CORD-19-Sentences  

CORD-19:4abc50cfc81265083d4cb2aed0a493bb704d0b5b JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-37 Sentence denotes viruses Rabies Control and Treatment:
T36220 0-37 Sentence denotes viruses Rabies Control and Treatment:
TextSentencer_T2 38-92 Sentence denotes From Prophylaxis to Strategies with Curative Potential
T53567 38-92 Sentence denotes From Prophylaxis to Strategies with Curative Potential
TextSentencer_T3 94-102 Sentence denotes Abstract
T911 94-102 Sentence denotes Abstract
TextSentencer_T4 103-192 Sentence denotes Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals.
T89480 103-192 Sentence denotes Rabies is an acute, fatal, neurological disease that affects almost all kinds of mammals.
TextSentencer_T5 193-394 Sentence denotes Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans.
T85362 193-394 Sentence denotes Vaccination (using an inactivated rabies vaccine), combined with administration of rabies immune globulin, is the only approved, effective method for post-exposure prophylaxis against rabies in humans.
TextSentencer_T6 395-582 Sentence denotes In the search for novel rabies control and treatment strategies, live-attenuated viruses have recently emerged as a practical and promising approach for immunizing and controlling rabies.
T35463 395-582 Sentence denotes In the search for novel rabies control and treatment strategies, live-attenuated viruses have recently emerged as a practical and promising approach for immunizing and controlling rabies.
TextSentencer_T7 583-871 Sentence denotes Unlike the conventional, inactivated rabies vaccine, live-attenuated viruses are genetically modified viruses that are able to replicate in an inoculated recipient without causing adverse effects, while still eliciting robust and effective immune responses against rabies virus infection.
T36503 583-871 Sentence denotes Unlike the conventional, inactivated rabies vaccine, live-attenuated viruses are genetically modified viruses that are able to replicate in an inoculated recipient without causing adverse effects, while still eliciting robust and effective immune responses against rabies virus infection.
TextSentencer_T8 872-1053 Sentence denotes A number of viruses with an intrinsic capacity that could be used as putative candidates for live-attenuated rabies vaccine have been intensively evaluated for therapeutic purposes.
T33450 872-1053 Sentence denotes A number of viruses with an intrinsic capacity that could be used as putative candidates for live-attenuated rabies vaccine have been intensively evaluated for therapeutic purposes.
TextSentencer_T9 1054-1291 Sentence denotes Additional novel strategies, such as a monoclonal antibody-based approach, nucleic acid-based vaccines, or small interfering RNAs (siRNAs) interfering with virus replication, could further add to the arena of strategies to combat rabies.
T82204 1054-1291 Sentence denotes Additional novel strategies, such as a monoclonal antibody-based approach, nucleic acid-based vaccines, or small interfering RNAs (siRNAs) interfering with virus replication, could further add to the arena of strategies to combat rabies.
TextSentencer_T10 1292-1432 Sentence denotes In this review, we highlight current advances in rabies therapy and discuss the role that they might have in the future of rabies treatment.
T49075 1292-1432 Sentence denotes In this review, we highlight current advances in rabies therapy and discuss the role that they might have in the future of rabies treatment.
TextSentencer_T11 1433-1654 Sentence denotes Given the pronounced and complex impact of rabies on a patient, a combination of these novel modalities has the potential to achieve maximal anti-rabies efficacy, or may even have promising curative effects in the future.
T80420 1433-1654 Sentence denotes Given the pronounced and complex impact of rabies on a patient, a combination of these novel modalities has the potential to achieve maximal anti-rabies efficacy, or may even have promising curative effects in the future.
TextSentencer_T12 1655-2051 Sentence denotes However, several hurdles regarding clinical safety considerations and public awareness should be overcome before these approaches can ultimately become clinically relevant therapies. exposed on the surface of the virus and is not only the major determinant of viral pathogenicity, but also the major protective antigen responsible for inducing protective immunity against rabies [2] [3] [4] [5] .
T97016 1655-2051 Sentence denotes However, several hurdles regarding clinical safety considerations and public awareness should be overcome before these approaches can ultimately become clinically relevant therapies. exposed on the surface of the virus and is not only the major determinant of viral pathogenicity, but also the major protective antigen responsible for inducing protective immunity against rabies [2] [3] [4] [5] .
TextSentencer_T13 2052-2188 Sentence denotes Fortunately, rabies can be a vaccine-preventable disease, provided that post-exposure prophylaxis (PEP) is given promptly and correctly.
T38610 2052-2188 Sentence denotes Fortunately, rabies can be a vaccine-preventable disease, provided that post-exposure prophylaxis (PEP) is given promptly and correctly.
TextSentencer_T14 2189-2300 Sentence denotes Protection against rabies correlates with the presence of rabies-specific virus-neutralizing antibodies (VNAs).
T49528 2189-2300 Sentence denotes Protection against rabies correlates with the presence of rabies-specific virus-neutralizing antibodies (VNAs).
TextSentencer_T15 2301-2438 Sentence denotes According to the WHO, VNA titers greater than 0.5 international units per mL serum can reliably provide protection to humans and animals.
T33040 2301-2438 Sentence denotes According to the WHO, VNA titers greater than 0.5 international units per mL serum can reliably provide protection to humans and animals.
TextSentencer_T16 2439-2649 Sentence denotes Currently, rabies-infected dogs are the major reason for the high incidence of human rabies, and therefore vaccinating dogs has been shown to be the most cost-effective strategy for preventing rabies in humans.
T13924 2439-2649 Sentence denotes Currently, rabies-infected dogs are the major reason for the high incidence of human rabies, and therefore vaccinating dogs has been shown to be the most cost-effective strategy for preventing rabies in humans.
TextSentencer_T17 2650-2794 Sentence denotes As reported by the WHO, vaccination coverage of 70% of the canine population can efficiently reduce virus transmission and prevent human rabies.
T73753 2650-2794 Sentence denotes As reported by the WHO, vaccination coverage of 70% of the canine population can efficiently reduce virus transmission and prevent human rabies.
TextSentencer_T18 2795-2971 Sentence denotes However, despite the fact that efficacious vaccines are readily available, rabies still has a high death rate, mainly due to the cost and accessibility of proper PEP treatment.
T80842 2795-2971 Sentence denotes However, despite the fact that efficacious vaccines are readily available, rabies still has a high death rate, mainly due to the cost and accessibility of proper PEP treatment.
TextSentencer_T19 2972-3247 Sentence denotes The current PEP schedule not only requires multiple injections but is also time-consuming, a problem that is even more pronounced due to the fact that RABV-specific immunoglobulin (RIG), which is both expensive and often in short supply, is required to treat severe exposure.
T7913 2972-3247 Sentence denotes The current PEP schedule not only requires multiple injections but is also time-consuming, a problem that is even more pronounced due to the fact that RABV-specific immunoglobulin (RIG), which is both expensive and often in short supply, is required to treat severe exposure.
TextSentencer_T20 3248-3378 Sentence denotes This creates a particular burden for rural regions of developing countries that suffer from the highest incidence rates of rabies.
T98678 3248-3378 Sentence denotes This creates a particular burden for rural regions of developing countries that suffer from the highest incidence rates of rabies.
TextSentencer_T21 3379-3581 Sentence denotes Therefore, the development of alternative, cost-effective vaccines that would induce sustained immunity after a single dose inoculation and could ideally clear virus infection from the CNS is warranted.
T6431 3379-3581 Sentence denotes Therefore, the development of alternative, cost-effective vaccines that would induce sustained immunity after a single dose inoculation and could ideally clear virus infection from the CNS is warranted.
TextSentencer_T22 3582-3880 Sentence denotes The advent of the reverse genetics technique has revolutionized the study of RABV, as well as other negative-strand RNA viruses, which has greatly advanced our understanding of the biology of these viruses and profoundly accelerated the development of novel vaccines against various pathogens [6] .
T81181 3582-3880 Sentence denotes The advent of the reverse genetics technique has revolutionized the study of RABV, as well as other negative-strand RNA viruses, which has greatly advanced our understanding of the biology of these viruses and profoundly accelerated the development of novel vaccines against various pathogens [6] .
TextSentencer_T23 3881-4208 Sentence denotes While a number of excellent reviews have been written focusing on reverse genetics of negative-strand RNA viruses, the biology of RABV, rabies vaccines, and the pathology and prophylaxis of rabies [6-10], this review rectifies the lack of focus on current strategies that have been evaluated for prevention or as PEP of rabies.
T72954 3881-4208 Sentence denotes While a number of excellent reviews have been written focusing on reverse genetics of negative-strand RNA viruses, the biology of RABV, rabies vaccines, and the pathology and prophylaxis of rabies [6-10], this review rectifies the lack of focus on current strategies that have been evaluated for prevention or as PEP of rabies.
TextSentencer_T24 4209-4368 Sentence denotes This review places particular emphasis on the most promising approaches using live-attenuated and/or recombinant vaccine platforms for preventive vaccinations.
T27206 4209-4368 Sentence denotes This review places particular emphasis on the most promising approaches using live-attenuated and/or recombinant vaccine platforms for preventive vaccinations.
TextSentencer_T25 4369-4602 Sentence denotes Other innovative modalities, such as monoclonal antibody-based platforms and small interfering RNAs (siRNAs) interfering with virus replication, which may deserve future research for rabies treatment, will also be briefly introduced.
T12324 4369-4602 Sentence denotes Other innovative modalities, such as monoclonal antibody-based platforms and small interfering RNAs (siRNAs) interfering with virus replication, which may deserve future research for rabies treatment, will also be briefly introduced.
TextSentencer_T26 4604-4749 Sentence denotes Rabies is an ancient neurological disease caused mainly by the rabies virus (RABV) and is almost invariably fatal once clinical symptoms develop.
T84317 4604-4749 Sentence denotes Rabies is an ancient neurological disease caused mainly by the rabies virus (RABV) and is almost invariably fatal once clinical symptoms develop.
TextSentencer_T27 4750-4903 Sentence denotes Currently, rabies continues to pose a serious public health threat in most areas of the world, especially in the developing countries of Asia and Africa.
T71978 4750-4903 Sentence denotes Currently, rabies continues to pose a serious public health threat in most areas of the world, especially in the developing countries of Asia and Africa.
TextSentencer_T28 4904-5071 Sentence denotes It has been estimated by the World Health Organization (WHO) that more than 55,000 annual human deaths are caused by rabies, through bites of rabid animals, worldwide.
T28667 4904-5071 Sentence denotes It has been estimated by the World Health Organization (WHO) that more than 55,000 annual human deaths are caused by rabies, through bites of rabid animals, worldwide.
TextSentencer_T29 5072-5295 Sentence denotes After the virus has entered the periphery site after exposure, it subsequently spreads into the central nervous system (CNS), causing neuronal dysfunction, which is most likely the main cause of the fatal outcome of rabies.
T63256 5072-5295 Sentence denotes After the virus has entered the periphery site after exposure, it subsequently spreads into the central nervous system (CNS), causing neuronal dysfunction, which is most likely the main cause of the fatal outcome of rabies.
TextSentencer_T30 5296-5393 Sentence denotes The causative agent RABV is the type species of the genus Lyssavirus in the family Rhabdoviridae.
T24284 5296-5393 Sentence denotes The causative agent RABV is the type species of the genus Lyssavirus in the family Rhabdoviridae.
TextSentencer_T31 5394-5656 Sentence denotes The RABV genome is a single-stranded, negative-sense RNA of approximately 12 kb, which encodes five structural proteins in the order (3 to 5 ) nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and RNA-dependent RNA polymerase (L) [1] .
T36627 5394-5656 Sentence denotes The RABV genome is a single-stranded, negative-sense RNA of approximately 12 kb, which encodes five structural proteins in the order (3 to 5 ) nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and RNA-dependent RNA polymerase (L) [1] .
TextSentencer_T32 5657-5852 Sentence denotes The negative-sense RNA genome is tightly encapsidated by N, P, and L proteins to form a ribonucleoprotein complex that is responsible for virus replication in the cytoplasm within infected cells.
T73471 5657-5852 Sentence denotes The negative-sense RNA genome is tightly encapsidated by N, P, and L proteins to form a ribonucleoprotein complex that is responsible for virus replication in the cytoplasm within infected cells.
TextSentencer_T33 5853-6034 Sentence denotes The RABV G protein is the only viral protein The recent advance of modern cell cultivation techniques has made it feasible to produce high-quality rabies vaccines from cell culture.
T17003 5853-6034 Sentence denotes The RABV G protein is the only viral protein The recent advance of modern cell cultivation techniques has made it feasible to produce high-quality rabies vaccines from cell culture.
TextSentencer_T34 6035-6293 Sentence denotes An important development was that, although RABV is highly neurotropic, it can lose its tissue tropism and adapt to in vitro cultured cells, a feature that can be utilized to propagate RABV in many different cell types, in order to achieve high virus yields.
T46387 6035-6293 Sentence denotes An important development was that, although RABV is highly neurotropic, it can lose its tissue tropism and adapt to in vitro cultured cells, a feature that can be utilized to propagate RABV in many different cell types, in order to achieve high virus yields.
TextSentencer_T35 6294-6490 Sentence denotes The first licensed human rabies vaccine developed from cell culture was the primary hamster kidney cell vaccine, which was created by cultivating viruses in primary hamster kidney cells [16, 17] .
T91917 6294-6490 Sentence denotes The first licensed human rabies vaccine developed from cell culture was the primary hamster kidney cell vaccine, which was created by cultivating viruses in primary hamster kidney cells [16, 17] .
TextSentencer_T36 6491-6733 Sentence denotes Subsequently, fixed RABV was adapted to the human diploid cell strain, initially using the lung-derived cell line WI-38, but subsequently switched to the fetal lung cell strain MRC-5, to produce the human diploid cell vaccine [18] [19] [20] .
T41638 6491-6733 Sentence denotes Subsequently, fixed RABV was adapted to the human diploid cell strain, initially using the lung-derived cell line WI-38, but subsequently switched to the fetal lung cell strain MRC-5, to produce the human diploid cell vaccine [18] [19] [20] .
TextSentencer_T37 6734-7032 Sentence denotes As the first purified, concentrated, and lyophilized rabies vaccine, the human diploid cell vaccine elicited significantly higher immunogenicity and caused much fewer adverse effects compared to other rabies vaccines, and was therefore recommended as the gold standard reference vaccine by the WHO.
T18448 6734-7032 Sentence denotes As the first purified, concentrated, and lyophilized rabies vaccine, the human diploid cell vaccine elicited significantly higher immunogenicity and caused much fewer adverse effects compared to other rabies vaccines, and was therefore recommended as the gold standard reference vaccine by the WHO.
TextSentencer_T38 7033-7268 Sentence denotes However, the lower virus yields and higher production costs make the human diploid cell vaccine difficult to scale up and can be generally unaffordable to most developing countries, where the majority of human deaths from rabies occur.
T43316 7033-7268 Sentence denotes However, the lower virus yields and higher production costs make the human diploid cell vaccine difficult to scale up and can be generally unaffordable to most developing countries, where the majority of human deaths from rabies occur.
TextSentencer_T39 7269-7526 Sentence denotes As an alternative, other cell culture vaccines, such as the purified duck/chick embryo cell vaccine, were developed and proved to be as effective as human diploid cell vaccine, and are now commonly used for human rabies prevention worldwide [21] [22] [23] .
T27797 7269-7526 Sentence denotes As an alternative, other cell culture vaccines, such as the purified duck/chick embryo cell vaccine, were developed and proved to be as effective as human diploid cell vaccine, and are now commonly used for human rabies prevention worldwide [21] [22] [23] .
TextSentencer_T40 7527-7720 Sentence denotes Nevertheless, as the primary culture cells inherently have a limited capacity to divide, they are technically difficult to adapt to large-scale industrial cultivation for vaccine manufacturing.
T24978 7527-7720 Sentence denotes Nevertheless, as the primary culture cells inherently have a limited capacity to divide, they are technically difficult to adapt to large-scale industrial cultivation for vaccine manufacturing.
TextSentencer_T41 7721-7817 Sentence denotes For this reason, the Vero cell line was used to produce purified Vero cell rabies vaccine [24] .
T83849 7721-7817 Sentence denotes For this reason, the Vero cell line was used to produce purified Vero cell rabies vaccine [24] .
TextSentencer_T42 7818-7965 Sentence denotes Vero cell cultivation can easily be scaled up and the virus titers produced in Vero cells are generally higher than those in primary culture cells.
T16593 7818-7965 Sentence denotes Vero cell cultivation can easily be scaled up and the virus titers produced in Vero cells are generally higher than those in primary culture cells.
TextSentencer_T43 7966-8073 Sentence denotes Importantly, the Vero cell line has a long history of being used in vaccines without safety concerns [25] .
T73631 7966-8073 Sentence denotes Importantly, the Vero cell line has a long history of being used in vaccines without safety concerns [25] .
TextSentencer_T44 8074-8230 Sentence denotes These advantages of Vero cells significantly reduce the costs of rabies vaccine production and make rabies vaccines affordable to most developing countries.
T53924 8074-8230 Sentence denotes These advantages of Vero cells significantly reduce the costs of rabies vaccine production and make rabies vaccines affordable to most developing countries.
TextSentencer_T45 8231-8366 Sentence denotes Undoubtedly, Vero cells will continue to be one of the most common and popular media for human rabies vaccine production in the future.
T15234 8231-8366 Sentence denotes Undoubtedly, Vero cells will continue to be one of the most common and popular media for human rabies vaccine production in the future.
TextSentencer_T46 8367-8505 Sentence denotes Unlike most other vaccines, however, rabies vaccines are designed to be prophylactic and administered primarily in a post-exposure manner.
T38246 8367-8505 Sentence denotes Unlike most other vaccines, however, rabies vaccines are designed to be prophylactic and administered primarily in a post-exposure manner.
TextSentencer_T47 8506-8625 Sentence denotes Due to the extremely high mortality of rabies, only inactivated rabies vaccines were approved for human rabies control.
T2622 8506-8625 Sentence denotes Due to the extremely high mortality of rabies, only inactivated rabies vaccines were approved for human rabies control.
TextSentencer_T48 8626-8809 Sentence denotes These classic inactivated rabies vaccines are fully protective against rabies, but only when administered pre-exposure or promptly post-exposure and generally given as multiple doses.
T50620 8626-8809 Sentence denotes These classic inactivated rabies vaccines are fully protective against rabies, but only when administered pre-exposure or promptly post-exposure and generally given as multiple doses.
TextSentencer_T49 8810-8970 Sentence denotes Once RABV enters the CNS or the symptoms develop, for example in the case of delayed vaccine inoculation, these inactivated vaccines are completely ineffective.
T56968 8810-8970 Sentence denotes Once RABV enters the CNS or the symptoms develop, for example in the case of delayed vaccine inoculation, these inactivated vaccines are completely ineffective.
TextSentencer_T50 8971-9311 Sentence denotes In contrast to inactivated viral vaccines, which can only induce CD4 + T cell and humoral responses, live-attenuated viruses could not only induce CD4 + T cell and humoral responses but also trigger CD8 + T cell responses, as well as innate immune responses that play pivotal roles in cellular immune response against viral infection [26] .
T87309 8971-9311 Sentence denotes In contrast to inactivated viral vaccines, which can only induce CD4 + T cell and humoral responses, live-attenuated viruses could not only induce CD4 + T cell and humoral responses but also trigger CD8 + T cell responses, as well as innate immune responses that play pivotal roles in cellular immune response against viral infection [26] .
TextSentencer_T51 9312-9561 Sentence denotes In addition, live-attenuated viruses could be produced economically and trigger long-lasting immunity with a single dose, which partially accounts for their wide use as vaccines against many diseases, such as smallpox, poliovirus, and measles [27] .
T51917 9312-9561 Sentence denotes In addition, live-attenuated viruses could be produced economically and trigger long-lasting immunity with a single dose, which partially accounts for their wide use as vaccines against many diseases, such as smallpox, poliovirus, and measles [27] .
TextSentencer_T52 9562-9854 Sentence denotes These characteristics of live-attenuated viruses make them ideal candidates for a future rabies vaccine with improved efficacy and potency to fulfill the ultimate goal of a one-dose rabies vaccine for human PEP, and especially benefit infected individuals who would otherwise die from rabies.
T7736 9562-9854 Sentence denotes These characteristics of live-attenuated viruses make them ideal candidates for a future rabies vaccine with improved efficacy and potency to fulfill the ultimate goal of a one-dose rabies vaccine for human PEP, and especially benefit infected individuals who would otherwise die from rabies.
TextSentencer_T53 9855-10135 Sentence denotes Currently, a number of recombinant live-attenuated viruses belonging to several families have been investigated as potential vaccines for rabies control (Table 1) , and encouraging results were obtained in experimental settings, which could pave the way for future rabies therapy.
T20699 9855-10135 Sentence denotes Currently, a number of recombinant live-attenuated viruses belonging to several families have been investigated as potential vaccines for rabies control (Table 1) , and encouraging results were obtained in experimental settings, which could pave the way for future rabies therapy.
TextSentencer_T54 10137-10360 Sentence denotes Since the first recovery of infectious RABV from cloned complementary DNA(cDNA), using reverse genetic techniques by Schnell et al., numerous studies have been performed to manipulate the RABV genome to combat rabies [40] .
T37820 10137-10360 Sentence denotes Since the first recovery of infectious RABV from cloned complementary DNA(cDNA), using reverse genetic techniques by Schnell et al., numerous studies have been performed to manipulate the RABV genome to combat rabies [40] .
TextSentencer_T55 10361-10578 Sentence denotes An important finding was that the virulent wild-type RABV can be attenuated through serial passages in cultured cells, and subsequent studies have identified the molecular basis for the attenuated phenotype [41, 42] .
T42874 10361-10578 Sentence denotes An important finding was that the virulent wild-type RABV can be attenuated through serial passages in cultured cells, and subsequent studies have identified the molecular basis for the attenuated phenotype [41, 42] .
TextSentencer_T56 10579-10852 Sentence denotes Recent studies have shown that live-attenuated RABV activates, while pathogenic RABV evades, the host innate immune responses in the CNS [43] , and it was further demonstrated that co-administration of attenuated RABV with street RABV protects animals against rabies [44] .
T60874 10579-10852 Sentence denotes Recent studies have shown that live-attenuated RABV activates, while pathogenic RABV evades, the host innate immune responses in the CNS [43] , and it was further demonstrated that co-administration of attenuated RABV with street RABV protects animals against rabies [44] .
TextSentencer_T57 10853-11187 Sentence denotes This can be partially explained by the fact that infection with live-attenuated RABV initially stimulates expression of neuronal cytokines, such as CXCL10, which further attract infiltration of inflammatory cells into CNS and boost induction of proinflammatory chemokines/cytokines, such as MIP-1α and interferon-γ (IFN-γ) in the CNS.
T90425 10853-11187 Sentence denotes This can be partially explained by the fact that infection with live-attenuated RABV initially stimulates expression of neuronal cytokines, such as CXCL10, which further attract infiltration of inflammatory cells into CNS and boost induction of proinflammatory chemokines/cytokines, such as MIP-1α and interferon-γ (IFN-γ) in the CNS.
TextSentencer_T58 11188-11360 Sentence denotes This cascade eventually leads to down regulation of the expression of tight junction proteins of the blood-brain barrier (BBB) and thus enhances BBB permeability [45, 46] .
T37751 11188-11360 Sentence denotes This cascade eventually leads to down regulation of the expression of tight junction proteins of the blood-brain barrier (BBB) and thus enhances BBB permeability [45, 46] .
TextSentencer_T59 11361-11713 Sentence denotes It has been demonstrated that enhancement of BBB permeability plays a crucial role in the immune clearance of RABV from the CNS, by allowing the infiltration of immune effectors, such as CD4 + T cells and VNAs, from the periphery into the CNS to clear viruses, and the failure to open the BBB leads to the lethal outcome of street RABV infection [47] .
T35865 11361-11713 Sentence denotes It has been demonstrated that enhancement of BBB permeability plays a crucial role in the immune clearance of RABV from the CNS, by allowing the infiltration of immune effectors, such as CD4 + T cells and VNAs, from the periphery into the CNS to clear viruses, and the failure to open the BBB leads to the lethal outcome of street RABV infection [47] .
TextSentencer_T60 11714-12075 Sentence denotes Interestingly, recent studies have demonstrated that a live replication-deficient RABV-based vaccine can induce both CD4 + T cell-dependent and independent B cell activation through the direct infection and stimulation of B cells, which might account for the rapid and potent induction of early protective immune responses by live RABV-based vaccines [48, 49] .
T57036 11714-12075 Sentence denotes Interestingly, recent studies have demonstrated that a live replication-deficient RABV-based vaccine can induce both CD4 + T cell-dependent and independent B cell activation through the direct infection and stimulation of B cells, which might account for the rapid and potent induction of early protective immune responses by live RABV-based vaccines [48, 49] .
TextSentencer_T61 12076-12216 Sentence denotes These studies indicate that it might be possible to develop therapeutics based on live-attenuated RABV for the treatment of clinical rabies.
T37705 12076-12216 Sentence denotes These studies indicate that it might be possible to develop therapeutics based on live-attenuated RABV for the treatment of clinical rabies.
TextSentencer_T62 12217-12610 Sentence denotes To further increase immunogenicity and address the safety issues associated with a live-attenuated RABV-based vaccine, several strategies have been employed, such as the construction of a replication-deficient virus, targeting specific viral genes, and the insertion of proinflammatory cytokines/chemokines into the viral backbone, using reverse genetic techniques to engineer the RABV genome.
T80739 12217-12610 Sentence denotes To further increase immunogenicity and address the safety issues associated with a live-attenuated RABV-based vaccine, several strategies have been employed, such as the construction of a replication-deficient virus, targeting specific viral genes, and the insertion of proinflammatory cytokines/chemokines into the viral backbone, using reverse genetic techniques to engineer the RABV genome.
TextSentencer_T63 12611-12667 Sentence denotes These strategies are briefly summarized in Table 2 [9] .
T32090 12611-12667 Sentence denotes These strategies are briefly summarized in Table 2 [9] .
TextSentencer_T64 12668-12868 Sentence denotes In general, live-attenuated recombinant RABV vaccines are not only safe, even in immunocompromised mice, but also elicit high VNA titers and prompt early immune responses against RABV infection [50] .
T89957 12668-12868 Sentence denotes In general, live-attenuated recombinant RABV vaccines are not only safe, even in immunocompromised mice, but also elicit high VNA titers and prompt early immune responses against RABV infection [50] .
TextSentencer_T65 12869-13131 Sentence denotes For example, a recombinant RABV expressing the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene payload can prevent mice from developing rabies when administered intracerebrally, at a dose of 10 7.0 PFU, as late as five days post-inoculation [51] .
T52333 12869-13131 Sentence denotes For example, a recombinant RABV expressing the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene payload can prevent mice from developing rabies when administered intracerebrally, at a dose of 10 7.0 PFU, as late as five days post-inoculation [51] .
TextSentencer_T66 13132-13437 Sentence denotes It should be noted that since most viral pathogens, including RABV, have a complex antigenic structure comprising different proteins that likely all contribute to the induction of a protective immune response, live-attenuated RABVs are probably the most promising candidates for humans as well as animals.
T41978 13132-13437 Sentence denotes It should be noted that since most viral pathogens, including RABV, have a complex antigenic structure comprising different proteins that likely all contribute to the induction of a protective immune response, live-attenuated RABVs are probably the most promising candidates for humans as well as animals.
TextSentencer_T67 13438-13819 Sentence denotes Moreover, as the efficacy of vaccination using a specific RABV strain correlates directly with the phylogenetic relationship of the vaccine strain with the circulating virus strains, specific RABV strains that are more closely phylogenetically related with the street isolates circulating in a region might be preferentially selected for rabies vaccine development in a given area.
T87763 13438-13819 Sentence denotes Moreover, as the efficacy of vaccination using a specific RABV strain correlates directly with the phylogenetic relationship of the vaccine strain with the circulating virus strains, specific RABV strains that are more closely phylogenetically related with the street isolates circulating in a region might be preferentially selected for rabies vaccine development in a given area.
TextSentencer_T68 13820-14100 Sentence denotes On the other hand, although live-attenuated RABV vaccines are superior in efficacy and are cost-effective for pre-and post-exposure prophylaxis of rabies, compared with conventional inactivated rabies vaccines, live-attenuated RABV vaccines have not been met with wide acceptance.
T48038 13820-14100 Sentence denotes On the other hand, although live-attenuated RABV vaccines are superior in efficacy and are cost-effective for pre-and post-exposure prophylaxis of rabies, compared with conventional inactivated rabies vaccines, live-attenuated RABV vaccines have not been met with wide acceptance.
TextSentencer_T69 14101-14358 Sentence denotes The major concern is safety (i.e., the potential risk of residual virulence and toxicity associated with live-attenuated vaccines, which might cause local reactions, allergic responses, or neurological complications, especially in immune-compromised hosts).
T51568 14101-14358 Sentence denotes The major concern is safety (i.e., the potential risk of residual virulence and toxicity associated with live-attenuated vaccines, which might cause local reactions, allergic responses, or neurological complications, especially in immune-compromised hosts).
TextSentencer_T70 14359-14545 Sentence denotes Furthermore, the possibility that live vaccines might revert to pathogenic wild-types or even recombine with other live agents, resulting in novel pathogenic agents, cannot be ruled out.
T11537 14359-14545 Sentence denotes Furthermore, the possibility that live vaccines might revert to pathogenic wild-types or even recombine with other live agents, resulting in novel pathogenic agents, cannot be ruled out.
TextSentencer_T71 14546-14630 Sentence denotes Additionally, there is concern about the stability of live-attenuated RABV vaccines.
T81627 14546-14630 Sentence denotes Additionally, there is concern about the stability of live-attenuated RABV vaccines.
TextSentencer_T72 14631-14927 Sentence denotes Considering that high temperatures might inactivate or degrade these live-attenuated RABV vaccines, there is a need for the development of appropriate stabilizers that can prevent the inactivation of these live vaccines, such as through the utilization of cold chain during storage and transport.
T59258 14631-14927 Sentence denotes Considering that high temperatures might inactivate or degrade these live-attenuated RABV vaccines, there is a need for the development of appropriate stabilizers that can prevent the inactivation of these live vaccines, such as through the utilization of cold chain during storage and transport.
TextSentencer_T73 14928-15091 Sentence denotes Further studies should focus on analyzing the effect of a combination of these strategies, in order to maximize the anti-rabies efficacy of a live-attenuated RABV.
T2461 14928-15091 Sentence denotes Further studies should focus on analyzing the effect of a combination of these strategies, in order to maximize the anti-rabies efficacy of a live-attenuated RABV.
TextSentencer_T74 15092-15214 Sentence denotes Vesicular stomatitis virus (VSV) is the prototypic species of Rhabdoviridae and is one of the best studied animal viruses.
T59318 15092-15214 Sentence denotes Vesicular stomatitis virus (VSV) is the prototypic species of Rhabdoviridae and is one of the best studied animal viruses.
TextSentencer_T75 15215-15333 Sentence denotes Although RABV and VSV are highly similar in their genome composition, the biology of RABV and VSV are quite different.
T68977 15215-15333 Sentence denotes Although RABV and VSV are highly similar in their genome composition, the biology of RABV and VSV are quite different.
TextSentencer_T76 15334-15606 Sentence denotes While RABV is a prototype neurotropic virus that causes fatal disease in humans and animals, VSV is an arthropod-borne virus that primarily affects rodents, cattle, pigs, and horses, and most infections of wild-type VSV are non-lethal and only manifest mild symptoms [1] .
T98220 15334-15606 Sentence denotes While RABV is a prototype neurotropic virus that causes fatal disease in humans and animals, VSV is an arthropod-borne virus that primarily affects rodents, cattle, pigs, and horses, and most infections of wild-type VSV are non-lethal and only manifest mild symptoms [1] .
TextSentencer_T77 15607-15806 Sentence denotes Importantly, pre-existing immunity to VSV in human populations is generally very low, and VSV infection of humans is essentially asymptomatic and limited to agricultural and laboratory workers [52] .
T59970 15607-15806 Sentence denotes Importantly, pre-existing immunity to VSV in human populations is generally very low, and VSV infection of humans is essentially asymptomatic and limited to agricultural and laboratory workers [52] .
TextSentencer_T78 15807-15997 Sentence denotes Similar to RABV, numerous strategies, such as gene deletion, have been performed to engineer the VSV genome, in order to increase its immunogenicity and decrease its potential pathogenicity.
T12901 15807-15997 Sentence denotes Similar to RABV, numerous strategies, such as gene deletion, have been performed to engineer the VSV genome, in order to increase its immunogenicity and decrease its potential pathogenicity.
TextSentencer_T79 15998-16150 Sentence denotes Along with gene deletion, M gene mutation and gene arrangement greatly advance the use of VSV as viral vectors for numerous problematic viral pathogens.
T45987 15998-16150 Sentence denotes Along with gene deletion, M gene mutation and gene arrangement greatly advance the use of VSV as viral vectors for numerous problematic viral pathogens.
TextSentencer_T80 16151-16306 Sentence denotes Interestingly, no studies have been performed investigating the efficacy of using VSV, engineered to express RABV G protein, for protection against rabies.
T13343 16151-16306 Sentence denotes Interestingly, no studies have been performed investigating the efficacy of using VSV, engineered to express RABV G protein, for protection against rabies.
TextSentencer_T81 16307-16465 Sentence denotes Given the wide application of VSV as a vaccine vector for other pathogenic viruses, we believe that VSV might represent an ideal candidate for rabies control.
T70849 16307-16465 Sentence denotes Given the wide application of VSV as a vaccine vector for other pathogenic viruses, we believe that VSV might represent an ideal candidate for rabies control.
TextSentencer_T82 16466-16678 Sentence denotes Parainfluenza Virus Type 5 (PIV5), previously known as Simian virus, is a non-segmented negative-strand RNA virus with a genome of about 15 kb in size and belongs to the Rubulavirus genus, Paramyxoviridae family.
T5600 16466-16678 Sentence denotes Parainfluenza Virus Type 5 (PIV5), previously known as Simian virus, is a non-segmented negative-strand RNA virus with a genome of about 15 kb in size and belongs to the Rubulavirus genus, Paramyxoviridae family.
TextSentencer_T83 16679-16879 Sentence denotes It has been shown that PIV5 infects a broad spectrum of cell lines without a significant cytopathic effect, which supports the growth of PIV5 in different cell lines to obtain high viral titers [30] .
T90098 16679-16879 Sentence denotes It has been shown that PIV5 infects a broad spectrum of cell lines without a significant cytopathic effect, which supports the growth of PIV5 in different cell lines to obtain high viral titers [30] .
TextSentencer_T84 16880-17107 Sentence denotes Importantly, kennel cough vaccines containing live PIV5 have been used in dogs for over 40 years without significant safety concerns for animals or humans, and no association of PIV5 with human diseases has been reported [29] .
T85197 16880-17107 Sentence denotes Importantly, kennel cough vaccines containing live PIV5 have been used in dogs for over 40 years without significant safety concerns for animals or humans, and no association of PIV5 with human diseases has been reported [29] .
TextSentencer_T85 17108-17205 Sentence denotes These features suggest that PIV5 could be used as a good vaccine vector for human rabies control.
T36305 17108-17205 Sentence denotes These features suggest that PIV5 could be used as a good vaccine vector for human rabies control.
TextSentencer_T86 17206-17673 Sentence denotes It has also been demonstrated that PIV5, expressing the RABV G gene (rPIV5-RV-G), elicits a robust immune response that protects against a lethal RABV challenge [30] . rPIV5-RV-G displayed a dose-dependent protection manner and a single dose of 10 6.0 PFU of rPIV5-RV-G was sufficient for 100% protection when administered via the intranasal route, while 90% protection was achieved when mice were vaccinated with 10 8.0 PFU of rPIV5-RV-G via the intramuscular route.
T65056 17206-17673 Sentence denotes It has also been demonstrated that PIV5, expressing the RABV G gene (rPIV5-RV-G), elicits a robust immune response that protects against a lethal RABV challenge [30] . rPIV5-RV-G displayed a dose-dependent protection manner and a single dose of 10 6.0 PFU of rPIV5-RV-G was sufficient for 100% protection when administered via the intranasal route, while 90% protection was achieved when mice were vaccinated with 10 8.0 PFU of rPIV5-RV-G via the intramuscular route.
TextSentencer_T87 17674-17857 Sentence denotes Furthermore, mice vaccinated orally with rPIV5-RV-G still showed a significant survival rate, with 50% protection when inoculated with a single dose of 10 8.0 PFU of rPIV5-RV-G [30] .
T47741 17674-17857 Sentence denotes Furthermore, mice vaccinated orally with rPIV5-RV-G still showed a significant survival rate, with 50% protection when inoculated with a single dose of 10 8.0 PFU of rPIV5-RV-G [30] .
TextSentencer_T88 17858-18061 Sentence denotes Most importantly, rPIV5-RV-G protected mice as late as six days after RABV challenge, with 50% protection when inoculated with a single dose of 10 7.0 PFU of rPIV5-RV-G via the intramuscular route [29] .
T42999 17858-18061 Sentence denotes Most importantly, rPIV5-RV-G protected mice as late as six days after RABV challenge, with 50% protection when inoculated with a single dose of 10 7.0 PFU of rPIV5-RV-G via the intramuscular route [29] .
TextSentencer_T89 18062-18171 Sentence denotes These results demonstrated that PIV5-G is a promising vaccine candidate for prevention and control of rabies.
T69626 18062-18171 Sentence denotes These results demonstrated that PIV5-G is a promising vaccine candidate for prevention and control of rabies.
TextSentencer_T90 18172-18409 Sentence denotes Newcastle disease virus (NDV) is a member of the genus Avulavirus of the family Paramyxoviridae, and is one of the virus vectors that are under clinical evaluation for oncolytic cancer therapy, gene therapy, and immune stimulation [53] .
T3133 18172-18409 Sentence denotes Newcastle disease virus (NDV) is a member of the genus Avulavirus of the family Paramyxoviridae, and is one of the virus vectors that are under clinical evaluation for oncolytic cancer therapy, gene therapy, and immune stimulation [53] .
TextSentencer_T91 18410-18595 Sentence denotes One of the obvious advantages of NDV is that it is a bird virus that has adapted only to the avian immune system and does not usually infect mammals due to host range restriction [31] .
T80516 18410-18595 Sentence denotes One of the obvious advantages of NDV is that it is a bird virus that has adapted only to the avian immune system and does not usually infect mammals due to host range restriction [31] .
TextSentencer_T92 18596-18880 Sentence denotes Several studies have shown that recombinant NDV, expressing the appropriate protective antigens, provided good protection against many pathogen infections, such as influenza virus, human respiratory syncytial virus (HRSV), and severe acute respiratory syndrome (SARS) [54] [55] [56] .
T47734 18596-18880 Sentence denotes Several studies have shown that recombinant NDV, expressing the appropriate protective antigens, provided good protection against many pathogen infections, such as influenza virus, human respiratory syncytial virus (HRSV), and severe acute respiratory syndrome (SARS) [54] [55] [56] .
TextSentencer_T93 18881-18972 Sentence denotes These results indicate that NDV is a promising vaccine vector for humans and other mammals.
T33549 18881-18972 Sentence denotes These results indicate that NDV is a promising vaccine vector for humans and other mammals.
TextSentencer_T94 18973-19125 Sentence denotes A recombinant NDV was constructed, expressing the G gene of the ERA strain (rL-RVG), to evaluate its ability to serve as a vaccine against rabies [31] .
T5794 18973-19125 Sentence denotes A recombinant NDV was constructed, expressing the G gene of the ERA strain (rL-RVG), to evaluate its ability to serve as a vaccine against rabies [31] .
TextSentencer_T95 19126-19333 Sentence denotes It was shown that rL-RVG grow to high titers in cultured cells (up to 10 9.8 50% egg infective doses/ml of allantoic fluid) and the expression of RABV G does not change the pathogenicity of the vector virus.
T24930 19126-19333 Sentence denotes It was shown that rL-RVG grow to high titers in cultured cells (up to 10 9.8 50% egg infective doses/ml of allantoic fluid) and the expression of RABV G does not change the pathogenicity of the vector virus.
TextSentencer_T96 19334-19501 Sentence denotes Furthermore, intramuscular vaccination with rL-RVG induced a substantial level of VNA production and provided complete protection from challenge with circulating RABV.
T43456 19334-19501 Sentence denotes Furthermore, intramuscular vaccination with rL-RVG induced a substantial level of VNA production and provided complete protection from challenge with circulating RABV.
TextSentencer_T97 19502-19766 Sentence denotes Most importantly, rL-RVG induced strong and long-lasting protective immune responses against rabies in dogs and cats, with a low vaccine dose of 10 8.3 50% egg infective doses completely protecting dogs from challenge with a street RABV for more than a year [31] .
T28880 19502-19766 Sentence denotes Most importantly, rL-RVG induced strong and long-lasting protective immune responses against rabies in dogs and cats, with a low vaccine dose of 10 8.3 50% egg infective doses completely protecting dogs from challenge with a street RABV for more than a year [31] .
TextSentencer_T98 19767-19976 Sentence denotes These results demonstrated that an NDV-vectored vaccine can be utilized to induce long-lasting systemic protective immunity against rabies in animals and humans in high-risk areas to control rabies infections.
T40139 19767-19976 Sentence denotes These results demonstrated that an NDV-vectored vaccine can be utilized to induce long-lasting systemic protective immunity against rabies in animals and humans in high-risk areas to control rabies infections.
TextSentencer_T99 19977-20068 Sentence denotes Open reading frame virus (ORFV) belongs to the Parapoxvirus genus in the Poxviridae family.
T49316 19977-20068 Sentence denotes Open reading frame virus (ORFV) belongs to the Parapoxvirus genus in the Poxviridae family.
TextSentencer_T100 20069-20578 Sentence denotes Due to its very restricted host range to sheep and goats, its skin tropism infection, and the absence of systemic virus spread, even in immunocompromised individuals or after intravenous injection of a high virus dose, a short-term vector specific immunity, and the robust and rapid stimulation of innate immune responses at the site of infection [57, 58] , ORFV has emerged as a novel virus vector system for expressing different foreign antigens and as vaccine candidates for other pathogenic viruses [32] .
T14020 20069-20578 Sentence denotes Due to its very restricted host range to sheep and goats, its skin tropism infection, and the absence of systemic virus spread, even in immunocompromised individuals or after intravenous injection of a high virus dose, a short-term vector specific immunity, and the robust and rapid stimulation of innate immune responses at the site of infection [57, 58] , ORFV has emerged as a novel virus vector system for expressing different foreign antigens and as vaccine candidates for other pathogenic viruses [32] .
TextSentencer_T101 20579-20865 Sentence denotes It has been shown that a Vero cell culture-adapted apathogenic ORFV strain, D1701-V, expressing the RABV G protein (D1701-V-RabG), correctly presents the RABV G protein on the surface of infected cells without the need for replication or production of infectious recombinant ORFV [32] .
T44830 20579-20865 Sentence denotes It has been shown that a Vero cell culture-adapted apathogenic ORFV strain, D1701-V, expressing the RABV G protein (D1701-V-RabG), correctly presents the RABV G protein on the surface of infected cells without the need for replication or production of infectious recombinant ORFV [32] .
TextSentencer_T102 20866-20989 Sentence denotes Furthermore, one single immunization with D1701-V-RabG stimulated high titers of RABV-specific VNA in mice, cats, and dogs.
T46029 20866-20989 Sentence denotes Furthermore, one single immunization with D1701-V-RabG stimulated high titers of RABV-specific VNA in mice, cats, and dogs.
TextSentencer_T103 20990-21179 Sentence denotes A single intramuscular inoculation of 10 7.0 PFU of D1701-V-RabG completely protected mice against an intracranial challenge with high lethal doses of the virulent RABV strain CVS-11 [32] .
T95350 20990-21179 Sentence denotes A single intramuscular inoculation of 10 7.0 PFU of D1701-V-RabG completely protected mice against an intracranial challenge with high lethal doses of the virulent RABV strain CVS-11 [32] .
TextSentencer_T104 21180-21314 Sentence denotes These results demonstrated that ORFV is a valuable virus vector to be used as vaccines for rabies control and treatment in the future.
T24644 21180-21314 Sentence denotes These results demonstrated that ORFV is a valuable virus vector to be used as vaccines for rabies control and treatment in the future.
TextSentencer_T105 21315-21449 Sentence denotes Vaccinia virus is a large, complex, enveloped double-stranded DNA virus belonging to the Orthopoxvirus genus in the Poxviridae family.
T76108 21315-21449 Sentence denotes Vaccinia virus is a large, complex, enveloped double-stranded DNA virus belonging to the Orthopoxvirus genus in the Poxviridae family.
TextSentencer_T106 21450-21575 Sentence denotes Similar to other poxviruses, vaccinia virus replicates uniquely and exclusively in the cytoplasm of the infected cells [59] .
T28853 21450-21575 Sentence denotes Similar to other poxviruses, vaccinia virus replicates uniquely and exclusively in the cytoplasm of the infected cells [59] .
TextSentencer_T107 21576-21677 Sentence denotes Vaccinia virus infection is generally very mild and is typically asymptomatic in healthy individuals.
T2647 21576-21677 Sentence denotes Vaccinia virus infection is generally very mild and is typically asymptomatic in healthy individuals.
TextSentencer_T108 21678-21994 Sentence denotes The most famous application of vaccinia virus in modern vaccinology is the successful use of vaccinia virus to eradicate smallpox, which is a milestone in the fight against infectious diseases during the history of mankind, and vaccinia virus is still being used as a live-virus vaccine against smallpox today [60] .
T66902 21678-21994 Sentence denotes The most famous application of vaccinia virus in modern vaccinology is the successful use of vaccinia virus to eradicate smallpox, which is a milestone in the fight against infectious diseases during the history of mankind, and vaccinia virus is still being used as a live-virus vaccine against smallpox today [60] .
TextSentencer_T109 21995-22120 Sentence denotes Several recombinant poxviruses have been licensed for use as vaccines against numerous pathogen infections, including rabies.
T2131 21995-22120 Sentence denotes Several recombinant poxviruses have been licensed for use as vaccines against numerous pathogen infections, including rabies.
TextSentencer_T110 22121-22334 Sentence denotes The first recombinant poxvirus licensed and used as a vaccine is the recombinant vaccinia virus Copenhagen strain, expressing a RABV G gene, which was inserted into the poxvirus thymidine kinase gene (V-RG) [60] .
T46712 22121-22334 Sentence denotes The first recombinant poxvirus licensed and used as a vaccine is the recombinant vaccinia virus Copenhagen strain, expressing a RABV G gene, which was inserted into the poxvirus thymidine kinase gene (V-RG) [60] .
TextSentencer_T111 22335-22486 Sentence denotes It has been suggested that oral rabies vaccination may be the only effective strategy for rabies elimination programs in domestic and wildlife animals.
T33449 22335-22486 Sentence denotes It has been suggested that oral rabies vaccination may be the only effective strategy for rabies elimination programs in domestic and wildlife animals.
TextSentencer_T112 22487-22738 Sentence denotes As a live virus vaccine, V-RG was one of the two vaccines (the other was the RABV SAG-2 strain) successfully used as oral baits to control rabies in wild animals, such as red foxes, raccoons, and coyotes, in North America and Western Europe [34, 35] .
T52914 22487-22738 Sentence denotes As a live virus vaccine, V-RG was one of the two vaccines (the other was the RABV SAG-2 strain) successfully used as oral baits to control rabies in wild animals, such as red foxes, raccoons, and coyotes, in North America and Western Europe [34, 35] .
TextSentencer_T113 22739-22862 Sentence denotes However, V-RG failed to induce adequate protection in skunks and dogs when administrated orally as a single dose [61, 62] .
T66104 22739-22862 Sentence denotes However, V-RG failed to induce adequate protection in skunks and dogs when administrated orally as a single dose [61, 62] .
TextSentencer_T114 22863-22987 Sentence denotes Moreover, V-RG has been associated with severe skin inflammation in humans who have occasional contact with the baits [63] .
T75135 22863-22987 Sentence denotes Moreover, V-RG has been associated with severe skin inflammation in humans who have occasional contact with the baits [63] .
TextSentencer_T115 22988-23158 Sentence denotes Another drawback of V-RG is the pre-existing, or vaccination-induced, vector immunity, which could inhibit the generation of sufficient anti-rabies immune response [64] .
T69252 22988-23158 Sentence denotes Another drawback of V-RG is the pre-existing, or vaccination-induced, vector immunity, which could inhibit the generation of sufficient anti-rabies immune response [64] .
TextSentencer_T116 23159-23394 Sentence denotes As an alternative, a safer, highly attenuated, and host-restricted variant of vaccinia virus, the modified vaccinia virus Ankara (MVA) strain, was developed through serial passages in primary chick embryo fibroblast cell culture [65] .
T13834 23159-23394 Sentence denotes As an alternative, a safer, highly attenuated, and host-restricted variant of vaccinia virus, the modified vaccinia virus Ankara (MVA) strain, was developed through serial passages in primary chick embryo fibroblast cell culture [65] .
TextSentencer_T117 23395-23625 Sentence denotes Unfortunately, a recombinant MVA expressing the RABV G gene was shown to be less immunogenic than V-RG, with up to two log titers of the recombinant MVA being required to elicit an equivalent VNA response in laboratory mice [60] .
T61427 23395-23625 Sentence denotes Unfortunately, a recombinant MVA expressing the RABV G gene was shown to be less immunogenic than V-RG, with up to two log titers of the recombinant MVA being required to elicit an equivalent VNA response in laboratory mice [60] .
TextSentencer_T118 23626-23752 Sentence denotes However, the recombinant MVA did elicit adequate protective immune response in dogs and raccoons by oral administration [66] .
T98703 23626-23752 Sentence denotes However, the recombinant MVA did elicit adequate protective immune response in dogs and raccoons by oral administration [66] .
TextSentencer_T119 23753-23933 Sentence denotes Other poxviral vectors, such as canarypox virus, raccoon poxvirus, capripoxvirus, and fowlpox virus, have also been used to generate recombinant live vaccines against rabies [60] .
T39455 23753-23933 Sentence denotes Other poxviral vectors, such as canarypox virus, raccoon poxvirus, capripoxvirus, and fowlpox virus, have also been used to generate recombinant live vaccines against rabies [60] .
TextSentencer_T120 23934-24032 Sentence denotes These vaccines generally have their limitations and are thus not ideal for use as rabies vaccines.
T53682 23934-24032 Sentence denotes These vaccines generally have their limitations and are thus not ideal for use as rabies vaccines.
TextSentencer_T121 24033-24250 Sentence denotes Adenoviruses are a family of non-enveloped double stranded DNA viruses with an icosahedral nucleocapsid that are pathogenic to a broad range of vertebrate hosts, such as reptiles, birds, mammals, and amphibians [67] .
T82889 24033-24250 Sentence denotes Adenoviruses are a family of non-enveloped double stranded DNA viruses with an icosahedral nucleocapsid that are pathogenic to a broad range of vertebrate hosts, such as reptiles, birds, mammals, and amphibians [67] .
TextSentencer_T122 24251-24465 Sentence denotes Adenovirus vectors have been shown to be highly efficacious and are capable of inducing strong antibody CD4 + and CD8 + T cell responses [68] , making them ideal candidates for gene therapy and vaccine development.
T6674 24251-24465 Sentence denotes Adenovirus vectors have been shown to be highly efficacious and are capable of inducing strong antibody CD4 + and CD8 + T cell responses [68] , making them ideal candidates for gene therapy and vaccine development.
TextSentencer_T123 24466-24753 Sentence denotes As human adenoviruses are by far the best characterized, most applications of adenoviruses, such as gene transfer studies and vaccine vectors, have been carried out with vectors based on the replication-defective human serotype 5 (HAdV-5), with the essential E1 or E3 gene deleted [69] .
T44664 24466-24753 Sentence denotes As human adenoviruses are by far the best characterized, most applications of adenoviruses, such as gene transfer studies and vaccine vectors, have been carried out with vectors based on the replication-defective human serotype 5 (HAdV-5), with the essential E1 or E3 gene deleted [69] .
TextSentencer_T124 24754-24861 Sentence denotes An E1-deleted HAdV-5 expressing the RABV G protein, Adrab.gp, was constructed and tested in mice [36, 37] .
T44845 24754-24861 Sentence denotes An E1-deleted HAdV-5 expressing the RABV G protein, Adrab.gp, was constructed and tested in mice [36, 37] .
TextSentencer_T125 24862-24985 Sentence denotes Mice immunized at birth with Adrab.gp developed antibodies to RABV and were protected against subsequent lethal challenges.
T42978 24862-24985 Sentence denotes Mice immunized at birth with Adrab.gp developed antibodies to RABV and were protected against subsequent lethal challenges.
TextSentencer_T126 24986-25161 Sentence denotes Furthermore, immune responses elicited by Adrab.gp were not impaired by maternal immunity, suggesting that Adrab.gp could be useful for immunization shortly after birth [37] .
T67673 24986-25161 Sentence denotes Furthermore, immune responses elicited by Adrab.gp were not impaired by maternal immunity, suggesting that Adrab.gp could be useful for immunization shortly after birth [37] .
TextSentencer_T127 25162-25303 Sentence denotes It was shown that Adrab.gp induced high titers of VNA against rabies in dogs previously immunized with the conventional rabies vaccine [70] .
T34220 25162-25303 Sentence denotes It was shown that Adrab.gp induced high titers of VNA against rabies in dogs previously immunized with the conventional rabies vaccine [70] .
TextSentencer_T128 25304-25489 Sentence denotes AdRG1.3, also known as ONRAB ® , is a replication-competent HAdV-5 vector, with an insertion of the RABV G gene into the E3 region, thus rendering the virus replication defective [71] .
T90504 25304-25489 Sentence denotes AdRG1.3, also known as ONRAB ® , is a replication-competent HAdV-5 vector, with an insertion of the RABV G gene into the E3 region, thus rendering the virus replication defective [71] .
TextSentencer_T129 25490-25758 Sentence denotes It was demonstrated that AdRG1.3 induced high levels of VNAs for protection against rabies, and importantly, AdRG1.3 was immunogenic and demonstrated significant protection as baits both to skunks and raccoons, for which the V-RG vaccine showed limited efficacy [72] .
T45080 25490-25758 Sentence denotes It was demonstrated that AdRG1.3 induced high levels of VNAs for protection against rabies, and importantly, AdRG1.3 was immunogenic and demonstrated significant protection as baits both to skunks and raccoons, for which the V-RG vaccine showed limited efficacy [72] .
TextSentencer_T130 25759-26150 Sentence denotes Besides HAdV-5, a number of other adenoviruses, such as the avirulent canine adenovirus type-2 [73] , chimpanzee adenovirus vector serotype SAd-V24 (also termed AdC68) [74] , and avian adenovirus Celo virus [75] , have also been investigated for use as rabies vaccines, and these recombinant adenoviruses generally elicit robust VNA production and provide adequate protection against rabies.
T30118 25759-26150 Sentence denotes Besides HAdV-5, a number of other adenoviruses, such as the avirulent canine adenovirus type-2 [73] , chimpanzee adenovirus vector serotype SAd-V24 (also termed AdC68) [74] , and avian adenovirus Celo virus [75] , have also been investigated for use as rabies vaccines, and these recombinant adenoviruses generally elicit robust VNA production and provide adequate protection against rabies.
TextSentencer_T131 26151-26337 Sentence denotes These results demonstrated that recombinant adenovirus-based vectors warrant further consideration for human rabies control and particularly for the oral vaccination of wildlife animals.
T78450 26151-26337 Sentence denotes These results demonstrated that recombinant adenovirus-based vectors warrant further consideration for human rabies control and particularly for the oral vaccination of wildlife animals.
TextSentencer_T132 26338-26569 Sentence denotes Pseudorabies Virus (PRV), also known as Suid herpesvirus 1 or Aujeszky s disease virus, is a member of herpesvirus type 1 virus, belonging to the Varicellovirus genus in the Alphaherpesvirinae subfamily of the Herpesviridae family.
T71156 26338-26569 Sentence denotes Pseudorabies Virus (PRV), also known as Suid herpesvirus 1 or Aujeszky s disease virus, is a member of herpesvirus type 1 virus, belonging to the Varicellovirus genus in the Alphaherpesvirinae subfamily of the Herpesviridae family.
TextSentencer_T133 26570-26681 Sentence denotes The genome of PRV is a linear, double-stranded DNA enclosed within a protective icosahedral nucleocapsid [76] .
T94290 26570-26681 Sentence denotes The genome of PRV is a linear, double-stranded DNA enclosed within a protective icosahedral nucleocapsid [76] .
TextSentencer_T134 26682-26783 Sentence denotes PRV is the main cause of Aujeszky s disease in swine and is endemic in most parts of the world [77] .
T76358 26682-26783 Sentence denotes PRV is the main cause of Aujeszky s disease in swine and is endemic in most parts of the world [77] .
TextSentencer_T135 26784-26960 Sentence denotes Recently, PRV has attracted much attention on disease control in swine agriculture, and has also been a useful model for the study of herpesvirus biology and neuronal pathways.
T86105 26784-26960 Sentence denotes Recently, PRV has attracted much attention on disease control in swine agriculture, and has also been a useful model for the study of herpesvirus biology and neuronal pathways.
TextSentencer_T136 26961-27107 Sentence denotes In addition, vectors based on PRV have been developed for delivery of viral antigens, to improve the efficacy of vaccines for pig pathogens [78] .
T14208 26961-27107 Sentence denotes In addition, vectors based on PRV have been developed for delivery of viral antigens, to improve the efficacy of vaccines for pig pathogens [78] .
TextSentencer_T137 27108-27253 Sentence denotes A recombinant PRV, expressing the RABV G gene (rPRV/eGFP/rgp), was constructed and analyzed for its efficacy for protection against rabies [38] .
T86317 27108-27253 Sentence denotes A recombinant PRV, expressing the RABV G gene (rPRV/eGFP/rgp), was constructed and analyzed for its efficacy for protection against rabies [38] .
TextSentencer_T138 27254-27644 Sentence denotes It was shown that the growth rate of rPRV/eGFP/rgp was comparable to that of the parent PRV strain. rPRV/eGFP/rgp was safe in dogs by oral and intramuscular routes of inoculation and induced protective immune responses against both pseudorabies and rabies in dogs, via a single oral inoculation of 2×10 7.0 PFU, with the VNAs produced by rPRV/eGFP/rgp maintaining for over six months [38] .
T50261 27254-27644 Sentence denotes It was shown that the growth rate of rPRV/eGFP/rgp was comparable to that of the parent PRV strain. rPRV/eGFP/rgp was safe in dogs by oral and intramuscular routes of inoculation and induced protective immune responses against both pseudorabies and rabies in dogs, via a single oral inoculation of 2×10 7.0 PFU, with the VNAs produced by rPRV/eGFP/rgp maintaining for over six months [38] .
TextSentencer_T139 27645-27776 Sentence denotes These results demonstrated that PRV may serve as an alternative live vector for the development of an oral rabies vaccine for dogs.
T1220 27645-27776 Sentence denotes These results demonstrated that PRV may serve as an alternative live vector for the development of an oral rabies vaccine for dogs.
TextSentencer_T140 27777-28068 Sentence denotes Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the type species of the Baculoviridae, a family of enveloped double-stranded DNA viruses that are specifically pathogenic to arthropods, and mainly affects insects of the orders Lepidoptera, Hymenoptera, and Diptera [79, 80] .
T99121 27777-28068 Sentence denotes Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the type species of the Baculoviridae, a family of enveloped double-stranded DNA viruses that are specifically pathogenic to arthropods, and mainly affects insects of the orders Lepidoptera, Hymenoptera, and Diptera [79, 80] .
TextSentencer_T141 28069-28339 Sentence denotes Due to the strict host specificity, baculoviruses are probably the most beneficial viruses to humans and have been used as bio-insecticides against forestry and agriculture pests and as vectors for virus-like particle expression and surface display techniques [81, 82] .
T9507 28069-28339 Sentence denotes Due to the strict host specificity, baculoviruses are probably the most beneficial viruses to humans and have been used as bio-insecticides against forestry and agriculture pests and as vectors for virus-like particle expression and surface display techniques [81, 82] .
TextSentencer_T142 28340-28522 Sentence denotes Most importantly, the baculovirus-insect expression system is one of the most popular and robust eukaryotic expression systems for heterologous gene expression in insect cells [83] .
T29827 28340-28522 Sentence denotes Most importantly, the baculovirus-insect expression system is one of the most popular and robust eukaryotic expression systems for heterologous gene expression in insect cells [83] .
TextSentencer_T143 28523-28676 Sentence denotes A recombinant AcMNPV, expressing the RABV G gene, was constructed under the control of the AcMNPV polyhedrin and the immediate early CMV promoters [39] .
T4102 28523-28676 Sentence denotes A recombinant AcMNPV, expressing the RABV G gene, was constructed under the control of the AcMNPV polyhedrin and the immediate early CMV promoters [39] .
TextSentencer_T144 28677-28827 Sentence denotes An in vitro study demonstrated that BV-RVG/RVG induced syncytium formation in insect cells and displayed efficient gene delivery into mammalian cells.
T11006 28677-28827 Sentence denotes An in vitro study demonstrated that BV-RVG/RVG induced syncytium formation in insect cells and displayed efficient gene delivery into mammalian cells.
TextSentencer_T145 28828-28984 Sentence denotes Importantly, mice intramuscularly immunized with BV-RVG/RVG developed high levels of VNAs and were completely protected against lethal RABV challenge [39] .
T5486 28828-28984 Sentence denotes Importantly, mice intramuscularly immunized with BV-RVG/RVG developed high levels of VNAs and were completely protected against lethal RABV challenge [39] .
TextSentencer_T146 28985-29125 Sentence denotes These results demonstrated that baculovirus can be used as an alternative strategy to develop a safe and efficacious vaccine against rabies.
T70915 28985-29125 Sentence denotes These results demonstrated that baculovirus can be used as an alternative strategy to develop a safe and efficacious vaccine against rabies.
TextSentencer_T147 29126-29539 Sentence denotes Although live-attenuated virus-based vaccines represent the most promising approach for rabies control and treatment, some other novel modalities have also been investigated for their potential role in rabies treatment, such as protein and peptide vaccine, nucleic acid-based vaccine, RNA interference (RNAi), and RIG, coupled with BBB permeability enhancing agents such as monocyte chemotactic protein-1 (MCP-1).
T96094 29126-29539 Sentence denotes Although live-attenuated virus-based vaccines represent the most promising approach for rabies control and treatment, some other novel modalities have also been investigated for their potential role in rabies treatment, such as protein and peptide vaccine, nucleic acid-based vaccine, RNA interference (RNAi), and RIG, coupled with BBB permeability enhancing agents such as monocyte chemotactic protein-1 (MCP-1).
TextSentencer_T148 29540-29864 Sentence denotes Still another promising approach is a bi-specific antibody (BsAb) with one arm targeting a receptor involved in the receptor-mediated transcytosis pathway of the brain while another one targets the RABV G protein, thus potentially enabling efficient transport of antibody across the BBB, in order to clear RABV from the CNS.
T76186 29540-29864 Sentence denotes Still another promising approach is a bi-specific antibody (BsAb) with one arm targeting a receptor involved in the receptor-mediated transcytosis pathway of the brain while another one targets the RABV G protein, thus potentially enabling efficient transport of antibody across the BBB, in order to clear RABV from the CNS.
TextSentencer_T149 29865-30166 Sentence denotes Several studies have investigated the efficacy of G protein (purified from infected cells) for rabies protection, based on the fact that RABV G protein is the major determinant of viral pathogenicity and is also the major protective antigen responsible for inducing protective immunity against rabies.
T42976 29865-30166 Sentence denotes Several studies have investigated the efficacy of G protein (purified from infected cells) for rabies protection, based on the fact that RABV G protein is the major determinant of viral pathogenicity and is also the major protective antigen responsible for inducing protective immunity against rabies.
TextSentencer_T150 30167-30448 Sentence denotes In one study, the RABV G protein was engineered into the yeast system and the yeast extracts containing the rabies G protein protected guinea pigs from a lethal RABV challenge when administered intramuscularly, but failed to protect mice via a lethal intracerebral challenge [84] .
T27921 30167-30448 Sentence denotes In one study, the RABV G protein was engineered into the yeast system and the yeast extracts containing the rabies G protein protected guinea pigs from a lethal RABV challenge when administered intramuscularly, but failed to protect mice via a lethal intracerebral challenge [84] .
TextSentencer_T151 30449-30706 Sentence denotes In another study, Sakamoto et al. showed that most rabies G protein expressed in yeast were not processed correctly and were therefore poorly immunogenic [85] , which might be ascribed to the structural complexity and multimeric propensity of the G protein.
T74702 30449-30706 Sentence denotes In another study, Sakamoto et al. showed that most rabies G protein expressed in yeast were not processed correctly and were therefore poorly immunogenic [85] , which might be ascribed to the structural complexity and multimeric propensity of the G protein.
TextSentencer_T152 30707-31005 Sentence denotes As mentioned above, a baculovirus-expressed G protein in insect cells was found to be antigenically conserved and immunogenic in mice [86] , and provided protection to raccoons against a lethal challenge with a street RABV via repeated oral immunization with G protein-containing cell lysate [87] .
T45811 30707-31005 Sentence denotes As mentioned above, a baculovirus-expressed G protein in insect cells was found to be antigenically conserved and immunogenic in mice [86] , and provided protection to raccoons against a lethal challenge with a street RABV via repeated oral immunization with G protein-containing cell lysate [87] .
TextSentencer_T153 31006-31163 Sentence denotes Furthermore, there are researchers using plants, such as maize and tobacco, to express RABV G protein to obtain the so-called edible vaccine [88] [89] [90] .
T25547 31006-31163 Sentence denotes Furthermore, there are researchers using plants, such as maize and tobacco, to express RABV G protein to obtain the so-called edible vaccine [88] [89] [90] .
TextSentencer_T154 31164-31516 Sentence denotes Although these forms of vaccines induced a detectable VNA response and protection against challenge in mice upon ingestion, thus potentially being generated at a low cost, several limitations were obvious, including immunogenicity, the stability of the vaccine in fruit, the degradation of the vaccine in the stomach and the intestinal immune response.
T53008 31164-31516 Sentence denotes Although these forms of vaccines induced a detectable VNA response and protection against challenge in mice upon ingestion, thus potentially being generated at a low cost, several limitations were obvious, including immunogenicity, the stability of the vaccine in fruit, the degradation of the vaccine in the stomach and the intestinal immune response.
TextSentencer_T155 31517-31706 Sentence denotes Therefore, despite that fact that edible vaccines are attractive and appealing options, much work must be conducted before they can become a viable option for an alternative rabies vaccine.
T577 31517-31706 Sentence denotes Therefore, despite that fact that edible vaccines are attractive and appealing options, much work must be conducted before they can become a viable option for an alternative rabies vaccine.
TextSentencer_T156 31707-31810 Sentence denotes Overall, protein subunit vaccines are often poorly immunogenic and can induce limited immune responses.
T67652 31707-31810 Sentence denotes Overall, protein subunit vaccines are often poorly immunogenic and can induce limited immune responses.
TextSentencer_T157 31811-32006 Sentence denotes It should also be noticed that, for therapeutic use of a vaccine given by injection, the expressed proteins must be extensively purified, which would likely render this approach cost-ineffective.
T67175 31811-32006 Sentence denotes It should also be noticed that, for therapeutic use of a vaccine given by injection, the expressed proteins must be extensively purified, which would likely render this approach cost-ineffective.
TextSentencer_T158 32007-32129 Sentence denotes Besides a protein subunit vaccine, peptide vaccines have also been conducted to test their efficacy for rabies protection.
T54120 32007-32129 Sentence denotes Besides a protein subunit vaccine, peptide vaccines have also been conducted to test their efficacy for rabies protection.
TextSentencer_T159 32130-32261 Sentence denotes A number of antigenic epitopes have been identified in RABV G protein, and peptides mimicking these epitopes have been synthesized.
T9879 32130-32261 Sentence denotes A number of antigenic epitopes have been identified in RABV G protein, and peptides mimicking these epitopes have been synthesized.
TextSentencer_T160 32262-32611 Sentence denotes It was shown that a peptide expressing a linear epitope of the G protein (named G5), located at aa 244-281 of the G protein, induces a strong humoral immune response in the absence of a carrier protein in immunized goats, which mounted high antibody titers and showed a strong avidity to both the G5 peptide and the purified surface G protein [91] .
T77434 32262-32611 Sentence denotes It was shown that a peptide expressing a linear epitope of the G protein (named G5), located at aa 244-281 of the G protein, induces a strong humoral immune response in the absence of a carrier protein in immunized goats, which mounted high antibody titers and showed a strong avidity to both the G5 peptide and the purified surface G protein [91] .
TextSentencer_T161 32612-32786 Sentence denotes However, the antibody produced weakly neutralized RABV carrying the G5 epitope and failed to neutralize escape mutants carrying a single point mutation in this epitope [91] .
T23213 32612-32786 Sentence denotes However, the antibody produced weakly neutralized RABV carrying the G5 epitope and failed to neutralize escape mutants carrying a single point mutation in this epitope [91] .
TextSentencer_T162 32787-33127 Sentence denotes Peptide mimotopes of the G protein (identified from a random constrained hexapeptide phage display library, using neutralizing human anti-RABV IgG antibodies), were shown to be matched to antigenic site III of the G protein, and these mimotopes were able to interact with the human anti-RABV IgG antibodies in a dose-dependent manner [92] .
T78587 32787-33127 Sentence denotes Peptide mimotopes of the G protein (identified from a random constrained hexapeptide phage display library, using neutralizing human anti-RABV IgG antibodies), were shown to be matched to antigenic site III of the G protein, and these mimotopes were able to interact with the human anti-RABV IgG antibodies in a dose-dependent manner [92] .
TextSentencer_T163 33128-33373 Sentence denotes While subcutaneous administration of the RABV G site III mimotope induced an anti-RABV G-specific IgG response in mice [92] , it does not address whether these mimotopes could elicit immune protection against a lethal challenge in a mouse model.
T38744 33128-33373 Sentence denotes While subcutaneous administration of the RABV G site III mimotope induced an anti-RABV G-specific IgG response in mice [92] , it does not address whether these mimotopes could elicit immune protection against a lethal challenge in a mouse model.
TextSentencer_T164 33374-33626 Sentence denotes On the other hand, a chimeric peptide containing antigenic determinants of the G protein (amino acids 253-275) and N protein (amino acids 404-418) was constructed to fuse with the coat protein of alfalfa mosaic virus in tobacco or spinach plants [90] .
T61708 33374-33626 Sentence denotes On the other hand, a chimeric peptide containing antigenic determinants of the G protein (amino acids 253-275) and N protein (amino acids 404-418) was constructed to fuse with the coat protein of alfalfa mosaic virus in tobacco or spinach plants [90] .
TextSentencer_T165 33627-34009 Sentence denotes The recombinant virus induced an immune response in mice and protected mice against challenge infection: following a single dose of conventional rabies virus vaccine, three of nine individuals showed detectable levels of RABV-neutralizing antibodies, indicating the potential of the plant virus-based expression systems as a supplementary oral booster for rabies vaccinations [90] .
T80211 33627-34009 Sentence denotes The recombinant virus induced an immune response in mice and protected mice against challenge infection: following a single dose of conventional rabies virus vaccine, three of nine individuals showed detectable levels of RABV-neutralizing antibodies, indicating the potential of the plant virus-based expression systems as a supplementary oral booster for rabies vaccinations [90] .
TextSentencer_T166 34010-34141 Sentence denotes However, the high variability of the G protein would compromise these peptide vaccines that induce antibodies to specific epitopes.
T38311 34010-34141 Sentence denotes However, the high variability of the G protein would compromise these peptide vaccines that induce antibodies to specific epitopes.
TextSentencer_T167 34142-34394 Sentence denotes Still, there are other novel approaches using peptides to target one or multiple critical steps in RABV replication; a case in point are peptides that mimic the RABV P protein, which are a core component of RABV transcription/replication complex [93] .
T36698 34142-34394 Sentence denotes Still, there are other novel approaches using peptides to target one or multiple critical steps in RABV replication; a case in point are peptides that mimic the RABV P protein, which are a core component of RABV transcription/replication complex [93] .
TextSentencer_T168 34395-34533 Sentence denotes Peptides containing the first 57 or 60 amino acids of P protein were shown to inhibit RABV but not VSV infection of BHK-21-T7 cells [93] .
T93153 34395-34533 Sentence denotes Peptides containing the first 57 or 60 amino acids of P protein were shown to inhibit RABV but not VSV infection of BHK-21-T7 cells [93] .
TextSentencer_T169 34534-34631 Sentence denotes Importantly, these peptides also significantly inhibit virus replication in neuronal cells [93] .
T34375 34534-34631 Sentence denotes Importantly, these peptides also significantly inhibit virus replication in neuronal cells [93] .
TextSentencer_T170 34632-34777 Sentence denotes These results implied that peptides that interfere with certain steps in viral replication hold promise as a therapeutic approach against rabies.
T93380 34632-34777 Sentence denotes These results implied that peptides that interfere with certain steps in viral replication hold promise as a therapeutic approach against rabies.
TextSentencer_T171 34778-34889 Sentence denotes As the next-generation vaccines, nucleic acid-based vaccines have drawn much attention in the past two decades.
T42971 34778-34889 Sentence denotes As the next-generation vaccines, nucleic acid-based vaccines have drawn much attention in the past two decades.
TextSentencer_T172 34890-34991 Sentence denotes Generally, nucleic acid vaccines are based on DNA or RNA that encodes a specific antigen of interest.
T61496 34890-34991 Sentence denotes Generally, nucleic acid vaccines are based on DNA or RNA that encodes a specific antigen of interest.
TextSentencer_T173 34992-35413 Sentence denotes Nucleic acid-based vaccines possess the capability to mimic a live infection by expressing antigens in situ after immunization without posing safety concerns and induce both humoral and cellular immune responses, and therefore have been widely explored for numerous types of disease control and cancer treatment, especially in circumstances where no vaccine exists or for replacing existing vaccines [94] [95] [96] [97] .
T46313 34992-35413 Sentence denotes Nucleic acid-based vaccines possess the capability to mimic a live infection by expressing antigens in situ after immunization without posing safety concerns and induce both humoral and cellular immune responses, and therefore have been widely explored for numerous types of disease control and cancer treatment, especially in circumstances where no vaccine exists or for replacing existing vaccines [94] [95] [96] [97] .
TextSentencer_T174 35414-35659 Sentence denotes Other advantages of nucleic acid-based vaccines include stability, low production costs, ease of development and purification, and scaling up of production being much simpler compared to that of purified protein vaccines or viral vaccines [69] .
T37121 35414-35659 Sentence denotes Other advantages of nucleic acid-based vaccines include stability, low production costs, ease of development and purification, and scaling up of production being much simpler compared to that of purified protein vaccines or viral vaccines [69] .
TextSentencer_T175 35660-35751 Sentence denotes A number of studies have been conducted to evaluate the efficacy of DNA vaccines to rabies.
T14971 35660-35751 Sentence denotes A number of studies have been conducted to evaluate the efficacy of DNA vaccines to rabies.
TextSentencer_T176 35752-35936 Sentence denotes A plasmid pSG5rab.gp that expresses the RABV G protein, under the control of the SV40 early promoter vector, was tested in mice for induction of rabies-specific immune responses [98] .
T82998 35752-35936 Sentence denotes A plasmid pSG5rab.gp that expresses the RABV G protein, under the control of the SV40 early promoter vector, was tested in mice for induction of rabies-specific immune responses [98] .
TextSentencer_T177 35937-36186 Sentence denotes Mice intramuscularly immunized with the pSG5rab.gp vector developed RABV G-specific cytolytic T cells, lymphokine-secreting T helper cells of the Th1 subset, and rabies VNAs, and were fully protected against a subsequent lethal RABV challenge [98] .
T24398 35937-36186 Sentence denotes Mice intramuscularly immunized with the pSG5rab.gp vector developed RABV G-specific cytolytic T cells, lymphokine-secreting T helper cells of the Th1 subset, and rabies VNAs, and were fully protected against a subsequent lethal RABV challenge [98] .
TextSentencer_T178 36187-36318 Sentence denotes A pClneo plasmid encoding the RABV G protein under the control of the CMV promoter (pGPV) was constructed and tested in dogs [99] .
T74313 36187-36318 Sentence denotes A pClneo plasmid encoding the RABV G protein under the control of the CMV promoter (pGPV) was constructed and tested in dogs [99] .
TextSentencer_T179 36319-36594 Sentence denotes Beagles intramuscularly immunized with pGPV developed high VNA titers against wild-type RABV and to a lesser extent, to European Bat Lyssaviruses (EBL1 and EBL2), and all vaccinated dogs were protected against a lethal RABV challenge with a wild-type dog rabies strain [99] .
T95120 36319-36594 Sentence denotes Beagles intramuscularly immunized with pGPV developed high VNA titers against wild-type RABV and to a lesser extent, to European Bat Lyssaviruses (EBL1 and EBL2), and all vaccinated dogs were protected against a lethal RABV challenge with a wild-type dog rabies strain [99] .
TextSentencer_T180 36595-36859 Sentence denotes Importantly, a comparison between the DNA vaccine and a traditional human diploid cell vaccine in monkeys showed that these two approaches elicited comparable primary and anamnestic VNA responses, and all vaccinated monkeys survived a lethal RABV challenge [100] .
T96157 36595-36859 Sentence denotes Importantly, a comparison between the DNA vaccine and a traditional human diploid cell vaccine in monkeys showed that these two approaches elicited comparable primary and anamnestic VNA responses, and all vaccinated monkeys survived a lethal RABV challenge [100] .
TextSentencer_T181 36860-37064 Sentence denotes Still, some researchers have explored the use of replicon-based self-replicating DNA vaccines derived from an alphavirus (Sindbis virus), to improve the biosafety and immunogenicity of DNA vaccine [101] .
T99290 36860-37064 Sentence denotes Still, some researchers have explored the use of replicon-based self-replicating DNA vaccines derived from an alphavirus (Sindbis virus), to improve the biosafety and immunogenicity of DNA vaccine [101] .
TextSentencer_T182 37065-37239 Sentence denotes This recombinant replicon expressed rabies G protein efficiently and induced apoptosis in transfected cells, an important event in the enhancement of immune responses [101] .
T19225 37065-37239 Sentence denotes This recombinant replicon expressed rabies G protein efficiently and induced apoptosis in transfected cells, an important event in the enhancement of immune responses [101] .
TextSentencer_T183 37240-37474 Sentence denotes Mice intramuscularly injected with this replicon-based rabies DNA vaccine induced comparable humoral and cellular immune responses, compared to commercial cell culture vaccines, but better than conventional rabies DNA vaccines [101] .
T36929 37240-37474 Sentence denotes Mice intramuscularly injected with this replicon-based rabies DNA vaccine induced comparable humoral and cellular immune responses, compared to commercial cell culture vaccines, but better than conventional rabies DNA vaccines [101] .
TextSentencer_T184 37475-37634 Sentence denotes In addition, both replicon-based rabies DNA vaccines and commercial cell culture vaccines conferred complete protection against a lethal RABV challenge [101] .
T65612 37475-37634 Sentence denotes In addition, both replicon-based rabies DNA vaccines and commercial cell culture vaccines conferred complete protection against a lethal RABV challenge [101] .
TextSentencer_T185 37635-37732 Sentence denotes These results clearly demonstrated that DNA vaccines are promising candidates for rabies control.
T70081 37635-37732 Sentence denotes These results clearly demonstrated that DNA vaccines are promising candidates for rabies control.
TextSentencer_T186 37733-37887 Sentence denotes Despite the tremendous advantages of DNA vaccines in mass vaccinations against rabies, several drawbacks of using DNA vaccines need further investigation.
T65042 37733-37887 Sentence denotes Despite the tremendous advantages of DNA vaccines in mass vaccinations against rabies, several drawbacks of using DNA vaccines need further investigation.
TextSentencer_T187 37888-38042 Sentence denotes The slow onset and modest induction of protective immune responses upon DNA vaccination precludes their use for post-exposure immunization against rabies.
T42636 37888-38042 Sentence denotes The slow onset and modest induction of protective immune responses upon DNA vaccination precludes their use for post-exposure immunization against rabies.
TextSentencer_T188 38043-38283 Sentence denotes This is probably due to the poor immunogenicity and inadequate uptake of DNA vaccines by cells at the inoculation site, thus multiple immunizations of high DNA doses are often required to produce enough antigen for optimal immune responses.
T72225 38043-38283 Sentence denotes This is probably due to the poor immunogenicity and inadequate uptake of DNA vaccines by cells at the inoculation site, thus multiple immunizations of high DNA doses are often required to produce enough antigen for optimal immune responses.
TextSentencer_T189 38284-38376 Sentence denotes A number of improvements have been made to increase the safety and efficacy of DNA vaccines.
T97836 38284-38376 Sentence denotes A number of improvements have been made to increase the safety and efficacy of DNA vaccines.
TextSentencer_T190 38377-38518 Sentence denotes To improve DNA uptake, electroporation has been used and was shown to generate comparable or superior levels of immune responses [102, 103] .
T33021 38377-38518 Sentence denotes To improve DNA uptake, electroporation has been used and was shown to generate comparable or superior levels of immune responses [102, 103] .
TextSentencer_T191 38519-39060 Sentence denotes To increase the immunogenicity and efficacy of DNA vaccines, several approaches have been conducted, including using chemical adjuvants [104, 105] , co-administrating plasmids expressing cytokines [106, 107] , modifying the targeted G protein [108, 109] , increasing the expression level of encoded proteins [94] , co-inoculating with a traditional inactivated rabies vaccine [110] , and optimizing DNA vaccine formulation, such as through targeted trafficking of a G protein to a lysosome supplemented with adjuvant Emulsigen-D [111, 112] .
T83818 38519-39060 Sentence denotes To increase the immunogenicity and efficacy of DNA vaccines, several approaches have been conducted, including using chemical adjuvants [104, 105] , co-administrating plasmids expressing cytokines [106, 107] , modifying the targeted G protein [108, 109] , increasing the expression level of encoded proteins [94] , co-inoculating with a traditional inactivated rabies vaccine [110] , and optimizing DNA vaccine formulation, such as through targeted trafficking of a G protein to a lysosome supplemented with adjuvant Emulsigen-D [111, 112] .
TextSentencer_T192 39061-39220 Sentence denotes These endeavors have significantly increased the immunogenicity and efficacy of DNA vaccines and extended their potential in preventing and controlling rabies.
T69820 39061-39220 Sentence denotes These endeavors have significantly increased the immunogenicity and efficacy of DNA vaccines and extended their potential in preventing and controlling rabies.
TextSentencer_T193 39221-39459 Sentence denotes However, risks still exist as to the integration of plasmid DNA into a host chromosome, the tolerance to the plasmid DNA vector and the antigen, autoimmunity, and the generation of a human anti-DNA immune response [94, [113] [114] [115] .
T56155 39221-39459 Sentence denotes However, risks still exist as to the integration of plasmid DNA into a host chromosome, the tolerance to the plasmid DNA vector and the antigen, autoimmunity, and the generation of a human anti-DNA immune response [94, [113] [114] [115] .
TextSentencer_T194 39460-39614 Sentence denotes For example, the integration of DNA into the host genome could result in the potential risk of long-term or even uncontrolled expression of the transgene.
T71108 39460-39614 Sentence denotes For example, the integration of DNA into the host genome could result in the potential risk of long-term or even uncontrolled expression of the transgene.
TextSentencer_T195 39615-39748 Sentence denotes Furthermore, the integration of DNA into the host genome may also modify the genetic information of the host and thus be tumorigenic.
T28290 39615-39748 Sentence denotes Furthermore, the integration of DNA into the host genome may also modify the genetic information of the host and thus be tumorigenic.
TextSentencer_T196 39749-39906 Sentence denotes Therefore, much effort is needed to unravel the action and mechanisms of DNA vaccines before they become a broadly useful vaccine and immunotherapy platform.
T53194 39749-39906 Sentence denotes Therefore, much effort is needed to unravel the action and mechanisms of DNA vaccines before they become a broadly useful vaccine and immunotherapy platform.
TextSentencer_T197 39907-40033 Sentence denotes Besides DNA vaccines, several studies have investigated the potential of vaccines based on RNA molecules for rabies treatment.
T64821 39907-40033 Sentence denotes Besides DNA vaccines, several studies have investigated the potential of vaccines based on RNA molecules for rabies treatment.
TextSentencer_T198 40034-40376 Sentence denotes Currently, two major forms of RNA vaccines have been developed based on the auto-replicative capacity of messenger RNA (mRNA): conventional non-amplifying mRNA vaccines and self-amplifying mRNA vaccines (also termed replicons) derived from an RNA virus vector such as the Semliki Forest virus (SFV) that maintains replicative activity [116] .
T37170 40034-40376 Sentence denotes Currently, two major forms of RNA vaccines have been developed based on the auto-replicative capacity of messenger RNA (mRNA): conventional non-amplifying mRNA vaccines and self-amplifying mRNA vaccines (also termed replicons) derived from an RNA virus vector such as the Semliki Forest virus (SFV) that maintains replicative activity [116] .
TextSentencer_T199 40377-40588 Sentence denotes As for the conventional non-amplifying mRNA-based rabies vaccines, it has been shown that an mRNA encoding RABV G gene induced potent VNAs, and antigen-specific CD4 + and CD8 + T cells in inoculated mice [117] .
T71573 40377-40588 Sentence denotes As for the conventional non-amplifying mRNA-based rabies vaccines, it has been shown that an mRNA encoding RABV G gene induced potent VNAs, and antigen-specific CD4 + and CD8 + T cells in inoculated mice [117] .
TextSentencer_T200 40589-40765 Sentence denotes Importantly, a mRNA-based rabies vaccine protected mice against lethal intracerebral challenge infection with an efficacy comparable to a commercial inactivated rabies vaccine.
T49635 40589-40765 Sentence denotes Importantly, a mRNA-based rabies vaccine protected mice against lethal intracerebral challenge infection with an efficacy comparable to a commercial inactivated rabies vaccine.
TextSentencer_T201 40766-40958 Sentence denotes Moreover, the mRNA-based rabies vaccine was also immunogenic in domestic pigs and elicited VNA levels comparable to those induced by full doses of commercial inactivated rabies vaccine [117] .
T53647 40766-40958 Sentence denotes Moreover, the mRNA-based rabies vaccine was also immunogenic in domestic pigs and elicited VNA levels comparable to those induced by full doses of commercial inactivated rabies vaccine [117] .
TextSentencer_T202 40959-41064 Sentence denotes This study demonstrated the promise of non-replicating mRNA rabies vaccines for the prevention of rabies.
T32591 40959-41064 Sentence denotes This study demonstrated the promise of non-replicating mRNA rabies vaccines for the prevention of rabies.
TextSentencer_T203 41065-41289 Sentence denotes In the case of self-amplifying mRNA-based rabies vaccines, it was shown that a recombinant SFV, carrying an RNA coding RABV G protein (SFV-RVGP), induced high expression levels of functionally trimeric RABV G protein [118] .
T54053 41065-41289 Sentence denotes In the case of self-amplifying mRNA-based rabies vaccines, it was shown that a recombinant SFV, carrying an RNA coding RABV G protein (SFV-RVGP), induced high expression levels of functionally trimeric RABV G protein [118] .
TextSentencer_T204 41290-41485 Sentence denotes Moreover, SFV-RVGP elicited comparable levels of antibodies to that of a commercial rabies vaccine, and was more effective than the protein vaccines in inducing a cellular immune response [119] .
T22221 41290-41485 Sentence denotes Moreover, SFV-RVGP elicited comparable levels of antibodies to that of a commercial rabies vaccine, and was more effective than the protein vaccines in inducing a cellular immune response [119] .
TextSentencer_T205 41486-41639 Sentence denotes While initial studies have used naked mRNA as the vaccine, much effort has been put into enhancing the delivery efficiency and potency of an RNA vaccine.
T79468 41486-41639 Sentence denotes While initial studies have used naked mRNA as the vaccine, much effort has been put into enhancing the delivery efficiency and potency of an RNA vaccine.
TextSentencer_T206 41640-41861 Sentence denotes To alleviate the degradation of RNA and enhance cellular uptake, methods such as gene gun, electroporation, liposomes, and cationic polymers have been used to obtain improved delivery systems for RNA vaccines [116, 120] .
T16972 41640-41861 Sentence denotes To alleviate the degradation of RNA and enhance cellular uptake, methods such as gene gun, electroporation, liposomes, and cationic polymers have been used to obtain improved delivery systems for RNA vaccines [116, 120] .
TextSentencer_T207 41862-42018 Sentence denotes Similar to DNA vaccines, chemical adjuvants, or co-administrating RNA expressing specific adjuvants, have been investigated to enhance immunogenicity [97] .
T63602 41862-42018 Sentence denotes Similar to DNA vaccines, chemical adjuvants, or co-administrating RNA expressing specific adjuvants, have been investigated to enhance immunogenicity [97] .
TextSentencer_T208 42019-42304 Sentence denotes Finally, as to the optimization of mRNA for vaccination, several approaches have been conducted to modify the RNA molecule directly, such as the modification of the 5 cap structure or the untranslated and the translated regions, to achieve high and long-term antigen expression [121] .
T3480 42019-42304 Sentence denotes Finally, as to the optimization of mRNA for vaccination, several approaches have been conducted to modify the RNA molecule directly, such as the modification of the 5 cap structure or the untranslated and the translated regions, to achieve high and long-term antigen expression [121] .
TextSentencer_T209 42305-42422 Sentence denotes Vaccination with RNA vaccines has become an increasingly promising strategy for disease control over the past decade.
T58212 42305-42422 Sentence denotes Vaccination with RNA vaccines has become an increasingly promising strategy for disease control over the past decade.
TextSentencer_T210 42423-42494 Sentence denotes Compared to DNA vaccines, RNA vaccines are superior in several aspects.
T64989 42423-42494 Sentence denotes Compared to DNA vaccines, RNA vaccines are superior in several aspects.
TextSentencer_T211 42495-42632 Sentence denotes Unlike DNA vaccines, which have a potential risk of integration with the host genome, vaccines based on RNA would eliminate this concern.
T98331 42495-42632 Sentence denotes Unlike DNA vaccines, which have a potential risk of integration with the host genome, vaccines based on RNA would eliminate this concern.
TextSentencer_T212 42633-42858 Sentence denotes In addition, DNA vaccines must be delivered into and transcribed within the nucleus to express the antigen, which is not only time-consuming but may be inefficient in some types of cells, such as non-dividing mature myocytes.
T47060 42633-42858 Sentence denotes In addition, DNA vaccines must be delivered into and transcribed within the nucleus to express the antigen, which is not only time-consuming but may be inefficient in some types of cells, such as non-dividing mature myocytes.
TextSentencer_T213 42859-43037 Sentence denotes On the contrary, RNA vaccines are directly translated in the cytoplasm, which not only obviates the need for delivery into the nucleus but also leads to rapid antigen expression.
T46786 42859-43037 Sentence denotes On the contrary, RNA vaccines are directly translated in the cytoplasm, which not only obviates the need for delivery into the nucleus but also leads to rapid antigen expression.
TextSentencer_T214 43038-43334 Sentence denotes Finally, it has long been known that RNA is a potent stimulator of innate immunity through signaling via pattern recognition receptors, such as the Toll-like receptors or the retinoic acid-inducible gene I-like receptors, and this adjuvant effect of RNA stimulates the host immune response [97] .
T76590 43038-43334 Sentence denotes Finally, it has long been known that RNA is a potent stimulator of innate immunity through signaling via pattern recognition receptors, such as the Toll-like receptors or the retinoic acid-inducible gene I-like receptors, and this adjuvant effect of RNA stimulates the host immune response [97] .
TextSentencer_T215 43335-43580 Sentence denotes Although it is argued that RNA is generally less stable than DNA, this in turn guarantees the tight control of the immunogenicity of RNA vaccines to efficiently limit vector-derived immunity and other safety issues due to the persistence of RNA.
T54458 43335-43580 Sentence denotes Although it is argued that RNA is generally less stable than DNA, this in turn guarantees the tight control of the immunogenicity of RNA vaccines to efficiently limit vector-derived immunity and other safety issues due to the persistence of RNA.
TextSentencer_T216 43581-43707 Sentence denotes These attributes of RNA vaccines make them an ideally adaptable and versatile vaccine platform for infectious disease control.
T41393 43581-43707 Sentence denotes These attributes of RNA vaccines make them an ideally adaptable and versatile vaccine platform for infectious disease control.
TextSentencer_T217 43708-44144 Sentence denotes Interfering RNA (siRNA)-Based Therapy siRNA, also known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules 21-23 bp in length, that functions within the RNAi pathway to interfere with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, thus leading to the disruption of protein translation and post-transcriptional gene silence [122, 123] .
T2770 43708-44144 Sentence denotes Interfering RNA (siRNA)-Based Therapy siRNA, also known as short interfering RNA or silencing RNA, is a class of double-stranded RNA molecules 21-23 bp in length, that functions within the RNAi pathway to interfere with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, thus leading to the disruption of protein translation and post-transcriptional gene silence [122, 123] .
TextSentencer_T218 44145-44404 Sentence denotes Due to its easy manipulation, powerful efficacy, and induction of little cytopathy, siRNA-based gene silencing of target genes has been considered one of the most promising approaches to achieve antiviral defense against various diseases and disorders [123] .
T63200 44145-44404 Sentence denotes Due to its easy manipulation, powerful efficacy, and induction of little cytopathy, siRNA-based gene silencing of target genes has been considered one of the most promising approaches to achieve antiviral defense against various diseases and disorders [123] .
TextSentencer_T219 44405-44570 Sentence denotes Initially, plasmids encoding siRNA, or another form of RNAi that target specific RABV genes, were constructed and tested for anti-rabies efficacy [124] [125] [126] .
T45 44405-44570 Sentence denotes Initially, plasmids encoding siRNA, or another form of RNAi that target specific RABV genes, were constructed and tested for anti-rabies efficacy [124] [125] [126] .
TextSentencer_T220 44571-44771 Sentence denotes Although the plasmid-based approaches achieved some degree of anti-rabies effect, the low efficiency of siRNA delivery hindered the substantial protection against RV through anti-rabies RNAi approach.
T76409 44571-44771 Sentence denotes Although the plasmid-based approaches achieved some degree of anti-rabies effect, the low efficiency of siRNA delivery hindered the substantial protection against RV through anti-rabies RNAi approach.
TextSentencer_T221 44772-44917 Sentence denotes To increase delivery efficiency, viral vectors, such as adenoviruses [127] [128] [129] or lentiviruses [130] , were used to express these siRNAs.
T64951 44772-44917 Sentence denotes To increase delivery efficiency, viral vectors, such as adenoviruses [127] [128] [129] or lentiviruses [130] , were used to express these siRNAs.
TextSentencer_T222 44918-45108 Sentence denotes Generally, these viral vector-based siRNAs efficiently inhibited corresponding gene expression and the RABV multiplication and conferred significant protection against lethal RABV challenge.
T62878 44918-45108 Sentence denotes Generally, these viral vector-based siRNAs efficiently inhibited corresponding gene expression and the RABV multiplication and conferred significant protection against lethal RABV challenge.
TextSentencer_T223 45109-45301 Sentence denotes As for silencing efficiency, two RABV genes (the highly conserved N and L genes) were generally chosen for targeting, although the P and G genes were also reported to have antiviral potential.
T82456 45109-45301 Sentence denotes As for silencing efficiency, two RABV genes (the highly conserved N and L genes) were generally chosen for targeting, although the P and G genes were also reported to have antiviral potential.
TextSentencer_T224 45302-45541 Sentence denotes Still, to overcome the safety issues related to viral vectors, a liposome was used to deliver siRNA-encoding plasmid and significantly increased the survival of RABV-infected mice compared to a non-liposome-mediated delivery method [131] .
T98019 45302-45541 Sentence denotes Still, to overcome the safety issues related to viral vectors, a liposome was used to deliver siRNA-encoding plasmid and significantly increased the survival of RABV-infected mice compared to a non-liposome-mediated delivery method [131] .
TextSentencer_T225 45542-45864 Sentence denotes Another promising delivery method has been proposed by Kumar et al., who have demonstrated that a short 29-amino-acid peptide, derived from the RABV G protein, which binds to the acetylcholine receptor exclusively expressed by neuronal cells, enables the transvascular delivery of siRNA across the BBB to the brain [132] .
T31901 45542-45864 Sentence denotes Another promising delivery method has been proposed by Kumar et al., who have demonstrated that a short 29-amino-acid peptide, derived from the RABV G protein, which binds to the acetylcholine receptor exclusively expressed by neuronal cells, enables the transvascular delivery of siRNA across the BBB to the brain [132] .
TextSentencer_T226 45865-46139 Sentence denotes A chimeric peptide, containing nonamer arginine residues added to the carboxy terminus of the 29-amino-acid peptide, was shown to bind and deliver siRNA to neuronal cells which lead to specific gene silencing within the brain in mice after intravenous administration [132] .
T64874 45865-46139 Sentence denotes A chimeric peptide, containing nonamer arginine residues added to the carboxy terminus of the 29-amino-acid peptide, was shown to bind and deliver siRNA to neuronal cells which lead to specific gene silencing within the brain in mice after intravenous administration [132] .
TextSentencer_T227 46140-46578 Sentence denotes Furthermore, intravenous treatment with a chimeric peptide-bound antiviral siRNA complex provided robust protection against a fatal Japanese encephalitis virus challenge in mice, and repeated administration of the chimeric peptide-siRNA complex did not induce inflammatory cytokines or anti-peptide antibodies, indicating that this chimeric peptide provides a safe and noninvasive approach for the delivery of siRNA across the BBB [132] .
T67821 46140-46578 Sentence denotes Furthermore, intravenous treatment with a chimeric peptide-bound antiviral siRNA complex provided robust protection against a fatal Japanese encephalitis virus challenge in mice, and repeated administration of the chimeric peptide-siRNA complex did not induce inflammatory cytokines or anti-peptide antibodies, indicating that this chimeric peptide provides a safe and noninvasive approach for the delivery of siRNA across the BBB [132] .
TextSentencer_T228 46579-46729 Sentence denotes Taken together, these results demonstrated that siRNAs-based approaches have the potential to be developed into new and effective anti-rabies therapy.
T79790 46579-46729 Sentence denotes Taken together, these results demonstrated that siRNAs-based approaches have the potential to be developed into new and effective anti-rabies therapy.
TextSentencer_T229 46730-46906 Sentence denotes RIG, a recombinant monoclonal antibody targeting a specific epitope of the G protein, is highly effective in neutralizing RABV in vitro or before the virus enters the CNS [7] .
T90728 46730-46906 Sentence denotes RIG, a recombinant monoclonal antibody targeting a specific epitope of the G protein, is highly effective in neutralizing RABV in vitro or before the virus enters the CNS [7] .
TextSentencer_T230 46907-47084 Sentence denotes It is an essential component of PEP, since it delivers passive immunity which is particularly important at early stages, before the host develops active immunity to the vaccine.
T3920 46907-47084 Sentence denotes It is an essential component of PEP, since it delivers passive immunity which is particularly important at early stages, before the host develops active immunity to the vaccine.
TextSentencer_T231 47085-47227 Sentence denotes However, once the virus accesses the CNS, these antibodies are restricted to crossing the immune-privileged BBB to neutralize virus infection.
T23195 47085-47227 Sentence denotes However, once the virus accesses the CNS, these antibodies are restricted to crossing the immune-privileged BBB to neutralize virus infection.
TextSentencer_T232 47228-47335 Sentence denotes Although, in theory, the antibody could be given intracerebrally, it is definitely not a practical therapy.
T75378 47228-47335 Sentence denotes Although, in theory, the antibody could be given intracerebrally, it is definitely not a practical therapy.
TextSentencer_T233 47336-47594 Sentence denotes On the other hand, it has been firmly established that enhancement of BBB permeability is required to allow the passage of VNAs into the CNS of activated B cells, in order to cross the BBB and release antibodies in situ for RABV clearance [133] [134] [135] .
T68794 47336-47594 Sentence denotes On the other hand, it has been firmly established that enhancement of BBB permeability is required to allow the passage of VNAs into the CNS of activated B cells, in order to cross the BBB and release antibodies in situ for RABV clearance [133] [134] [135] .
TextSentencer_T234 47595-47724 Sentence denotes As mentioned above, a live-attenuated virus could transiently enhance the BBB permeability, although this raises safety concerns.
T2148 47595-47724 Sentence denotes As mentioned above, a live-attenuated virus could transiently enhance the BBB permeability, although this raises safety concerns.
TextSentencer_T235 47725-47915 Sentence denotes An alternative way is to use agents, such as the cytokine MCP-1 or hyperosmotic solution, to enhance the BBB permeability, thus allowing antibodies to pass through the BBB and enter the CNS.
T30808 47725-47915 Sentence denotes An alternative way is to use agents, such as the cytokine MCP-1 or hyperosmotic solution, to enhance the BBB permeability, thus allowing antibodies to pass through the BBB and enter the CNS.
TextSentencer_T236 47916-48183 Sentence denotes It was shown in mice that intravenously administered VNAs are crucial in the clearance of RABV from the CNS and could prevent the development of rabies in both immunocompetent and immunocompromised mice, as long as the BBB permeability is enhanced using MCP-1 [133] .
T91078 47916-48183 Sentence denotes It was shown in mice that intravenously administered VNAs are crucial in the clearance of RABV from the CNS and could prevent the development of rabies in both immunocompetent and immunocompromised mice, as long as the BBB permeability is enhanced using MCP-1 [133] .
TextSentencer_T237 48184-48369 Sentence denotes In rats, the breakdown of BBB permeability using hypertonic arabinose, combined with passively administered virus-neutralizing mAb 8-10E, prolonged the survival of infected rats [134] .
T44472 48184-48369 Sentence denotes In rats, the breakdown of BBB permeability using hypertonic arabinose, combined with passively administered virus-neutralizing mAb 8-10E, prolonged the survival of infected rats [134] .
TextSentencer_T238 48370-48473 Sentence denotes Interestingly, mAb 8-10E treatment alone partially increased the survival rate of infected rats [134] .
T17122 48370-48473 Sentence denotes Interestingly, mAb 8-10E treatment alone partially increased the survival rate of infected rats [134] .
TextSentencer_T239 48474-48618 Sentence denotes These results demonstrate that simultaneous administration of VNAs and BBB permeability-enhancing agents might be a therapy for clinical rabies.
T66857 48474-48618 Sentence denotes These results demonstrate that simultaneous administration of VNAs and BBB permeability-enhancing agents might be a therapy for clinical rabies.
TextSentencer_T240 48619-48925 Sentence denotes However, considering that BBB permeability-enhancing agents might negatively affect the function of CNS integrity through uncontrolled BBB enhancement, precautions should be taken to preserve homeostasis and avoid adding to new neuronal damage of the CNS when using these BBB permeability-enhancing agents.
T20998 48619-48925 Sentence denotes However, considering that BBB permeability-enhancing agents might negatively affect the function of CNS integrity through uncontrolled BBB enhancement, precautions should be taken to preserve homeostasis and avoid adding to new neuronal damage of the CNS when using these BBB permeability-enhancing agents.
TextSentencer_T241 48926-49066 Sentence denotes BsAb is composed of two binding specificities for two different antigens, or two different epitopes of an antigen, in one antibody molecule.
T84301 48926-49066 Sentence denotes BsAb is composed of two binding specificities for two different antigens, or two different epitopes of an antigen, in one antibody molecule.
TextSentencer_T242 49067-49205 Sentence denotes BsAb is a newly emerging area in modern biology and is one of the most promising and exciting advancements in cancer immunotherapy [136] .
T90498 49067-49205 Sentence denotes BsAb is a newly emerging area in modern biology and is one of the most promising and exciting advancements in cancer immunotherapy [136] .
TextSentencer_T243 49206-49418 Sentence denotes The purpose of BsAb is to recognize and target two different antigens simultaneously, thus realizing the desired therapeutic effects that cannot be achieved by a combination of two monospecific antibodies [137] .
T37105 49206-49418 Sentence denotes The purpose of BsAb is to recognize and target two different antigens simultaneously, thus realizing the desired therapeutic effects that cannot be achieved by a combination of two monospecific antibodies [137] .
TextSentencer_T244 49419-49652 Sentence denotes In cancer immunotherapy, one of the most obvious advantages of BsAb is its ability to redirect immune effector cells to the proximity of targeted tumor cells, thus improving the tumor-killing potential of these immune effector cells.
T24675 49419-49652 Sentence denotes In cancer immunotherapy, one of the most obvious advantages of BsAb is its ability to redirect immune effector cells to the proximity of targeted tumor cells, thus improving the tumor-killing potential of these immune effector cells.
TextSentencer_T245 49653-49895 Sentence denotes This prototypic form of BsAb is generally composed of two linked single-chain fragment variables with one targeting molecule present on immune effector cells, such as the CD3 found on T cells, while the other targets a tumor-specific antigen.
T78297 49653-49895 Sentence denotes This prototypic form of BsAb is generally composed of two linked single-chain fragment variables with one targeting molecule present on immune effector cells, such as the CD3 found on T cells, while the other targets a tumor-specific antigen.
TextSentencer_T246 49896-49967 Sentence denotes Currently, no studies have been reported that use BsAb to treat rabies.
T97838 49896-49967 Sentence denotes Currently, no studies have been reported that use BsAb to treat rabies.
TextSentencer_T247 49968-50106 Sentence denotes As mentioned above, sufficient levels of VNAs and the enhancement of BBB permeability are critical for the clearance of RABV from the CNS.
T63259 49968-50106 Sentence denotes As mentioned above, sufficient levels of VNAs and the enhancement of BBB permeability are critical for the clearance of RABV from the CNS.
TextSentencer_T248 50107-50374 Sentence denotes As live-attenuated viruses pose safety concerns while BBB permeability-enhancing agents can cause unwanted neurological complications due to the disruption of normal BBB integrity, the ideal approach is to deliver VNAs without altering the normal function of the BBB.
T193 50107-50374 Sentence denotes As live-attenuated viruses pose safety concerns while BBB permeability-enhancing agents can cause unwanted neurological complications due to the disruption of normal BBB integrity, the ideal approach is to deliver VNAs without altering the normal function of the BBB.
TextSentencer_T249 50375-50747 Sentence denotes Endogenous BBB receptors involved in the normal receptor-mediated transcytosis (RMT) pathways that function to transport macromolecules such as insulin and transferrin into the brain are ideal targets that can be utilized to deliver biologics; a case in point are rabies VNAs, which can be delivered to the CNS without interfering with the normal functionality of the BBB.
T52018 50375-50747 Sentence denotes Endogenous BBB receptors involved in the normal receptor-mediated transcytosis (RMT) pathways that function to transport macromolecules such as insulin and transferrin into the brain are ideal targets that can be utilized to deliver biologics; a case in point are rabies VNAs, which can be delivered to the CNS without interfering with the normal functionality of the BBB.
TextSentencer_T250 50748-50929 Sentence denotes Such receptors include two well-characterized transferrin receptors [138] and an insulin receptor [139] , or the recently identified solute carrier CD98 heavy chain (CD98hc) [140] .
T5808 50748-50929 Sentence denotes Such receptors include two well-characterized transferrin receptors [138] and an insulin receptor [139] , or the recently identified solute carrier CD98 heavy chain (CD98hc) [140] .
TextSentencer_T251 50930-51067 Sentence denotes Therefore, targeting these receptors can act as a molecular Trojan horse to ferry biologics fused to the antibody into the brain via RMT.
T94430 50930-51067 Sentence denotes Therefore, targeting these receptors can act as a molecular Trojan horse to ferry biologics fused to the antibody into the brain via RMT.
TextSentencer_T252 51068-51233 Sentence denotes Consequently, a BsAb for rabies treatment could be constructed with one arm targeting one of the endogenous BBB receptors while the other targets the RABV G protein.
T45420 51068-51233 Sentence denotes Consequently, a BsAb for rabies treatment could be constructed with one arm targeting one of the endogenous BBB receptors while the other targets the RABV G protein.
TextSentencer_T253 51234-51424 Sentence denotes Theoretically, this BsAb could pass through the BBB while retaining the ability to neutralize RABV in the CNS, thus potentially indicating a novel therapy for rabies treatment in the future.
T65984 51234-51424 Sentence denotes Theoretically, this BsAb could pass through the BBB while retaining the ability to neutralize RABV in the CNS, thus potentially indicating a novel therapy for rabies treatment in the future.
TextSentencer_T254 51425-51528 Sentence denotes Rabies continues to pose a severe burden to public health and is ranked one of the most fatal diseases.
T53170 51425-51528 Sentence denotes Rabies continues to pose a severe burden to public health and is ranked one of the most fatal diseases.
TextSentencer_T255 51529-51620 Sentence denotes It causes tens of thousands of human deaths annually, particularly in developing countries.
T68950 51529-51620 Sentence denotes It causes tens of thousands of human deaths annually, particularly in developing countries.
TextSentencer_T256 51621-51737 Sentence denotes Currently, dogs remain the main source of rabies and are responsible for almost 99% of fatal rabies cases in humans.
T32859 51621-51737 Sentence denotes Currently, dogs remain the main source of rabies and are responsible for almost 99% of fatal rabies cases in humans.
TextSentencer_T257 51738-51853 Sentence denotes Since the first development of the rabies vaccine by Pasteur, human rabies vaccines have been improved and refined.
T32838 51738-51853 Sentence denotes Since the first development of the rabies vaccine by Pasteur, human rabies vaccines have been improved and refined.
TextSentencer_T258 51854-52047 Sentence denotes Current cell culture rabies vaccines for humans are highly efficacious, safe, and easily accessible in most parts of the world, which in turn has enabled the control of rabies in these regions.
T68385 51854-52047 Sentence denotes Current cell culture rabies vaccines for humans are highly efficacious, safe, and easily accessible in most parts of the world, which in turn has enabled the control of rabies in these regions.
TextSentencer_T259 52048-52215 Sentence denotes Therefore, in terms of rabies exposure, as long as prompt and correct PEP are administered, there is no need for further development of rabies vaccine for current PEP.
T66323 52048-52215 Sentence denotes Therefore, in terms of rabies exposure, as long as prompt and correct PEP are administered, there is no need for further development of rabies vaccine for current PEP.
TextSentencer_T260 52216-52379 Sentence denotes In high-risk regions, a shift from PEP to application of routine pre-exposure vaccination, especially for vulnerable children and old people, should be considered.
T23332 52216-52379 Sentence denotes In high-risk regions, a shift from PEP to application of routine pre-exposure vaccination, especially for vulnerable children and old people, should be considered.
TextSentencer_T261 52380-52613 Sentence denotes This approach is expected to effectively and dramatically reduce the incidence of rabies cases, although a prompt and simplified PEP is still needed after pre-exposure rabies vaccination for complete protection after rabies exposure.
T43897 52380-52613 Sentence denotes This approach is expected to effectively and dramatically reduce the incidence of rabies cases, although a prompt and simplified PEP is still needed after pre-exposure rabies vaccination for complete protection after rabies exposure.
TextSentencer_T262 52614-52841 Sentence denotes However, rabies remains endemic to many parts of the developing world where the resources of appropriate PEP are limited, the infrastructure and facility are inadequate, and, most importantly, awareness about rabies is lacking.
T79401 52614-52841 Sentence denotes However, rabies remains endemic to many parts of the developing world where the resources of appropriate PEP are limited, the infrastructure and facility are inadequate, and, most importantly, awareness about rabies is lacking.
TextSentencer_T263 52842-52920 Sentence denotes In these cases, inexpensive, safe, and effective vaccines are urgently needed.
T43732 52842-52920 Sentence denotes In these cases, inexpensive, safe, and effective vaccines are urgently needed.
TextSentencer_T264 52921-53125 Sentence denotes This situation is even more pronounced given the fact that the most important and probably the only practical way to control rabies globally is the mass vaccination of dogs as well as wildlife reservoirs.
T49710 52921-53125 Sentence denotes This situation is even more pronounced given the fact that the most important and probably the only practical way to control rabies globally is the mass vaccination of dogs as well as wildlife reservoirs.
TextSentencer_T265 53126-53263 Sentence denotes To accomplish this goal, efficacious oral vaccines that can be given in reduced or single doses should be developed to be cost-effective.
T16143 53126-53263 Sentence denotes To accomplish this goal, efficacious oral vaccines that can be given in reduced or single doses should be developed to be cost-effective.
TextSentencer_T266 53264-53567 Sentence denotes In contrast to the steady improvement in the availability and quality of cell culture-derived rabies vaccines and RIGs, there has been a consistent lack of interest in developing antiviral therapy for patients who have missed the deadline for valid vaccination or whose symptoms have already manifested.
T24595 53264-53567 Sentence denotes In contrast to the steady improvement in the availability and quality of cell culture-derived rabies vaccines and RIGs, there has been a consistent lack of interest in developing antiviral therapy for patients who have missed the deadline for valid vaccination or whose symptoms have already manifested.
TextSentencer_T267 53568-53715 Sentence denotes As of now, no effective antiviral therapy is available for these patients and death is inevitable, in most instances accompanied by agonizing pain.
T55369 53568-53715 Sentence denotes As of now, no effective antiviral therapy is available for these patients and death is inevitable, in most instances accompanied by agonizing pain.
TextSentencer_T268 53716-53883 Sentence denotes Fortunately, recent advances in rabies treatment have generated promising tools for preventing and eradicating rabies, at least in murine and non-human primate models.
T52254 53716-53883 Sentence denotes Fortunately, recent advances in rabies treatment have generated promising tools for preventing and eradicating rabies, at least in murine and non-human primate models.
TextSentencer_T269 53884-53988 Sentence denotes These developments provide hope for realizing the goal of curing patients who are suffering from rabies.
T72301 53884-53988 Sentence denotes These developments provide hope for realizing the goal of curing patients who are suffering from rabies.
TextSentencer_T270 53989-54191 Sentence denotes The rationale for rabies therapy is that RABV may stay at the entry site for days or weeks before reaching the CNS and causing symptoms, providing valuable time to limit and control the virus infection.
T550 53989-54191 Sentence denotes The rationale for rabies therapy is that RABV may stay at the entry site for days or weeks before reaching the CNS and causing symptoms, providing valuable time to limit and control the virus infection.
TextSentencer_T271 54192-54296 Sentence denotes Of the developments in rabies therapy, live-attenuated virus based vaccines might be the most promising.
T35556 54192-54296 Sentence denotes Of the developments in rabies therapy, live-attenuated virus based vaccines might be the most promising.
TextSentencer_T272 54297-54443 Sentence denotes For a successful PEP, vaccines should rapidly induce potent protective immune responses and ideally would at the same time require less or no RIG.
T49079 54297-54443 Sentence denotes For a successful PEP, vaccines should rapidly induce potent protective immune responses and ideally would at the same time require less or no RIG.
TextSentencer_T273 54444-54546 Sentence denotes Live-attenuated virus-based vaccines match all these requirements and hold the promise to be curative.
T12003 54444-54546 Sentence denotes Live-attenuated virus-based vaccines match all these requirements and hold the promise to be curative.
TextSentencer_T274 54547-54788 Sentence denotes Most of the concerns about the use of live-attenuated virus-based vaccines come from the assumption regarding the potential risk of residual virulence and toxicity, instability, reversion to pathogenic wild-types, or recombination in nature.
T12476 54547-54788 Sentence denotes Most of the concerns about the use of live-attenuated virus-based vaccines come from the assumption regarding the potential risk of residual virulence and toxicity, instability, reversion to pathogenic wild-types, or recombination in nature.
TextSentencer_T275 54789-55174 Sentence denotes However, with the development of modern technology, these live-attenuated viruses used for vaccines are generally replication-deficient or restricted; their pathogenicity is commonly maximally or completely abolished and, after systemic manipulation of their genome, these viruses are theoretically highly stable and irreversible and virulence restoration could be effectively avoided.
T3856 54789-55174 Sentence denotes However, with the development of modern technology, these live-attenuated viruses used for vaccines are generally replication-deficient or restricted; their pathogenicity is commonly maximally or completely abolished and, after systemic manipulation of their genome, these viruses are theoretically highly stable and irreversible and virulence restoration could be effectively avoided.
TextSentencer_T276 55175-55431 Sentence denotes Currently, a number of live-attenuated virus based vaccines for human use have been widely used, and current data have firmly demonstrated that rabies vaccines based on live-attenuated RABV or HAdV-5 caused no adverse events or safety concerns [141, 142] .
T91405 55175-55431 Sentence denotes Currently, a number of live-attenuated virus based vaccines for human use have been widely used, and current data have firmly demonstrated that rabies vaccines based on live-attenuated RABV or HAdV-5 caused no adverse events or safety concerns [141, 142] .
TextSentencer_T277 55432-55739 Sentence denotes Nevertheless, as with any genetically modified agent, enhanced surveillance and ecological monitoring are necessary to evaluate the relative risks of the environmental release of such viruses, given the possibility of recombination and genetic material exchange in nature, even if this is a very rare event.
T63128 55432-55739 Sentence denotes Nevertheless, as with any genetically modified agent, enhanced surveillance and ecological monitoring are necessary to evaluate the relative risks of the environmental release of such viruses, given the possibility of recombination and genetic material exchange in nature, even if this is a very rare event.
TextSentencer_T278 55740-55844 Sentence denotes Development of other novel non-viral biological treatments for rabies has also been progressing rapidly.
T5342 55740-55844 Sentence denotes Development of other novel non-viral biological treatments for rabies has also been progressing rapidly.
TextSentencer_T279 55845-56066 Sentence denotes Within the near future, there should be an increase in the number of available rabies biologics, especially with our deeper understanding of the pathogenesis of rabies and the interactions between viral and host proteins.
T11697 55845-56066 Sentence denotes Within the near future, there should be an increase in the number of available rabies biologics, especially with our deeper understanding of the pathogenesis of rabies and the interactions between viral and host proteins.
TextSentencer_T280 56067-56311 Sentence denotes These advancements have led to novel modalities based on gene transfer technology such as protein subunit and peptide vaccine, nucleic acid-based vaccines, and small molecules that function to interfere with the replication/spread of the virus.
T66109 56067-56311 Sentence denotes These advancements have led to novel modalities based on gene transfer technology such as protein subunit and peptide vaccine, nucleic acid-based vaccines, and small molecules that function to interfere with the replication/spread of the virus.
TextSentencer_T281 56312-56593 Sentence denotes Nevertheless, as these forms of vaccines might result in delayed immune responses because of antigen expression/accumulation and immunogenicity, for efficient PEP, proper adjuvants would probably be needed to increase and accelerate the immune responses elicited by these vaccines.
T40644 56312-56593 Sentence denotes Nevertheless, as these forms of vaccines might result in delayed immune responses because of antigen expression/accumulation and immunogenicity, for efficient PEP, proper adjuvants would probably be needed to increase and accelerate the immune responses elicited by these vaccines.
TextSentencer_T282 56594-56890 Sentence denotes However, given the ability to elicit potent and broad immune responses, the excellent safety profile, and the rapid response to newly emerging pathogens of nucleic acid-based vaccines, especially RNA vaccines, the prospects for their application as therapeutic rabies vaccines are very promising.
T53824 56594-56890 Sentence denotes However, given the ability to elicit potent and broad immune responses, the excellent safety profile, and the rapid response to newly emerging pathogens of nucleic acid-based vaccines, especially RNA vaccines, the prospects for their application as therapeutic rabies vaccines are very promising.
TextSentencer_T283 56891-57069 Sentence denotes Moreover, research on siRNAs targeting RABV essential genes has also gained a lot of potential in terms of delaying the process of RABV infection and allowing PEP to take effect.
T88114 56891-57069 Sentence denotes Moreover, research on siRNAs targeting RABV essential genes has also gained a lot of potential in terms of delaying the process of RABV infection and allowing PEP to take effect.
TextSentencer_T284 57070-57272 Sentence denotes Recent progress on proper delivery systems has potentiated the future use of not only siRNA but also other therapeutic molecules such as small-molecule drugs [143] to cross the BBB for rabies treatment.
T88385 57070-57272 Sentence denotes Recent progress on proper delivery systems has potentiated the future use of not only siRNA but also other therapeutic molecules such as small-molecule drugs [143] to cross the BBB for rabies treatment.
TextSentencer_T285 57273-57590 Sentence denotes Furthermore, a lot of interest has been focused on the development of monoclonal antibodies as potential alternatives for the limited and expansive RIG and, given the rapid advances in antibody engineering, it can be envisioned that in the near future some monoclonal antibodies would be licensed as adjuncts for RIG.
T25850 57273-57590 Sentence denotes Furthermore, a lot of interest has been focused on the development of monoclonal antibodies as potential alternatives for the limited and expansive RIG and, given the rapid advances in antibody engineering, it can be envisioned that in the near future some monoclonal antibodies would be licensed as adjuncts for RIG.
TextSentencer_T286 57591-57806 Sentence denotes As a novel form of monoclonal antibodies, BsAb has demonstrated powerful application in cancer immunotherapy and warrant further investigation in rabies treatment given their potentially noninvasive BBB penetration.
T15565 57591-57806 Sentence denotes As a novel form of monoclonal antibodies, BsAb has demonstrated powerful application in cancer immunotherapy and warrant further investigation in rabies treatment given their potentially noninvasive BBB penetration.
TextSentencer_T287 57807-57928 Sentence denotes Ongoing preclinical and clinical studies on these novel approaches would certainly shed light on future rabies treatment.
T37736 57807-57928 Sentence denotes Ongoing preclinical and clinical studies on these novel approaches would certainly shed light on future rabies treatment.
TextSentencer_T288 57929-58037 Sentence denotes Antiviral therapy is an important component of future efforts to develop effective therapy for human rabies.
T31368 57929-58037 Sentence denotes Antiviral therapy is an important component of future efforts to develop effective therapy for human rabies.
TextSentencer_T289 58038-58104 Sentence denotes We have never been so close to controlling and even curing rabies.
T51734 58038-58104 Sentence denotes We have never been so close to controlling and even curing rabies.
TextSentencer_T290 58105-58274 Sentence denotes Within the next few years, the burden of human and canine rabies will decrease in many developing countries and mortality due to rabies will be effectively brought down.
T66714 58105-58274 Sentence denotes Within the next few years, the burden of human and canine rabies will decrease in many developing countries and mortality due to rabies will be effectively brought down.
TextSentencer_T291 58275-58362 Sentence denotes However, it should be noted that there are still many open questions in rabies therapy.
T92047 58275-58362 Sentence denotes However, it should be noted that there are still many open questions in rabies therapy.
TextSentencer_T292 58363-58459 Sentence denotes If future anti-rabies therapies are developed, a relevant animal model is needed for evaluation.
T11890 58363-58459 Sentence denotes If future anti-rabies therapies are developed, a relevant animal model is needed for evaluation.
TextSentencer_T293 58460-58602 Sentence denotes Moreover, the genetic and antigenic diversity of different RABV strains with sequence differences might negatively compromise these therapies.
T38944 58460-58602 Sentence denotes Moreover, the genetic and antigenic diversity of different RABV strains with sequence differences might negatively compromise these therapies.
TextSentencer_T294 58603-58830 Sentence denotes Current rabies interventions are mainly focused on viruses from phylogroup I and future vaccine development should take other members of Lyssavirus into consideration to create a vaccine with broad-spectrum protection efficacy.
T18741 58603-58830 Sentence denotes Current rabies interventions are mainly focused on viruses from phylogroup I and future vaccine development should take other members of Lyssavirus into consideration to create a vaccine with broad-spectrum protection efficacy.
TextSentencer_T295 58831-59158 Sentence denotes These pan-lyssavirus vaccines could be realized through recombinant viruses coding for the G protein of several lyssaviruses, RABV coding for additional Gs from different lyssaviruses, or chimeric G combined from different lyssaviruses, and are thus expected to provide protection against other members of the lyssavirus genus.
T35904 58831-59158 Sentence denotes These pan-lyssavirus vaccines could be realized through recombinant viruses coding for the G protein of several lyssaviruses, RABV coding for additional Gs from different lyssaviruses, or chimeric G combined from different lyssaviruses, and are thus expected to provide protection against other members of the lyssavirus genus.
TextSentencer_T296 59159-59388 Sentence denotes Moreover, as RABV infection causes severe neuronal dysfunction and injury, it is equally important to ameliorate the neuronal damage induced by viral infection as well as clear RABV from the CNS for complete recovery from rabies.
T90568 59159-59388 Sentence denotes Moreover, as RABV infection causes severe neuronal dysfunction and injury, it is equally important to ameliorate the neuronal damage induced by viral infection as well as clear RABV from the CNS for complete recovery from rabies.
TextSentencer_T297 59389-59665 Sentence denotes Lastly, it is important to note that while some promising results have been achieved in animal models that PEP (with live-attenuated virus-based rabies vaccines) were effective, even when administered late after challenge infection, these treatments were largely prophylactic.
T73752 59389-59665 Sentence denotes Lastly, it is important to note that while some promising results have been achieved in animal models that PEP (with live-attenuated virus-based rabies vaccines) were effective, even when administered late after challenge infection, these treatments were largely prophylactic.
TextSentencer_T298 59666-59829 Sentence denotes Therefore, these treatments have not been shown to be curative, as the animals were not exhibiting any clinical signs at the time when the treatment was performed.
T24412 59666-59829 Sentence denotes Therefore, these treatments have not been shown to be curative, as the animals were not exhibiting any clinical signs at the time when the treatment was performed.
TextSentencer_T299 59830-59910 Sentence denotes Currently there is no solid, scientific evidence for any curative interventions.
T29995 59830-59910 Sentence denotes Currently there is no solid, scientific evidence for any curative interventions.
TextSentencer_T300 59911-60015 Sentence denotes More studies are needed to further investigate the potential of curative interventions for clinical use.
T62119 59911-60015 Sentence denotes More studies are needed to further investigate the potential of curative interventions for clinical use.
TextSentencer_T301 60016-60227 Sentence denotes In the future, appropriate combinations of a rabies vaccine, antiviral drugs, immunotherapy, and neuroprotective therapy could profoundly reshape rabies treatment and benefit more patients suffering from rabies.
T18491 60016-60227 Sentence denotes In the future, appropriate combinations of a rabies vaccine, antiviral drugs, immunotherapy, and neuroprotective therapy could profoundly reshape rabies treatment and benefit more patients suffering from rabies.