GlaxoSmithKline (Switzerland)

RTS,S/AS01, an adjuvanted subunit malaria vaccine, induces protective but short-lived anti-Plasmodium falciparum circumsporozoite protein (CSP) antibody titers. To better understand the lack of sustained protection post-vaccination, we analyzed CSP-specific B cells over time in malaria-naive individuals following immunization with RTS,S/AS01 followed by controlled malaria infection. Longitudinal analyses revealed a shift in the repertoire and regional protein specificity of CSP-specific B cells over time. Early post-vaccine responses were dominated by class-switched memory B cells (MBCs) specific for the NANP-repeat region of CSP, epitopes associated with protective antibodies. However, the frequency of NANP-repeat-specific MBCs declines, while longer-term memory responses, including responses both before and after a malaria challenge, had increased frequencies of MBCs specific for the C-terminus of CSP. Despite class-switching and affinity maturation, C-term monoclonal antibodies derived from these MBCs failed to protect mice against a transgenic parasite challenge. Taken together, these findings suggest that RTS,S/AS01 induces a transient, protective NANP-repeat-specific B cell response that is subsequently replaced by B cells with non-protective reactivities, potentially explaining its limited long-term efficacy.

Immuno-oncology (IO) agents and pemetrexed are approved for the first-line (1L) maintenance treatment (1LMT) of advanced/metastatic non-small cell lung cancer (a/mNSCLC). This international retrospective chart review assessed real-world treatment patterns and outcomes in patients with a/mNSCLC lacking targetable mutations. Oncologists from seven countries (Canada, France, Germany, Italy, Spain, UK, USA) provided deidentified, medical chart-derived data on randomly selected adults with a/mNSCLC who remained stable or responded to 1L chemotherapy + IO. Treatment patterns, overall survival (OS), progression-free survival (PFS), and healthcare resource utilization (HCRU) were compared by maintenance treatment use following propensity score weighting. The effects of adding pemetrexed to IO-containing 1LMT was investigated in patients with non-squamous/mixed histology. Of 942 patients analyzed, 680 initiated 1LMT. After weighting, 1LMT was associated with longer median PFS (17.7 vs 7.1months; HR [95%CI] 0.63 [0.41-0.85]), similar OS (31.7 vs 31.0months; 0.82 [0.47-1.17]), and fewer mean monthly hospitalizations (0.03 vs 0.1; p < 0.01) versus no 1LMT. Among 469 patients with non-squamous/mixed histology who initiated an IO-containing 1LMT, 283 received IO only while 186 received IO + pemetrexed. Median time to treatment discontinuation (20.0 vs 11.0months; p < 0.001), PFS (21.1 vs 11.1months; HR [95%CI] 0.56 [0.37-0.76]), and OS (35.3 vs 27.3months; 0.70 [0.41-0.98]) were longer for patients receiving IO only versus IO + pemetrexed. Fewer patients administered IO only experienced fatigue (28.3% vs 39.8% [IO + pemetrexed]; p < 0.05) and anemia (16.6% vs 31.2%; p < 0.001). 1LMT was associated with significantly longer PFS and similar OS, without substantially increasing HCRU, among the current study population with a/mNSCLC. Adding pemetrexed to 1LM IO did not confer significant clinical benefit in patients with non-squamous/mixed histology and these patients incurred more adverse events. Additional 1LMT options are needed to further improve clinical outcomes.

In this phase 3 trial of an investigational maternal respiratory syncytial virus prefusion F protein-based vaccine (RSVPreF3-Mat), a higher rate of preterm birth was observed in the vaccine (6.8%) versus the placebo group (4.9%). Trial enrollment and vaccination were stopped. Results of investigations into this safety signal were reported previously. Here, we describe end-of-trial efficacy, immunogenicity, and safety results. Women 18-49 years old were randomized 2:1 to receive 1 dose of RSVPreF3-Mat (n = 3557) or placebo (n = 1771) at 240/7-340/7 weeks' gestation. Primary outcomes were any and severe medically assessed RSV-associated lower respiratory tract disease (MA-RSV-LRTD) in infants until 6 months postbirth and safety until 12 months postbirth. Other efficacy outcomes were evaluated, along with immunogenicity (until 6 months postpartum/birth) and safety in mothers and infants. Efficacy (with 95% credible interval) in infants until 6 months postbirth was 65.5% (37.5%-82.0%) against any MA-RSV-LRTD, 69.0% (33.0%-87.6%) against severe MA-RSV-LRTD, and 50.1% (-3.6% to 75.8%) against RSV hospitalization; it waned over time thereafter. Efficacy against MA-RSV-LRTD was 47.8% (-25.8% to 77.3%) in low- and middle-income and 75.9% (46.1%-91.5%) in high-income countries. RSVPreF3-Mat induced a substantial increase in RSV-A neutralization titers in mothers, with efficient transplacental transfer of antibodies that persisted in infants until at least 6 months postbirth. Consistent with the high titers of transplacentally transferred antibodies, this trial suggests a reduced risk of any/severe MA-RSV-LRTD and RSV hospitalization until 6 months postbirth in infants born to mothers immunized with RSVPreF3-Mat during pregnancy. However, vaccine development was terminated due to an identified preterm birth risk. Clinical Trials Registration. NCT04605159.

Within the causal association paradigm, a method is proposed to assess the validity of a continuous outcome as a surrogate for a binary true endpoint. The methodology is based on a previously introduced information-theoretic definition of surrogacy and has two main steps. In the first step, a new model is proposed to describe the joint distribution of the potential outcomes associated with the putative surrogate and the true endpoint of interest. The identifiability issues inherent to this type of models are handled via sensitivity analysis. In the second step, a metric of surrogacy new to this setting, the so-called individual causal association is presented. The methodology is studied in detail using theoretical considerations, some simulations, and data from a randomized clinical trial evaluating an inactivated quadrivalent influenza vaccine. A user-friendly R package Surrogate is provided to carry out the evaluation exercise.

I.AbstractThe Coronavirus Disease 2019 (COVID-19) has demonstrated that accurate forecasts of infection and mortality rates are essential for informing healthcare resource allocation, designing countermeasures, implementing public health policies, and increasing public awareness. However, there exist a multitude of modeling methodologies, and their relative performances in accurately forecasting pandemic dynamics are not currently comprehensively understood.In this paper, we introduce the non-mechanistic MIT-LCP forecasting model, and assess and compare its performance to various mechanistic and non-mechanistic models that have been proposed for forecasting COVID-19 dynamics. We performed a comprehensive experimental evaluation which covered the time period of November 2020 to April 2021, in order to determine the relative performances of MIT-LCP and seven other forecasting models from the United States’ Centers for Disease Control and Prevention (CDC) Forecast Hub.Our results show that there exist forecasting scenarios well-suited to both mechanistic and non-mechanistic models, with mechanistic models being particularly performant for forecasts that are further in the future when recent data may not be as informative, and non-mechanistic models being more effective with shorter prediction horizons when recent representative data is available. Improving our understanding of which forecasting approaches are more reliable, and in which forecasting scenarios, can assist effective pandemic preparation and management.

The assurance of a future clinical trial is a key quantitative tool for decision‐making in drug development. It is derived from prior knowledge (Bayesian approach) about the clinical endpoint of interest, typically from previous clinical trials. In this paper, we examine assurance in the specific context of vaccine development, where early development (Phase 2) is often based on immunological endpoints (e.g., antibody levels), while the confirmatory trial (Phase 3) is based on the clinical endpoint (very large sample sizes and long follow‐up). Our proposal is to use the Phase 2 vaccine efficacy predicted by the immunological endpoint (using a model estimated from epidemiological studies) as prior information for the calculation of the assurance.

8033 Background: Belantamab mafodotin (GSK2857916; belamaf; BLENREP) is a B-cell maturation antigen (BCMA)-targeting antibody–drug conjugate approved in the US and EU as a monotherapy for the treatment of adult patients with RRMM. Ocular events (OEs) during the pivotal DREAMM-2 trial (NCT03525678) included corneal exam findings (punctate keratopathy and microcyst-like epithelial changes), BCVA changes, and ocular symptoms. Dose reductions or delays based on corneal exam findings and BCVA were used to manage OEs. Here we performed a post hoc investigation of relationships between corneal exam findings, BCVA changes, and patient-reported ocular symptoms to explore if BCVA changes and symptoms could guide dosing, rather than corneal exams. Methods: Eye evaluations (including a corneal exam and BCVA assessment of Snellen visual acuity) were performed on all patients receiving single-agent belamaf (2.5 mg/kg) by ophthalmologists at baseline and prior to each belamaf dose. Changes in the corneal epithelium (Ker) and BCVA were both assessed as per protocol-defined criteria and assessment of grade (Gr) was based on the worse eye. BCVA grading was relative to baseline. Patient-reported ocular symptoms were reported as per the Common Terminology Criteria for Adverse Events. Results: In 12.5% of eye evaluations Gr 3–4 Ker was associated with minimal or no (Gr ≤1) BCVA changes. When patient-reported ocular symptoms were also considered, only 7.5% of evaluations found Gr 3–4 Ker with Gr ≤1 BCVA changes or ocular symptoms. Mild or no (Gr ≤2) Ker was associated with Gr ≤1 BCVA changes in 59.5% of evaluations, or in 38.8% of evaluations with no ocular symptoms reported. Overall, Gr 3–4 Ker were found in 24.9% of evaluations; by contrast, patients had Gr 2–4 BCVA changes or ocular symptoms in 53.7% of evaluations. Association of corneal epithelium changes (Ker) with BCVA changes and ocular symptoms. Conclusions: These findings highlight that BCVA changes and ocular symptoms should be further investigated to determine if they can be used as alternatives (eg, frequency of eye examinations based on symptoms) for the management of belamaf dosing to potentially reduce the burden on patients and healthcare professionals. Clinical trial information: NCT03525678. [Table: see text]