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    • br Funding This study was supported

    2018-10-23


    Funding This study was supported by the Natural Science Foundation of Fujian Province (grant nos. 2015J01451, 2016J01508, 2016J01513), the Training Project for Young and Middle-Aged Core Talents of Health System of Fujian Province (grant nos. 2015-ZQN-JC-7, 2015-ZQN-JC-22), the Science and Technology Plan Projects of Fujian Province (grant no. 2014Y0019), the National Clinical Key Specialty Construction Program of China (grant no. 2013-544) and the Ministry of Health of the People\'s Republic of China (grant no. WKJ2016-2-05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
    Specific Author Contributions
    Conflict of Interest Statement
    Acknowledgements
    Introduction Respiratory syncytial virus (RSV) causes severe lower respiratory tract infection (LRTI), especially in infants <6months old and the elderly, posing public health concerns worldwide. The results of a recent study based on the global mortality surveillance from 1990 to 2010 suggested that the cause of the highest mortality rate in infants is LRTI and that the most frequent causative agent of LRTI in infants is RSV (Lozano et al., 2012). It is also suggested that among contagious pathogens RSV is the second largest cause of mortality in infants next to the Plasmodium parasite (Lozano et al., 2012). As a disease burden associated with RSV infection, high risk for the development of 17-DMAG manufacturer in children who experience RSV bronchiolitis in infancy has been demonstrated (Bacharier et al., 2012). In addition, results of recent clinical research in the UK estimated that the year-to-year mortality rate in the elderly, and the number of elderly outpatients associated with RSV infection are more consistent than those of influenza (Flu), and that the average mortality rate of RSV and the number of RSV patients over the years are comparable with or higher than those of Flu (Fleming et al., 2015). Results of the research also suggested that rates of both the mortality and the hospitalization attributable to RSV infection are higher in the high risk group of the elderly, defined as chronic conditions indicative of risk for severe influenza as per UK recommendations for influenza vaccination, than those in the non-risk group of the elderly (Fleming et al., 2015). Thus, prophylactic measures, i.e., vaccines especially for infants and elderly, are required for controlling RSV infections worldwide, but no approved vaccines are currently available. According to WHO reports and a PATH program, there are a number of different types of RSV vaccine candidates in a variety of development stages, whereas one of the greatest regulatory issues on RSV vaccines is that there are no consolidated immunological biomarkers. Also, an international serum standard is required to normalize data between different tests and different laboratories for the clinical evaluation of vaccine efficacy. The difficulty lies in the fact that infants\' active antibody responses are hardly discriminated from pre-existing passively transferred maternal antibodies in infants. It is also suggested that regulatory authorities should harmonize and standardize the evaluation methods of biomarkers by using standard reagents and reference materials with common procedures (Higgins et al., 2016). Palivizumab, an antibody drug targeting antigenic site II of the RSV fusion protein (F protein), is available for the prevention of severe RSV illness in certain infants and children who are at high risk. The drug can help prevent development of serious RSV diseases, yet with limited efficacy (Groothuis et al., 1993; Parnes et al., 2003; The IMpact-RSV Study Group, 1998). The results of palivizumab\'s clinical trials in preterm infants showed that 40μg/mL of serum palivizumab corresponds to 7.3 log2 of the neutralization titer, enabling a 55% reduction of the hospitalization associated with RSV infections (The IMpact-RSV Study Group, 1998). The results of the past clinical research showed that participants with naturally acquired serum neutralization titers of 6.0 log2 or more to RSV group A and 8.0 log2 or more to RSV group B resulted in approximately 70% reduction in not having an RSV related-hospitalization (Piedra et al., 2003). The results of clinical studies on the prophylactic intravenous administration of RSV immune globulin to high risk infants and on serological assessment of RSV patients <6months old have suggested that the sera with neutralization titers >1:200 or 8.0 log2 confer protection against LRTI (Blaser and Valentine, 2008; Groothuis et al., 1993; Wright et al., 2002). Another clinical study focused on the RSV-specific antibody kinetics in mother-infant pairs in Bangladesh, and demonstrated a strong correlation between maternal RSV antibody titers at the third trimester and at birth with efficient trans-placental antibody transfer to the fetus (Chu et al., 2014). Reduced risk of LRTI was associated with higher cord blood neutralization titers above 8.0 log2 (Chu et al., 2014). Taken together, these findings suggest that serum neutralization titers of >8.0 log2 or serum palivizumab-like neutralization antibodies (PLNA) of >40μg/mL correlate with protection against RSV.