since its first discovery in the 1950s , human respiratory syncytial virus ( hrsv ) has been recognized as the leading viral pathogen of severe respiratory tract diseases in infants and young children . hrsv causes yearly epidemics , and it is estimated that hrsv infection results in hospitalizations of > 3 million children under 5 years of age1 ) . most children are infected during the first year of life , all are infected by age 3 , and recurrent infections occur throughout life , possibly due to incomplete rsv immunity2 ) . an increased incidence of asthma has been also associated with severe hrsv infection in the lower respiratory tract3 ) . hrsv also causes severe diseases in the elderly that are associated with comparable mortality as influenza4 ) . hrsv is a member of paramyxoviridae family of the non - segmented negative - strand rna viruses . hrsv could be divided into 2 antigenic subgroups , a and b , according to their reactive patterns to monoclonal antibodies . these subtypes co - circulate , and the predominance of 1 subtype over the other seems to vary by year and location . the rsv genome contains genes for 11 proteins , including transmembrane proteins g , f , and sh . the antigenic diversity of hrsv is mainly associated with the amino acid heterogeneity of g protein , in which homology comparison shows only -53% identity between the a and b subgroups7 ) . recent evidence demonstrated that the recombinant adenovirus - based vaccine - expressing g protein of subtype a perfectly protects immune mice from hrsv challenge of a related subtype a isolate but only partially protects mice from hrsv challenge with the b isolate subtype8 ) . these results suggest that the protective efficacy of g protein - based hrsv vaccine over 2 hrsv subtypes depends on the sequence employed in the vaccine . animal models for hrsv infection and disease are indispensible in the research of prophylactic vaccines and novel therapies for hrsv disease . an ideal model should reproduce all aspects of hrsv disease in humans , such as clinical signs of illness , relevant pathological alterations , and susceptibility to viral replication . chimpanzees are the most appropriate model to fit the criteria and are primarily used for vaccine studies ; however , economical and ethical burdens restrict their use in hrsv research . as such the cotton rat has become a standard rodent animal for studying hrsv disease since it is semi - permissive for hrsv replication and shows some clinical signs of hrsv disease . inbred laboratory mice have been the most popular animal for experimental hrsv infection and disease , although they are less susceptible to viral replication and show limited symptoms and signs of the illness . the availability of numerous genetically modified strains and mouse - specific tools make this species the most popular animal model for hrsv research . neonates with hrsv infection are more susceptible to diseases such as bronchiolitis , interstitial pneumonitis , and alveolitis . structural immaturity of the respiratory system and an underdeveloped immune system may contribute to hrsv infection severity . several cohort studies suggested that hrsv infection in the lower respiratory tract of infants is closely connected to later development of asthma . a prospective cohort study in finland demonstrated that severe bronchiolitis requiring hospitalization in infancy was a significant risk factor for asthma that extends into adolescence9 ) . in a study in sweden , hospitalization for hrsv bronchiolitis in the first year of life was the significant risk factor for asthma and allergy patterns in patients at > 18 years of age10 ) . another study also demonstrated relevance between hrsv severity and the development of asthma in a cohort of > 95,000 infants11 ) . in a mouse model , it was shown that 1- or 3-week - old age groups could provoke increased airway hyperresponsiveness ( ahr ) after primary rsv infection12 ) . however , when the infected mice were later re - exposed to the rsv , the initial rsv infection at 1 week of age resulted in enhanced ahr , mucus production , and airway eosinophilia compared with the initial rsv infection of weanling mice12 ) . due to the failure of the formalin - inactivated rsv ( fi - rsv ) vaccine in 1969 , it has been proposed that an understanding of the immune system of infants is very important for both the treatment of severe hrsv infection and vaccine development13 ) . throughout these studies , it is thought that the age of initial hrsv infection is one of the important factors of severity of viral infection - associated bronchiolitis and is a strong predictor of the development of asthma . pre - existing allergic symptoms such as genetic tendencies and prior exposure to an allergen can lead to increased th2-dominant immune responses against hrsv infection . several genetic studies in cytokines reported that hrsv - induced respiratory disease and asthma share genetic factors14 ) . polymorphisms in the chemokine receptor 5 , interleukin ( il)-4 , il-10 , il-13 , and transforming growth factor- genes were associated with hrsv - associated bronchiolitis severity . some environmental risk factors such as daycare attendance , the presence of siblings , passive smoke exposure , and allergic sensitization to foods during the first years of life are important in the association between hrsv infection and asthma15 ) . makela et al.16 ) revealed that prior airway exposure to ovalbumin increases hrsv - induced ahr and the accumulation of th2 cytokine - producing t lymphocytes , granulocytes ( eosinophils and neutrophils ) , and cd8 + t cells in the lungs . severity of hrsv infection in early life is associated with an increased production of th2 cytokines , which could influence the later immune response to inhaled pathogens17 ) , and reduced and delayed interferon ( ifn)- responses18 ) . han et al.19 ) demonstrated that hrsv infection in the neonatal stage resulted in reduced ifn- production compared with infection in the weanling or adult stage as well as the development of ahr and goblet cell hyperplasia in a mouse model . when re - infected with rsv later , the sequelae such as enhanced ahr , increased il-13 production associated with mucus hyperproduction , and eosinophilia were worsened . the role of ifn- in the severity of rsv - mediated respiratory disease is not yet well defined . however , the relationship between ifn- production and pulmonary sequelae suggests that ifn- plays an important role in deciding the lesion of rsv - mediated disease . the production of a viral pathogen - specific immunoglobulin ( ig ) is an important event in host defense against virus infection . in earlier studies in the hrsv field , most investigators were concerned with antibodies of the iga , igg , and igm isotypes in nasopharyngeal secretions during hrsv infection . they suggested that these igs bound to rsv - infected cells20 ) . since welliver et al.3 ) reported about rsv - specific ige in 1981 , several studies have proved the existence of rsv - specific ige in infants and children with severe hrsv infection - induced disease21 - 24 ) . in these studies , they consistently demonstrated that hrsv - infected patients with wheezing had higher titers of virus - specific ige than patients infected with hrsv who did not have wheezing . furthermore , hrsv - specific ige was highly correlated with hrsv infection severity . in a mouse model , it was proven that the production of rsv - specific ige is highly correlated with the development of rsv - mediated wheezing and post - allergen - triggered asthma25,26 ) . however , it is unclear how hrsv leads to upregulation of virus - specific ige production in both infected humans and mice . the basic feature , effector functions , and roles of eosinophils have been studied in various disease states . most researchers believe that eosinophils are major pathophysiological mediators in respiratory disease and asthma27 ) . likewise , eosinophils have been considered end - stage effector cells in asthma and other respiratory disease like hrsv infection . however , it is not well known whether eosinophils are directly responsible for the immunopathology induced by hrsv infection , play an unexpected role in the host immune system , or are simply bystander cell phenotypes28 ) . on the other hand , some investigators argue that eosinophils show a protective effect in various diseases . if major functions of eosinophils are harmful to the host , the cell types will not consistently persist . eosinophils have secretory ribonuclease that can directly affect the single - stranded rna genome of rsv27 ) . phipps et al.29 ) investigated rsv clearance in wild - type and eosinophil - enriched il-5 transgenic mice and suggested that rsv clearance proceeded more efficiently in the il-5 transgenic mice . although hrsv infection is associated with pulmonary eosinophilia , eosinophils have not been clearly linked to the hrsv - mediated progression to asthma either mechanistically or pathophysiologically . a further study is needed to clarify how eosinophils are involved in the sequelae of hrsv infection . the infected individual induces a broad range of immune responses to clear the hrsv infection , but these immune responses are also known to contribute to the clinical manifestations of hrsv diseases . antibody responses have been proven sufficient to prevent or restrict the primary infection as evidenced by palivizumab , a humanized monoclonal antibody that is currently used as a passive prophylaxis against hrsv infection in high - risk populations30 ) . however , once rsv infection is established , t - cell responses are required to completely eliminate the virus31 ) . t cells also play important roles in pulmonary inflammation , in which cytokines secreted by t cells provoke severe lung pathology marked by a massive infiltration of immune cells32 ) . in the initial trial of the fi - rsv vaccine in the late 1960s , the vaccine proved to be poorly protective against but rather although the mechanism of this vaccine - induced disease enhancement remains not completely understood , it is proposed that fi - rsv induces unusual antibody responses with little neutralizing activity compared with that induced by natural hrsv infection34 ) . subsequent studies demonstrated that fi - rsv induced imbalanced th2-type cd4 t - cell responses in experimental animal models35 - 37 ) . thus , vaccine - enhanced disease following vaccination appears to be associated with massive pulmonary inflammation initiated by vaccine - primed th2-type cd4 t cells . g glycoprotein , the major rsv attachment protein , is thought to be an important protective antigen against rsv infection38 ) . the central domain of g protein is relatively conserved between strains and subtypes and contains several protective b - cell epitopes39 - 41 ) . numerous studies have suggested that priming with g protein is associated with the induction of a polarized th2-type response similar to that induced by fi - rsv , which leads to pulmonary eosinophilia upon rsv challenge of g - immunized mice39,42 - 45 ) . however , in the presence of an immunodominant cytotoxic t lymphocyte ( ctl ) epitope from m2 protein , g protein - primed mice did not develop pulmonary eosinophilia during hrsv challenge46 ) . thus , it is likely that the absence of a th1-promoting effect of rsv - specific ctls , rather than the g protein itself , is responsible for the th2-biased response . it has recently been suggested that g - specific immune responses are not solely the basis for vaccine - enhanced illness and should not be excluded from potential vaccine strategies47 - 49 ) . based on these findings , it should be emphasized that the fine balance between protective immunity and vaccine - induced immunopathology is one of the most important issues to be considered in the development of safe hrsv vaccines . since the most serious hrsv disease occurs at 2 to 7 months of age , immunization should be started within the first few weeks of life . however , several major obstacles must be overcome to enable the development of a pediatric hrsv vaccine . first , the immune system of young infants is relatively immature compared to that of older children and adults . as such , hrsv vaccines targeting the newborn population should be immunogenic enough to induce protective immunity in a relatively immature immune environment . second , maternal antibodies might interfere with the actions of administered vaccines , especially in the first few weeks of life50 ) . to ensure vaccination success , it might be necessary for effective vaccines to avoid the compromising activity of maternal antibodies . third , the failure of the early vaccine trial with fi - rsv significantly increased the safety standards for hrsv vaccines , which could be associated with detrimental vaccine - enhanced illness . thus , new vaccine candidates should be thoroughly verified to have little vaccine - associated pathology and illness . one of the major strategies for hrsv vaccine is the use of live - attenuated rsv strains for intranasal administration that mimic natural infection . several live - attenuated hrsv vaccine candidates have been developed by conventional cold passage methods and subsequently evaluated in several clinical stages51,52 ) . a second - generation live - attenuated hrsv has been also generated by reverse genetics ( ra2cp strains ) and tested in hrsv - nave 1- to 2-month - old infants , and protective immunity could be achieved in a majority of the vaccine recipients53,54 ) . however , for this live - attenuated hrsv platform , it is quite challenging to determine whether the balance between over- and under - attenuation is most appropriate for a safe and effective vaccine . due to the potential for disease exacerbation , the use of inactivated or subunit vaccines had been considered inappropriate in the pediatric population . however , several hrsv - derived proteins and their derivatives as recombinant subunit vaccines have been evaluated in preclinical and clinical stages . purified f and g proteins from hrsv - infected mammalian cells and f / g chimeric proteins produced in insect cells generated humoral responses similar to those observed in fi - rsv vaccination in rodent models55,56 ) . however , the use of appropriate adjuvants was shown to enhance the immunogenicity of subunit vaccines57,58 ) . another subunit vaccine , bbg2na , which consists of a g protein region covering amino acids 130 to 230 and the albumin - binding domain of streptococcal protein g , has also been evaluated in preclinical and clinical testing59,60 ) . bbg2na was well tolerated in phase ii studies , but the trial was stopped due to a limited number of unexpected adverse events61 ) . viral vectored vaccines employing platforms such as the vaccinia virus6 ) , adenovirus49,62,63 ) , sendai virus64 ) , and parainfluenza virus65 ) , have been developed and evaluated as hrsv vaccine candidates . most of these candidates exhibited significant immunogenicity and protective immunity in animal models , showing the possibility of further development . other forms of vaccines using replicon - based non - replicating viral vectors or virus - like particles66,67 ) , live bacteria68 ) , and avian virus69 ) have been also reported to be immunogenic and induce varying degrees of protective immunity in mouse studies . vaccination of dna plasmids expressing f or g protein has shown only a limited degree of protection against hrsv challenge70,71 ) . for many years , the development of an hrsv vaccine has been a high priority in many public health agendas . as mentioned above , numerous vaccine strategies have been tested or are being tested for further development . needless to say , basic research into rsv virology and immunology will provide important information in vaccine development . once we understand the enigmatic immune evasion and immunopathology of hrsv more clearly , we will be able to advance the development of hrsv vaccines . more serious awareness of the social and economical burden of hrsv diseases must also occur . we are hopeful that our great efforts into hrsv vaccine development will soon achieve the goal of safe and effective vaccines in the near future .
human respiratory syncytial virus ( hrsv ) is a major cause of severe respiratory tract illnesses in infants and young children worldwide . despite its importance as a respiratory pathogen , 
 there is currently no licensed vaccine for hrsv . 
 following failure of the initial trial of formalin - inactivated virus particle vaccine , continuous efforts have been made for the development of safe and efficacious vaccines against hrsv . 
 however , several obstacles persist that delay the development of hrsv vaccine , such as the immature immune system of newborn infants and the possible th2-biased immune responses leading to subsequent vaccine - enhanced diseases . 
 many hrsv vaccine strategies are currently being developed and evaluated , including live - attenuated viruses , subunit - based , and vector - based candidates . in this review , 
 the current hrsv vaccines are overviewed and the safety issues regarding asthma and vaccine - induced pathology are discussed .