Immunogenicity Outcomes Research Articles

Comparison of immunogenicity and safety outcomes of a malaria vaccine FMP013/ALFQ in rhesus macaques (Macaca mulatta) of Indian and Chinese origin

BackgroundIndian-origin rhesus (InR) are preferred for research, but strict export restrictions continue to limit their use. Chinese-origin rhesus (ChR), although easier to procure, are genetically distinct from InR and differ in their immune response to infectious agents, such as the Simian Immunodeficiency Virus. The most advanced malaria vaccine, RTS,S (GlaxoSmithKline), is based on the circumsporozoite protein (CSP) of Plasmodium falciparum. The efficacy of RTS,S vaccine in the field remains low and short-lived; efforts are underway to improve CSP-based vaccines. Rhesus models can accelerate preclinical down-selection of the next generation of malaria vaccines. This study was used to determine if the safety and immunogenicity outcomes following vaccination with a CSP vaccine would differ in the InR and ChR models, given the genetic differences between the two sub-populations of rhesus.MethodsThe FMP013 vaccine, was composed of nearly full-length soluble P. falciparum CSP produced in Escherichia coli and was adjuvanted with the Army liposomal formulation (ALFQ). Three doses of the vaccine were administered in InR and ChR (n = 6) at 1-month intervals and the antibody and T cell responses were assessed.ResultsLocal and systemic toxicity profile of FMP013 vaccine in InR and ChR were similar and they revealed that the FMP013 vaccine was safe and caused only mild and transient inflammatory adverse reactions. Following the first 2 vaccines, there was a slower acquisition of antibodies to the CSP repeat region in ChR. However after the 3rd vaccination the titers in the two models were comparable. The ChR group repeat-specific antibodies had higher avidity and ChR group showed higher inhibition of liver stage development activity compared to InR. There was no difference in T-cell responses to the FMP013 vaccine between the two models.ConclusionsA difference in the quality of serological responses was detected between the two sub-populations of rhesus. However, both models confirmed that FMP013/ALFQ vaccine was safe, highly immunogenic, elicited functional antibodies and T-cell responses. Overall, the data suggests that rhesus of Indian and Chinese origins can be interchangeably used to compare the safety and immunogenicity of next-generation of malaria vaccines and adjuvants.

Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV-related disease in females and males.

Comparison of different human papillomavirus (HPV) vaccine types and dose schedules for prevention of HPV-related disease in females and males.

LB13. Trivalent Hepatitis B (HepB) Vaccine Yields Superior Seroprotection Rates in Adults: Results from the Phase 3 Double-Blind, Randomized Study Comparing Immunogenicity and Safety of a 3-Dose Regimen of Sci-B-Vac™ and Engerix B® (PROTECT)

BackgroundMany adults fail to achieve seroprotection after receiving 3 doses of monovalent HepB vaccines such as Engerix-B® and the response decreases with age and with common co-morbidities. Sci-B-Vac™ is a trivalent HepB vaccine produced in mammalian cells, adjuvanted with aluminum hydroxide, which in addition to small S antigen, contains preS1 and preS2 antigens expressing highly immunogenic T- and B-cell epitopes that may enhance seroprotection rates (SPR) in adults.MethodsIn a multicentre study, the immunogenicity of 10 µg dose of Sci-B-Vac™ was compared with a 20-µg dose of Engerix-B® given at days 0, 28, and 168 (NCT03393754). Randomization was stratified by study center and age (18–44, 45–64, ≥65 years). Immunogenicity, including SPR (% subjects with anti-HBs levels ≥10 mIU/mL), and safety outcomes were followed to Day 336. The co-primary objectives were (1) non-inferiority in adults ≥18 years and (2) superiority in adults ≥45 years of SPR, 4 weeks after the third dose.ResultsOf 1,607 randomized subjects, 42.3% were from United States, 41.6% EU, and 16.1% Canada. Males (38.5%) and females (61.5%) were enrolled to 18–44 (18.6%), 45–64 (44.6%), and ≥ 65 year (36.8%) age groups. Both co-primary endpoints were met. In the non-inferiority analysis, SPR in Sci-B-Vac™ recipients aged ≥18 years was 91.4% vs. 76.5% for Engerix-B®; SPR difference: 14.9%; 95% confidence interval (CI) [11.2%, 18.6%]. Superiority analysis showed that SPR in Sci-B-Vac™ recipients aged ≥45 years was 89.4% vs. 73.1% for Engerix-B®—SPR difference: 16.4%; 95% CI [12.2%, 20.7%] (figure). Significantly higher SPR for Sci-B-Vac™ vs. Engerix-B® was noted in subgroups (gender, BMI, diabetes, smoking and particularly age—SPR difference for 45–64 (14.7% [9.8–19.8%]) and ≥ 65 (18.9% [11.6–26.1%]) years. No major safety signals were observed; solicited and unsolicited adverse events were consistent with the known vaccine safety profiles.ConclusionSci-B-Vac™ met immunogenicity endpoints for non-inferiority in adults aged ≥ 8 years and was superior in adults aged ≥45 years, compared with the monovalent vaccine, Engerix-B®. Sci-B-Vac™ SPR was higher compared with Engerix-B® in key subgroups. No safety signals were observed and safety and tolerability were consistent with the known profile of Sci-B-Vac™. DisclosuresTimo Vesikari, MD, VBI (Grant/Research Support, I have received funding from VBI to carry out the reported clinical trial in Finland), Joanne M. Langley, MD, VBI Vaccines (Grant/Research Support), Johanna Spaans, BSc, MSc, VBI Vaccines (Employee), Nathalie Machluf, PhD, SciVac Ltd. (Employee), Dave Anderson, PhD, VBI Vaccines, Inc. (Employee, Shareholder), Vlad Popovic, MD, VBI Vaccines (Employee), Francisco Diaz-Mitoma, MD, VBI Vaccines, Inc. (Consultant, Shareholder, Independent Contractor). Other Authors: No reported disclosures.

Neoantigen Dissimilarity to the Self-Proteome Predicts Immunogenicity and Response to Immune Checkpoint Blockade.

Despite improved methods for MHC affinity prediction, the vast majority of computationally predicted tumor neoantigens are not immunogenic experimentally, indicating that high-quality neoantigens are beyond current algorithms to discern. To enrich for neoantigens with the greatest likelihood of immunogenicity, we developed an analytic method to parse neoantigen quality through rational biological criteria across five clinical datasets for 318 cancer patients. We explored four quality metrics, including analysis of dissimilarity to the non-mutated proteome that was predictive of peptide immunogenicity. In patient tumors, neoantigens with high dissimilarity were unique, enriched for hydrophobic sequences, and correlated with survival after PD-1 checkpoint therapy in patients with non-small cell lung cancer independent of predicted MHC affinity. We incorporated our neoantigen quality analysis methodology into an open-source tool, antigen.garnish, to predict immunogenic peptides from bulk computationally predicted neoantigens for which the immunogenic "hit rate" is currently low.

Long-term Safety of Epoetin Alfa-epbx for the Treatment of Anemia in ESKD: Pooled Analyses of Randomized and Open-label Studies

Rationale & ObjectiveEpoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx.Study DesignPooled analyses of previously conducted studies.Setting & ParticipantsHemodialysis patients with anemia.InterventionsData from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576).OutcomesAdverse events (AEs), immunogenicity, and other outcomes were assessed.ResultsIncidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia.LimitationsEpoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies.ConclusionsThis analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment.FundingThis study was funded by Hospira Inc, which was acquired by Pfizer Inc in September 2015.Trial RegistrationClinicalTrials.gov EPOE-10-13 (NCT01473420); EPOE-10-01 (NCT01473407); EPOE-11-04 (NCT01628120); EPOE-11-03 (NCT01628107).

ELARA: A phase II, single-arm, multicenter, open-label trial investigating the efficacy and safety of tisagenlecleucel in adult patients with refractory/relapsed follicular lymphoma (r/r FL).

TPS7573 Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor-T cell (CAR-T) therapy that was approved for the treatment of pediatric and young adult patients up to 25 years of age with r/r B-cell acute lymphoblastic leukemia in 2017 (Maude et al. NEJM. 2018), as well as for the treatment of adult patients with r/r diffuse large B-cell lymphoma in 2018 (Schuster et al. NEJM. 2018). FL is the second most common non-Hodgkin lymphoma in the Western hemisphere, with limited treatment options in patients refractory to or relapsing after standard therapies. In a phase 2a study of patients with r/r CD19+ lymphomas, 10 of 14 (71%) patients with r/r FL treated with tisagenlecleucel achieved a durable complete remission at a median follow-up of 28.6 months (Schuster et al. NEJM. 2017). Here we introduce ELARA, a phase 2 study evaluating the efficacy and safety of tisagenlecleucel in patients with r/r FL. Methods: ELARA is a phase 2, single-arm, multicenter, open label trial. Eligible patients must be ≥18 years of age, have radiographically measurable grade 1, 2, or 3A r/r FL that is refractory to a second or later line of systemic therapy (including an anti-CD20 antibody and an alkylator), or relapsed within 6 months after completion of a second or later line of systemic therapy, or relapsed during anti-CD20 antibody maintenance (following ≥2 lines of therapy as above) or within 6 months after maintenance completion, or relapsed after autologous hematopoietic stem cell transplant (HSCT). Patients with central nervous system involvement, or those who received prior anti-CD19 therapy, gene therapy, adoptive T-cell therapy, or allogeneic HSCT are not eligible. The primary endpoint of this study is complete response rate based on Lugano classification response criteria. Secondary outcomes include overall response rate, duration of response, overall survival, cellular kinetics, immunogenicity, safety, and patient-reported outcomes. Estimated enrollment for this study is 113 patients. The study is currently open to patient enrollment. Clinical trial information: NCT03568461.

MRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials

BackgroundWe evaluated safety and immunogenicity of the first mRNA vaccines against potentially pandemic avian H10N8 and H7N9 influenza viruses. MethodsTwo randomized, placebo-controlled, double-blind, phase 1 clinical trials enrolled participants between December 2015 and August 2017 at single centers in Germany (H10N8) and USA (H7N9). Healthy adults (ages 18–64 years for H10N8 study; 18–49 years for H7N9 study) participated. Participants received vaccine or placebo in a 2-dose vaccination series 3 weeks apart. H10N8 intramuscular (IM) dose levels of 25, 50, 75, 100, and 400 µg and intradermal dose levels of 25 and 50 µg were evaluated. H7N9 IM 10-, 25-, and 50-µg dose levels were evaluated; 2-dose series 6 months apart was also evaluated. Primary endpoints were safety (adverse events) and tolerability. Secondary immunogenicity outcomes included humoral (hemagglutination inhibition [HAI], microneutralization [MN] assays) and cell-mediated responses (ELISPOT assay). ResultsH10N8 and H7N9 mRNA IM vaccines demonstrated favorable safety and reactogenicity profiles. No vaccine-related serious adverse event was reported. For H10N8 (N = 201), 100-µg IM dose induced HAI titers ≥ 1:40 in 100% and MN titers ≥ 1:20 in 87.0% of participants. The 25-µg intradermal dose induced HAI titers > 1:40 in 64.7% of participants compared to 34.5% of participants receiving the IM dose. For H7N9 (N = 156), IM doses of 10, 25, and 50 µg achieved HAI titers ≥ 1:40 in 36.0%, 96.3%, and 89.7% of participants, respectively. MN titers ≥ 1:20 were achieved by 100% in the 10- and 25-µg groups and 96.6% in the 50-µg group. Seroconversion rates were 78.3% (HAI) and 87.0% (MN) for H10N8 (100 µg IM) and 96.3% (HAI) and 100% (MN) in H7N9 (50 µg). Significant cell-mediated responses were not detected in either study. ConclusionsThe first mRNA vaccines against H10N8 and H7N9 influenza viruses were well tolerated and elicited robust humoral immune responses.ClinicalTrials.gov NCT03076385 and NCT03345043.

Alternative-Dose versus Standard-Dose Trivalent Influenza Vaccines for Immunocompromised Patients: A Meta-Analysis of Randomised Control Trials

The study compared immunogenicity and safety between alternative higher-dose and standard-dose trivalent vaccines in immunocompromised individuals. A literature search was performed using the PubMed, Embase, and Cochrane databases from inception until March 2019 to identify studies comparing the immunogenicity of alternative higher-dose (including high-dose, double-dose, and booster-dose vaccines) and standard-dose trivalent influenza vaccines in patients who underwent transplantation or chemotherapy. Effect estimates from the individual studies were derived and calculated using the DerSimonian and Laird random-effect model. The protocol for this systematic review is registered with PROSPERO (number CRD42019129220). Eight relevant studies involving 1020 patients were included in the systematic review and meta-analysis. The meta-analysis demonstrated that the higher-dose strategy provided had significantly superior seroconversion and seroprotection for A/H1N1 strains than the standard dose. Regarding H3N2 and B strains, no differences in immunogenicity responses were noted. No differences in safety were observed between the vaccination strategies. Alternative higher-dose vaccination strategies appear to associate with superior immunogenicity responses for A/H1N1 strains, and the strategies were generally well tolerated in immunocompromised populations. Future studies should clarify the optimal timing, frequency and dose of vaccination and assess whether these strategies improve vaccine immunogenicity and clinical outcomes.

Somatic PRAME Deletions Are Associated with Decreased Immunogenicity, Apoptosis Resistance and Poor Outcomes in Diffuse Large B-Cell Lymphoma

Background: The current standard of care in diffuse large B-cell lymphoma (DLBCL) consists of chemotherapy and therapeutic monoclonal antibodies that have significantly improved patient outcomes over the past 15 years. However, a large proportion of patients suffer from refractory or relapsed disease. Therefore, the development of new therapeutic strategies for this subgroup of patients, who are threatened by a high chance of disease-related death, represents an important unmet clinical need.Methods: We enrolled into our study 347 de novo DLBCL patients uniformly treated with R-CHOP from the BC Cancer population-based cohort between September 2000 and January 2012. RNAseq and high-resolution copy number analysis were performed and correlated with clinical outcome data and tumor microenvironment composition. We also performed functional studies to investigate PRAME-mediated memory T-cell responses and gene expression changes.Results: We discovered novel, highly focal deletions of 22q11.22, including the PRAME gene in 13% (44/338) of the cases. The deletions cluster in a narrow chromosomal region that includes a very small number of genes (VpreB1, ZNF280A/B, PRAME, GGTLC2, miR-650). Of clinical importance, 22q11.22 deletions were found significantly more frequently in germinal centre B-cell-like (GCB) type DLBCL (17% (31/180) vs. activated B-cell-like (ABC) type: 8% (8/98), P < 0.01), and were also significantly associated with worse outcome, which was specifically observed in GCB-DLBCL (5-year disease specific survival, non-PRAME-deleted: 84.5% vs. PRAME-deleted: 67.2%, P = 0.026). Homozygous deletions were more strongly associated with poor outcome than heterozygous deletions. Interestingly, 90% of PRAME-deleted cases were Ig-lambda restricted (P < 0.001).PRAME is a prominent member of the cancer testis antigen (CTA) family of proteins that are expressed in various types of cancers, but not in normal tissues, including normal mature B-cells, apart from male germinal cells. Due to the cancer-specific expression of CTAs, these molecules are considered promising targets for cancer immunotherapy using cytotoxic T-cells and tumor vaccination approaches. To determine the association with tumor microenvironment composition, we analyzed CD4/CD8 flow cytometry data from DLBCL patient samples. The numbers of CD4 and CD8-positive T cells were significantly lower in PRAME-deleted cases compared to wild type (CD4: P < 0.001, CD8: P = 0.013). Notably, RNAseq analysis revealed that the HLA-A*0201 genotype was seen significantly more often in PRAME deleted cases (PRAME wt: 2.5% vs. PRAME deleted: 10.8%, P = 0.005). In order to functionally characterize its interaction with the immune microenvironment, we utilized enzyme-linked immunoSpot (ELISPOT) assays to investigate memory T-cell reactions of patient-derived T cells to PRAME antigens using patient-derived peripheral blood mononuclear cells (PBMC) and measured IFN-g production (7 control healthy donors, 4 PRAME-deleted and 4-wild type patients). While T cells from PRAME-replete patients had no reaction to PRAME antigens, PRAME-deleted patient-derived T-cells had significant reactions to 4 independent PRAME peptides. These data suggest that PRAME-deleted tumor cells can escape from cytotoxic T-cell attack to gain growth advantage.Next, we performed PRAME knock-out (KO) experiments using CRISPR/Cas9 genome editing to clarify the cell autonomous effects of PRAME deletions. Using 2 different cell lines (Karpas422 and SUDHL-4), we found TNFSF10 (TRAIL) expression was significantly down-regulated in homozygous PRAME-KO cell lines compared to wild type. The soluble form of TRAIL (sTRAIL) was also reduced, as measured with enzyme-linked immunosorbent assays. These results suggest that PRAME downregulated cells may contribute to cell survival via TRAIL and sTRAIL reduction.Conclusion: We identified recurrent PRAME deletions and characterized their clinical and functional role in DLBCL. Our findings contribute to the understanding of cell-autonomous and extrinsic roles of PRAME deletions in lymphomagenesis and may lead to the discovery of new therapeutic avenues to simultaneously treat the tumor and the host. DisclosuresGascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Celgene: Consultancy, Honoraria. Steidl:Tioma: Research Funding; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy; Nanostring: Patents & Royalties: patent holding.

A Bayesian design for phase I cancer therapeutic vaccine trials.

Phase I clinical trials are the first step in drug development to test a new drug or drug combination on humans. Typical designs of Phase I trials use toxicity as the primary endpoint and aim to find the maximum tolerable dosage. However, these designs are poorly applicable for the development of cancer therapeutic vaccines because the expected safety concerns for these vaccines are not as much as cytotoxic agents. The primary objectives of a cancer therapeutic vaccine phase I trial thus often include determining whether the vaccine shows biologic activity and the minimum dose necessary to achieve a full immune or even clinical response. In this paper, we propose a new Bayesian phase I trial design that allows simultaneous evaluation of safety and immunogenicity outcomes. We demonstrate the proposed clinical trial design by both a numeric study and a therapeutic human papillomavirus vaccine trial.

Influence of early adalimumab serum levels on immunogenicity and long‐term outcome of anti‐TNF naive Crohn's disease patients: the usefulness of rapid testing

Proactive testing of adalimumab serum levels is debated. To study the association between adalimumab serum levels at week 4 and the development of anti-adalimumab drug antibodies and long-term outcome in anti-TNF naive Crohn's disease patients. Serum samples from 116 biologically naive Crohn's disease patients with active disease were prospectively collected at baseline, and weeks 4 and 12. Adalimumab serum levels were measured using the RIDA® QUICK adalimumab lateral flow assay and anti-adalimumab drug antibodies were determined using a drug-resistant assay. Pharmacokinetic data were studied in relation to clinical outcome. Patients who stopped adalimumab by week 12 due to persisting symptoms were considered primary non-responders, whereas initial improvement with increasing symptoms after week 12 was considered loss of response. Adalimumab continuation until the end of follow-up was considered sustained clinical benefit. Patients with low serum levels at week 4 (<8.3μg/mL) were at significantly higher risk of being anti-adalimumab positive by week 12 (46.7% vs 13.0%, P=0.009). After a median follow-up of 89weeks, dose-escalation and sustained clinical benefit were observed in 37.1% and 48.3% of patients. The 21.4% of patients who were anti-adalimumab drug antibody positive by week 12, had a significantly higher need of dose escalation (P<0.001), and experienced sustained clinical benefit less frequently due to primary non-response or secondary loss of response (P=0.02). Our findings support early monitoring of adalimumab serum levels to guide dose optimisation, which may prevent immunogenicity and influence long-term outcome. We validated a novel lateral flow assay for quantitative determination of adalimumab levels, facilitating physicians to optimise therapy immediately at the outpatient clinic.

Safety and Immunogenicity of Measles Vaccination in HIV-Infected and HIV-Exposed Uninfected Children: A Systematic Review and Meta-Analysis

BackgroundHIV-infected and HIV-exposed uninfected (HEU) children have an increased risk of measles that may be due to altered immune responses or suboptimal timing of measles vaccination. We aimed to evaluate the safety and immunogenicity of measles vaccination in HIV-infected and HEU children. MethodsFor this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, CINAHL, Global Health Library and IndMED on May 9, 2018. Studies were included if they reported on safety or seroresponse (either seroprotection/seropositivity/seroconversion) after measles vaccination in HIV-infected or HEU children. We calculated pooled estimates to compare immunogenicity outcomes between HIV-infected, HEU and HIV-unexposed children, using risk ratios [RRs] (with 95%CIs). PROSPERO registration number: CRD42017057411. FindingsSeventy-one studies met the inclusion criteria (15,363 children). Twenty-eight studies reported on safety; vaccine-associated adverse events and deaths were uncommon. Sixty-two studies reported on immunogenicity, 27 were included in the meta-analysis. HIV-infected children had lower seroresponse rates after primary vaccination compared with HIV-unexposed (RR 0.74; 95%CI: 0.61–0.90, I2 = 85.9%) and HEU children (0.78; 0.69–0.88, I2 = 77.1%), which was mitigated by antiretroviral therapy and time interval between vaccination and serology. HEU and HIV-unexposed children had similar seroresponses. Vaccination at 6-months resulted in similar proportions of HIV-infected children having seroresponse compared with HIV-unexposed (0.96; 0.77–1.19) and HEU children (1.00; 0.73–1.37, I2 = 63.7%). InterpretationPrimary measles vaccination at 6-months of age may provide protection against measles during early infancy in settings with high prevalence of maternal HIV-infection, however, further studies are needed to evaluate this strategy in HEU children and HIV-infected children receiving antiretroviral therapy. FundingSouth African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation in Vaccine Preventable Diseases; Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.

346 - in Anti-TNF Naïve Crohn's Disease Patients Low Adalimumab Serum Levels at Week 4 Provoke Immunogenicity and Influence Therapy Outcome

346 - in Anti-TNF Naïve Crohn's Disease Patients Low Adalimumab Serum Levels at Week 4 Provoke Immunogenicity and Influence Therapy Outcome

Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial

A vaccine that prevents pulmonary tuberculosis in adults is needed to halt transmission in endemic regions. This trial aimed to assess the safety and immunogenicity of three administrations at varying doses of antigen and adjuvant of an investigational vaccine (ID93 + GLA-SE) compared with placebo in previously BCG-vaccinated healthy adults in a tuberculosis endemic country. In this randomised, double-blind, placebo-controlled phase 1 trial, we enrolled HIV-negative, previously BCG-vaccinated adults (aged 18-50 years), with no evidence of previous or current tuberculosis disease, from among community volunteers in the Worcester region of Western Cape, South Africa. Participants were randomly assigned to receive varying doses of ID93 + GLA-SE or saline placebo at day 0, day 28, and day 112. Enrolment into each cohort was sequential. Cohort 1 participants were Mycobacterium tuberculosis uninfected (as defined by negative QuantiFERON [QFT] status), and received 10 μg ID93 plus 2 μg GLA-SE, or placebo; in cohorts 2-4, QFT-negative or positive participants received escalating doses of vaccine or placebo. Cohort 2 received 2 μg ID93 plus 2 μg GLA-SE; cohort 3 received 10 μg ID93 plus 2 μg GLA-SE; and cohort 4 received 10 μg ID93 plus 5 μg GLA-SE. Dose cohort allocation was sequential; randomisation within a cohort was according to a randomly-generated sequence (3 to 1 in cohort 1, 5 to 1 in cohorts 2-4). The primary endpoint was safety of ID93 + GLA-SE as defined by solicited and unsolicited adverse events up to 28 days after each study injection and serious adverse events for the duration of the study. Specific immune responses were measured by intracellular cytokine staining, flow cytometry, and ELISA. All analyses were done according to intention to treat, with additional per-protocol analyses for immunogenicity outcomes. This trial is registered with ClinicalTrials.gov, number NCT01927159. Between Aug 30, 2013, and Sept 4, 2014, 227 individuals consented to participate; 213 were screened (three participants were not included as study number was already met and 11 withdrew consent before screening occurred, mostly due to relocation or demands of employment). 66 healthy, HIV-negative adults were randomly allocated to receive the vaccine (n=54) or placebo (n=12). All study participants received day 0 and day 28 study injections; five participants did not receive an injection on day 112. ID93 + GLA-SE was well tolerated; no severe or serious vaccine-related adverse events were recorded. Vaccine dose did not affect frequency or severity of adverse events, but mild injection site adverse events and flu-like symptoms were common in M tuberculosis-infected participants compared with uninfected participants. Vaccination induced durable antigen-specific IgG and Th1 cellular responses, which peaked after two administrations. Vaccine dose did not affect magnitude, kinetics, or profile of antibody and cellular responses. Earlier boosting and greater T-cell differentiation and effector-like profiles were seen in M tuberculosis-infected than in uninfected vaccinees. Escalating doses of ID93 + GLA-SE induced similar antigen-specific CD4-positive T cell and humoral responses, with an acceptable safety profile in BCG-immunised, M tuberculosis-infected individuals. The T-cell differentiation profiles in M tuberculosis-infected vaccinees suggest priming through natural infection. While cohort sample sizes in this phase 1 trial were small and results should be interpreted in context, these data support efficacy testing of two administrations of the lowest (2 μg) ID93 vaccine dose in tuberculosis endemic populations. Aeras and the Paul G Allen Family Foundation.

Are two doses of human papillomavirus vaccine sufficient for girls aged 15–18 years? Results from a cohort study in India

Extending two-dose recommendations of HPV vaccine to girls between 15 and 18 years will reduce program cost and improve compliance. Immunogenicity and vaccine targeted HPV infection outcomes were compared between 1795 girls aged 15–18 years receiving two (1–180 days) and 1515 girls of same age receiving three (1–60–180 days) doses. Immunogenicity outcomes in 15–18 year old two-dose recipients were also compared with the 10–14 year old three-dose (N = 2833) and two-dose (N = 3184) recipients. The 15–18 year old two-dose recipients had non-inferior L1-binding antibody titres at seven months against vaccine-targeted HPV types compared to three-dose recipients at 15–18 years and three-dose recipients at 10–14 years of age. Neutralizing antibody titres at 18 months in 15–18 year old two-dose recipients were non-inferior to same age three-dose recipients for all except HPV 18. The titres were inferior to those in the 10–14 year old three-dose recipients for all targeted types. Frequency of incident infections from vaccine-targeted HPV types in the 15–18 year old two-dose recipients was similar to the three dose recipients. None of the girls receiving two or three doses had persistent infection from vaccine-targeted types. These findings support that two doses of HPV vaccine can be extended to girls aged 15–18 years.

Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.

P396 Pharmacokinetics, immunogenicity and clinical outcomes of golimumab from the PURSUIT PEDS ulcerative colitis study long-term (through week 126) extension

P396 Pharmacokinetics, immunogenicity and clinical outcomes of golimumab from the PURSUIT PEDS ulcerative colitis study long-term (through week 126) extension

P527 Low adalimumab serum levels at Week 4 provoke immunogenicity and influence therapy outcome in anti-TNF naïve Crohn’s disease patients

P527 Low adalimumab serum levels at Week 4 provoke immunogenicity and influence therapy outcome in anti-TNF naïve Crohn’s disease patients

Efficacy, immunogenicity, and safety of a 9-valent human papillomavirus vaccine in Latin American girls, boys, and young women

BackgroundA 9-valent human papillomavirus (HPV6/11/16/18/31/33/45/52/58; 9vHPV) vaccine was developed to expand coverage of the previously developed quadrivalent (HPV6/11/16/18; qHPV) vaccine. MethodsEfficacy, immunogenicity, and safety outcomes were assessed in Latin American participants enrolled in 2 international studies of the 9vHPV vaccine, including a randomized, double-blinded, controlled with qHPV vaccine, efficacy, immunogenicity, and safety study in young women aged 16–26 years, and an immunogenicity and safety study in girls and boys aged 9–15 years. Participants (N=5312) received vaccination at Day 1, Month 2, and Month 6. Gynecological swabs were collected regularly in young women for cytological and HPV DNA testing. Serum was analyzed for HPV antibodies in all participants. Adverse events (AEs) were also monitored in all participants. ResultsThe 9vHPV vaccine prevented HPV 31-, 33-, 45-, 52-, and 58-related high-grade cervical, vulvar, and vaginal dysplasia with 92.3% efficacy (95% confidence interval 54.4, 99.6). Anti-HPV6, 11, 16, and 18 geometric mean titers at Month 7 were similar in the 9vHPV and qHPV vaccination groups. Anti-HPV antibody responses following vaccination were higher among girls and boys than in young women. Most (>99%) 9vHPV vaccine recipients seroconverted for all 9 HPV types at Month 7. Antibody responses to the 9 HPV types persisted over 5 years. The most common AEs were injection-site related, mostly of mild to moderate intensity. ConclusionsThe 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Latin American young women, girls, and boys. These data support 9vHPV vaccination programs in Latin America, a region with substantial cervical cancer burden.

How Close Are We to Profiling Immunogenicity Risk Using In Silico Algorithms and In Vitro Methods?: an Industry Perspective

In silico HLA-binding algorithms and in vitro T cell-based assays as predictive tools for human immunogenicity risk have made inroads in the biotherapeutic drug discovery and development process. Currently, these tools are being used only for candidate selection or characterization and not for making a go/no-go decision for further development. A clear limitation for a broader implementation is the lack of correlation between the predicted T cell epitope content/immune reactivity potential of a biotherapeutic and the subsequent ADA-related clinical immunogenicity outcome. The current state of technologies and their pros and cons were discussed as a part of the 2016 AAPS National Biotechnology Conference in a themed session. A review of the advances in the area and the session talks along with the ensuing discussions are summarized in this commentary.