Sánchez Luna M, Manzoni P, Paes B, Baraldi E, Cossey V, Kugelman A, Chawla R, Dotta A, Rodríguez Fernández R, Resch B, Carbonell-Estrany X.
Respiratory syncytial virus (RSV) infection is a leading cause of hospitalisation in early childhood and palivizumab is the only licensed intervention for prevention. Palivizumab guidelines should reflect the latest evidence, in addition to costs-effectiveness and healthcare budgetary considerations. RSV experts from Europe, Canada and Israel undertook a systematic review of the evidence over the last 5 years and developed recommendations regarding prophylaxis in industrialised countries. Almost 400 publications were reviewed. This group recommended palivizumab for: preterm infants (<29 and ≤31 weeks gestational age [wGA] and ≤9 and ≤6 months of age, respectively; high-risk 32-35 wGA), former preterm children ≤24 months with chronic lung disease/bronchopulmonary dysplasia, children ≤24 months with significant congenital heart disease; and other high-risk populations, such as children ≤24 months with Down syndrome, pulmonary/neuromuscular disorders, immunocompromised, and cystic fibrosis. Up to 5 monthly doses should be administered over the RSV season. It is our impression that the adoption of these guidelines would help reduce the burden of RSV.
Ascough S, Vlachantoni I, Kalyan M, Haijema BJ, Wallin- Weber S, Dijkstra-Tiekstra M, Ahmed MS, Roosmalen M van, Grimaldi R, Zhang Q, Leenhouts K, Openshaw PJ and Chiu C.
Despite numerous years of research we are still lacking a safe and effective RSV vaccine. This process is hindered by numerous problems: the lack of a correlate of protection being one of them.That this has major consequences for vaccine development, is illustrated by the study performed by Stephanie Ascough, Peter Openshaw and colleagues. In their paper they describe the results of a randomized controlled, phase 1 trial of a novel needle-free RSV vaccine: SynGEM. The vaccine is based on a stable pre-fusion F antigen of the virus, and uses a bacterium-like-particle (BLP) as an immune-enhancing carrier. The study confirms that the vaccine is safe and that it is capable of inducing a mild (about 2 to 3-fold), but prolonged, increase in RSV-specific antibodies. However, the study didn’t reach the endpoint threshold and for now, SynGEM is withheld from proceeding to next phase trials.
This study illustrates, that the lack of a correlate of protection brings an uncertainty to the table, which could lead to the premature termination of a potentially effective RSV vaccine. The use of a human challenge model (HCM) in RSV vaccine development would offer the possibility to circumvent this insecurity. Furthermore it might accelerate RSV-vaccine development.
Written by Sjanna Besteman
Sachs N, Papaspyropoulos A, Zomer-van Ommen DD, Heo I, Böttinger L, Klay D, Weeber Huelsz-Prince FG, Iakobachvili N, Amatngalim GD, Ligt de J , Hoeck van A , Proost N, Viveen MC, Lyubimova A, Teeven L, Derakhshan S, Korving J, Begthel H, Dekkers JF, Kumawat K, Ramos E, Oosterhout van MFM, Offerhaus GJ, Wiener DJ, Olimpio EP, Dijkstra KK, Smit EF, Linden van der M, Jaksani S, Ven van de M, Jonkers J , Rios AC, Voest EE, Moorsel van CHM, Ent van der CK, Cuppen E , Oudenaarden van A, Coenjaerts FE, Meyaard L, Bont LJ, Peters PJ, Tans SJ, Zon van JS, Boj SF, Vries RG, Beekman JM & Clevers H.
Sachs from UMC Utrecht developed human airway organoids (miniature lungs) that offer the possibility to study RSV in an human in vitro model. The authors show that RSV replicates well in human airway organoids and that infection can be inhibited after pre-treatment with palivizumab. Furthermore, RSV caused epithelial changes that mimic disease characteristics such as epithelial shedding, syncytia formation and alterations of the cytoskeleton. Also, there was an upregulation of antiviral genes and an enhanced secretion of cytokines such as IP-10. Both of these findings reflect the immune responses following RSV infection in infants. Lastly, human airway organoids offer the possibility to study the interaction between immune cells and the RSV infected epithelium. The latter is of major importance to increase the knowledge on RSV immune signalling.
Altogether, RSV – infected airway organoids offer the possibility to study numerous aspects of RSV disease, including airway remodelling, immune cell interaction and treatment possibilities.
Written by Sjanna Besteman
Severe Morbidity And Mortality Associated With Respiratory Syncytial Virus Versus Influenza Infection In Hospitalized Older Adults
Ackerson B, Tseng HF, Sy LS, Solano Z, Slezak J, Luo Y, Fischetti CA, Shinde V
A large cohort of adults >=60 years hospitalised with laboratory confirmed RSV or influenza infection during 5 consecutive seasons were investigated. The study showed that older adults hospitalised with RSV were slightly older and more likely to have baseline co-morbidity conditions than those with influenza. Regarding hospitalisation outcome, they had longer length of hospital stay, greater odds of pneumonia, ICU admission, COPD exacerbation, chronic bronchiolitis, emphysema and one-year mortality than those with influenza, even after adjustment for baseline comorbidities. This might reflect the increased use of antiviral therapies for influenza in recent years and differences of clinical severity in RSV and influenza infection. The findings highlight the substantial morbidity and mortality associated with RSV infection in hospital settings in the expanding population of older adults who could benefit from RSV vaccines and antivirals
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.