Lineage-matched versus mismatched influenza B vaccine effectiveness following seasons of marginal influenza B circulation.

BACKGROUND: Several countries have recently transitioned from the trivalent inactivated influenza vaccine (TIV) to the quadrivalent inactivated influenza vaccine (QIV) in order to outweigh influenza B vaccine-mismatch. However, few studies thus far evaluated its benefits versus the TIV in a systematic manner. Our objective was to compare the QIV VE with lineage-mismatched TIV VE. METHODS: We estimated the 2015-2016, 2017-2018, 2019-2020 end-of season influenza B VE against laboratory-confirmed influenza-like illness (ILI) among community patients, using the test-negative design. VE was estimated for pre-determined age groups and for moving age intervals of 15 years. RESULTS: Since 2011-2012 season, alternate seasons in Israel were dominated by influenza B circulation. Compared with the lineage-mismatched TIV used during the 2015-2016 and 2017-2018 seasons, the 2019-2020 QIV showed the highest all-ages VE, with VE estimates of 56.9 (95% CI 30.1 to 73.4), 16.5 (95% CI -22.5 to 43.1) and -25.8 (95% CI -85.3 to 14.6) for the 2019-2020, 2017-2018 and 2015-2016 seasons, respectively. The 2019-2020 VE point estimated were the highest for the 0.5-4, 5-17 and 18-44 years age groups and for more 15-year age intervals as compared to the other seasons. CONCLUSIONS: Our results support the rapid transition from the TIV to the QIV.

Predominance of a Drifted Influenza A (H3N2) Clade and its Association with Age-specific Influenza Vaccine Effectiveness Variations, Influenza Season 2018-2019.

Background: Influenza A (H3N2) clade 3C.3a was the predominant influenza virus in Israel throughout the 2018-2019 season, constituting a drift from the influenza A (H3N2) vaccine. We estimated the end-of season vaccine effectiveness (VE) by age, among community patients with influenza-like illness (ILI), considering the hemagglutinin (HA) gene mutations and amino acid substitutions of influenza A (H3N2) viruses detected. Methods: Nose-throat samples were analyzed for the presence of influenza virus, type/subtype, and HA gene sequence. HA gene sequences and amino acid substitutions were compared to the influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like 2018-2019 vaccine virus, and a phylogenetic tree was generated. Influenza VE against influenza A (H3N2) was estimated using the test-negative design. VE was estimated by age group and by 15 year moving age intervals. Results: In total, 90% of the influenza A (H3N2) viruses belonged to the 3C.3a clade, constituting a unique situation in the northern hemisphere. Adjusted all-age influenza A (H3N2) VE was -3.5% (95% CI: -51.2 to 29.1). Although adjusted VEs were very low among infants, children, and young adults, a VE of 45% (95% CI: -19.2 to 74.6) was estimated among adults aged ≥45 years old. Conclusions: The higher VE point estimates among older adults may be related to previous exposure to similar influenza viruses.

Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.

CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2-/-;Flt3ITD AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.