Efficacy and Safety of Pimodivir Combined with Standard-of-care in Hospitalized and Non-hospitalized High-risk Adolescents and Adults with Influenza A Infection.

BACKGROUND: An unmet need exists for effective antivirals to treat patients hospitalized with influenza. The results of 2 Phase 3 studies evaluating the efficacy and safety of pimodivir in combination with investigator-chosen standard-of-care (SoC) treatment are presented. METHODS: Hospitalized patients (hospital study; NCT03376321) and high-risk outpatients (outpatient study; NCT03381196) with laboratory-confirmed influenza A infection were randomized 1:1 to 600 mg pimodivir twice daily (BID) + SoC, or placebo BID + SoC for 5 days. For most patients SoC included oseltamivir. Primary endpoints were Hospital Recovery Scale (HRS) at Day 6 (hospital study) and median time to resolution (TTR) of influenza-related symptoms (outpatient study). RESULTS: Pimodivir + SoC (oseltamivir) treatment showed no clinical benefit over placebo + SoC on HRS at Day 6 (common odds ratio, 0.943 [95% CI, 0.609-1.462], P = .397; hospital study). A shorter median TTR of 7 symptoms was estimated with pimodivir + SoC versus placebo (92.6 hours [95% CI, 77.6-104.2] versus 105.1 hours [95% CI, 92.7-128.6], P = .0216; outpatient study). CONCLUSION: Pimodivir + SoC showed no additional clinical benefit versus SoC treatment alone in hospitalized patients. Pimodivir + SoC demonstrated shorter TTR of influenza symptoms versus placebo + SoC in high-risk outpatients.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.