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Background In 2018, the World Health Organization estimated up to 650,000 influenza-related respiratory deaths occur annually. Cidara therapeutics is developing a novel class of potent, long-acting antiviral Fc-conjugates (AVCs) against influenza that in a single molecule combine a surface-acting antiviral agent with the Fc domain of a human IgG1 antibody. AVCs function by inhibiting viral replication while simultaneously engaging the immune system, providing a multimodal mechanism of action. Here we present efficacy data on an AVC development candidate against influenza A and B. Methods Efficacy studies were conducted in female BALB/c mice (6–8 weeks) challenged intranasally with 3x the LD95 of influenza A/Puerto Rico/8/1934 (H1N1) or B/Malaysia/2506/04. CB-012 or CB-012b (CB-012 with slightly modified Fc) was administered as a single intravenous (IV) dose 2 hours after challenge. Oseltamivir was dosed orally, twice daily for 5 days in the influenza A study. Vehicle and appropriate Fc controls were included. Body weights (BW) and mortality were monitored for 2 weeks; animals with 20% BW loss, or moribund, were scored as a death. Results In an initial study of CB-012 against influenza A, a single IV dose of 0.4 mg/kg was fully protective and statistically significant compared with the Fc control (P = 0.0027). In contrast, mice treated with oseltamivir at 5 mg/kg twice daily for 5 days were not protected; only the higher 20 mg/kg dose was fully protective. Importantly, mice treated with CB-012 (0.4 mg/kg) showed a transient BW loss of 1% compared with 14% in mice of the oseltamivir (20 mg/kg) group, although treatment was initiated at the same time. In a second study against influenza B, CB-012b was fully protective with a single IV dose at 0.3 mg/kg (P = 0.0027). In contrast, vehicle and Fc control groups reached mortality by day 6. BW loss in the CB-012b 0.3 mg/kg group was transient and <4% overall during the study. Conclusion The novel AVCs CB-012 and CB-012b demonstrated robust efficacy in multiple influenza models. In conjunction with previous findings against influenza A (H3N2), the data on CB-012 support its potential as a candidate against seasonal influenza. The continued development of CB-012 for the prevention and treatment of influenza is warranted. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]