Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2–induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

Understanding the magnitude of responses to vaccination during the ongoing SARS-CoV-2 pandemic is essential for ultimate mitigation of the disease. Here, we describe a cohort of 102 subjects (70 COVID-19-naïve, 32 COVID-19-experienced) who received two doses of one of the mRNA vaccines (BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna)). We document that a single exposure to antigen via infection or vaccination induces a variable antibody response which is affected by age, gender, race, and co-morbidities. In response to a second antigen dose, both COVID-19-naïve and experienced subjects exhibited elevated levels of anti-spike and SARS-CoV-2 neutralizing activity; however, COVID-19-experienced individuals achieved higher antibody levels and neutralization activity as a group. The COVID-19-experienced subjects exhibited no significant increase in antibody or neutralization titer in response to the second vaccine dose (i.e., third antigen exposure). Finally, we found that COVID-19-naïve individuals who received the Moderna vaccine exhibited a more robust boost response to the second vaccine dose (p = 0.004) as compared to the response to Pfizer–BioNTech. Ongoing studies with this cohort will continue to contribute to our understanding of the range and durability of responses to SARS-CoV-2 mRNA vaccines.

The Ebola virus (EBOV) causes severe disease in humans, and animal models are needed to evaluate the efficacy of vaccines and therapeutics. While non-human primate (NHP) and rodent EBOV infection models have been well characterized, there is a growing need for an intermediate model. Here, we provide the first report of a small-particle aerosol (AE) EBOV ferret model and disease progression compared with the intramuscular (IM) EBOV ferret model. EBOV infection of ferrets by either route resulted in uniform lethality in 5–6.5 days post infection (dpi) in a dose-dependent manner, with IM-infected ferrets succumbing significantly earlier than AE-infected ferrets. EBOV disease progression differed between AE and IM routes, with significant viremia and presence of virus in target organs occurring earlier in the AE model. In contrast, significant fever, clinical signs of disease, liver pathology, and systemic inflammation occurred earlier in the IM EBOV model. Hepatocellular damage and splenic pathology were noted in both models, while pronounced lung pathology and renal impairment were exclusive to the AE and IM models, respectively. These results demonstrate that small-particle AE and IM ferret EBOV models share numerous common features with NHP and human EBOV infection by these routes and will therefore be useful for the development of vaccine and therapeutic countermeasures.