SARS-CoV-2 viral dynamic modeling to inform model selection and timing and efficacy of antiviral therapy

Mathematical models of viral dynamics have been reported to describe adequately the dynamic changes of severe acute respiratory syndrome-coronavirus 2 viral load within an individual host. In this study, eight published viral dynamic models were assessed, and model selection was performed. Viral load data were collected from a community surveillance study, including 2155 measurements from 162 patients (124 household and 38 non-household contacts). An extended version of the target-cell limited model that includes an eclipse phase and an immune response component that enhances viral clearance described best the data. In general, the parameter estimates showed good precision (relative standard error <10), apart from the death rate of infected cells. The parameter estimates were used to simulate the outcomes of a clinical trial of the antiviral tixagevimab-cilgavimab, a monoclonal antibody combination which blocks infection of the target cells by neutralizing the virus. The simulated outcome of the effectiveness of the antiviral therapy in controlling viral replication was in a good agreement with the clinical trial data. Early treatment with high antiviral efficacy is important for desired therapeutic outcome

Exploring the role of antiviral nasal sprays in the control of emerging respiratory infections in the community

Introduction: The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission. We explore the benefits and challenges of the use of antibody-based nasal sprays prior and post exposure to the virus. Methods: The classic susceptible-exposed-infectious-removed (SEIR) mathematical model was extended to describe the potential population-level impact of intranasal antibody prophylaxis on controlling the spread of an emerging respiratory infection in the community. Results: Intranasal administration of monoclonal antibodies provides only a short-term protection to the mucosal surface. Consequently, sustained intranasal antibody prophylaxis of a substantial proportion of the population would be needed to contain infections. Post-exposure prophylaxis against the development of severe disease would be essential for the overall reduction in hospital admissions. Conclusion: Antibody-based nasal sprays could provide protection against infection to individuals that are likely to be exposed to the virus. Large-scale administration for a long period of time would be challenging. Intranasal antibody prophylaxis alone cannot prevent community-wide transmission of the virus. It could be used along with other protective measures, such as non-pharmaceutical interventions, to bridge the time required to develop and produce effective vaccines, and complement active immunisation strategies.</p

SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies

Neither vaccination nor natural infection result in long-lasting protection against SARS-COV-2 infection and transmission, but both reduce the risk of severe COVID-19. To generate insights into optimal vaccination strategies for prevention of severe COVID-19 in the population, we extended a Susceptible-Exposed-Infectious-Removed (SEIR) mathematical model to compare the impact of vaccines that are highly protective against severe COVID-19 but not against infection and transmission, with those that block SARS-CoV-2 infection. Our analysis shows that vaccination strategies focusing on the prevention of severe COVID-19 are more effective than those focusing on creating of herd immunity. Key uncertainties that would affect the choice of vaccination strategies are: (1) the duration of protection against severe disease, (2) the protection against severe disease from variants that escape vaccine-induced immunity, (3) the incidence of long-COVID and level of protection provided by the vaccine, and (4) the rate of serious adverse events following vaccination, stratified by demographic variables

A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine. These data provide a proof-of-concept for broad, pre-exposure protection against a potential future pandemic using the intranasal administration route. Studies in humans should assess if autonomous administration of a broadly-neutralizing monoclonal antibody is safe and effective and can thus contribute to pandemic preparedness.</p

A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine. These data provide a proof-of-concept for broad, pre-exposure protection against a potential future pandemic using the intranasal administration route. Studies in humans should assess if autonomous administration of a broadly-neutralizing monoclonal antibody is safe and effective and can thus contribute to pandemic preparedness.</p