trivalent influenza vaccine (Istivac / Mutagrip S / Mutagrip)

A Phase 2 Trial Evaluating the Immunogenicity and Safety of an mRNA-Based Seasonal Influenza Vaccine Candidate Encoding Hemagglutinin and Neuraminidase.

Moldt Brian B, Ubeda Rafael A RA, Murray Alexander V AV, Tima Giresse G et al.

Influenza vaccines targeting both hemagglutinin (HA) and neuraminidase (NA) might offer broader protection than current vaccines, which primarily target HA. This randomized phase 2 study evaluated the immunogenicity and safety of an investigational mRNA-based trivalent seasonal influenza vaccine encoding HA and NA from A/H1N1, A/H3N2, and B/Victoria (FLUm3HA-3NA). Participants aged 18-64 years (younger adults) or 65-85 years (older adults) received one of several mRNA vaccine formulations-each containing different influenza A and B HA mRNA doses-or an age-appropriate licensed seasonal influenza vaccine as a comparator. Four formulations per age cohort were tested in part 1 of the study, and one formulation per age cohort in part 2. Day-29 hemagglutination inhibition (HI) and NA inhibition (NI) responses were assessed as primary and secondary endpoints, respectively, safety/reactogenicity as the secondary, and virus neutralization as the tertiary endpoint. A total of 250 younger and 260 older adults were vaccinated in part 1; 161 and 162, respectively, in part 2. All FLUm3HA-3NA formulations induced HI, NI, and neutralizing responses above baseline. In part 1, HI responses against A/H1N1 and A/H3N2 were similar or higher after FLUm3HA-3NA than after comparator vaccination in both age groups. For B/Victoria, HI responses were lower or similar versus comparator vaccination in younger adults and similar or higher in older adults. In part 2, HI responses were similar or higher with FLUm3HA-3NA versus comparators for A/H1N1 and A/H3N2, and lower for B/Victoria in both age groups. In both study parts and both age groups, NI titers were higher for all three strains with FLUm3HA-3NA versus comparators, and neutralizing titers were similar or higher for A/H1N1 and A/H3N2 and similar for B/Victoria. No safety concerns were identified. FLUm3HA-3NA induced HI, NI, and neutralizing responses, with an acceptable safety profile. The results support further development, including optimization of the influenza B HI response. ClinicalTrials.gov: NCT06431607.

A Phase 1/2 Trial Evaluating the Safety and Immunogenicity of an mRNA-based Seasonal Influenza Vaccine Candidate Encoding Hemagglutinin and Neuraminidase.

De Coster Ilse I, Cardona Jose F JF, Ferguson Murdo M, Leroux-Roels Isabel I et al.

Hemagglutinin (HA) is the principal immunologic target of most licensed seasonal influenza vaccines. Targeting both HA and neuraminidase (NA) might improve vaccine effectiveness. This randomized phase 1/2 study evaluated an investigational mRNA-based quadrivalent seasonal influenza vaccine, encoding HA and NA of A/H1N1, A/H3N2, B/Victoria, and B/Yamagata (FLUm4HA-4NA). In phase 1, adults aged 18-50 years received either one of twelve mRNA vaccine formulations of varying HA-only or HA and NA mRNA doses, or a licensed quadrivalent seasonal influenza comparator. In phase 2, participants aged 18-64 years (younger adults) and 65-85 years (older adults) received FLUm4HA-4NA (three groups per age category, with different HA/NA mRNA doses) or age-appropriate licensed quadrivalent comparator. Primary endpoints were safety/reactogenicity, and hemagglutination inhibition [HI] and NA inhibition [NI] responses against the four seasonal strains at day 29. Cross-reactive HI/NI responses against drifted strains, virus neutralization, and HA-/NA-specific cell-mediated immunity were evaluated in phase 2 as tertiary objectives. A total of 293 participants (21-25 per group) were vaccinated in phase 1, 480 younger (108-137 per group) and 483 older adults (117-125 per group) in phase 2. Solicited events were more frequent with FLUm4HA-4NA than comparators and were mostly short-lived and mild or moderate. No deaths or vaccine-related serious adverse events were reported. Post-vaccination HI and neutralizing titers in the FLUm4HA-4NA groups were similar or higher for the A strains and lower for the B strains versus comparators. NI responses exceeded those of comparators for all four strains. HI and NI titers against evaluated drifted A strains were similar or higher after FLUm4HA-4NA than after comparator vaccination. HA-specific CD4+ and CD8+ T-cell responses were generally higher after FLUm4HA-4NA than comparator vaccination. FLUm4HA-4NA showed an acceptable safety profile and humoral and cellular immunogenicity in the study population, supporting further development and formulation optimization to improve influenza B HI responses. ClinicalTrials.gov: NCT05823974; euclinicaltrials.eu: 2022-502308-66-00.

Myeloid cell expression of the VDR and parathyroid hormone control the host response to influenza infection in mice.

Tang Mengzhu M, Froelich Nicole E NE, Hanna Nicholas J NJ, Weaver Veronika C VC et al.

Respiratory infections caused by seasonal influenza viruses remain a major global health burden. Vitamin D receptor (VDR) signaling regulates immune responses, but the role of the VDR and its interaction with parathyroid hormone (PTH) in host resistance to H1N1 influenza infection is not understood. Global VDR knockout (KO) mice, or myeloid (M) deletion of the VDR (M-VDR KO) and the respective wildtype (WT) littermates were infected with H1N1 influenza virus. Additional experiments treated WT mice with intermittent PTH or vehicle and then infected them with a H1N1 influenza A virus. Disease severity, mortality, viral burden and clearance, lung pathology, and inflammatory cytokine responses were evaluated. H1N1 influenza infection of WT mice resulted in non-lethal disease, whereas VDR KO mice had 21% mortality, delayed viral clearance, more severe symptoms and lung pathology. The increased severity of respiratory disease was accompanied by higher type I and II interferon responses in the lungs. M-VDR KO mice had increased disease severity and delayed viral clearance compared to WT littermates. PTH-treated WT mice had increased clinical scores, influenza M gene, and cytokine responses compared to vehicle treated WT mice. The work describes a novel paradigm in which the vitamin D-PTH axis governs host resistance to influenza virus disease by controlling the amount of inflammation and the amount of virus in the lung. In addition, the data suggest that VDR expression in myeloid cells is critical for controlling the early innate immune response to influenza viruses.

A 79-Year-Old Man With Encephalopathy, Ataxia, and Severe Functional Decline After Influenza Infection: A Clinical Vignette.

Hassan Bilaal B, Tarin Marisol M, Sarapao Shaquila S, Balch Robert J RJ