Jeffrey L. Stein

The ability of influenza virus to undergo rapid antigenic shift to elude humoral immunity highlights the need for effective broad-spectrum influenza antivirals for treatment, prophylaxis and pandemic preparedness. Strategies providing durable, universal influenza protection in healthy and high-risk populations are urgently needed. Here we describe the design and preclinical characterization of CD388, a first-in-class antiviral drug-Fc conjugate (DFC), in mice and cynomolgus macaques. CD388 comprises a multivalent conjugate of the influenza virus neuraminidase inhibitor zanamivir, linked to a CH1-Fc hybrid domain of human IgG1 engineered for extended half-life. CD388 improves the antiviral activity of zanamivir, demonstrating potent, universal activity across influenza A and B viruses, including high pathogenicity and neuraminidase inhibitor resistant strains, a low potential for resistance development and potent efficacy in lethal mouse infection models. These results suggest that CD388 has the potential for universal prevention of influenza A and B in healthy and high-risk populations.

SUMMARY The ability of the influenza virus to elude humoral immunity by rapid antigenic shift presents a sustained and urgent threat to human health. Globally, seasonal influenza causes an estimated 3 - 5 million cases of severe disease and 300,000 - 500,000 deaths annually, with increased potential for mortality during pandemics 1 . The recent outbreaks of avian H5N1 in bird populations, subsequent spread to cattle and appearance in humans, highlight the need for effective broad-spectrum influenza antivirals for treatment, prophylaxis and pandemic preparedness. The narrow, strain-specific immunity induced by current seasonal vaccines and mismatches between vaccine strains and circulating viruses result in limited vaccine effectiveness (VE) rates 2 . Furthermore, VE is even lower in immune-compromised and - senescent populations 3 . Strategies that provide durable, universal influenza protection in healthy and high-risk populations are urgently needed. Here, we describe CD388, a first-in-class antiviral drug-Fc conjugate (DFC) in clinical trials for seasonal influenza prevention ( NCT05285137 and NCT05523089 ). CD388 comprises a multivalent small molecule inhibitor of influenza virus neuraminidase (NA) linked to a C H 1-Fc hybrid domain of human IgG1 engineered for extended half-life. CD388 demonstrated potent, universal activity across influenza A and B viruses, including high pathogenicity and NA resistant strains, a low potential for resistance development, and efficacy in lethal mouse infection models. CD388 is the first therapeutic with the potential for universal prevention of influenza A and B in healthy and high-risk populations.

Workload management is a critical concern in shared control of unmanned ground vehicles. In response to this challenge, prior studies have developed methods to estimate human operators’ workload by analyzing their physiological data. However, these studies have primarily adopted a single-model-single-feature or a single-model-multiple-feature approach. The present study proposes a Bayesian inference model to estimate workload, which leverages different machine learning models for different features. We conducted a human subject experiment with 24 participants, in which a human operator teleoperated a simulated High Mobility Multipurpose Wheeled Vehicle (HMMWV) with the help from an autonomy while performing a surveillance task simultaneously. Participants’ eye-related features, including gaze trajectory and pupil size change, were used as the physiological input to the proposed Bayesian inference model. Results show that the Bayesian inference model achieves a 0.823 F1 score, 0.824 precision, and 0.821 recall, outperforming the single models.