Alejandro Diaz-Diaz, Cristina Garcia-Maurino, Alejandro Jordan-Villegas, Jeffrey Naples, Octavio Ramilo and Asuncion Mejias
Antimicrobial resistance (AMR) is one of the biggest threats to mankind. It is related to massive use of antibiotics for bacterial infection, in particular respiratory infections. Antibiotics are also used, often unnecessary in case of respiratory viral infections, including RSV infection. However, recent studies suggest that the complex interaction between the respiratory microbiome, the host’s immune response and the virus may have an impact on the pathogenesis and severity of RSV infection. in this paper Diaz-Diaz elegantly reviews the more complex role of potentially protective and pathogenic airway bacteria in patients with RSV infection. Diaz-Diaz et al summarize the current evidence regarding the epidemiologic link, the mechanisms of viral–bacterial interactions, and the associations between the upper respiratory tract microbiome and RSV disease severity. This paper shows that we need to address the complex interplay between RSV infection and the airway microbiome to optimize use of antibiotics and, thereby, improve the short-term and long-term outcome of children with RSV infection.
A landscape review of the published research output relating to respiratory syncytial virus (RSV) in North & Central America and Europe between 2011-2015
Amir Kirolos, Alex Christides, Shiau Xian, Rachel Reeves, Harish Nair, Harry Campbell
The high disease burden of respiratory syncytial virus (RSV) infection and renewed focus on developing a vaccine has led to sustained interest in published RSV-related research. The majority of this research comes from Europe and North/Central America and this landscape review aimed to identify and characterize RSV-related research published during 2011-2015 in these geographical areas.
This review identifies key regions and research institutionswhich contributed to RSV-related research during 2011-2015 as well as the donor agencies which supported this research. Further research investment is required in a number of countries. More research in theelderly and in high-risk adults is required given the lack of studies per- taining to these populations. Researchers and those commissioning re- search can use the data from this review to identify productive research institutions and geographical gaps in RSV research.
Jessica Marcandalli, Brooke Fiala, Sebastian Ols, Karin Loré, Laurent Perez, Neil P. King
Self-assembling proteins are promising inducers of a strong antibody response, because they enable multivalent antigen presentation. Jessica Marcandalli and colleagues designed such a self-assembling protein nanoparticle vaccine, based on prefusion-stabilized RSV-F antigen. It is a computational vaccine that consists of multiple nanoparticles fused to 20 pre-F trimers, resulting in a high density of pre-F antigens. The study shows a 10 fold higher neutralizing antibody response in mice and non-human primates, compared to the response to trimeric form of RSV-pre-F protein.
Marcandalli et al. hereby offer a new do-it-yourself protocol to customize RSV structure-based vaccines. With this ever expanding RSV vaccine development - toolbox we are getting closer to finding a suitable RSV-vaccine every day.
Pou C, Nkulikiyimfura D, Henckel E, Olin A, Lakshmikanth T, Mikes J, Wang J, Chen Y, Bernardsson AK, Gustafsson A, Bohlin K, Brodin P.
Virscan is a novel diagnostic tool to measure antibodies against >1000 viral strains. It shows previous viral exposures of an individual person. Christian Pou and colleagues used Virscan to get understand antibody transfer from mothers to their infants. The authors compared the antibody repertoire against RSV, amongst other viruses, of preterm and term infants. Despite a higher IgG concentration in term infants, both groups had the same antibody repertoire. Furthermore, the RSV-neutralizing capacity in plasma of preterm and term infants did not differ. This is surprising because it’s is generally accepted that maternal antibody transfer occurs in the third trimester, and that extremely premature children lack this passive immunity and therefor are more prone to develop RSV. It’s fascinating that preterm infants would have the same repertoire and functionally active RSV-antibodies as term infants. Nevertheless, it leaves us with the question what the precise role is of maternal RSV antibodies in RSV immunity in preterm infants. As the number of participants in this complex study was low, future research should aim to confirm these findings and help us understand transfer of specific vaccine-induced antibodies.
Barlotta A, Pirillo P, Stocchero M, Donato F, Giordano G, Bont L, Zanconato S, Carraro S and Baraldi E.
Background. Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing.
Methods. Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchi- olitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses.
Results. We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physi- cian-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children.
Conclusion. This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing.
Keywords. Bronchiolitis; metabolomics; pediatrics; recurrent wheezing; urine; mass spectrometry; citric acid cycle.
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.