An RNA vaccine expressing the rabies virus glycoprotein was tested in a phase I dose escalation study in rabies virus-seronegative human volunteers between 18—40 years of age [ 59 ]. The vaccine was either given on days 0, 28, and 56 or on days 0, 7, and Some individuals were boosted 1 year later.
Overall, the RNA vaccine was more reactogenic than human diploid cell strain rabies vaccines or fowl embryo vaccines, which in the initial trials reported a few cases of mild local side effects but no systemic reactions [ 60 , 61 ]. Overall this vaccine is not suited for human rabies PrEP; in spite of three doses VNA responses remained below the level needed for protection in a significant percentage of vaccine recipients, immunological memory was poor, and the vaccine caused more frequent and more severe adverse events than currently used rabies vaccines.
Production of viral vectors is more complicated and costly than that of DNA vaccines. The other disadvantage of viral vector vaccines is that as a rule they can only be used once in an individual as VNAs induced against the vector backbone will reduce vaccine uptake and thereby expression and immunogenicity of the vaccine antigen upon its use for a boost [ 62 , 63 ]. Similar to DNA vaccines viral vectors carry PAMPs, which will elicit inflammatory responses needed for initiating adaptive immune responses [ 64 ].
Viral vectors have the advantage over DNA vaccines that they enter cells more efficiently upon binding to cell surface receptors, which as a rule renders them more immunogenic. One viral vector vaccine based on a vaccinia virus recombinant expressing the rabies virus glycoprotein termed VR-G is licensed for immunization of wild-live animals [ 65 ], another called Purevax Rabies, based on a canarypox virus, is used for vaccination of domestic cats [ 66 ].
VR-G is too reactogenic for use in humans as was demonstrated upon inadvertent infection of individuals with contact to the vaccine [ 67 , 68 ]. The rabies canarypox vaccine was tested in humans [ 69 ]. It was found to be safe but less immunogenic compared to a traditional inactivated rabies vaccine. Adenoviruses Ads have been vectored to express foreign antigen [ 70 ]. The Ad genome can be modified by inserting a gene into the deleted early E 3 domain which contains genes that are not essential for viral growth.
Alternatively, an expression cassette can be placed into the deleted E1 domain. Genes encoded by E1 are crucial for Ad replication and their deletion renders Ad vectors replication-defective. Packaging lines are available that transcomplement the deleted E1 genes thereby allowing for efficient growth of E1-deleted Ad vectors.
Ads are common species-specific pathogens that have been isolated from different types of animals ranging from humans to frogs. Most humans become infected with Ads at an early age and develop Ad-specific VNAs which dampen infection with the same virus. Immune responses to vaccines based on common human serotypes of Ad are thus commonly attenuated due to their neutralization [ 63 ].
This can be circumvented by the use of vaccine backbones based on Ads isolated from other species such as chimpanzees [ 63 ]. Although chimpanzee Ads AdC are phylogenetically grouped within human Ads [ 71 ] and share many of their characteristics, they neither circulated in humans nor do they show cross-neutralization by antibodies to human serotype Ads [ 72 ]. A human serotype 5 E3-deleted replication-competent Ad HAdV-5 vector called ONRAB expressing the glycoprotein of rabies was developed for oral immunization of foxes, raccoons, and skunks.
ONRAB although replication-competent in humans cannot replicate in any of these species. The same vaccine backbone with an E1-deletion expressing the glycoprotein of the Evelyn Rokitniki Abelseth ERA strain of rabies was tested in mice and found to afford complete protection after a single immunization [ 75 ]; nevertheless, immunogenicity and efficacy were attenuated if mice were initially immunized with an unrelated HAdV-5 vector and therefore carried neutralizing antibodies to the vaccine backbone at the time of their immunization [ 62 ].
A replication-defective AdC serotype 68 AdC68 vector expressing the same antigen was equally effective in mice [ 76 ]. This vector after a single low dose given IM provided long-term protection to nonhuman primates against a potentially lethal challenge with street rabies virus [ 77 ].
The vector was further modified by replacing the AdC68 E4 open reading frames orf 6 and 7 with those of HAd-V5, which increases vector yield on cell lines containing the HAd-V5 E1 during production. Orf6 complexes with a gene product of E1 to facilitate mRNA export and this interaction may be more effective between gene products derived from the same virus.
The E1-deleted, E4 modified AdC68rab. Studies thus far showed that the vector can be stabilized to permit storage at ambient temperatures [ 78 ]. This construct if shown to be safe and immunogenic in clinical trials may thus provide a cost-effective alternative to current rabies vaccine for more widespread rabies PrEP.
The worldwide death toll caused by rabies virus has unfortunately remained remarkably stable over the last two decades and it disproportionally affects children below the age of Vaccination programs for domestic or wildlife animals have successful reduced human rabies in some countries but have failed especially in less developed countries of Africa and Asia. Alternative measures should be contemplated to lessen the impact of rabies on human health such as less expensive and more immunogenic vaccines as discussed in this chapter.
National Center for Biotechnology Information , U. Journal List Vaccines Basel v. Vaccines Basel. Published online Jun Hildegund C. Author information Article notes Copyright and License information Disclaimer. Received Jun 3; Accepted Jun This article has been cited by other articles in PMC. Abstract Although vaccines are available, rabies still claims more than 55, human lives each year.
Introduction Rabies continues to claim upwards of 55,00 human lives each year [ 1 ]. Vaccine-induced Correlates of Protection Numerous studies have shown that protection against rabies virus infection is mediated by virus neutralizing antibodies VNAs against the viral glycoprotein [ 8 , 9 , 10 ] that is expressed as trimers on the surface of the virion. Current Rabies Vaccines Licensed rabies vaccines for human use are based on inactivated purified rabies virus grown either in tissue culture or in embryonated duck or chicken eggs.
Novel Rabies Vaccine Candidates A plethora of novel rabies vaccines based mainly on the viral glycoprotein have been tested in animals using mainly PEP regimens. Vaccines Suited for PEP 5. Adjuvanted Rabies Vaccines Adjuvants enhance inflammatory responses that are essential for antigen-driven stimulation of naive B and T cells [ 33 , 34 ]. Protein Vaccines The rabies virus glycoprotein forms trimers on the virion and most VNAs bind to conformation-dependent epitopes [ 40 ], which has made it difficult to develop a correctly folded effective protein-based rabies vaccine.
Genetically Modified, Inactivated Rabies Virus Rabies virus can be modified by reverse genetics [ 41 ]. RNA Vaccines An RNA vaccine expressing the rabies virus glycoprotein was tested in a phase I dose escalation study in rabies virus-seronegative human volunteers between 18—40 years of age [ 59 ].
Conclusions The worldwide death toll caused by rabies virus has unfortunately remained remarkably stable over the last two decades and it disproportionally affects children below the age of Funding This research received no external funding.
Conflicts of Interest The author declares no conflict of interest. References 1. Hampson K. Estimating the global burden of endemic canine rabies. PLoS Negl. Velasco-Villa A. Successful strategies implemented towards the elimination of canine rabies in the Western Hemisphere. Antiviral Res. Yang D. Yahiaoui F. The epidemiology of dog rabies in Algeria: Retrospective national study of dog rabies cases, determination of vaccination coverage and immune response evaluation of three commercial used vaccines.
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Lodmell D. As a result, it is understood that the cost of therapy has resulted in its shortage from government sector hospitals, which are already stricken by the current government's austerity drive, but it is also less likely to be found in private pharmacies due to its cost burden on inventory.
After the cuts on imports with an escalation in dollar price and regional tension on the Kashmir issue, the availability of these medicines has been severely hampered. Although the ban on pharmaceuticals has been lifted on imports from India, it has not improved as yet.
The solution lies in the production of rabies vaccines and RIG in Pakistan and taking measures to limit the population of stray dogs, and vaccinating the existing animal population that can be vectors of rabies virus.
On the other hand, the government should ensure the availability of rabies vaccines and take measures for their proper storage in rural and urban districts. National Center for Biotechnology Information , U. J Med Virol. Author information Article notes Copyright and License information Disclaimer.
Ali Ahmed, Email: ude. Corresponding author. Email: ude. Received Apr 11; Accepted Apr It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
This article has been cited by other articles in PMC. Dear Editor,. Khan S. Boy dies of rabies in Larkana due to unavailability of vaccine.
The News. September 18, Masood T. May 27, Is Pakistan prepared to tackle the coronavirus epidemic? Drugs Ther Perspect. J Med Allied Sci. BMC Public Health. Salahuddin N. Sanaa News. March 1,
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