Safety and Immunogenicity of MF59-Adjuvanted Cell Culture-Derived A/H5N1 Subunit Influenza Virus Vaccine: Dose-Finding Clinical Trials in Adults and the Elderly.

BACKGROUND: A/H5N1 influenza viruses have high pandemic potential; consequently, vaccines need to be produced rapidly. MF59® adjuvant reduces the antigen required per dose, allowing for dose sparing and more rapid vaccine availability. METHODS: Two multicenter, phase II trials were conducted to evaluate the safety and immunogenicity of an MF59-adjuvanted, cell culture-derived, A/H5N1 vaccine (aH5N1c) among 979 adult (18-64 years old) and 1393 elderly (≥65 years old) subjects. Participants were equally randomized to receive 2 full-dose (7.5 µg of hemagglutinin antigen per dose) or 2 half-dose aH5N1c vaccinations 3 weeks apart. Outcomes were based on Center for Biologics Evaluation Research and Review (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria (titers ≥1:40 and seroconversions on day 43). Solicited reactions and adverse events were assessed (www.clinicaltrials.gov: NCT01776541 and NCT01766921). RESULTS: CBER and CHMP criteria were met by both age groups. CBER criteria for hemagglutination titers were met for the full-dose formulation. Solicited reaction frequencies tended to be higher in the full-dose group and were of mild to moderate intensity. No vaccine-related serious adverse events occurred. CONCLUSIONS: In adult and elderly participants, the full-dose aH5N1c vaccine formulation was well tolerated and met US and European licensure criteria for pandemic vaccines.

Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents - Results from a randomized, controlled, observer-blind phase II study.

BACKGROUND: Neisseria meningitidis serogroups A, B, C, W and Y cause most meningococcal disease worldwide. An investigational MenABCWY vaccine combining serogroup B antigens and a meningococcal ACWY CRM197-glycoconjugate vaccine (MenACWY-CRM) could provide protection against all 5 serogroups. Complement mediated bactericidal activity induced by MenABCWY was tested against a panel of 110 randomly-selected serogroup B strains causing invasive disease in the US to evaluate the vaccine's breadth of coverage (BoC). METHODS: We conducted this observer-blind study (NCT02140762) and its extension (NCT02285777) in 8 centers in the US. Adolescents aged 10-18 years were randomized (1:1) to receive either 3 MenABCWY doses (MenABCWY group), on a 0, 2, 6-month (M) schedule or a single MenACWY-CRM dose at M2 and placebo at 0,6-M (Control group). MenABCWY BoC was calculated as (1 - relative risk) × 100 (relative risk = ratio between the percentage of samples seronegative at 1:4 dilution against the selected strains in the MenABCWY vs Control group). BoC was determined at 1 M and 4 M after 2 and 3 doses, using an endogenous complement serum bactericidal assay. Immunogenicity and safety were assessed. RESULTS: 301 and 189 adolescents were vaccinated in the parent and extension study, respectively. At 1 M post-vaccination, the BoC of MenABCWY across the 110 serogroup B strains was 67% (95%CI: 65-69) after 2 doses and 71% (95%CI: 69-73) after 3 doses. BoC decreased to 44% (95%CI: 41-47) and 51% (95%CI: 48-55) at 4 M after 2 and 3 MenABCWY doses, respectively. Robust immune responses to antigen-specific test strains for each serogroup were observed at all timepoints in the MenABCWY group. No reactogenicity or safety concerns arose during the study. CONCLUSION: Two or 3 doses of MenABCWY showed similar BoC against the panel of invasive US serogroup B isolates and comparable immunogenicity against the antigen-specific test strains, with no safety concerns identified.

Celyad's novel CAR T-cell therapy for solid malignancies.

Celyad recently initiated several clinical trials with the CYAD-01 product, a natural killer group 2D (NKG2D)-based chimeric antigen receptor (CAR), in both solid and hematologic tumor types. This review discusses the unique properties of CYAD-01, expecting to provide a new paradigm to fight against solid tumors.

Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types.

INTRODUCTION: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. METHODS AND ANALYSIS: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109 NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. ETHICS APPROVAL AND DISSEMINATION: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03018405, EudraCT 2016-003312-12; Pre-result.

Antibody persistence 5 years after vaccination at 2 to 10 years of age with Quadrivalent MenACWY-CRM conjugate vaccine, and responses to a booster vaccination.

BACKGROUND: In a multi-center extension study, children 2-10 years of age, initially vaccinated with one or two doses (2-5 year-olds) or one dose (6-10 year-olds) of quadrivalent meningococcal CRM197-conjugate vaccine (MenACWY-CRM), were assessed five years later for antibody persistence and booster response using serum bactericidal assay with human complement (hSBA). METHODS: Children 7-10 and 11-15 years of age, who received MenACWY-CRM in the original study, and age-matched vaccine-naïve children, were enrolled in this extension study. After an initial blood draw, children received one dose of MenACWY-CRM as booster or primary dose, with a second blood draw 28 days later. RESULTS: hSBA titers decreased five years after primary vaccination, but were higher than in non-vaccinated controls against serogroups C, W and Y, with substantial proportions having titers ≥8: 7-22% for A, 32-57% for C, 74-83% for W, and 48-54% for Y. Previously-vaccinated children demonstrated booster responses to revaccination against all four serogroups. Responses to primary vaccination in vaccine-naïve controls were lower and similar to primary responses observed in the original study. All vaccinations were generally well tolerated, with no safety concern raised. CONCLUSIONS: Approximately half the children vaccinated as 2-10 year-olds maintained protective antibodies against serogroups C, W and Y five years later, but fewer did against serogroup A. Declining titers five years after vaccination and robust booster responses suggest that five years may be an appropriate interval to revaccinate children, subject to epidemiology and delivery considerations.