Generalized ROC methods for immunogenicity data analysis of vaccine phase I studies in a seropositive population

Immunogenicity data from phase 1 vaccine studies can be difficult to interpret, especially in seropositive populations and when multiple assays are used. We developed 3 statistical methods (Youden index [YI] threshold, receiver-operating characteristic relative to baseline [ROC-B], and ROC of postdose levels [ROC-P]) to characterize complex immunogenicity data by assessing the proportion of a study population that achieved values above thresholds. The YI method calculates a single threshold per assay. Both ROC methods construct ROC curves for individual assays and surfaces for assay combinations to assess degree of separation of postdose values from a reference distribution; the ROC-B method uses overall predose values as the reference distribution and the ROC-P method uses pooled postdose values. All methods are applicable to a seropositive population with overlapping distributions of baseline and postdose measurements and can evaluate results of multiple assays jointly. The ROC-P method is also applicable when postdose levels are fully separated from baseline levels, as is common in a seronegative population. These methods were demonstrated using data from a phase 1a study of respiratory syncytial virus vaccines formulated with and without an adjuvant in a seropositive population of adults aged ≥60 years. All 3 methods provided a comprehensive assessment of vaccine immunogenicity effects with results presented in easily interpretable formats. In the example data, the methods demonstrated antigen dose response trend and contribution of adjuvant to response in multiple assays individually and jointly where optimal responses in assay combinations (humoral and cellular) are important

Passive and active immunization against respiratory syncytial virus for the young and old

Introduction: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants worldwide and also causes significant disease in the elderly. Despite 60 years of RSV research and vaccine development, there is only one approved medicine to prevent RSV infections. Palivizumab, a monoclonal antibody (mAb) against the RSV fusion (F) protein, is indicated for preterm infants and children at high-risk for RSV infections. It is an active time in RSV vaccine and mAb development with 14 vaccines and 2 mAbs currently being tested in clinical trials as of 13 February 2017. Active vaccination of women in the third trimester or passive immunization of infants with a mAb are particularly attractive approaches as the most severe disease occurs within the first 6 months of life. Areas covered: Here, we review current approaches for preventing RSV in the young and old, describe proposed clinical endpoints for studies in pediatric and adult clinical trials and highlight results from recent and ongoing clinical studies. Expert commentary: With 16 candidates in clinical development, approval of the first RSV vaccine or mAb for the prevention of RSV in all infants or the elderly is likely to occur in the next five years

The MIDORA trial: a phase II, randomised, double-blind, placebo-controlled, mechanistic insight and dosage optimisation study of the efficacy and safety of dazodalibep in patients with rheumatoid arthritis

Objectives To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA).Methods This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309.Results The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (−1.83±0.28 to −1.90±0.27; p<0.05) relative to PBO (−1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication.Conclusions DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals.Trial registration number NCT0416399

Idiopathic CD4(+) T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7

Idiopathic CD4(+) T lymphocytopenia (ICL) is a rare heterogeneous disorder defined by CD4(+) T-cell counts below 300 cells/μL in the absence of human immunodeficiency virus (HIV) infection or other known immune deficiency disorders. Here, we report the expansion of immature/transitional B cells in patients with ICL, which is associated with elevated serum levels of IL-7. Both the percentage of immature/transitional B cells and levels of IL-7 were inversely correlated with levels of CD4(+) T-cell counts and directly correlated to each other. Further analyses of B cells indicated that, in contrast to the activating effects of HIV disease on mature B cells, the expansion of immature/transitional B cells in patients with ICL occurred at the expense of memory B cells. These findings extend previous reports on primary immunodeficiencies as well as HIV disease by suggesting that CD4(+) T-cell lymphopenia has an impact on human B-cell development either directly or indirectly via the associated elevation of IL-7 levels

Antibody and B cell responses to an investigational adjuvanted RSV vaccine for older adults

Background: Infections with respiratory syncytial virus (RSV) cause significant morbidity and hospitalization in older adults. We studied the humoral, mucosal and B cell responses of an investigational adjuvanted RSV sF vaccine, MEDI7510, in older adults. Methods: In a substudy of a randomized (1:1), double-blind, placebo-controlled study of MEDI7510 in adults ≥60 years of age, we collected blood and nasal secretions at days 0, 8, 29, 91 and 180 post-vaccination to measure F-specific IgG and IgA antibodies by ELISA, and plasmablasts and memory B cells by IgA/IgG dual-color fluorospot. Results: The 27 vaccine- and 18 placebo-recipients had a mean age of 73 years and included 24 women. Among vaccinees, 93% had significant increases in F-specific plasma IgG 85% had increased plasma IgA; 74% had increased nasal IgG and 26% nasal IgA; 93% had IgG and 89% IgA plasmablasts on Day 8 post-immunization; and 82% had IgG and 7.4% IgA memory B cell responses to the vaccine. Vaccinees <70 years of age and women had the highest responses to the vaccine. Conclusions: This adjuvanted vaccine generated robust humoral immune responses in older adults, including RSV F-specific systemic and mucosal antibodies and memory B cells. Nevertheless, age ≥70 years was associated with decreased immunogenicity of the adjuvanted vaccine

An Adjuvanted, Postfusion F Protein-Based Vaccine Did Not Prevent Respiratory Syncytial Virus Illness in Older Adults

Background: Respiratory syncytial virus (RSV) is an important cause of illness in older adults. This study assessed efficacy of a vaccine for prevention of RSV-associated acute respiratory illness (ARI), defined by specified symptoms with virologic confirmation. Methods: This phase 2b study evaluated RSV postfusion F protein (120 µg) with glucopyranosyl lipid adjuvant (5 µg) in 2% stable emulsion. Subjects aged ≥60 years were randomly assigned at a ratio of 1:1 to receive vaccine or placebo (all received inactivated influenza vaccine). Ill subjects recorded symptoms and provided blood and nasal swab samples. Results: In the per-protocol population (n = 1894), the incidence of RSV-associated ARI occurring ≥14 days after dosing was 1.7% and 1.6% in the vaccine and placebo groups, respectively, for a vaccine efficacy (VE) of -7.1% (90% confidence interval [CI], -106.9%-44.3%). Efficacy was not observed in secondary analyses that included seroresponse to nonvaccine RSV antigens (VE, 8.9%; 90% CI, -28.5%-35.4%) or symptoms combined with seroresponse (VE, 10.0%; 90% CI, -45.4%-44.4%). On day 29, 92.9% of vaccinees had an anti-F immunoglobulin G antibody seroresponse. Overall, 48.5% and 30.9% of RSV vaccine recipients reported local and systemic solicited symptoms, respectively. Conclusion: The RSV vaccine was immunogenic but did not protect older adults from RSV illness. Clinical Trials Registration: NCT02508194