Habibi MS, Thwaites RS, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel TT, Moffatt MF, Johansson C, Chiu C, Openshaw PJM
Why does RSV exposure in one individual lead to disease, while another individual does not experience symptoms at all? Besides, how can a virus reinfect individuals that already have a specific viral immune response available? In this Science paper, Habibi and his colleagues present mucosal neutrophil activation as a new factor involved in RSV susceptibility and protection. They studied the nasal mucosa by transcriptional and proteomic analyses in 58 healthy volunteers right before RSV inoculation and during the following days of infection. An active neutrophilic inflammatory status in the airways at the time of viral exposure was found to predispose to symptomatic infection. This effect might be mediated by a reduction in antiviral inflammatory responses directly after viral exposure. In addition, an early immune response to the infection with enriched IL-17 signaling and corresponding pathways was associated with protection from RSV-related symptoms. Further experiments in mice showed that chemokine induced neutrophil recruitment to the airway before viral exposure enhances disease severity and leads to an elevated cytotoxic CD8+ T cell response. These findings shed light on mechanisms of viral susceptibility and suggest new targets for RSV intervention. Furthermore, neutrophilic inflammation of the airways might not only be important in RSV infection, but in other viral respiratory diseases as well, such as in the SARS-CoV-2 infection.
Karron RA, Atwell JE, McFarland EJ, Cunningham CK, Muresan P, Perlowski C, Libous J, Spector SA, Yogev R, Aziz M, Woods S, Wanionek K, Collins PL, Buchholz UJ
Live-attenuated RSV vaccines are probably effective in young children. This is an important conclusion from Ruth Karron and co-workers after analyzing data from seven previous trials. According to the PATH snapshot of RSV vaccines, there are seven live-attenuated RSV vaccines in phase 1 clinical trials while none have progressed into phase 2. Karron showed that RSV positive respiratory infections requiring medical attention were reduced by 67% after receiving one of the more promising vaccines in this analysis of past phase I clinical trials. The authors combined data from previous live-attenuated vaccine candidates administered intranasally to 241 children aged 6 to 24 months in total. Five of seven vaccines, referred to as “more promising”, induced a ≥4-fold increase of neutralizing antibodies titers in at least 80% of recipients. Antibody titers of vaccinated children increased by more than 14-fold after being later exposed to wild-type RSV, indicating a substantial memory immune response. While high antibody titers likely reflect a good immune response overall and do not act alone to protect against RSV, one dose might be sufficient to protect infants during RSV season. Based on this study, intranasal live-attenuated vaccines have substantial potential to protects young children after the protection granted by maternal antibodies wears off. It is time for a phase 2 proof-of-concept study demonstrating the full potential of live-attenuated RSV vaccines in young infants.
Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, Simões EAF, Swamy GK, Agrawal S, Ahmed K, August A, Baqui AH, Calvert A, Chen J, Cho I, Cotton MF, Cutland CL, Englund JA, Fix A, Gonik B, Hammitt L, Heath PT, de Jesus JN, Jones CE, Khalil A, Kimberlin DW, Libster R, Llapur CJ, Lucero M, Pérez Marc G, Marshall HS, Masenya MS, Martinón‐Torres F, Meece JK, Nolan TM, Osman A, Perrett KP, Plested JS, Richmond PC, Snape MD, Shakib JH, Shinde V, Stoney T, Thomas DN, Tita AT, Varner MW, Vatish M, Vrbicky K, Wen J, Zaman K, Zar HJ, Glenn GM, and Fries LF, for the Prepare Study Group
Novavax shows an almost 40% reduction in medically significant RSV-associated LRTIs, in their phase 3 randomized controlled trial with the support of the Bill and Melinda Gates foundation. They recruited healthy pregnant women, at 28 weeks through 36 weeks of gestation, before the start of the RSV season. They were randomly assigned with an overall 2:1 ratio to receive a RSV fusion (F) protein nanoparticle vaccine or placebo. In total, 4636 women were enrolled. The vaccine was safe, with a percentage of infants with a RSV-associated, medically significant lower respiratory tract infection of 1.5% in the vaccine group versus 2.4% in the placebo group (vaccine efficacy was 39.4%). This difference was not sufficient according to FDA-required prespecified criteria of vaccine efficacy. Interestingly, in the vaccine group RSV-related hospitalisations and all-cause pneumonia were significantly reduced by 44% and approx. 50%, respectively. Adding to that, a higher vaccine efficacy was seen in low- or middle-income countries (LMIC), where prevention of RSV is most needed. An explanation for the differential effect in high income countries versus LMIC is still being sought. For now, the faith of the first safe and efficacious RSV vaccine remains uncertain.
This summary is written by Roy Zuurbier
Sesterhenn F, Yang C, Bonet J, Cramer JT, Wen X, Wang Y, Chiang CI, Abriata LA, Kucharska I, Castoro G, Vollers SS, Galloux M, Dheilly E, Rosset S, Corthésy P, Georgeon S, Villard M, Richard CA, Descamps D, Delgado T, Oricchio E,
Rameix-Welti MA, Más V, Ervin S, Eléouët JF, Riffault S, Bates JT, Julien JP, Li Y, Jardetzky T, Krey T, Correia BE
You can make your own computationally designed protein-based vaccine using TopoBuilder, a protein design algorithm. Sesterhenn and colleagues made a stable RSV F protein in prefusion conformation. They showed that this engineered protein was immunogenic in mice and induced neutralizing antibodies in non-human primates using prime-boost schemes. Neutralizing antibody levels was at least as high as palivizumab concentrations known to be protective. The vaccine may now be further developed. Obviously, this technology which allows generating vaccines against other pathogens has a promising future.
Mueller S, Stauft CB, Kalkeri R, Koidei F, Kushnir A, Tasker S, Coleman JR.
A novel codon-deoptimized RSV vaccine protected African Green Monkeys against viral replication and induced neutralizing antibodies as well as cellular IFNg response against RSV. Deoptimized vaccines are generated in vitro with the aim to impair replication in human cells through multiple synonymous codon changes. The idea is that the amino acid order is not changed. The vaccine was tested in African Green Monkeys challenged with RSV A2. Replication of MinL4.0 was decreased a 100-fold compared to wild-type A2. Anectodally, the investigators report that there was one animal with preexistent neutralizing antibodies who still responded to MinL4.0 suggesting the vaccine can be used in exposed individuals. The vaccine has been developed by Codagenix Inc with support of NIAID. The vaccine will now be tested as a mucosal vaccine in humans.
Cicconi P, Jones C, Sarkar E, Silva-Reyes L, Klenerman P, de Lara C, Hutchings C, Moris P, Janssens M, Lisette LA, Picciolato M, Leach A, Gonzalez-Lopez A, Dieussaert I and D.Snap M.
This paper presents the results of a novel chimpanzee-derived replication-deficient adenoviral vector vaccine against RSV (ChAd155-RSV), based on 3 RSV viral proteins including F (fusion), N(nucleocapsid), and M2-1 (antitermination). Although the intended use is in the infant population, this phase 1 first-in-human study aimed to investigate safety, reactogenicity, and immunogenicity of ChAd155-RSV in healthy adults aged 18–45 years. Adenoviral vector vaccines have shown to be able to elicit long-term cellular and humoral immune responses and are efficient in delivering foreign antigens into host cells. Although potent, the immune response elicited by this type of vaccine is dependent on the recipient’s immune status. While ChAd155-RSV antibodies could decrease the overall efficacy of the vaccine and preexisting anti-RSV NAb could mask the humoral response, a vaccine response was seen in about 60% of the high-dosage group and 20% in the low-dosage group. The key value of this study is confirmation of the ability of viral vector vaccines to intrinsically promote a combined cellular and humoral immune response to one of the most important pathogens in infancy. With low levels of preexisting antibodies against both RSV and adenovirus in the pediatric population, the potency of these vaccines in eliciting a vaccine response may be higher compared to the adult population.
Uusitupa E, Waris M, Heikkinen T.
Over the past years results on the associations between RSV loads and severe manifestations of the RSV illness were contradictory. Nevertheless, association between viral load and severity of illness in contributive for the use of antivirals in RSV disease. Heikkinen and colleagues conducted a prospective cohort study of respiratory outpatient naturally infected children. During each episode of respiratory illness, children were clinically examined, nasal swaps for virus sampling were taken and daily symptoms were recorded. In 201 new onset RSV infections, Heikkinen and colleagues show that children with higher viral load had significantly longer durations of respiratory compared to children with lower viral load. The findings in this largest outpatient study so far on this topic, support the concept that viral load drives the severity of RSV disease in children. RSV infected children might benefit of the reduction of RSV viral load by RSV antivirals.
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