Antiviral mechanisms of two broad-spectrum monoclonal antibodies for rabies prophylaxis and therapy

Rabies is an acute and lethal encephalomyelitis caused by lyssaviruses, among which rabies virus (RABV) is the most prevalent and important for public health. Although preventable through the post-exposure administration of rabies vaccine and immunoglobulins (RIGs), the disease is almost invariably fatal since the onset of clinical signs. Two human neutralizing monoclonal antibodies (mAbs), RVC20 and RVC58, have been shown to be effective in treating symptomatic rabies. To better understand how these mAbs work, we conducted structural modeling and in vitro assays to analyze their mechanisms of action, including their ability to mediate Fc-dependent effector functions. Our results indicate that both RVC20 and RVC58 recognize and lock the RABV-G protein in its pre-fusion conformation. RVC58 was shown to neutralize more potently the extra-cellular virus, while RVC20 mainly acts by reducing viral spreading from infected cells. Importantly, RVC20 was more effective in promoting effector functions compared to RVC58 and 17C7-RAB1 mAbs, the latter of which is approved for human rabies post-exposure treatment. These results provide valuable insights into the multiple mechanisms of action of RVC20 and RVC58 mAbs, offering relevant information for the development of these mAbs as treatment for human rabies

Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20-RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response

From COVID-19 Pandemic to Patient Safety: A New "Spring" for Telemedicine or a Boomerang Effect?

During the Covid-19 health emergency, telemedicine was an essential asset through which health systems strengthened their response during the critical phase of the pandemic. According to the post-pandemic economic reform plans of many countries, telemedicine will not be limited to a tool for responding to an emergency condition but it will become a structural resource that will contribute to the reorganization of Healthcare Systems and enable the transfer of part of health care from the hospital to the home-based care. However, scientific evidences have shown that health care delivered through telemedicine can be burdened by numerous ethical and legal issues. Although there is an emerging discussion on patient safety issues related to the use of telemedicine, there is a lack of reseraches specifically designed to investigate patient safety. On the contrary, it would be necessary to determine standards and specific application rules in order to ensure safety. This paper examines the telemedicine-risk profiles and proposes a position statement for clinical risk management to support continuous improvement in the safety of health care delivered through telemedicine

Rabies and canine distemper virus epidemics in the red fox population of Northern Italy (2006–2010)

Since 2006 the red fox (Vulpes vulpes) population in north-eastern Italy has experienced an epidemic of canine distemper virus (CDV). Additionally, in 2008, after a thirteen-year absence from Italy, fox rabies was re-introduced in the Udine province at the national border with Slovenia. Disease intervention strategies are being developed and implemented to control rabies in this area and minimise risk to human health. Here we present empirical data and the epidemiological picture relating to these epidemics in the period 2006-2010. Of important significance for epidemiological studies of wild animals, basic mathematical models are developed to exploit information collected from the surveillance program on dead and/or living animals in order to assess the incidence of infection. These models are also used to estimate the rate of transmission of both diseases and the rate of vaccination, while correcting for a bias in early collection of CDV samples. We found that the rate of rabies transmission was roughly twice that of CDV, with an estimated effective contact between infected and susceptible fox leading to a new infection occurring once every 3 days for rabies, and once a week for CDV. We also inferred that during the early stage of the CDV epidemic, a bias in the monitoring protocol resulted in a positive sample being almost 10 times more likely to be collected than a negative sample. We estimated the rate of intake of oral vaccine at 0.006 per day, allowing us to estimate that roughly 68% of the foxes would be immunised. This was confirmed by field observations. Finally we discuss the implications for the eco-epidemiological dynamics of both epidemics in relation to control measures

Efficacy of conventional versus innovative therapies for treating skin wounds in veterinary medicine

open16siINTRODUCTION: The skin is the largest organ of mammals. The loss of skin integrity may induce important dysfunctions or even death. For superficial wounds, the endogenous healing mechanisms in combination with traditional wound care are sufficient to achieve functional repair. In contrast, in larger wounds, like third and fourth degree burns, chronic wound or deep ulcers it is difficult to obtain the restitutio ad integrum and fibrosis and/or scar tissue develops1,2. The aim of this study was to verify the efficacy of conventional and innovative topic treatments on skin regeneration, induced experimentally in sheep. To achieve this goal different types of investigations (clinical, molecular, histological, immunohistochemical) were performed. METHODS: Six skin lesions (4x4cm) were surgically created on the back of six healthy adult sheep; every single wound was destined, in a randomized way, to one of the following treatments: Acemannan gel, Manuka Honey, hyaluronic acid, Plasma3 (ionized gas), allogeneic mesenchymal stem cells isolated from peripheral blood (PB-MSCs). The sixth wound was the placebo. Biopsies were collected with a surgical punch (0,6x0,6 cm) at time T0, T15 and T40 days. Lesions were clinically evaluated considering the presence and color of wound fluid, the state of hydration, the wound surface/surroundings and other parameters. Histological examinations considered crust formation, re-epithelization and epidermal thickness, dermis edema, extension of granulation tissue, acute and chronic inflammation. Immunohistochemistry for evaluation of inflammation, vascularization and cell proliferation was performed using CD3, CD20, MHCII, von Willebrand factor (vWF) and KI67 antibodies. Furthermore, Real time-PCR investigated genes as V ascular endothelial growth factors (VEGF), Transforming growth factor beta 1(TGFβ1), Vimentin (VIM), Collagen 1α1 (Col1α1) and hair Keratin (hKER). RESULTS: Clinically, the lesions treated with plasma healed more rapidly respect to other treatments and a reduced bacterial load was observed. At T7 wounds treated with stem cells and plasma were less macerated than lesions treated with other therapies. At T15 the wounds treated with hyaluronic acid showed a normal state of hydration while lesions treated with Manuka Honey exhibited a normal hydration from the third week only (Acemannan gel at fourth week). From the second week onwards all wounds did not show presence of fluid and exhibited a dry and clean secondary layer. All lesions, excluded wounds treated with acemannan gel, presented a red (hyaluronic acid and plasma) and dark red (Manuka Honey, PB-MSCs) granulation tissue starting from the first week. Molecular analysis showed a correspondence between clinical and molecular/histologic results. For instance, VEGF mRNA expression confirms angiogenetic events observed at histological level while TGF-β, CD3 and CD20 mRNA/protein expression indicated the presence/absence of inflammation in the used treatments. DISCUSSION & CONCLUSIONS: Innovative therapies led to surprising results regarding regeneration of mammalian skin. Indeed, on the basis of clinical analysis, wounds treated with plasma and MSC healed more rapidly. Further examinations are ongoing in order to elucidate possible mechanisms explaining these differences. REFERENCES: 1S.Y. Broeckx, S. Maes, T. Martinello, et al (2014) Equine epidermis: a source of epithelial-like stem/progenitor cells with in vitro and in vivo regenerative capacities Stem Cells Dev, pp 1134-48. 2J.H. Spaas, C. Gomiero, S.Y. Broeckx, et al (2016) Wound healing markers after autologous and allogeneic epithelial-like stem cell treatment Cytotherapy 2016 (in press). 3E. Martines, M. Zuin, R. Cavazzana, et al. (2009) A novel plasma source for sterilization of living tissues, New J. Phys. 11, 115014.openPatruno, MARCO VINCENZO; Gomiero, Chiara; Martinello, Tiziana; Perazzi, Anna; Gemignani, F; DE BENEDICTIS, GIULIA MARIA; Ferro, Silvia; Zuin, M; Martines, E; Cordaro, Luigi; Brun, Paola; Maccatrozzo, Lisa; Broeckx, Sy; Spaas, Jh; Chiers, K; Iacopetti, IlariaPatruno, MARCO VINCENZO; Gomiero, Chiara; Martinello, Tiziana; Perazzi, Anna; Gemignani, F; DE BENEDICTIS, GIULIA MARIA; Ferro, Silvia; Zuin, M; Martines, E; Cordaro, Luigi; Brun, Paola; Maccatrozzo, Lisa; Broeckx, Sy; Spaas, Jh; Chiers, K; Iacopetti, Ilari

Reassortant Avian Influenza Virus (H5N1) in Poultry, Nigeria, 2007

Reassortant Influenza Virus (H5N1) in Poultry, Nigeria, 200

From syndemic lesson after COVID-19 pandemic to a “systemic clinical risk management” proposal in the perspective of the ethics of job well done

The syndemic framework proposed by the 2021–2030 World Health Organization (WHO) action plan for patient safety and the introduction of enabling technologies in health services involve a more effective interpretation of the data to understand causation. Based on the Systemic Theory, this communication proposes the “Systemic Clinical Risk Management” (SCRM) to improve the Quality of Care and Patient Safety. This is a new Clinical Risk Management model capable of developing the ability to observe and synthesize different elements in ways that lead to in-depth interventions to achieve solutions aligned with the sustainable development of health services. In order to avoid uncontrolled decision-making related to the use of enabling technologies, we devised an internal Learning Algorithm Risk Management (LARM) level based on a Bayesian approach. Moreover, according to the ethics of Job Well Done, the SCRM, instead of giving an opinion on events that have already occurred, proposes a bioethical co-working because it suggests the best way to act from a scientific point of view

Disease control tools to secure animal and public health in a densely populated world

Animal health is a prerequisite for global health, economic development, food security, food quality, and poverty reduction, while mitigating against climate change and biodiversity loss. We did a qualitative review of 53 infectious diseases in terrestrial animals with data from DISCONTOOLS, a specialist database and prioritisation model focusing on research gaps for improving infectious disease control in animals. Many diseases do not have any appropriate control tools, but the prioritisation model suggests that we should focus international efforts on Nipah virus infection, African swine fever, contagious bovine pleuropneumonia, peste des petits ruminants, sheeppox and goatpox, avian influenza, Rift Valley fever, foot and mouth disease, and bovine tuberculosis, for the greatest impact on the UN's Sustainable Development Goals. Easy to use and accurate diagnostics are available for many animal diseases. However, there is an urgent need for the development of stable and durable diagnostics that can differentiate infected animals from vaccinated animals, to exploit rapid technological advances, and to make diagnostics widely available and affordable. Veterinary vaccines are important for dealing with endemic, new, and emerging diseases. However, fundamental research is needed to improve the convenience of use and duration of immunity, and to establish performant marker vaccines. The largest gap in animal pharmaceuticals is the threat of pathogens developing resistance to available drugs, in particular for bacterial and parasitic (protozoal, helminth, and arthropod) pathogens. We propose and discuss five research priorities for animal health that will help to deliver a sustainable and healthy planet: vaccinology, antimicrobial resistance, climate mitigation and adaptation, digital health, and epidemic preparedness

Development of broad‐spectrum human monoclonal antibodies for rabies post‐exposure prophylaxis

Currently available rabies post‐exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad‐spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non‐RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20–RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post‐vaccination antibody response

Disease control tools to secure animal and public health in a densely populated world

Animal health is a prerequisite for global health, economic development, food security, food quality, and poverty reduction, while mitigating against climate change and biodiversity loss. We did a qualitative review of 53 infectious diseases in terrestrial animals with data from DISCONTOOLS, a specialist database and prioritisation model focusing on research gaps for improving infectious disease control in animals. Many diseases do not have any appropriate control tools, but the prioritisation model suggests that we should focus international efforts on Nipah virus infection, African swine fever, contagious bovine pleuropneumonia, peste des petits ruminants, sheeppox and goatpox, avian influenza, Rift Valley fever, foot and mouth disease, and bovine tuberculosis, for the greatest impact on the UN's Sustainable Development Goals. Easy to use and accurate diagnostics are available for many animal diseases. However, there is an urgent need for the development of stable and durable diagnostics that can differentiate infected animals from vaccinated animals, to exploit rapid technological advances, and to make diagnostics widely available and affordable. Veterinary vaccines are important for dealing with endemic, new, and emerging diseases. However, fundamental research is needed to improve the convenience of use and duration of immunity, and to establish performant marker vaccines. The largest gap in animal pharmaceuticals is the threat of pathogens developing resistance to available drugs, in particular for bacterial and parasitic (protozoal, helminth, and arthropod) pathogens. We propose and discuss five research priorities for animal health that will help to deliver a sustainable and healthy planet: vaccinology, antimicrobial resistance, climate mitigation and adaptation, digital health, and epidemic preparedness