Human Metapneumovirus (hMPV) Infection and MPV467 Treatment in Immunocompromised Cotton Rats <i>Sigmodon hispidus</i>

Human metapneumovirus (hMPV) is an important cause of respiratory disease in immunocompromised individuals, yet hMPV infection has not been modeled before in immunocompromised animals. In this work, cotton rats S. hispidus immunosuppressed by cyclophosphamide were infected with hMPV, and viral replication and pulmonary inflammation in these animals were compared to those in normal hMPV-infected S. hispidus. The efficacy of prophylactic and therapeutic administration of the anti-hMPV antibody MPV467 was also evaluated. Immunosuppressed animals had higher pulmonary and nasal titers of hMPV on day 5 post-infection compared to normal animals, and large amounts of hMPV were still present in the respiratory tract of immunosuppressed animals on days 7 and 9 post-infection, indicating prolonged viral replication. Immunosuppression was accompanied by reduced pulmonary histopathology in hMPV-infected cotton rats compared to normal animals; however, a delayed increase in pathology and pulmonary chemokine expression was seen in immunosuppressed cotton rats. Prophylactic and therapeutic MPV467 treatments protected both upper and lower respiratory tracts against hMPV infection. The lung pathology and pulmonary expression of IP-10 and MIP-1α mRNA were reduced by therapeutic MPV467 administration. These results indicate that immunosuppressed cotton rats represent a useful model for studying hMPV pathogenesis and for evaluating therapeutics that could alleviate hMPV-induced disease in immunocompromised subjects

Human Metapneumovirus (hMPV) Infection and MPV467 Treatment in Immunocompromised Cotton Rats Sigmodon hispidus

Human metapneumovirus (hMPV) is an important cause of respiratory disease in immunocompromised individuals, yet hMPV infection has not been modeled before in immunocompromised animals. In this work, cotton rats S. hispidus immunosuppressed by cyclophosphamide were infected with hMPV, and viral replication and pulmonary inflammation in these animals were compared to those in normal hMPV-infected S. hispidus. The efficacy of prophylactic and therapeutic administration of the anti-hMPV antibody MPV467 was also evaluated. Immunosuppressed animals had higher pulmonary and nasal titers of hMPV on day 5 post-infection compared to normal animals, and large amounts of hMPV were still present in the respiratory tract of immunosuppressed animals on days 7 and 9 post-infection, indicating prolonged viral replication. Immunosuppression was accompanied by reduced pulmonary histopathology in hMPV-infected cotton rats compared to normal animals; however, a delayed increase in pathology and pulmonary chemokine expression was seen in immunosuppressed cotton rats. Prophylactic and therapeutic MPV467 treatments protected both upper and lower respiratory tracts against hMPV infection. The lung pathology and pulmonary expression of IP-10 and MIP-1&alpha; mRNA were reduced by therapeutic MPV467 administration. These results indicate that immunosuppressed cotton rats represent a useful model for studying hMPV pathogenesis and for evaluating therapeutics that could alleviate hMPV-induced disease in immunocompromised subjects

The Role of Interleukin-converting Enzyme in Fas-mediated Apoptosis in HIV-1 Infection

Apoptosis of CD4 � lymphocytes is partially responsible for the depletion of these cells in HIV-infected individuals. CD4 � lymphocytes from HIV-1–infected patients express higher membrane levels of the Fas receptor, and are particularly susceptible to apoptosis after Fas triggering. IL-1�– converting enzyme (ICE) is a key enzyme of the apoptotic machinery involved in Fas-mediated apoptosis of normal lymphocytes. The role of ICE in mediating the increased susceptibility of CD4 � lymphocytes from HIV-1–infected patients to apoptosis has not been examined. In this study, we found that ICE mRNA was present in T cells from both HIV-1–infected patients and controls. Active ICE proteins, p10 and p20, were demonstrated by immunoblot in lymphocytes from HIV-1–infected patients and in normal lymphocyte

Challenges and opportunities in RSV vaccine development: Meeting report from FDA/NIH workshop

Respiratory syncytial virus (RSV) is the most common cause of serious acute lower respiratory illness in infants and young children and a significant cause of disease burden in the elderly and immunocompromised. There are no licensed RSV vaccines to address this significant public health need. While advances in vaccine technologies have led to a recent resurgence in RSV vaccine development, the immune correlates of protection against RSV and the immunology of vaccine-associated enhanced respiratory disease (ERD) remain poorly understood. FDA\u27s Center for Biologics Evaluation and Research (CBER) and NIH\u27s National Institute of Allergy and Infectious Diseases (NIAID) organized and co-sponsored an RSV Vaccines Workshop in Bethesda, Maryland on June 1 and 2, 2015. The goal of the conference was to convene scientists, regulators, and industry stakeholders to discuss approaches to RSV vaccine development within the context of three target populations - infants and children, pregnant women, and individuals \u3e60years of age. The agenda included topics related to RSV vaccine development in general, as well as considerations specific to each target population, such as clinical and serological endpoints. The meeting focused on vaccine development for high income countries (HIC), because issues relevant to vaccine development for low and middle income countries (LMIC) have been discussed in other forums. This manuscript summarizes the discussion of clinical, scientific, and regulatory perspectives, research gaps, and lessons learned

Report of the WHO technical consultation on the evaluation of respiratory syncytial virus prevention cost effectiveness in low- and middle-income countries, April 7-8, 2022

Abstract: Policymakers often rely on impact and cost-effectiveness evaluations to inform decisions about the introduction of health interventions in low- and middle-income countries (LMICs); however, cost-effectiveness results for the same health intervention can differ by the choice of parameter inputs, modelling assumptions, and geography. Anticipating the near-term availability of new respiratory syncytial virus (RSV) prevention products, WHO convened a two-day virtual consultation in April 2022 with stakeholder groups and global experts in health economics, epidemiology, and vaccine implementation. The objective was to review methods, parameterization, and results of existing cost-effectiveness analyses for RSV prevention in LMICs; identify the most influential inputs and data limitations; and recommend and prioritize future data gathering and research to improve RSV prevention impact estimates in LMICs. Epidemiological parameters identified as both influential and uncertain were those associated with RSV hospitalization and death, specifically setting-specific hospitalization rates and RSV-attributable death rates. Influential economic parameters included product price, delivery costs, willingnessto-pay for health on the part of potential donors, and the cost of RSV-associated hospitalization. Some of the influential parameters identified at this meeting should be more precisely measured by further research. Other influential economic parameters that are highly uncertain may not be resolved, and it is appropriate to use sensitivity analyses to explore these within cost-effectiveness evaluations. This report highlights the presentations and major discussions of the meeting