Rayavara K, Kurosky A, Stafford SJ, Garg NJ, Brasier AR, Garofalo RP, Hosakote YM
The first epithelial molecular events upon infection define the size and direction of the inflammatory response, which ultimately defines disease in RSV infected patients. Rayavara and collegues shed a light on this complex process. Previously, this group showed that RSV promotes the release of high mobility group box 1 (HMGB1) by airway epithelial cells. HMGB1 is a nuclear protein, which becomes an alarmin after secretion to the extracellular space to induce an inflammatory response.
In the current study they show, that HMGB1 forms a link between the infected respiratory epithelium and the response by immune cells. After RSV infection, HMGB1 is expressed by airway epithelial cells. This process is dependent on TLR4 and is mediated by the MAPK and NF-kB pathway. Blocking of TLR4 or the NF-kB pathway in AECs, decreases the expression of HMGB1. Next they show that HMGB1 stimulates primary immune cells, such as monocytes and macrophages, to produce inflammatory cytokines and chemokines.
Blocking the HMGB1 pathway, under an umbrella of antiviral treatment, might limit immune pathology and thereby ameliorate the course of disease in children with RSV infection.
THE SIGNIFICANCE OF HUMAN RESPIRATORY SYNCYTIAL VIRUS (HRSV) IN CHILDREN FROM GHANA WITH ACUTE LOWER RESPIRATORY TRACT INFECTION: A MOLECULAR EPIDEMIOLOGY ANALYSIS.
Obodai E, Odoom JK, Adiku T, Goka B, Wolff T, Biere B, Schweiger B, Reiche J.
Summary: The molecular epidemiology of RSV infection is increasingly thought to be essential to understand how the virus spreads around the world every year. RSV molecular epidemiology also informs developers of therapeutics about potential sensitivity or resistance of the virus to specific drugs. Altogether, data of about 1000 specimens have been published, most from developed countries. The World Health Organization has started a pilot to perform RSV surveillance, probably including viral sequencing. Data from poor resource settings have been prioritized. To that end it is important to note this paper form researchers from Ghana and Germany who were able to provide valuable sequence data from a study performed in 2006-2014 in which 127 RSV positive children were included. The results show the evaluation of RSV-A (ON1) and RSV-B strains (BA9) in Ghana. These data will add significantly to our understanding of viral behavior over time in low and middle income countries (LMIC)
Nyiro JU, Munywoki P, Kamau1 E, Agoti C, Gichuki A, Etyang T, Otieno G, Noke DJ
This paper reports the epidemiological data of respiratory viruses at nine outpatient health facilities in rural coastal Kenya as well as in hospital settings. More than half (53.7%) of participants with ARI symptoms were from children younger than 5 years. The most common respiratory viruses detected were rhinovirus, influenza virus, coronavirus, parainfluenza virus, respiratory syncytial virus (RSV) and adenovirus. In hospital settings with young children admitted to hospitals, the frequency of RSV and adenovirus was significantly higher, indicating they were more commonly associated with severe disease. More data tracking temporality and seasonality of viral prevalence over multiple years as well as discussion on viral co-infections would strengthen the evidence.
Mazur NI, Horsley N, Englund JA, Nederend M, Magaret A, Kumar A, Jacobino SR, de Haan CAM, Khatry SK, LeClerq SC, Steinhoff MC, Tielsch JM, Katz J, Graham BS, Bont LJ, Leusen JHW, Chu HY
Maternal RSV vaccines are on the verge of establishment. Protection by maternal vaccination is mainly based on transplacental antibody (Ab) transfer. Antibody transfer via breast milk might offer additional protection. The immunological correlate for protection against RSV, by maternal antibodies transferred via breast milk, is unknown. Mazur and colleagues are the first to show that breast milk derived antibodies directed against pre-F RSV play an important role in the protection against RSV infection.
They conducted a study among 174 infants under the age of 6 months. Infants were stratified by risk factors into a group with and a group without RSV. While pre-F IgA Ab did not differ between the two groups, pre-F IgG Ab was significantly lower in the group with RSV. Although the difference between the two groups was small it does suggest the potential role of pre-F IgG antibodies as a correlate of protection against RSV respiratory tract infection.
Induction of pre-F IgG in breast milk by maternal vaccination will probably transfer protection to infants against RSV disease, additional to transplacental antibody transfer.
This review was written by Sjanna Besteman
Geerdink RJ, Hennus MP, Westerlaken GHA, Abrahams AC, Albers KI, Walk J, Wesselink E, Janssen R, Bont L, Meyaard L.
How to hold neutrophils in check
During RSV bronchiolitis neutrophils are the most abundant immune cells in the lung. Neutrophils are known to produce neutrophil extra cellular traps (NETs) which can induce injury to epithelial cells and hence contribute to disease severity. Neutrophils express several inhibitory receptors including LAIR-1. Whether targeting this receptor could diminish NET release is the question Geerdink and colleagues answer in their article. Their study demonstrates that sputum neutrophils from the lungs of RSV infected patients are highly activated and show increased LAIR-1 expression compared to blood derived neutrophils. More strikingly; targeting LAIR-1 with antibodies inhibited NET formation by 50%. This finding offers an innovative strategy that, together with newly developed antiviral, could contribute to the treatment of RSV bronchiolitis.
The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates.
Mazur NI, Higgins D, Nunes MC, Melero JA, Langedijk AC, Horsley N, Buchholz UJ, Openshaw PJ, Mc Lellan JS, Englund JA, Meijas A, KArron RA, Simōes EA, Knezevic I, Ramilo O, Piedra PA, Chu HY, Falsey AR, Nair H, Kragten-Tabatabaie L, Greenough A, Baraldi E, Papadopoulus NG, Vekenmans J, Polack FP, Powell M, Satav A, Walsh EE, Stein RT, Graham BS, Bont LJ, Respiratory Syncytial Virus Network (ReSViNET) Foundation.
The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development. The candidates include mAbs and vaccines using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based. Late-phase RSV vaccine trial failures highlight gaps in knowledge regarding immunological protection and provide lessons for future development. In this Review, we highlight promising new approaches for RSV vaccine design and provide a comprehensive overview of RSV vaccine candidates and mAbs in clinical development to prevent one of the most common and severe infectious diseases in young children and older adults worldwide.
Obando-Pacheco P, Justicia-Grande AJ, Rivero-Calle I, Rodríguez-Tenreiro C, Sly P, Ramilo O, Mejías A, Baraldi E, Papadopoulos NG, Nair H, Nunes MC, Kragten-Tabatabaie L, Heikkinen T, Greenough A, Stein RT, Mazoni P, Bont L, Martinón-Torres F.
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in children. By the age of 1 year, 60%-70% of children have been infected by RSV. In addition, early-life RSV infection is associated with the development of recurrent wheezing and asthma in infancy and childhood. The need for precise epidemiologic data regarding RSV as a worldwide pathogen has been growing steadily as novel RSV therapeutics are reaching the final stages of development. To optimize the prevention, diagnosis, and treatment of RSV infection in a timely manner, knowledge about the differences in the timing of the RSV epidemics worldwide is needed. Previous analyses, based on literature reviews of individual reports obtained from medical databases, have failed to provide global country seasonality patterns. Until recently, only certain countries have been recording RSV incidence through their own surveillance systems. This analysis was based on national RSV surveillance reports and medical databases from 27 countries worldwide. This is the first study to use original-source, high-quality surveillance data to establish a global, robust, and homogeneous report on global country-specific RSV seasonality.
The burden of respiratory syncytial virus (RSV) associated acute lower respiratory infections in children with Down syndrome: A systematic review and meta-analysis.
Chan M, Park JJ, Shi T, Martinón-Torres F, Bont L, Nair H, Respiratory Syncytial Virus Network (ReSViNET).
Acute lower respiratory tract infections (ALRIs) caused by respiratory syncytial virus (RSV) are a leading cause of hospitalization in infants. Numerous risk factors have been identified in the aetiology of severe RSV-associated ALRI necessitating hospitalisation, including prematurity and congenital heart disease. Down syndrome (DS), a common genetic disorder associated with congenital and dysmorphic features, has recently been identified as an independent risk factor for RSV-associated ALRI requiring hospitalisation; however, the disease burden of RSV-associated ALRI in this population has not yet been established. Similarly, the impact of DS as an independent risk factor has not yet been quantified. We aimed therefore to estimate the incidence of admissions in children with DS, and by comparing this with unaffected children, to quantify the risk of DS independent of other risk factors.
Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, Moldt B, Khan A, Svabek C, McAuliffe JM, Wrapp D, Patel NK, Cook KE, Richter BWM, Ryan PC, Yuan AQ, Suzich JA.
Most children with severe RSV infection were previously healthy term children. Palivizumab, the only approved agent for RSV prophylaxis, is limited to high-risk infants, and the cost associated with the requirement for dosing throughout the RSV season makes its use impractical for all infants. This paper describes the development of a monoclonal antibody as potential RSV prophylaxis for all infants with a single intramuscular dose. MEDI8897 has >50-fold higher activity than palivizumab. More than threefold increased half-life. Considering the half-life its use may be an option to protect all infants from RSV disease with once-per-RSV-season dosing.
Heikkinen T, Ojala E, Waris M.
We analyzed the burden of RSV in a prospective cohort study of children aged ≤13 years during two consecutive respiratory seasons in Turku, Finland (2231 child-seasons of follow-up). Of 6001 medically attended respiratory infections, 302 (5%) were caused by RSV. Per 1000 children, the average annual RSV incidence rates among children aged <3, 3-6, and 7-13 years were 275, 117, and 46, respectively. In children aged <3 years, acute otitis media developed in 58%, and 66% of children in this age group received antibiotics. The mean duration of RSV illness was longest (13.0 days) and the rate of parental work absenteeism highest (136 days per 100 children with RSV) in children aged <3 years. The burden of RSV is particularly great among outpatient children aged <3 years, and young children are an important target group for the development of RSV vaccines and antivirals.