Recent Approaches in Hantavirus Vaccine Development
Recent Approaches in Hantavirus Vaccine Development
Rodent-borne hantaviruses are associated with two main clinical disorders in humans: hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome. Although hantavirus diseases can be life threatening and numerous research efforts are focused on the development of hantavirus prevention, no specific antiviral therapy is yet available and, at this time, no WHO-approved vaccine has gained widespread acceptance. This review will summarize the current knowledge and recent progress as well as new speculative approaches in the development of hantavirus vaccines.
Hantavirus is a genus in the family Bunyaviridae, containing 22 different hantavirus species ( Table 1 ). These viruses are the only hemorrhagic fever viruses with a worldwide distribution, including the temperate regions of the northern hemisphere. Increased risk of human disease occurs through exposure to aerosolized excreta of infected wild rodents, which are the main reservoirs and carriers of hantaviruses in nature.
Hantaviruses are the etiologic agents for two acute febrile disorders of man: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both disorders are associated with initial acute thrombocytopenia and changes in vascular permeability, and both disorders may have pulmonary and/or renal symptoms (see "Symptoms of Hantavirus Disease"). The majority of hantavirus serotypes known prior to 1993 had the kidney as the primary target organ, explaining why, historically, the first nomenclature of the disease (in the western world) was nephropathia epidemica (NE). Nowadays, the most commonly used name for this infection is the official WHO denomination HFRS. This term is now mainly used for describing Hantaan virus-induced disease in Asia and Eastern Russia, where the clinical picture is often more severe than in Puumala virus-induced NE, which is prevalent in Europe. The Sin Nombre virus, however, isolated after a 1993 epidemic in the USA, seems to primarily affect the lungs, where it causes a viral form of adult respiratory distress syndrome, originally known as HPS. Since it became clear that the heart is also heavily affected, leading to intractable cardiovascular shock and death, the disease name hantavirus cardiopulmonary syndrome is preferred by some authors.
Although only recently recognized, hantaviruses are not to be considered 'new' or even 'emerging' viruses, since phylogenetic studies provided evidence that they are the product of millions of years of coevolution with their respective rodent hosts. This explains the differences between hantaviruses of the New and the Old World, but also some common features.
Since 1993, approximately 2500 cases of HPS have been reported from the New World, with case fatality rates ranging between 30 and 40%; whereas, from a country such as China, a total number of 1,256,431 HFRS cases have been reported between 1950 and 1997, with 44,304 registered deaths (3.53%). The record year so far was 1986, with 115,985 confirmed cases and 2561 (2.2%) deaths. In European Russia, the republic of Bashkiria is the most endemic region, with 9000 cases in 1997 and 34 fatalities in a population of 4.1 million.
Hantaviruses are not known to productively infect arthropods but instead are maintained in nature in persistently infected rodents and are transmitted in infectious aerosols of urine, feces or saliva. This contrasts with the other human and animal Bunyaviridae pathogens, such as Crimean-Congo hemorrhagic fever virus transmitted by ticks, the sandfly fever viruses (phleboviruses) causing Toscana virus meningo-encephalitis and Pappataci fever transmitted by sandflies, and the Rift valley fever virus transmitted by mosquitoes. Both Crimean-Congo hemorrhagic fever viruses and Pappataci viruses are present in south Europe, and can mimic hantavirus disease to a great extent. Phylogeny and epidemiology of hantaviruses are closely linked to those of their respective rodent reservoirs, to a degree almost unique in zoonotic diseases. Each hantavirus serotype has its own principal rodent vector, its own geographic distribution and its own more or less specific clinical expression. There are, however, regions where biotopes of different rodent species, carrying different hantavirus serotypes, overlap with each other, giving rise to complex situations of diagnostic pinpointing. An example is Central Europe, where the Dobrava-Belgrade virus, Hantaan virus and Puumala virus may be sympatric.
Similar to all members of the family Bunyaviridae, the genome is negative sensed trisegmented and the hantavirus coding strategy is considered to be the simplest of the five genera (Figure 1). The large (L) segment of approximately 6500 nucleotides encodes an RNA-dependent RNA polymerase; the medium (M) segment, approximately 3600-3800 nucleotides long, encodes two glycoproteins (Gn and Gc); and the small (S) segment, approximately 1700-2100 nucleotides long, encodes a nucleocapsid protein (Np).
(Enlarge Image)
Figure 1.
Hantavirus particle. L = Large; M = Medium; S = Small.
Although numerous research efforts have been undertaken, more than 30 years after its discovery there is still no safe and effective vaccine that is WHO licensed or antiviral treatment against hantavirus infections. The main treatment of severe HPS or HFRS cases is purely supportive, often in intensive care unit surroundings. This means mechanical ventilation or even extracorporeal membrane oxygenation for HPS and all forms of extracorporeal blood purification (mostly hemodialysis) for HFRS. Except for the drug ribavirin, there is no specific treatment for hantavirus infections. However, ribavirin is not widely available and should only be given intravenously and early in the clinical course. Ribavirin remains limited to quickly recognized (e.g., during an epidemic) and severe forms of disease, where the clinician cannot wait for serological results for his diagnosis and has outweighed the potential benefits of this medication to its non-negligible side effects (mainly anemia). In practice, this is applicable only for outbreaks of severe Hantaan virus disease in Korea and, particularly, in China, where encouraging results have been obtained, but only when ribavirin is given in the first 5 days after onset. In a limited field study of HPS in the USA, no convincing beneficial effect could be demonstrated with ribavirin.
Until now, there is no WHO-approved hantavirus vaccine available. However, at least three different inactivated vaccines, based on purified suckling-mouse brains, golden hamster kidney cells or Mongolian gerbil kidney cells, were developed in Korea and/or China, and which are being used only locally. A variety of vaccine approaches, however, have been investigated using both inactivated virus and recombinant DNA technology. These approaches will be further discussed later in this review.
Abstract and Introduction
Abstract
Rodent-borne hantaviruses are associated with two main clinical disorders in humans: hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome. Although hantavirus diseases can be life threatening and numerous research efforts are focused on the development of hantavirus prevention, no specific antiviral therapy is yet available and, at this time, no WHO-approved vaccine has gained widespread acceptance. This review will summarize the current knowledge and recent progress as well as new speculative approaches in the development of hantavirus vaccines.
Introduction
Hantavirus is a genus in the family Bunyaviridae, containing 22 different hantavirus species ( Table 1 ). These viruses are the only hemorrhagic fever viruses with a worldwide distribution, including the temperate regions of the northern hemisphere. Increased risk of human disease occurs through exposure to aerosolized excreta of infected wild rodents, which are the main reservoirs and carriers of hantaviruses in nature.
Hantaviruses are the etiologic agents for two acute febrile disorders of man: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Both disorders are associated with initial acute thrombocytopenia and changes in vascular permeability, and both disorders may have pulmonary and/or renal symptoms (see "Symptoms of Hantavirus Disease"). The majority of hantavirus serotypes known prior to 1993 had the kidney as the primary target organ, explaining why, historically, the first nomenclature of the disease (in the western world) was nephropathia epidemica (NE). Nowadays, the most commonly used name for this infection is the official WHO denomination HFRS. This term is now mainly used for describing Hantaan virus-induced disease in Asia and Eastern Russia, where the clinical picture is often more severe than in Puumala virus-induced NE, which is prevalent in Europe. The Sin Nombre virus, however, isolated after a 1993 epidemic in the USA, seems to primarily affect the lungs, where it causes a viral form of adult respiratory distress syndrome, originally known as HPS. Since it became clear that the heart is also heavily affected, leading to intractable cardiovascular shock and death, the disease name hantavirus cardiopulmonary syndrome is preferred by some authors.
Although only recently recognized, hantaviruses are not to be considered 'new' or even 'emerging' viruses, since phylogenetic studies provided evidence that they are the product of millions of years of coevolution with their respective rodent hosts. This explains the differences between hantaviruses of the New and the Old World, but also some common features.
Since 1993, approximately 2500 cases of HPS have been reported from the New World, with case fatality rates ranging between 30 and 40%; whereas, from a country such as China, a total number of 1,256,431 HFRS cases have been reported between 1950 and 1997, with 44,304 registered deaths (3.53%). The record year so far was 1986, with 115,985 confirmed cases and 2561 (2.2%) deaths. In European Russia, the republic of Bashkiria is the most endemic region, with 9000 cases in 1997 and 34 fatalities in a population of 4.1 million.
Hantaviruses are not known to productively infect arthropods but instead are maintained in nature in persistently infected rodents and are transmitted in infectious aerosols of urine, feces or saliva. This contrasts with the other human and animal Bunyaviridae pathogens, such as Crimean-Congo hemorrhagic fever virus transmitted by ticks, the sandfly fever viruses (phleboviruses) causing Toscana virus meningo-encephalitis and Pappataci fever transmitted by sandflies, and the Rift valley fever virus transmitted by mosquitoes. Both Crimean-Congo hemorrhagic fever viruses and Pappataci viruses are present in south Europe, and can mimic hantavirus disease to a great extent. Phylogeny and epidemiology of hantaviruses are closely linked to those of their respective rodent reservoirs, to a degree almost unique in zoonotic diseases. Each hantavirus serotype has its own principal rodent vector, its own geographic distribution and its own more or less specific clinical expression. There are, however, regions where biotopes of different rodent species, carrying different hantavirus serotypes, overlap with each other, giving rise to complex situations of diagnostic pinpointing. An example is Central Europe, where the Dobrava-Belgrade virus, Hantaan virus and Puumala virus may be sympatric.
Similar to all members of the family Bunyaviridae, the genome is negative sensed trisegmented and the hantavirus coding strategy is considered to be the simplest of the five genera (Figure 1). The large (L) segment of approximately 6500 nucleotides encodes an RNA-dependent RNA polymerase; the medium (M) segment, approximately 3600-3800 nucleotides long, encodes two glycoproteins (Gn and Gc); and the small (S) segment, approximately 1700-2100 nucleotides long, encodes a nucleocapsid protein (Np).
(Enlarge Image)
Figure 1.
Hantavirus particle. L = Large; M = Medium; S = Small.
Although numerous research efforts have been undertaken, more than 30 years after its discovery there is still no safe and effective vaccine that is WHO licensed or antiviral treatment against hantavirus infections. The main treatment of severe HPS or HFRS cases is purely supportive, often in intensive care unit surroundings. This means mechanical ventilation or even extracorporeal membrane oxygenation for HPS and all forms of extracorporeal blood purification (mostly hemodialysis) for HFRS. Except for the drug ribavirin, there is no specific treatment for hantavirus infections. However, ribavirin is not widely available and should only be given intravenously and early in the clinical course. Ribavirin remains limited to quickly recognized (e.g., during an epidemic) and severe forms of disease, where the clinician cannot wait for serological results for his diagnosis and has outweighed the potential benefits of this medication to its non-negligible side effects (mainly anemia). In practice, this is applicable only for outbreaks of severe Hantaan virus disease in Korea and, particularly, in China, where encouraging results have been obtained, but only when ribavirin is given in the first 5 days after onset. In a limited field study of HPS in the USA, no convincing beneficial effect could be demonstrated with ribavirin.
Until now, there is no WHO-approved hantavirus vaccine available. However, at least three different inactivated vaccines, based on purified suckling-mouse brains, golden hamster kidney cells or Mongolian gerbil kidney cells, were developed in Korea and/or China, and which are being used only locally. A variety of vaccine approaches, however, have been investigated using both inactivated virus and recombinant DNA technology. These approaches will be further discussed later in this review.
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