Neutrophil-endothelial interactions in respiratory syncytial virus bronchiolitis, a potential for prediction of severity of disease?
Amadu Juliana, Rens Zonneveld, Frans B. Plötz, Matthijs van Meurs, Jan Wilsschute
The exact molecular mechanism of neutrophil migration into the airway in respiratorysyncytial virus (RSV) infection is little studied.This paper reviews the to date evidence of activation of endothelial cells and neutrophils, interaction of neutrophils with endothelial cells and migration across endothelial cells in Respiratory Syncytial Virus (RSV) infection. In addition, the possible clinical relevance of systemically measurable soluble endothelial adhesion molecules is reviewed. The limited number of studies showed increased levels of soluble cell adhesion molecules (CAMs) in RSV LRTI but could not assess associations of soluble CAM levels with clinical outcomes.
Finally, this paper describes the to date evidence for the deleterious effects of neutrophils in RSV infection. Juliana at al. describe how massive influx of neutrophils also causes damage and consequently more symptoms. Assuming that there is a massive efflux of neutrophils into the lungs with subsequent endothelial and epithelial damage, and that this is the basis for severe disease, the authors propose larger studies and simultaneous measurements of markers of neutrophil and endothelial activation and integrity for prediction of severe disease.
A phase 2, randomized, double-blind, placebo-controlled trial of presatovir for the treatment of respiratory syncytial virus upper respiratory tract infection in hematopoietic-cell transplant recipients
Chemaly RF, Dadwal SS, Bergeron A, Ljungman P, Kim YJ, Cheng GS, Pipavath SN, Limaye AP, Blanchard E, Winston DJ, Stiff PJ, Zuckerman T, Lachance S, Rahav G, Small CB, Mullane KM, Patron RL, Lee DG, Hirsch HH, Waghmare A, McKevitt M, Jordan R, Guo Y, German P, Porter DP, Gossage DL, Watkins TR, Marty FM, Chien JW, Boeckh M.
RSV treatment options are currently limited, and various RSV antivirals are currently under clinical development. Presatovir (GS-5806) is an oral RSV fusion inhibitor with potent and selective anti-RSV activity in vitro and a terminal half-life of ~34 hours. During a human challenge study, presatovir reduced RSV viral load and severity of clinical disease. A phase 2, randomized, double-blind, placebo-controlled trial was conducted to assess the safety, tolerability and efficacy of presatovir among HCT patients with RSV upper respiratory tract infection (URTI). In total, 189 patients with diagnosed RSV URTI ≤6 days and without new abnormalities on a chest X-ray <48 hours before start of study treatment were recruited. Patients received presatovir 2000 mg (4 x 50 mg tablets) or placebo orally or by nasogastric tube on days 1, 5, 9, 13, and 17, and were followed through day 28. Presatovir had a favorable safety profile, but the co-primary endpoints (time-weighted average change in nasal viral load between day 1-9 and proportion of patients that developed lower respiratory tract complications between day 1-28) were not achieved. However, in a post-hoc exploratory analysis, significantly more patients with lymphopenia (<200 cells/µL) developed lower respiratory tract complications in the placebo group. This interesting finding suggests that antiviral treatment might be beneficial in RSV URTI patients with most severe T-cell defect to prevent deterioration to severe lower respiratory tract infection (LRTI).
This summary is written by Yvette Lowensteyn
Ruth A. Karron, Cindy Luongo, Jocelyn San Mateo, Kimberli Wanionek, Peter L. Collins, Ursula J. Buchholz, and the RSVPed Team
The RSV/NS2/1313/I1314L is an intranasal vaccine that contains two attenuating elements in the RSV strain: deletion of the NS2 gene and deletion of the codon 1313. The deletions are stabilized with the substitution of isoleucine at codon 1314. This vaccine induced an immunogenic response in nonhuman primates. A phase 1 double-blind, randomized, placebo-controlled trial was conducted at the Center for Immunization Research (CIR) between 2013 and 2018 in RSV-seronegative and RSV-seropositive children aged 12-59 months. RSV-seronegative children received a single dose of 10 5 or 10 6 PFU and RSV-seropositive children received a single dose of 10 6 PFU. The authors demonstrated that none of the RSV-seropositive children had a ≥4-fold rise in RSV F serum IgG titer. By contrast, 53% of RSV-seronegative children who received 10 5 PFU, developed RSV neutralizing antibodies and F
IgG responses. In RSV-seronegative children receiving 10 6 PFU, even 80% developed RSV neutralizing antibodies and a similar rise in RSV-F IgG antibodies. This indicates that the RSV vaccine is a proper and genetically stable candidate in RSV-seronegative children, which deserves further clinical evaluation in seronegative children.
This review was written by Safia Laqqa under the supervision of Louis Bont
Tang A, Chen Z, Cox KS, Su HP, Callahan C, Fridman A, Zhang L, Patel SB, Cejas PJ, Swoyer R, Touch S, Citron MP, Govindarajan D, Luo B, Eddins M, Reid JC, Soisson SM, Galli J, Wang D, Wen Z, Heidecker GW, Casimiro DR, DiStefano DJ & Vora KA.
RB1 is a human monoclonal antibody that binds to site IV of the RSV F glycoprotein and is 50 times more potent than palivizumab. Tang and colleagues describe the crystal structure of RB1 and how it recognizes both RSV preF and RSV postF. They show that natural resistance occurs in less than one percent of more than 3000 isolates available in GenBank. The authors also demonstrate excellent neutralization of clinical isolates. RB1 is different from MEDI8897 because it binds to another site of RSV F, it recognized both preF and postF and appears to have a lower frequency of natural resistant clinical isolates. MK-1654 is an extended half-life version of RB1 (half-life 70-85 days) by introduction of a YTE mutation of the Fc part of the antibody. Merck is aims to develop MK-1654 for use in preterm as well as term children. The results of a phase 1-2 trial are expected in 2022 (www.clinicaltrials.gov). This paper shows that MK-1654 as the potential to be developed as a universal RSV passive immunization solution.
Crank MC, Ruckwardt TJ, Chen M, Morabito1 KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Kumar A, Chang LA, Moin SM, Hill JP, DiPiazza AT, Schwartz RM, Kueltzo1 L, Cooper JW, Chen P, Stein JA, Carlton1 K, Gall JG, Nason MC, Kwong PD, Chen1 GL, Mascola JR,McLellan JS, Ledgerwood JE, Graham BS, the VRC 317 Study Team
This RSV subunit vaccine has smoothly passed the first hurdle in clinical development. DS-Cav1 is stabilized trimer of the prefusion conformation of the RSV-F protein. The vaccine was clinically evaluated by the same researchers of the Vaccine Research Center (VRC) of the Nation Institute of Health (NIH) only a few years after demonstrating the existence of the prefusion and postfusion RSV-F variants. Immunogenicity of this apparently safe vaccine was tested in a diverse group of 40 healthy adults up to 12 weeks after vaccination. Remarkably, the vaccine resulted in an increase in neutralization that was larger than the increase in binding to RSV F. Twelve weeks after vaccination, neutralization of RSV A was still increased 5 to 10-fold, while a 3 to 5-fold increase in RSV B neutralization was observed. The boost of neutralization was mediated by antibodies against preF and shared pre/post F epitopes, but not by antibodies against epitopes only present at postF. Using preF and postF probes, the authors show that the vaccine elicits a boost in memory preF B-cells, but not postF B-cells. Taken together, DS-Cav1 shows superiority to previous subunit vaccines by inducing higher levels of neutralizing antibodies with a relatively low induction of non-neutralizing antibodies.
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.