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.
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