ReviewRespiratory Syncytial Virus: Pathology, therapeutic drugs and prophylaxis
Introduction
Human Respiratory Syncytial Virus (hRSV) is the major cause of bronchiolitis and lower tract illness, affecting nearly 70% of infants before the age of one year and approximately 100% of children by age of two [1], [2], [3]. Approximately 30 million of children younger than five years old suffer from acute lower respiratory infection due to hRSV, out of which 10% require hospitalization [4], [5]. HRSV causes approximately 200,000 deaths per year, most of the cases take place in developing countries and include mainly children younger than 5 years of age [4]. This virus causes wide complications to premature born patients as well as infants suffering of congenital heart disease and immune deficiency [6], [7]. Further, 2% of young children infected with this virus and hospitalized due severe bronchiolitis show symptoms of central nervous system (CNS) alterations, such as seizures, central apnea and encephalopathy, among others [4], [8], [9], [10], [11], [12]. Recently, an increase in the number of cases of encephalopathy associated to hRSV infection has been described [12]. Further, a recent study has shown that hRSV can be detected in the CNS of infected animals 30 days after infection causing significantly reduced performance in learning and behavioral tests [13]. Therefore, it is a high priority worldwide to generate either a vaccine against hRSV to prevent the respiratory disease or new therapeutic drugs to treat severe infection and reduce the potential long-term effects caused by infection with this virus.
Up to date, therapeutic treatments for hRSV infection have consisted of antiviral molecules. One of the most successful treatments has been a humanized monoclonal antibody against hRSV F glycoprotein known as Palivizumab [14], [15]. This neutralizing antibody was shown to be able to reduce hRSV-associated hospitalization rates by 55%, as compared to placebo [16], [17]. However, monthly antibody re-administration is required to prevent viral dissemination and this passive immunization is not effective for all young children [18], [19]. Further, due to its high costs, in most countries Palivizumab is prescribed only for high-risk children.
Only few years after the virus was identified, a formalin-inactivated hRSV preparation (FI-hRSV) was used in a field trial during the mid-1960s as an initial attempt to vaccinate against the virus. Unfortunately, after natural infection with hRSV, children that were immunized with this formulation showed an exacerbated pulmonary disease and suffered more severe symptoms than unvaccinated children [20]. Data explaining the failure of FI-hRSV as a vaccine were obtained after decades of research and suggested that immunization with this formalin-inactivated hRSV vaccine promoted an allergic-like response in the lungs [21], [22]. In animal models of hRSV infection, such as cotton rats, immunization with inactivated virus followed by challenge with infective hRSV also induces eosinophil and neutrophil infiltration to the airways [23], [24]. Further, deposition of immune complexes and complement activation is another characteristic observed in both animal models and infected patients [25], a feature that seems to be exacerbated by immunization with formalin-inactivated hRSV. This is due to the establishment of unbalanced Th1–Th2 polarized responses, which are characterized by the secretion of pro-inflammatory cytokines that drive excessive infiltration of eosinophils and neutrophils into the lungs [26]. It is likely that modification of viral epitopes by formalin and the development of low affinity antibodies against modified hRSV antigens could have contributed to the damaging immune response triggered by this early vaccine approach [24].
After the above-mentioned FI-hRSV vaccine failed, several new strategies aiming at inducing protective immunity against hRSV infection have arisen during the past 50 years. However, to date no efficient and affordable products are available for public health systems to counteract the disease. In this review we will discuss the most recent knowledge about the pathology caused by hRSV and the experimental drugs and vaccine developed up to date as an attempt to prevent or treat hRSV infection in humans.
Section snippets
Molecular characteristics of hRSV
hRSV was first isolated at the end of the 50s and its name is due to its property to generate syncytia on infected cells in culture [27], [28], [29]. HRSV belongs to the Mononegavirales order, Paramixoviridae family and pneumovirus genus. Other members of this family are measles (MeV), mumps (MuV) and human metapneumovirus (hMPV), among others [30]. HRSV consists of an enveloped non-segmented, negative-sensed and single-stranded RNA genome of 15.2 kb, which has 10 genes that are transcribed in
Respiratory pathology caused by hRSV infection
The clinical manifestations of the pathology caused by hRSV are common to other respiratory viral infections. The first symptoms of infection are rhinitis, cough, fever and nasal congestion [32], [35], [46]. The severity of the illness is due both to host and viral factors. Prematurity, low birth weight, cardiopulmonary disease, bronchopulmonary dysplasia and immunodeficiency are the most common host risk factors that account for severe bronchiolitis caused by hRSV [47], [48]. Infants under one
HRSV and host immune response
HRSV infection triggers the secretion of several pro-inflammatory molecules that initiate the immune response against this virus (Fig. 1) [45]. The immune response due to the viral infection is characterized by an exacerbated inflammation and weak T cell immunity [26], [45], [62]. The most commonly secreted molecules by epithelial cells in response to hRSV infection are IL-6, IL-8/CXCL8, IL-10, TNF-α, RANTES/CCL5, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, MIP-2/CXCL2, IP-10/CXCL10 and
Development of therapeutic drugs and vaccine against hRSV
Although several drugs have been shown to reduce hRSV infection, currently only Rivabirin is allowed for human use. However the use of this molecule remains controversial due to concerns relative to cost/efficacy issues, as well as potential side effects [112], [113]. Drugs have been developed to target several steps of the infectious cycle of virus, such as entry, replication and transcription (Fig. 2). These approaches can be significant as they can directly impair the viral infective cycle,
The use of hRSV-F glycoprotein as target for drug and vaccine design
Recently, fragment antibodies called “Nanobodies” have been evaluated as treatment against hRSV infection [123], [124]. Thus, heavy chain against F-hRSV glycoprotein has been evaluated as an efficient hRSV neutralizing tool in HEp-2 cells. The neutralizing capacity of this molecule was about 4000-fold higher as compared to whole classical anti-F antibodies [125]. In vivo, nanobodies were found to be efficient at preventing infection and excessive airway inflammation [123]. These nanobodies are
Strategies to target the hRSV-N protein
One of the most efficient experimental drugs against hRSV is RSV-604, which targets the N nucleoprotein, interfering with the replicative cycle of the virus [140]. This molecule is currently being tested in phase II trials, which have shown promising results despite the tendency of hRSV to acquire mutations during long exposure to the drug [141].
siRNA targeting methods against N, P and L, interfering with replication cycle was found to reduce viral titers in the lungs [142], [143], [144], [145]
Vaccine development based on hRSV-G glycoprotein
Studies on hRSV-G glycoprotein have been focused on recombinant viruses, which could be an efficient strategy for reducing hRSV pathology. Two recombinant hRSV particles (rhRSV and ΔG-hRSV) were found to be protective against hRSV challenge in vivo with no enhanced disease phenomenon, described by low pulmonary inflammation. Replication level of these 2 particles was either null or low; leading to the conclusion that G would play an important role in hRSV replication [149]. Unfortunately,
Peptides-based vaccines against h-RSV M2 protein
TriVax is a combination of M2 CD8+ immunodominant peptide combined with poly I:C and anti-CD40 co-stimulatory antibody [153]. Immunization with this formulation increased the production of M2-specific CD8+ T cells that have CTL activity [153]. Vaccination promoted the secretion of IFN-γ, IL-2 and TNF-α by those CD8+ T cells and reduced the pathology-associated effects caused by a hRSV strain that generates the production of mucin in the airways. This vaccine approach was able to reduce mucin
Alternative strategies to generate hRSV vaccines
An attenuated viral particle, cpts-248/404, was found to be a good candidate among the low-temperature attenuated particles. Infants vaccinated with this particle did not manifest lower respiratory tract infection, but the upper airway was found affected after immunization [120], [154]. Later, a derived attenuated particle from cpt-248/404 mutated for SH and L protein named rA2cp248/404/1030ΔSH has been found to generate an efficient IgG and IgA specific response against hRSV in 44% of the 1–2
Immune protection induced by maternal immunization
As newborns are the population most affected by severe complications after hRSV infection, maternal immunization during pregnancy is also an important point to consider. Maternal antibodies are passively transferred to babies by placenta and breast milk [160], [161]. Only few studies related to maternal antibody transfer are published in the hRSV vaccine field [162]. A recent study using FI-hRSV particles in animal models showed increased antibody titers and less severe disease in pups [163].
Concluding remarks
The knowledge about hRSV is wide and a significant numbers of products have been tested against the disease. Some of these products have therapeutic promising anti-viral effect against the disease and others are already candidate prophylactic vaccine in newborns. Several drugs shown promising effects against the pathology in vivo in animal models, but also many of these drugs probably will not reach clinical studies. Thus a significant fraction of the work still remains to be completed, such as
Acknowledgements
This study was supported by the following grants: FONDO NACIONAL DE CIENCIA Y TECNOLOGIA DE CHILE (FONDECYT numbers 1140010, 1110604, 1100971, 1131012 and 1110397), Millennium Institute of Immunology and Immunotherapy P09/016-F and Grant “Nouvelles Equipes-nouvelles thématiques” from the La Région Pays De La Loire. RSG and KB are supported by the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT). AMK is a Chaire De La Région Pays De La Loire, Chercheur Étranger D’excellence,
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