Monoclonal antibodies for prophylaxis and therapy of respiratory syncytial virus, SARS-CoV-2, human immunodeficiency virus, rabies and bacterial infections: an update from the World Association of Infectious Diseases and Immunological Disorders and the Italian Society of Antinfective Therapy.

Monoclonal antibodies (mABs) are safe and effective proteins produced in laboratory that may be used to target a single epitope of a highly conserved protein of a virus or a bacterial pathogen. For this purpose, the epitope is selected among those that play the major role as targets for prevention of infection or tissue damage. In this paper, characteristics of the most important mABs that have been licensed and used or are in advanced stages of development for use in prophylaxis and therapy of infectious diseases are discussed. We showed that a great number of mABs effective against virus or bacterial infections have been developed, although only in a small number of cases these are licensed for use in clinical practice and have reached the market. Although some examples of therapeutic efficacy have been shown, not unlike more traditional antiviral or antibacterial treatments, their efficacy is significantly greater in prophylaxis or early post-exposure treatment. Although in many cases the use of vaccines is more effective and cost-effective than that of mABs, for many infectious diseases no vaccines have yet been developed and licensed. Furthermore, in emergency situations, like in epidemics or pandemics, the availability of mABs can be an attractive adjunct to our armament to reduce the impact. Finally, the availability of mABs against bacteria can be an important alternative, when multidrug-resistant strains are involved.

Design and characterization of chimeric Rabies-SARS-CoV-2 virus-like particles for vaccine purposes.

Due to the high number of doses required to achieve adequate coverage in the context of COVID-19 pandemics, there is a great need for novel vaccine developments. In this field, there have been research approaches that focused on the production of SARS-CoV-2 virus-like particles. These are promising vaccine candidates as their structure is similar to that of native virions but they lack the genome, constituting a biosafe alternative. In order to produce these structures using mammal cells, it has been established that all four structural proteins must be expressed. Here we report the generation and characterization of a novel chimeric virus-like particle (VLP) that can be produced by the expression of a single novel fusion protein that contains SARS-CoV-2 spike (S) ectodomain fused to rabies glycoprotein membrane anchoring region in HEK293 cells. This protein is structurally similar to native S and can autonomously bud forming enveloped VLPs that resemble native virions both in size and in morphology, displaying S ectodomain and receptor binding domain (RBD) on their surface. As a proof of concept, we analyzed the immunogenicity of this vaccine candidate in mice and confirmed the generation of anti-S, anti-RBD, and neutralizing antibodies. KEY POINTS: • A novel fusion rabies glycoprotein containing S ectodomain was designed. • Fusion protein formed cVLPs that were morphologically similar to SARS-CoV-2 virions. • cVLPs induced anti-S, anti-RBD, and neutralizing antibodies in mice.

An inactivated recombinant rabies virus chimerically expressed RBD induces humoral and cellular immunity against SARS-CoV-2 and RABV.

Many studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various animals and transmit among animals, and even to humans, posing a threat to humans and animals. There is an urgent need to develop inexpensive and efficient animal vaccines to prevent and control coronavirus disease 2019 (COVID-19) in animals. Rabies virus (RABV) is another important zoonotic pathogen that infects almost all warm-blooded animals and poses a great public health threat. The present study constructed two recombinant chimeric viruses expressing the S1 and RBD proteins of the SARS-CoV-2 Wuhan01 strain based on a reverse genetic system of the RABV SRV9 strain and evaluated their immunogenicity in mice, cats and dogs. The results showed that both inactivated recombinant viruses induced durable neutralizing antibodies against SARS-CoV-2 and RABV and a strong cellular immune response in mice. Notably, inactivated SRV-nCoV-RBD induced earlier antibody production than SRV-nCoV-S1, which was maintained at high levels for longer periods. Inactivated SRV-nCoV-RBD induced neutralizing antibodies against both SARS-CoV-2 and RABV in cats and dogs, with a relatively broad-spectrum cross-neutralization capability against the SARS-CoV-2 pseudoviruses including Alpha, Beta, Gamma, Delta, and Omicron, showing potential to be used as a safe bivalent vaccine candidate against COVID-19 and rabies in animals.

Increase in rabies cases during COVID-19 pandemic: Is there a connection?

Increase in rabies cases during COVID-19 pandemic: Is there a connection?

Rabies surveillance in the United States during 2021.

OBJECTIVE: To provide epidemiological information on the occurrence of animal and human rabies in the US during 2021 and summaries of 2021 rabies surveillance for Canada and Mexico. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided data on animals submitted for rabies testing in 2021. Data were analyzed temporally and geographically to assess trends in domestic animal and wildlife rabies cases. RESULTS: During 2021, 54 US jurisdictions reported 3,663 rabid animals, representing an 18.2% decrease from the 4,479 cases reported in 2020. Texas (n = 456 [12.4%]), Virginia (297 [8.1%]), Pennsylvania (287 [7.8%]), North Carolina (248 [6.8%]), New York (237 [6.5%]), California (220 [6.0%]), and New Jersey (201 [5.5%]) together accounted for > 50% of all animal rabies cases reported in 2021. Of the total reported rabid animals, 3,352 (91.5%) involved wildlife, with bats (n = 1,241 [33.9%]), raccoons (1,030 [28.1%]), skunks (691 [18.9%]), and foxes (314 [8.6%]) representing the primary hosts confirmed with rabies. Rabid cats (216 [5.9%]), cattle (40 [1.1%]), and dogs (36 [1.0%]) accounted for 94% of rabies cases involving domestic animals in 2021. Five human rabies deaths were reported in 2021. CLINICAL RELEVANCE: The number of animal rabies cases reported in the US decreased significantly during 2021; this is thought to be due to factors related to the COVID-19 pandemic.

Rabies: who should care?

Rabies is the deadliest viral infection known, with no reliable treatment, and although it is entirely preventable, rabies continues to kill more than 60,000 people every year, mostly children in countries where dog rabies is endemic. America is only 1 generation away from the time when rabies killed more than 10,000 animals and 50 Americans every year, but 3 to 5 Americans continue to die annually from rabies. Distressingly, > 50,000 Americans undergo rabies prevention therapy every year after exposure to potentially rabid animals. While enormous progress has been made, more must be done to defeat this ancient but persistent, fatal zoonosis. In the US, lack of public awareness and ambivalence are the greatest dangers imposed by rabies, resulting in unnecessary exposures, anxiety, and risk. Veterinarians have a special role in informing and reassuring the public about prevention and protection from rabies. This summary of current facts and future advances about rabies will assist veterinarians in informing their clients about the disease.

Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2.

Identification of bona fide functional receptors and elucidation of the mechanism of receptor-mediated virus entry are important to reveal targets for developing therapeutics against rabies virus (RABV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our previous studies suggest that metabotropic glutamate receptor subtype 2 (mGluR2) functions as an entry receptor for RABV in vitro, and is an important internalization factor for SARS-CoV-2 in vitro and in vivo. Here, we demonstrate that mGluR2 facilitates RABV internalization in vitro and infection in vivo. We found that transferrin receptor 1 (TfR1) interacts with mGluR2 and internalizes with mGluR2 and RABV in the same clathrin-coated pit. Knockdown of TfR1 blocks agonist-triggered internalization of mGluR2. Importantly, TfR1 also interacts with the SARS-CoV-2 spike protein and is important for SARS-CoV-2 internalization. Our findings identify a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry, and reveal TfR1 as a potential target for therapeutics against RABV and SARS-CoV-2. IMPORTANCE We previously found that metabotropic glutamate receptor subtype 2 (mGluR2) is an entry receptor for RABV in vitro, and an important internalization factor for SARS-CoV-2 in vitro and in vivo. However, whether mGluR2 is required for RABV infection in vivo was unknown. In addition, how mGluR2 mediates the internalization of RABV and SARS-CoV-2 needed to be resolved. Here, we found that mGluR2 gene knockout mice survived a lethal challenge with RABV. To our knowledge, mGluR2 is the first host factor to be definitively shown to play an important role in RABV street virus infection in vivo. We further found that transferrin receptor protein 1 (TfR1) directly interacts and cooperates with mGluR2 to regulate the endocytosis of RABV and SARS-CoV-2. Our study identifies a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry and opens a new door for the development of therapeutics against RABV and SARS-CoV-2.

Drivers of Spatial Expansions of Vampire Bat Rabies in Colombia.

Spatial expansions of vampire bat-transmitted rabies (VBR) are increasing the risk of lethal infections in livestock and humans in Latin America. Identifying the drivers of these expansions could improve current approaches to surveillance and prevention. We aimed to identify if VBR spatial expansions are occurring in Colombia and test factors associated with these expansions. We analyzed 2336 VBR outbreaks in livestock reported to the National Animal Health Agency (Instituto Colombiano Agropecuario-ICA) affecting 297 municipalities from 2000-2019. The area affected by VBR changed through time and was correlated to the reported number of outbreaks each year. Consistent with spatial expansions, some municipalities reported VBR outbreaks for the first time each year and nearly half of the estimated infected area in 2010-2019 did not report outbreaks in the previous decade. However, the number of newly infected municipalities decreased between 2000-2019, suggesting decelerating spatial expansions. Municipalities infected later had lower cattle populations and were located further from the local reporting offices of the ICA. Reducing the VBR burden in Colombia requires improving vaccination coverage in both endemic and newly infected areas while improving surveillance capacity in increasingly remote areas with lower cattle populations where rabies is emerging.

A Single Dose of the Deactivated Rabies-Virus Vectored COVID-19 Vaccine, CORAVAX, Is Highly Efficacious and Alleviates Lung Inflammation in the Hamster Model.

Without sufficient herd immunity through either vaccination or natural infection, the coronavirus disease 2019 pandemic is unlikely to be controlled. Waning immunity with the currently approved vaccines suggests the need to evaluate vaccines causing the induction of long-term responses. Here, we report the immunogenicity and efficacy of our adjuvanted single-dose Rabies-vectored SARS-CoV-2 S1 vaccine, CORAVAX, in hamsters. CORAVAX induces high SARS-CoV-2 S1-specific and virus-neutralizing antibodies (VNAs) that prevent weight loss, viral loads, disease, lung inflammation, and the cytokine storm in hamsters. We also observed high Rabies VNA titers. In summary, CORAVAX is a promising dual-antigen vaccine candidate for clinical evaluation against SARS-CoV-2 and Rabies virus.

[Effects of Covid-19 Pandemic on the Vaccine Activities on a Reference Immunization Center in Treichville, Côte D'ivoire]. / Effets de la Pandémie à Covid-19 sur les Activités Vaccinales D'un Centre de Vaccination de Référence de Treichville en Côte D'ivoire.

Introduction: Since March 11, 2020, Côte d'Ivoire has been affected by the coronavirus epidemic, declared that same day as pandemic by WHO. March 11, 2021, one year after the pandemic, Côte d'Ivoire has notified 36,824 cases of Covid-19 patients and among them 211 have died. As of May 31, 2020, Côte d'Ivoire had already notified 2,833 cases and 33 deaths. At that time, false rumors were circulating in Africa about the setting up of clinical trials on candidate vaccines. The impact of these rumors on the overall use of health services had to be measured and in particular on vaccination centers. Objectives: The objective of this study was to determine the effects of the pandemic on the activities of the immunization services of the National Institute of Public Hygiene in Abidjan, which comprises four departments: International Vaccination Center, Community Vaccination Service, Rabies Center, and Vaccination Unit of the Expanded Program on Immunization. The study was based on activity reports of the immunization services. Results: At the International Vaccination Center, activities fell by about 50% in March, 86% in April and 82% in May in comparison with 2018 and 2019. Activities of Community Vaccination Service decreased by about 26% in March and 99% in April and May. At the Rabies Control Center, this reduction was estimated at 38% in April and 45% in May. The highest losses were for yellow fever and meningitis vaccines. Conclusion: The drop in attendance at vaccination services could increase the risk of epidemics, especially yellow fever, which are recurrent in Abidjan. Intensive awareness and catch-up actions should be carried out and further studies performed to assess the impact of the pandemic on immunization activities.

United Against Rabies Forum: The One Health Concept at Work.

Human deaths from rabies are preventable and can be eliminated by applying a systematic One Health approach. However, this ancient disease still threatens the lives of millions of people in up to 150 countries and kills an estimated 59, 000 people every year. Rabies today is largely a disease of poverty, almost always linked to dog bites, with most deaths occurring in neglected communities in Africa and Asia. The disease places an immense economic burden on its victims, a cost that far outweighs the investment needed to control it. A global framework for rabies elimination in humans is set out in Zero by 30: The Global Strategic Plan to end human deaths from dog-mediated rabies by 2030. Despite the existence of proven control strategies and agreement on the path to eliminating human rabies deaths, mortality numbers from rabies remain high, and COVID-19 has set back efforts even further. But COVID-19 has also highlighted the value of a One Health approach to zoonotic disease and pandemic prevention. Rabies control programs offer a practical route to building One Health capacities that can also address other zoonotic threats, including those with pandemic potential. The United Against Rabies Forum aims to accelerate progress on rabies elimination while applying a One Health approach. The Forum promotes cross-sector collaboration among stakeholders and supports countries in their rabies elimination efforts. Increased political engagement and resource mobilization, both internationally and nationally, will be needed to achieve global rabies goals and can also make One Health implementation a reality.

Making genomic surveillance deliver: A lineage classification and nomenclature system to inform rabies elimination.

The availability of pathogen sequence data and use of genomic surveillance is rapidly increasing. Genomic tools and classification systems need updating to reflect this. Here, rabies virus is used as an example to showcase the potential value of updated genomic tools to enhance surveillance to better understand epidemiological dynamics and improve disease control. Previous studies have described the evolutionary history of rabies virus, however the resulting taxonomy lacks the definition necessary to identify incursions, lineage turnover and transmission routes at high resolution. Here we propose a lineage classification system based on the dynamic nomenclature used for SARS-CoV-2, defining a lineage by phylogenetic methods for tracking virus spread and comparing sequences across geographic areas. We demonstrate this system through application to the globally distributed Cosmopolitan clade of rabies virus, defining 96 total lineages within the clade, beyond the 22 previously reported. We further show how integration of this tool with a new rabies virus sequence data resource (RABV-GLUE) enables rapid application, for example, highlighting lineage dynamics relevant to control and elimination programmes, such as identifying importations and their sources, as well as areas of persistence and routes of virus movement, including transboundary incursions. This system and the tools developed should be useful for coordinating and targeting control programmes and monitoring progress as countries work towards eliminating dog-mediated rabies, as well as having potential for broader application to the surveillance of other viruses.

Rabies surveillance in the United States during 2020.

OBJECTIVE: To provide epidemiological information on animal and human cases of rabies in the US during 2020 and summaries of 2020 rabies surveillance for Canada and Mexico. ANIMALS: All animals submitted for laboratory diagnosis of rabies in the US during 2020. PROCEDURES: State and territorial public health departments and USDA Wildlife Services provided 2020 rabies surveillance data. Data were analyzed temporally and geographically to assess trends in domestic and wildlife rabies cases. RESULTS: During 2020, 54 jurisdictions submitted 87,895 animal samples for rabies testing, of which 85,483 (97.3%) had a conclusive (positive or negative) test result. Of these, 4,479 (5.2%) tested positive for rabies, representing a 4.5% decrease from the 4,690 cases reported in 2019. Texas (n = 580 [12.9%]), Pennsylvania (371 [8.3%]), Virginia (351 [7.8%]), New York (346 [7.7%]), North Carolina (301 [6.7%]), New Jersey (257 [5.7%]), Maryland (256 [5.7%]), and California (248 [5.5%]) together accounted for > 60% of all animal rabies cases reported in 2020. Of the total reported rabid animals, 4,090 (91.3%) involved wildlife, with raccoons (n = 1,403 [31.3%]), bats (1,400 [31.3%]), skunks (846 [18.9%]), and foxes (338 [7.5%]) representing the primary hosts confirmed with rabies. Rabid cats (288 [6.4%]), cattle (43 [1.0%]), and dogs (37 [0.8%]) accounted for 95% of rabies cases involving domestic animals in 2020. No human rabies cases were reported in 2020. CONCLUSIONS AND CLINICAL RELEVANCE: For the first time since 2006, the number of samples submitted for rabies testing in the US was < 90,000; this is thought to be due to factors related to the COVID-19 pandemic, as similar decreases in sample submission were also reported by Canada and Mexico.

The impact of COVID-19 pandemic on rabies post-exposure prophylaxis services in Asia.

Human rabies is a preventable disease through post-exposure prophylaxis (PEP) in rabies endemic countries where enzootic cycle of dog rabies occurs. The COVID­19 pandemic has induced an unprecedented challenge for under-funded and already stretched health­care systems particularly in low- and middle-income countries, which are unfortunately bearing a huge burden of human rabies. An analysis of hospital-based PEP data in India, Nepal, Sri Lanka, and Thailand, focus group discussion and key informant interview have been carried out to better understand the impact of Covid-19 pandemic in human rabies prophylaxis. It is necessary to better prepare for human rabies prophylaxis in future pandemics based on lesson learnt from current pandemic. The PEP should be categorized as an emergency medical service, and it should be part of the hospital medical emergency. Mass dog vaccination against rabies should be accelerated to reduce the risk of potential bite of roaming dogs and pet dogs in communities. It is a wise decision to invest in cost-effective preparedness, i.e., mass dog vaccination rather than costly response, i.e., human rabies prophylaxis.

Rabies Elimination in Rural Kenya: Need for Improved Availability of Human Vaccines, Awareness and Knowledge on Rabies and Its Management Among Healthcare Workers.

Background: In Africa, rabies causes an estimated 24,000 human deaths annually. Mass dog vaccinations coupled with timely post-exposure prophylaxis (PEP) for dog-bite patients are the main interventions to eliminate human rabies deaths. A well-informed healthcare workforce and the availability and accessibility of rabies biologicals at health facilities are critical in reducing rabies deaths. We assessed awareness and knowledge regarding rabies and the management of rabies among healthcare workers, and PEP availability in rural eastern Kenya. Methodology: We interviewed 73 healthcare workers from 42 healthcare units in 13 wards in Makueni and Kibwezi West sub-counties, Makueni County, Kenya in November 2018. Data on demographics, years of work experience, knowledge of rabies, management of bite and rabies patients, and availability of rabies biologicals were collected and analyzed. Results: Rabies PEP vaccines were available in only 5 (12%) of 42 health facilities. None of the health facilities had rabies immunoglobulins in stock at the time of the study. PEP was primarily administered intramuscularly, with only 11% (n = 8) of the healthcare workers and 17% (7/42) healthcare facilities aware of the dose-sparing intradermal route. Less than a quarter of the healthcare workers were aware of the World Health Organization categorization of bite wounds that guides the use of PEP. Eighteen percent (n = 13) of healthcare workers reported they would administer PEP for category I exposures even though PEP is not recommended for this category of exposure. Only one of six respondents with acute encephalitis consultation considered rabies as a differential diagnosis highlighting the low index of suspicion for rabies. Conclusion: The availability and use of PEP for rabies was sub-optimal. We identified two urgent needs to support rabies elimination programmes: improving availability and access to PEP; and targeted training of the healthcare workers to improve awareness on bite wound management, judicious use of PEP including appropriate risk assessment following bites and the use of the dose-sparing intradermal route in facilities seeing multiple bite patients. Global and domestic funding plan that address these gaps in the human health sector is needed for efficient rabies elimination in Africa.

Compatibility between a rabies vaccine and two canine combined vaccines against canine distemper, adenovirosis, parvovirosis, parainfluenza virus disease and leptospirosis, with or without canine coronavirus.

In many countries, vaccination programs still require dogs to be vaccinated against rabies in addition to Canine distemper virus (CDV), adenovirus (CAV), parvovirus (CPV), parainfluenza virus (CPiV), Leptospira (L) or Canine coronavirus (CCV= Cv). Few vaccines containing all these antigens are commercially available and, unless compatibility between the vaccines was demonstrated, concurrent administration of a DAPPi-L(Cv) vaccine and a vaccine against rabies should not be recommended. This may be of concern for practitioners who wish to vaccinate dogs with all components on the same day. This study aimed at evaluating immunological compatibility between a monovalent rabies vaccine (Rabisin™) and two large combination vaccines against CDV, CAV, CPV, CPiV with 2 leptospira components +Cv (Recombitek® C6/Cv) or with 4 Leptospira components (Recombitek® C8), when injected concomitantly at two separate injection sites. Fourteen days after administration of the rabies vaccine, with or without concomitant administration of combo vaccines, all dogs had seroconverted against rabies and maintained protective titers over the duration of the study. In addition, 100% of the puppies vaccinated with one or the other combo vaccines seroconverted against CDV, CAV, CPV, CPiV (CCV) and Leptospira, whatever the vaccination group. Lack of immunological interference between Rabisin™ and all components of the Recombitek® C6/Cv or Recombitek® C8 Combo vaccines was demonstrated by non-inferiority analysis, except for CDV in the Recombitek®C8+ Rabisin™ group. Based on these results, a concomitant administration of Rabisin™ with Recombitek® C6/Cv or Recombitek® C8 can be recommended in daily practice, which can be essential for facilitating vaccination compliance.

The Importance of Accurate Host Species Identification in the Framework of Rabies Surveillance, Control and Elimination.

Accurate host identification is paramount to understand disease epidemiology and to apply appropriate control measures. This is especially important for multi-host pathogens such as the rabies virus, a major and almost invariably fatal zoonosis that has mobilized unanimous engagement at an international level towards the final goal of zero human deaths due to canine rabies. Currently, diagnostic laboratories implement a standardized identification using taxonomic keys. However, this method is challenged by high and undiscovered biodiversity, decomposition of carcasses and subjective misevaluation, as has been attested to by findings from a cohort of 242 archived specimens collected across Sub-Saharan Africa and submitted for rabies diagnosis. We applied two simple and cheap methods targeting the Cytochrome b and Cytochrome c oxidase subunit I to confirm the initial classification. We therefore suggest prioritizing a standardized protocol that includes, as a first step, the implementation of taxonomic keys at a family or subfamily level, followed by the molecular characterization of the host species.