Improving human rabies post-exposure prophylaxis Blumberg, Lucille; Rupprecht, Charles E
The Lancet infectious diseases,
December 2019, 2019-12-00, 20191201, Letnik:
19, Številka:
12
Journal Article
Recenzirano
Historically, the intradermal route has been considered a favourable alternative to the subcutaneous or intramuscular delivery of immunogens during vaccination against several infectious diseases, ...including smallpox, tuberculosis, influenza, polio, and rabies.2 The skin is a highly effective anatomical barrier to the surrounding environment and a functionally responsive tissue under immunological surveillance, with production of diverse antigen-presenting cells to respond to invasive pathogens.3 During the second half of the 20th century, as rabies vaccines improved gradually in potency and safety, intradermal administration became an increasingly attractive strategy to investigate heightened immunogenicity, dose sparing, and health economic benefits for both pre-exposure prophylaxis and post-exposure prophylaxis in human populations at risk, especially in low and middle-income countries.4–6 However, intradermal vaccination is not widely used for human rabies pre-exposure and post-exposure prophylaxis, with most regimens given intramuscularly over 2–4 weeks. ...even without approval, WHO has supported intradermal vaccination for decades.9 Broader use of the new shortened regimen beyond the clinical study stage might convince more public health agencies in low and middle-income countries in Africa, Asia, and the Americas to reconsider use of intradermal vaccination for human rabies prevention. Enhanced post-marketing surveillance and development of an adverse event reporting system for vaccines might also help to weigh-up any disadvantages associated with local reactions or patient non-compliance with the advantages of greater product availability and cost savings to exposed patients.
: Rabies is a major viral zoonosis and neglected tropical disease, with a global distribution. Humans, domestic animals, and wild mammals are susceptible to infection. Etiological agents reside in ...the Order Mononegavirales, Family Rhabdoviridae, Genus Lyssavirus. This acute, progressive encephalitis causes the highest case fatality of any conventional infectious disease. Tens of millions of humans become exposed annually to the bites of infected mammals, predominantly in Asia and Africa. Despite the existence of effective vaccines and immune globulins, tens of thousands of people, typically children in the developing world, succumb.
: Concentrating upon both historical and major published references from the peer-reviewed literature over the past 5 years, we describe current biologics for rabies prevention, newly recommended principles for prophylaxis, and relevant future products in the developmental pipeline.
: Modern human rabies biologics are pure, potent, safe, and efficacious, when used in a timely and appropriate manner. Few individuals survive after clinical signs. Anti-viral compounds are not licensed. Experimental therapy, while obviously desirable, is highly controversial. Education on bite prevention and integrated risk management are critical. Access to affordable care, dose-sparing, and shortened regimens of human rabies biologics remain key.
Rates of evolution span orders of magnitude among RNA viruses with important implications for viral transmission and emergence. Although the tempo of viral evolution is often ascribed to viral ...features such as mutation rates and transmission mode, these factors alone cannot explain variation among closely related viruses, where host biology might operate more strongly on viral evolution. Here, we analyzed sequence data from hundreds of rabies viruses collected from bats throughout the Americas to describe dramatic variation in the speed of rabies virus evolution when circulating in ecologically distinct reservoir species. Integration of ecological and genetic data through a comparative bayesian analysis revealed that viral evolutionary rates were labile following historical jumps between bat species and nearly four times faster in tropical and subtropical bats compared to temperate species. The association between geography and viral evolution could not be explained by host metabolism, phylogeny or variable selection pressures, and instead appeared to be a consequence of reduced seasonality in bat activity and virus transmission associated with climate. Our results demonstrate a key role for host ecology in shaping the tempo of evolution in multi-host viruses and highlight the power of comparative phylogenetic methods to identify the host and environmental features that influence transmission dynamics.
In nature, rabies virus (RABV; genus Lyssavirus, family Rhabdoviridae) represents an assemblage of phylogenetic lineages, associated with specific mammalian host species. Although it is generally ...accepted that RABV evolved originally in bats and further shifted to carnivores, mechanisms of such host shifts are poorly understood, and examples are rarely present in surveillance data. Outbreaks in carnivores caused by a RABV variant, associated with big brown bats, occurred repeatedly during 2001-2009 in the Flagstaff area of Arizona. After each outbreak, extensive control campaigns were undertaken, with no reports of further rabies cases in carnivores for the next several years. However, questions remained whether all outbreaks were caused by a single introduction and further perpetuation of bat RABV in carnivore populations, or each outbreak was caused by an independent introduction of a bat virus. Another question of concern was related to adaptive changes in the RABV genome associated with host shifts. To address these questions, we sequenced and analyzed 66 complete and 20 nearly complete RABV genomes, including those from the Flagstaff area and other similar outbreaks in carnivores, caused by bat RABVs, and representatives of the major RABV lineages circulating in North America and worldwide. Phylogenetic analysis demonstrated that each Flagstaff outbreak was caused by an independent introduction of bat RABV into populations of carnivores. Positive selection analysis confirmed the absence of post-shift changes in RABV genes. In contrast, convergent evolution analysis demonstrated several amino acids in the N, P, G and L proteins, which might be significant for pre-adaptation of bat viruses to cause effective infection in carnivores. The substitution S/T₂₄₂ in the viral glycoprotein is of particular merit, as a similar substitution was suggested for pathogenicity of Nishigahara RABV strain. Roles of the amino acid changes, detected in our study, require additional investigations, using reverse genetics and other approaches.
Apologies for the brief intermission imposed by the pandemic, between the opening piece of our Special Issue “Lyssaviruses and Rabies: Prevention, Control and Elimination” and this closing act of ...commentary ...
In the United States and Canada, the most recent documented cases of rabies have been attributed to bat rabies viruses (RABV). We undertook this systematic review in an effort to summarize and ...enhance understanding of the risk of infection for individuals who have been potentially exposed to a suspect or confirmed rabid bat. United States rabies surveillance summaries documented a total of 41 human bat-rabies virus variant verified non-transplant cases between 1990 and 2015. All cases were fatal. Seven (17.1%) of 41 cases reported a bite from a bat. Ten (24.3%) cases had unprotected physical contact (UPC); these included seven cases that had a bat land or crawl on them (contact with claws) and one case that touched a bat's teeth. Seven (17.1%) cases had probable UPC. Insectivorous bat teeth are extremely sharp and highly efficient for predation upon arthropod prey. Bats also have sharp claws on the end of their thumbs and feet. One of the most common bat RABV variants has an ability to replicate in non-neural cells. Questioning individuals about unprotected contact with bat teeth and claws (including a bat landing or crawling on a person) may help identify additional exposures.
Rabies is a neglected zoonotic disease that is preventable in humans by appropriate post-exposure prophylaxis (PEP). However, current PEP relies on polyclonal immune globulin products purified from ...pooled human (HRIG) or equine (ERIG) plasma that are either in chronic shortage or in association with safety concerns. Here, we present the development of an antibody cocktail, SYN023, made of two novel monoclonal antibodies (MAb) CTB011 and CTB012 that could serve as safer and more cost-effective alternatives to the current RIG products. Both CTB011 and CTB012 are humanized MAbs that bind to non-overlapping epitopes on the rabies virus (RABV) glycoprotein (G) with sub-nanomolar affinities. Sequence analysis revealed that many of the critical residues in binding are highly conserved across different species of lyssaviruses. When combined at a 1:1 ratio, CTB011/CTB012 exhibited neutralization capabilities equivalent or superior to HRIG against 10 North American street RABV isolates in vitro and 15 prevalent Chinese RABV strains in animal models. Finally, SYN023, at a dosage of 0.03 mg/kg, was able to offer the same degree of protection as standard HRIG administration (20 IU/kg) in Syrian hamsters challenged with a highly virulent bat (Tadarida brasiliensis) RABV variant. Taken together, the high-potency and broad-spectrum neutralization demonstrated by SYN023 make it an effective candidate for human rabies PEP consideration.
Background Human rabies remains a significant public health problem in Africa with outbreaks reported in most countries. In Nigeria-the most populous country in Africa-rabies causes a significant ...public health burden partly due to perennial obstacles to implementing a national prevention and control program. Methods We conducted a scoping review using standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify and select published articles from Nigeria during 1978-2020 reporting on rabies virus infections (human, canine, livestock, and wildlife), canine bites, knowledge, attitudes and practices (KAP) surveys on rabies and canine ecology studies. We extracted information on study location, year and additional details of each study such as rabies prevalence, general characteristics of offending dogs, dog vaccination status and health-seeking behaviours. Findings Between 1978 and 2020, 90 published articles met our inclusion criteria. The prevalence of rabies virus antigen detection varied between 3% and 28%, with more studies in the north. Most bites were unprovoked from dog bite studies (36.4%-97%), by dogs with low vaccination rates (12-38%). A more significant proportion of biting dogs were owned (31-90%). Laboratory confirmation for biting was available for only a small proportion of studies (6%; n = 2/32). Of the dogs surveyed during ecology studies, indigenous dogs accounted for the majority (62-98%), used mostly for security purposes (52-98%), with the vaccination rate between 15% and 38% in most states. Studies conducted in areas distant from rabies diagnostic facilities accounted for more human rabies cases and fewer dog rabies cases. Conclusion Significant improvements are necessary to achieve the elimination of human rabies mediated via dogs by 2030.
Bartonellae are phylogenetically diverse, intracellular bacteria commonly found in mammals. Previous studies have demonstrated that bats have a high prevalence and diversity of Bartonella infections ...globally. Isolates (n = 42) were obtained from five bat species in four provinces of Thailand and analyzed using sequences of the citrate synthase gene (gltA). Sequences clustered into seven distinct genogroups; four of these genogroups displayed similarity with Bartonella spp. sequences from other bats in Southeast Asia, Africa, and Eastern Europe. Thirty of the isolates representing these seven genogroups were further characterized by sequencing four additional loci (ftsZ, nuoG, rpoB, and ITS) to clarify their evolutionary relationships with other Bartonella species and to assess patterns of diversity among strains. Among the seven genogroups, there were differences in the number of sequence variants, ranging from 1-5, and the amount of nucleotide divergence, ranging from 0.035-3.9%. Overall, these seven genogroups meet the criteria for distinction as novel Bartonella species, with sequence divergence among genogroups ranging from 6.4-15.8%. Evidence of intra- and intercontinental phylogenetic relationships and instances of homologous recombination among Bartonella genogroups in related bat species were found in Thai bats.
Rabies is a neglected zoonotic disease that has no effective treatment after onset of illness. However the disease can be prevented effectively by prompt administration of post exposure prophylaxis ...which includes administration of passive immunizing antibodies (Rabies Immune Globulin, RIG). Currently, human RIG suffers from many restrictions including limited availability, batch-to batch inconsistencies and potential for contamination with blood-borne pathogens. Anti-rabies monoclonal antibodies (mAbs) have been identified as a promising alternative to RIG. Here, we applied a plant-based transient expression system to achieve rapid, high level production and efficacy of the two highly potent anti-rabies mAbs E559 and 62-71-3. Expression levels of up to 490 mg/kg of recombinant mAbs were obtained in Nicotiana benthamiana glycosylation mutants by using a viral based transient expression system. The plant-made E559 and 62-71-3, carrying human-type fucose-free N-glycans, assembled properly and were structurally sound as determined by mass spectrometry and calorimetric density measurements. Both mAbs efficiently neutralised diverse rabies virus variants in vitro. Importantly, E559 and 62-71-3 exhibited enhanced protection against rabies virus compared to human RIG in a hamster model post-exposure challenge trial. Collectively, our results provide the basis for the development of a multi-mAb based alternative to RIG.
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