Adulto , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B/efeitos adversos , Humanos , Diálise Renal/efeitos adversosRESUMO
The hepatitis B virus is highly infectious and can cause incurable liver disease, leading to high morbidity rates, increased healthcare utilization, and high mortality. Multiple preventative hepatitis B vaccine options have been available for decades, but adherence to the traditional 6-month vaccine schedule for the approved 3-dose series remains low in adult populations at risk of hepatitis B exposure. A 2-dose hepatitis B vaccine (HEPLISAV-B) approved by the US Food and Drug Administration in 2017 induces rapid seroprotection within 1 month and has a safety profile comparable to a commonly used 3-dose vaccine. In a previous cost-effectiveness study, HEPLISAV-B had a favorable cost-effectiveness profile for multiple at-risk populations. The goal of the current analysis was to update and extend previous findings by evaluating cost-effectiveness of HEPLISAV-B compared with a 3-dose vaccine (Engerix-B) in selected adult populations, including patients with diabetes, chronic liver or kidney disease, end-stage renal disease, healthcare personnel, travelers to countries with endemic hepatitis B, and a public health population. Cost-effectiveness was measured as incremental cost-effectiveness ratios using a health economics Markov model that accounts for adherence rates, seroprotection rates, healthcare costs, and current pricing considerations. Patients progressed between a series of health states, and the difference in lifetime spending and survival for individuals receiving either HEPLISAV-B or Engerix-B was estimated from the perspective of a US managed care payer, HEPLISAV-B had favorable cost-effectiveness profiles for patients with diabetes, healthcare personnel, travelers, and patients with chronic liver disease and dominant incremental cost-effectiveness ratios for patients with chronic kidney disease and end-stage renal disease. A probabilistic sensitivity analysis supported the robustness of the cost-effectiveness profiles, and an additional analysis indicated that HEPLISAV-B was cost-effective in the general adult population. Overall, HEPLISAV-B was cost-effective in multiple adult populations recommended for HBV vaccination in the United States.
Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Análise Custo-Benefício , Hepatite B/prevenção & controle , Vírus da Hepatite B , Humanos , Esquemas de Imunização , Estados Unidos , VacinaçãoRESUMO
Importance: Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low. Objective: To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum]). Design, Setting, and Participants: This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020. Exposures: Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine). Main Outcomes and Measures: Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome). Results: Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata. Conclusions and Relevance: In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.
Assuntos
Vacinas contra Hepatite B/administração & dosagem , Hepatite B/prevenção & controle , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Vacinação/tendências , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Hepatite B/imunologia , Humanos , Programas de Imunização/estatística & dados numéricos , Esquemas de Imunização , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Risco , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricosRESUMO
BACKGROUND: Hepatitis B virus (HBV) remains a major public health issue, although it is a vaccine-preventable disease. Adults with diabetes are at greater risk of contracting HBV than the general population. Commonly used 3-dose HBV vaccines have reduced immunogenicity in older individuals and in those with diabetes mellitus. METHODS: In this post hoc analysis of a phase 3 clinical trial, participants with type 2 diabetes mellitus aged 60-70â¯years received either 2-dose HBsAg/CpG 1018 (HEPLISAV-B®, nâ¯=â¯327) at 0 and 4â¯weeks and placebo at 24â¯weeks or 3-dose HBsAg/alum (Engerix-B®, nâ¯=â¯153) at 0, 4, and 24â¯weeks. Immunogenicity, including seroprotection rate (SPR) at week 28, and safety were assessed by subgroup (sex, body mass index, and smoking status). SPR was defined as antibody against hepatitis B surface antigen serum concentration ≥10â¯mIU/mL. RESULTS: The SPR at week 28 was significantly higher with HBsAg/CpG 1018 (85.8% [235/274]) than with HBsAg/alum (58.5% [76/130]) in the per-protocol analysis, for an overall difference of 27.3% (95% CI, 18.0-36.8). SPRs with HBsAg/CpG 1018 were consistently markedly higher compared with HBsAg/alum, regardless of sex, body mass index, or smoking status. Adverse events and deaths were comparable between groups. CONCLUSIONS: Two-dose HBsAg/CpG 1018 provides a higher level of seroprotection against HBV than does a 3-dose vaccine (HBsAg/alum) with a similar safety profile in patients aged 60-70â¯years with type 2 diabetes mellitus. Study identifier: NCT02117934.
Assuntos
Diabetes Mellitus Tipo 2/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/imunologia , Hepatite B/imunologia , Imunogenicidade da Vacina/imunologia , Oligodesoxirribonucleotídeos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Idoso , Feminino , Anticorpos Anti-Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258-69. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.
Assuntos
Imunoterapia/métodos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/radioterapia , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinação , Adulto JovemRESUMO
PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250-7. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Hepatitis B virus infection remains an important global public health problem. Approved alum-adjuvanted vaccines are well tolerated but require three doses and have reduced immunogenicity in adults. A two-dose vaccine containing hepatitis B surface antigen combined with a novel, Toll-like receptor 9 agonist adjuvant (HBsAg-1018 [HEPLISAV-B®]) has demonstrated significantly higher seroprotection rates than a three dose vaccine. METHODS: A post hoc analysis compared the safety of HBsAg-1018 with HBsAg-Eng (Engerix-B®), in three randomized, observer-blinded, active-controlled, multi-center phase 3 trials in adults. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. RESULTS: Post-injection reactions, adverse events, medically attended adverse events, and new-onset immune-mediated adverse events were balanced between vaccine groups. Anti-nuclear antibodies, anti-double stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and antiphospholipid antibodies were balanced between groups. A transient increase in anti-beta2 glycoprotein 1 IgM was observed in the HBsAg-1018 group but was not associated with a thrombotic event. Serious adverse events and deaths were generally balanced between groups. CONCLUSION: HBsAg-1018 had a similar safety profile to HBsAg-Eng. With improved immunogenicity and fewer doses over a shorter time, HBsAg-1018 has the potential to provide improved seroprotection and a significant public health benefit to adults 18â¯years of age or older.
Assuntos
Adjuvantes Imunológicos/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Receptor Toll-Like 9/agonistas , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Idoso , Feminino , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Hepatitis B virus infection remains an important public health problem in the United States. Currently approved alum-adjuvanted vaccines require three doses and have reduced immunogenicity in adults, particularly in those who have diabetes mellitus, or are older, male, obese, or who smoke. METHODS: Phase 3 observer-blinded, randomized (2:1 HBsAg-1018 [HEPLISAV-B™]:HBsAg-Eng [Engerix-B®]), active-controlled trial in adults 18-70â¯years of age. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. The primary immunogenicity endpoint assessed the noninferiority of the seroprotection rate at week 28 in participants with type 2 diabetes mellitus. Secondary endpoints included seroprotection rates in the total trial population and by age, sex, body mass index, and smoking status. RESULTS: Among 8374 participants randomized, 961 participants in the per-protocol population had type 2 diabetes mellitus. In diabetes participants, the seroprotection rate in the HBsAg-1018 group at week 28 was 90.0%, compared with 65.1% in the HBsAg-Eng group, with a difference of 24.9% (95% CI: 19.3%, 30.7%), which met the prospectively-defined criteria for noninferiority and statistical significance. In the total study per-protocol population (Nâ¯=â¯6826) and each pre-specified subpopulation, the seroprotection rate in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group. CONCLUSION: Two doses of HBsAg-1018, administered over 4â¯weeks, induced significantly higher seroprotection rates than three doses of HBsAg-Eng, given over 24â¯weeks, in adults with factors known to reduce the immune response to hepatitis B vaccines as well as in those without those factors. With fewer doses in a shorter time, and greater immunogenicity, HBsAg-1018 has the potential to significantly improve protection against hepatitis B in adults at risk for hepatitis B infection. Trial Registration clinicaltrials.gov Identifier: NCT02117934.
Assuntos
Antígenos de Superfície da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Imunogenicidade da Vacina , Receptor Toll-Like 9/agonistas , Adolescente , Adulto , Idoso , Diabetes Mellitus Tipo 2/imunologia , Feminino , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite B/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Immunologic response to a complete vaccine regimen of currently licensed alum-adjuvanted hepatitis B vaccines is reduced in several subpopulations, including older adults, men, obese persons, and smokers. Two phase 3 trials in healthy adults demonstrated that 2 doses over 1 month of an investigational hepatitis B vaccine (HBsAg-1018) induced superior seroprotection rates (SPRs) to 3 doses over 6 months of the licensed vaccine Engerix-B (HBsAg-Eng). METHODS: An exploratory analysis of immunogenicity was conducted in subpopulations from pooled data for the 2 phase 3 trials. RESULTS: In each subpopulation, the peak SPR in the HBsAg-1018 group was statistically significantly higher than the peak SPR in the HBsAg-Eng group. Peak HBsAg-1018 SPRs ranged from 91.6% to 99.7%, while peak HBsAg-Eng SPRs ranged from 67.7% to 92.9%. CONCLUSION: In these exploratory analyses, 2 doses of HBsAg-1018 induced statistically significantly higher rates of seroprotection than 3 doses of HBsAg-Eng across all subpopulations.