RÉSUMÉ
Objective: This study compared clinical and immunological responses to coinfection challenge of beef calves mucosally primed and differentially boosted with commercial combination vaccines containing antigens against bovine coronavirus (BCoV), bovine parainfluenza virus Type 3 (BPIV3), and bovine respiratory syncytial virus (BRSV). Animals: Nineteen commercial beef heifers. Procedure: At birth, calves were mucosally (IN) primed with modified-live virus (MLV) vaccines, differentially boosted by injection of either combination MLV (IN-MLV) or inactivated virus (IN-KV) vaccines at a mean age of 44 d, and then challenged by coinfection with BCoV, BPIV3, and BRSV at weaning. Results: Both groups were similarly protected from clinical disease and had anamnestic neutralizing antibody responses to all 3 viruses. The IN-KV group shed more BCoV, and less BPIV3 and BRSV, than the IN-MLV group. Conclusion: These data indicated similar clinical and immunological protection between IN-MLV and IN-KV; however, shed of virus varied. Clinical relevance: Whereas boosting with KV or MLV appeared to have similar efficacy, viral shed differences may affect disease control.
Efficacité comparative des vaccins vivants modifiés et inactivés pour stimuler les réponses au virus respiratoire syncytial bovin, au virus parainfluenza bovin de type 3 et au coronavirus bovin après amorçage via la muqueuse de veaux de boucherie nouveau-nés. Objectif: Cette étude a comparé les réponses cliniques et immunologiques à une co-infection de veaux de boucherie amorcés par voie muqueuse et différentiellement stimulés avec des vaccins combinés commerciaux contenant des antigènes contre le coronavirus bovin (BCoV), le virus parainfluenza bovin de type 3 (BPIV3) et le virus respiratoire syncytial bovin (BRSV). Animaux: Dix-neuf génisses de boucherie commerciales. Procédure: À la naissance, les veaux ont été vaccinés au niveau des muqueuses (IN) avec des vaccins à virus vivants modifiés (MLV), stimulés de manière différentielle par l'injection de vaccins combinés MLV (IN-MLV) ou de virus inactivés (IN-KV) à un âge moyen de 44 jours. puis provoqué par une co-infection avec BCoV, BPIV3 et BRSV au sevrage. Résultats: Les deux groupes étaient protégés de la même manière contre la maladie clinique et présentaient des réponses anamnestiques en anticorps neutralisants contre les 3 virus. Le groupe IN-KV a excrété plus de BCoV et moins de BPIV3 et de BRSV que le groupe IN-MLV. Conclusion: Ces données indiquent une protection clinique et immunologique similaire entre IN-MLV et IN-KV; cependant, l'excrétion du virus variait. Pertinence clinique: Alors que le rappel avec KV ou MLV semble avoir une efficacité similaire, les différences d'excrétion virale peuvent affecter la limitation de la maladie.(Traduit par Dr Serge Messier).
Sujet(s)
Animaux nouveau-nés , Maladies des bovins , Coronavirus bovin , Virus parainfluenza bovin de type 3 , Infections à virus respiratoire syncytial , Virus respiratoire syncytial bovin , Vaccins inactivés , Vaccins antiviraux , Animaux , Bovins , Coronavirus bovin/immunologie , Virus parainfluenza bovin de type 3/immunologie , Virus respiratoire syncytial bovin/immunologie , Maladies des bovins/prévention et contrôle , Maladies des bovins/virologie , Maladies des bovins/immunologie , Femelle , Vaccins inactivés/immunologie , Vaccins inactivés/administration et posologie , Infections à virus respiratoire syncytial/médecine vétérinaire , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins antiviraux/immunologie , Vaccins antiviraux/administration et posologie , Animaux nouveau-nés/immunologie , Infections à coronavirus/médecine vétérinaire , Infections à coronavirus/prévention et contrôle , Infections à coronavirus/immunologie , Infections à coronavirus/virologie , Anticorps antiviraux/sang , Vaccins atténués/immunologie , Vaccins atténués/administration et posologie , Infections à respirovirus/médecine vétérinaire , Infections à respirovirus/prévention et contrôle , Infections à respirovirus/immunologie , Rappel de vaccin/médecine vétérinaireRÉSUMÉ
Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We hypothesized that disulfides restricting the initial stages of the conformational switch could offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides that supported our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.
Sujet(s)
Disulfures , Protéines de fusion virale , Disulfures/composition chimique , Animaux , Protéines de fusion virale/immunologie , Protéines de fusion virale/composition chimique , Humains , Infections à virus respiratoire syncytial/immunologie , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/virologie , Stabilité protéique , Conception assistée par ordinateur , Conformation des protéines , Virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Rats , Modèles moléculairesRÉSUMÉ
The Ad26.RSV.preF/RSV preF protein vaccine has previously demonstrated efficacyin protecting older adults against respiratory syncytial virus (RSV)-related lower respiratory tract disease in a phase 2b study. This study compared the immunogenicity of vaccine clinical trial material (CTM) representative of phase 2b clinical studies with CTM used in phase 3 clinical studies. A total of 248 adults aged 60-75 years, randomized in a 1:1 ratio, received one dose of either phase 3 CTM or phase 2b CTM. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-d, 28-d, and 6-month periods post-vaccination, respectively. RSV preF-ELISA antibody titers and RSV neutralizing titers were measured before and 14 d after vaccination. The phase 3 CTM-induced preF-ELISA response at Day 15, in terms of geometric mean titer, was shown to be non-inferior to that induced by phase 2b CTM. The RSV neutralizing antibody titers were also similar in the two groups at Day 15. The safety profile in terms of solicited AEs, unsolicited AEs, or SAEs was in general similar between the phase 3 CTM and phase 2b CTM groups, and solicited AEs were mostly mild to moderate in intensity. No related SAEs were reported, and no safety concerns were identified.
Sujet(s)
Anticorps neutralisants , Anticorps antiviraux , Vaccins contre les virus respiratoires syncytiaux , Humains , Adulte d'âge moyen , Sujet âgé , Mâle , Femelle , Anticorps antiviraux/sang , Anticorps neutralisants/sang , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/effets indésirables , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Immunogénicité des vaccins , Test ELISA , Virus respiratoire syncytial humain/immunologie , Effets secondaires indésirables des médicaments/épidémiologieRÉSUMÉ
RSV infection remains a serious threat to the children all over the world, especially, in the low-middle income countries. Vaccine delivery via the mucosa holds great potential for inducing local immune responses in the respiratory tract. Previously, we reported the development of highly immunogenic RSV virus-like-particles (RSV-VLPs) based on the conformationally stable prefusogenic-F protein (preFg), glycoprotein and matrix protein. Here, to explore whether mucosal delivery of RSV-VLPs is an effective strategy to induce RSV-specific mucosal and systemic immunity, RSV-VLPs were administered via the nasal, sublingual and pulmonary routes to BALB/c mice. The results demonstrate that immunization with the VLPs via the mucosal routes induced minimal mucosal response and yet facilitated modest levels of serum IgG antibodies, enhanced T cell responses and the expression of the lung-homing marker CXCR3 on splenocytes. Immunization with VLPs via all three mucosal routes provided protection against RSV challenge with no signs of RSV induced pathology.
Sujet(s)
Anticorps antiviraux , Souris de lignée BALB C , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Vaccins à pseudo-particules virales , Protéines de fusion virale , Protéines de la matrice virale , Animaux , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Souris , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Vaccins à pseudo-particules virales/immunologie , Vaccins à pseudo-particules virales/administration et posologie , Protéines de fusion virale/immunologie , Protéines de fusion virale/génétique , Protéines de fusion virale/administration et posologie , Femelle , Protéines de la matrice virale/immunologie , Protéines de la matrice virale/administration et posologie , Protéines de la matrice virale/génétique , Immunité muqueuse , Immunoglobuline G/sang , Immunoglobuline G/immunologie , Virus respiratoire syncytial humain/immunologie , Poumon/virologie , Poumon/immunologie , Glycoprotéines/immunologie , Glycoprotéines/administration et posologie , Administration par voie muqueuse , Virus respiratoires syncytiaux/immunologie , Lymphocytes T/immunologieRÉSUMÉ
BACKGROUND: The key correlate of protection of respiratory syncytial virus (RSV) vaccines and monoclonal antibodies (mAbs) is virus neutralization, measured via sera obtained through venipuncture. Dried blood obtained with a finger prick can simplify acquisition, processing, storage, and transport in trials and thereby reduce costs. In this study, we validate an assay to measure RSV neutralization in dried capillary blood. METHODS: Functional antibodies were compared between matched serum and dried blood samples from a phase 1 trial with RSM01, an investigational anti-RSV prefusion F mAb. Hep-2 cells were infected with a serial dilution of sample-virus mixture by using RSV-A2-mKate to determine the half-maximal inhibitory concentration. Stability of dried blood was evaluated over time and during temperature stress. RESULTS: Functional antibodies in dried blood were highly correlated with serum (R2 = 0.98, P < .0001). The precision of the assay for dried blood was similar to serum. The function of mAb remained stable for 9 months at room temperature and frozen dried blood samples. CONCLUSIONS: We demonstrated the feasibility of measuring RSV neutralization using dried blood as a patient-centered solution that may replace serology testing in trials against RSV or other viruses, such as influenza and SARS-CoV-2. Clinical Trials Registration. NCT05118386 (ClinicalTrials.gov).
Sujet(s)
Anticorps neutralisants , Anticorps antiviraux , Infections à virus respiratoire syncytial , Virus respiratoire syncytial humain , Humains , Anticorps neutralisants/sang , Anticorps neutralisants/immunologie , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Virus respiratoire syncytial humain/immunologie , Infections à virus respiratoire syncytial/immunologie , Dépistage sur goutte de sang séché/méthodes , Tests de neutralisation/méthodes , Anticorps monoclonaux/immunologieRÉSUMÉ
Background: Follicular helper T cells (Tfh) are pivotal in B cell responses. Activation of the purinergic receptor P2X7 on Tfh cells regulates their activity. We investigated the ATP-P2X7R axis in circulating Tfh (cTfh) cells during Respiratory Syncytial Virus (RSV) infection. Methods: We analyzed two cohorts: children with RSV infection (moderate, n=30; severe, n=21) and healthy children (n=23). We utilized ELISA to quantify the levels of PreF RSV protein-specific IgG antibodies, IL-21 cytokine, and soluble P2X7R (sP2X7R) in both plasma and nasopharyngeal aspirates (NPA). Additionally, luminometry was employed to determine ATP levels in plasma, NPA and supernatant culture. The frequency of cTfh cells, P2X7R expression, and plasmablasts were assessed by flow cytometry. To evaluate apoptosis, proliferation, and IL-21 production by cTfh cells, we cultured PBMCs in the presence of Bz-ATP and/or P2X7R antagonist (KN-62) and a flow cytometry analysis was performed. Results: In children with severe RSV disease, we observed diminished titers of neutralizing anti-PreF IgG antibodies. Additionally, severe infections, compared to moderate cases, were associated with fewer cTfh cells and reduced plasma levels of IL-21. Our investigation revealed dysregulation in the ATP-P2X7R pathway during RSV infection. This was characterized by elevated ATP levels in both plasma and NPA samples, increased expression of P2X7R on cTfh cells, lower levels of sP2X7R, and heightened ATP release from PBMCs upon stimulation, particularly evident in severe cases. Importantly, ATP exposure decreased cTfh proliferative response and IL-21 production, while promoting their apoptosis. The P2X7R antagonist KN-62 mitigated these effects. Furthermore, disease severity positively correlated with ATP levels in plasma and NPA samples and inversely correlated with cTfh frequency. Conclusion: Our findings indicate that activation of the ATP-P2X7R pathway during RSV infection may contribute to limiting the cTfh cell compartment by promoting cell death and dysfunction, ultimately leading to increased disease severity.
Sujet(s)
Adénosine triphosphate , Récepteurs purinergiques P2X7 , Infections à virus respiratoire syncytial , Lymphocytes T auxiliaires folliculaires , Humains , Infections à virus respiratoire syncytial/immunologie , Infections à virus respiratoire syncytial/métabolisme , Récepteurs purinergiques P2X7/métabolisme , Adénosine triphosphate/métabolisme , Mâle , Nourrisson , Femelle , Lymphocytes T auxiliaires folliculaires/immunologie , Lymphocytes T auxiliaires folliculaires/métabolisme , Enfant d'âge préscolaire , Transduction du signal , Interleukines/métabolisme , Interleukines/immunologie , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Enfant , Virus respiratoire syncytial humain/immunologieRÉSUMÉ
BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds. METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1. RESULTS: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related. CONCLUSIONS: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov).
Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged ≥60 years during at least 1 RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until 3 years after vaccination of adults aged ≥60 years from 5 countries. Here, we report the results of an interim analysis until 1 year after vaccination with 1 dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident 1 month after vaccination, after which it declined but persisted for at least 1 year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least 1 RSV season.
Sujet(s)
Anticorps antiviraux , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Virus respiratoire syncytial humain , Humains , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Vaccins contre les virus respiratoires syncytiaux/effets indésirables , Mâle , Femelle , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Anticorps antiviraux/sang , Sujet âgé , Adulte d'âge moyen , Virus respiratoire syncytial humain/immunologie , Protéines de fusion virale/immunologie , Protéines de fusion virale/administration et posologie , Anticorps neutralisants/sang , Immunogénicité des vaccins , Sujet âgé de 80 ans ou plus , Adjuvants vaccinaux/administration et posologieRÉSUMÉ
Influenza A Virus (IAV) and Respiratory Syncytial Virus (RSV) are both responsible for millions of severe respiratory tract infections every year worldwide. Effective vaccines able to prevent transmission and severe disease, are important measures to reduce the burden for the global health system. Despite the strong systemic immune responses induced upon current parental immunizations, this vaccination strategy fails to promote a robust mucosal immune response. Here, we investigated the immunogenicity and efficacy of a mucosal adenoviral vector vaccine to tackle both pathogens simultaneously at their entry site. For this purpose, BALB/c mice were immunized intranasally with adenoviral vectors (Ad) encoding the influenza-derived proteins, hemagglutinin (HA) and nucleoprotein (NP), in combination with an Ad encoding for the RSV fusion (F) protein. The mucosal combinatory vaccine induced neutralizing antibodies as well as local IgA responses against both viruses. Moreover, the vaccine elicited pulmonary CD8+ and CD4+ tissue resident memory T cells (TRM) against the immunodominant epitopes of RSV-F and IAV-NP. Furthermore, the addition of Ad-TGFß or Ad-CCL17 as mucosal adjuvant enhanced the formation of functional CD8+ TRM responses against the conserved IAV-NP. Consequently, the combinatory vaccine not only provided protection against subsequent infections with RSV, but also against heterosubtypic challenges with pH1N1 or H3N2 strains. In conclusion, we present here a potent combinatory vaccine for mucosal applications, which provides protection against two of the most relevant respiratory viruses.
Sujet(s)
Anticorps antiviraux , Immunité muqueuse , Virus de la grippe A , Vaccins antigrippaux , Souris de lignée BALB C , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Animaux , Souris , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins antigrippaux/immunologie , Vaccins antigrippaux/administration et posologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Anticorps antiviraux/immunologie , Virus de la grippe A/immunologie , Femelle , Infections à Orthomyxoviridae/immunologie , Infections à Orthomyxoviridae/prévention et contrôle , Virus respiratoires syncytiaux/immunologie , Anticorps neutralisants/immunologie , Anticorps neutralisants/sang , Vaccins combinés/immunologie , Vaccins combinés/administration et posologie , Humains , Adenoviridae/immunologie , Adenoviridae/génétique , Vecteurs génétiquesRÉSUMÉ
Respiratory syncytial virus (RSV) remains the primary cause of lower respiratory tract infections, particularly in infants and the elderly. In this study, we employed reverse genetics to generate a chimeric influenza virus expressing neuraminidase-3F protein conjugate with three repeats of the RSV F protein protective epitope inserted into the NA gene of A/California/7/2009 ca (CA/AA ca), resulting in rFlu/RSV/NA-3F (hereafter, rFRN3). The expression of NA-3F protein was confirmed by Western blotting. The morphology and temperature-sensitive phenotype of rFRN3 were similar to CA/AA ca. Its immunogenicity and protective efficiency were evaluated in BALB/c mice and cotton rats. Intranasal administration of rFRN3 elicited robust humoral, cellular, and to some extent, mucosal immune responses. Compared to controls, rFRN3 protected animals from RSV infection, attenuated lung injury, and reduced viral titers in the nose and lungs post-RSV challenge. These results demonstrate that rFRN3 can trigger RSV-specific immune responses and thus exhibits potent protective efficacy. The "dual vaccine" approach of a cold-adapted influenza vector RSV vaccine will improve the prophylaxis of influenza and RSV infection. rFRN3 thus warrants further clinical investigations as a candidate RSV vaccine.
Sujet(s)
Anticorps antiviraux , Vecteurs génétiques , Souris de lignée BALB C , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Sigmodontinae , Animaux , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Vaccins contre les virus respiratoires syncytiaux/génétique , Femelle , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Souris , Vecteurs génétiques/génétique , Vecteurs génétiques/immunologie , Poumon/virologie , Poumon/immunologie , Poumon/anatomopathologie , Administration par voie nasale , Basse température , Vaccins synthétiques/immunologie , Vaccins synthétiques/administration et posologie , Vaccins synthétiques/génétique , Modèles animaux de maladie humaine , Protéines de fusion virale/immunologie , Protéines de fusion virale/génétique , Immunité muqueuse , , Charge viraleRÉSUMÉ
This review article will summarize the vaccines and monoclonal antibodies currently under evaluation for the prevention of RSV disease in older infants, toddlers and young children. We will review the rationale for passive protection during the first months of life, and the role of active immunization afterwards, either with live attenuated, protein-based or mRNA vaccines.
Sujet(s)
Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Humains , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Nourrisson , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/usage thérapeutique , Enfant d'âge préscolaire , Immunisation passive , Anticorps monoclonaux/usage thérapeutique , Vaccins atténués/immunologie , Virus respiratoire syncytial humain/immunologieRÉSUMÉ
Newborns and young infants are at risk for severe respiratory syncytial virus (RSV) lower respiratory tract infection. Passive immunity is the mainstay of infection prevention in this cohort. Transplacental transfer of maternal antibodies provides the newborn with immediate protection from life-threatening infections, however, is dependent upon gestational age, birth weight, mother's age, recent maternal vaccination, maternal nutritional status, maternal immunocompetence and medical conditions, and placental integrity. Efficient transplacental transfer of RSV-neutralizing antibodies have led to the development and approval of maternal RSV immunization for the protection of the newborn. Additionally, administration of RSV-specific antibodies to infants leads to high serum titers of RSV-neutralizing antibodies and further protection from severe disease.
Sujet(s)
Anticorps antiviraux , Immunité acquise d'origine maternelle , Immunisation passive , Infections à virus respiratoire syncytial , Humains , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Immunisation passive/méthodes , Nouveau-né , Nourrisson , Femelle , Anticorps antiviraux/sang , Anticorps neutralisants/sang , Anticorps neutralisants/immunologie , Virus respiratoire syncytial humain/immunologie , Grossesse , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologieSujet(s)
Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Vaccins à ARNm , Humains , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Infections à virus respiratoire syncytial/virologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Virus respiratoire syncytial humain/immunologie , États-Unis , Autorisation d'exercer , Vaccins synthétiques/immunologie , Virus respiratoires syncytiaux/immunologie , Food and Drug Administration (USA)RÉSUMÉ
Respiratory syncytial virus is the major cause of respiratory viral infections, particularly in infants, immunocompromised populations, and the elderly (over 65 years old), the prevention of RSV infection has become a priority. In this study, we generated a chimeric influenza virus, termed LAIV/RSV/HA-3F, using reverse genetics technology which contained three repeats of the RSV fusion protein neutralizing epitope site II to the N terminal in the background of the hemagglutinin (HA) gene of cold adapted influenza vaccine A/California/7/2009 ca. LAIV/RSV/HA-3F exhibited cold-adapted (ca) and attenuated (att) phenotype. BALB/c mice immunized intranasally with LAIV/RSV/HA-3F showed robust immunogenicity, inducing viral-specific antibody responses against both influenza and RSV, eliciting RSV-specific humoral, cellular and mucosal immune responses. LAIV/RSV/HA-3F also conferred protection as indicated by reduced viral titers and improved lung histopathological alterations against live RSV virus challenge. Mechanismly, single-cell RNA sequencing (scRNA-seq) and single-cell T cell antigen receptor (TCR) sequencing were employed to characterize the immune responses triggered by chimeric RSV vaccine, displaying that LAIV/RSV/HA-3F provided protection mainly via interferon-γ (IFN-γ). Moreover, we found that LAIV/RSV/HA-3F significantly inhibited viral replication in the challenged lung and protected against subsequent RSV challenge in cotton rats without causing lung disease. Taken together, our findings demonstrated that LAIV/RSV/HA-3F has potential as a promising bivalent vaccine with dual purpose candidate for the prevention of influenza and RSV, and preclinical and clinical studies warrant further investigations.
Sujet(s)
Anticorps antiviraux , Épitopes , Vaccins antigrippaux , Souris de lignée BALB C , Infections à virus respiratoire syncytial , Sigmodontinae , Protéines de fusion virale , Animaux , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins antigrippaux/immunologie , Vaccins antigrippaux/administration et posologie , Vaccins antigrippaux/génétique , Souris , Protéines de fusion virale/immunologie , Protéines de fusion virale/génétique , Épitopes/immunologie , Épitopes/génétique , Anticorps antiviraux/immunologie , Anticorps antiviraux/sang , Femelle , Virus respiratoires syncytiaux/immunologie , Virus respiratoires syncytiaux/génétique , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Poumon/virologie , Poumon/immunologie , Poumon/anatomopathologie , Humains , Basse température , Anticorps neutralisants/immunologie , Anticorps neutralisants/sang , Virus respiratoire syncytial humain/immunologie , Virus respiratoire syncytial humain/génétique , Infections à Orthomyxoviridae/prévention et contrôle , Infections à Orthomyxoviridae/immunologieRÉSUMÉ
BACKGROUND: Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. METHODS: Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. RESULTS: H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. CONCLUSIONS: H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.
Sujet(s)
Modèles animaux de maladie humaine , Monocytes , Infections à virus respiratoire syncytial , Charge virale , Animaux , Infections à virus respiratoire syncytial/immunologie , Souris , Monocytes/immunologie , Nematospiroides dubius/immunologie , Poumon/immunologie , Poumon/virologie , Infections à Strongylida/immunologie , Virus respiratoires syncytiaux/immunologie , Interféron de type I/métabolismeSujet(s)
Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Virus respiratoire syncytial humain , Humains , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/effets indésirables , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Virus respiratoire syncytial humain/immunologie , Adulte , Anticorps antiviraux/sang , Mâle , Femelle , Protéines de fusion virale/immunologie , Adulte d'âge moyen , , Jeune adulteSujet(s)
Agrément de médicaments , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Food and Drug Administration (USA) , Humains , États-Unis , Vaccins contre les virus respiratoires syncytiaux/immunologie , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , ARN messager/génétique , Vaccins synthétiques/immunologieRÉSUMÉ
Respiratory syncytial virus (RSV) infection is an acute respiratory infection caused by RSV. It occurs worldwide, and for over 50 years, several attempts have been made to research and develop vaccines to prevent RSV infection; effective preventive vaccines are eagerly awaited. The RSV fusion (F) protein, which has gained attention as a vaccine antigen, causes a dynamic structural change from the preF to postF state. Therefore, the structural changes in proteins must be regulated to produce a vaccine antigen that can efficiently induce antibodies with high virus-neutralizing activity. We successfully discovered several mutations that stabilized the antigen site Ø in the preF state, trimerized it, and improved the level of protein expression through observation and computational analysis of the RSV-F protein structure and amino acid mutation analysis of RSV strains. The four RSV-F protein mutants that resulted from the combination of these effective mutations stably conserved a wide range of preF- and trimeric preF-specific epitopes with high virus-neutralizing activity. Absorption assay using human serum revealed that mutants constructed bound to antibodies with virus-neutralizing activity that were induced by natural RSV infection, whereas they hardly bound to anti-postF antibodies without virus-neutralizing activity. Furthermore, mouse immunization demonstrated that our constructed mutants induced a high percentage of antibodies that bind to the preF-specific antigen site. These characteristics suggest that the mutants constructed can be superior vaccine antigens from the viewpoint of RSV infection prevention effect and safety.
Sujet(s)
Anticorps neutralisants , Anticorps antiviraux , Antigènes viraux , Infections à virus respiratoire syncytial , Vaccins contre les virus respiratoires syncytiaux , Protéines de fusion virale , Animaux , Humains , Protéines de fusion virale/immunologie , Protéines de fusion virale/génétique , Vaccins contre les virus respiratoires syncytiaux/immunologie , Vaccins contre les virus respiratoires syncytiaux/génétique , Vaccins contre les virus respiratoires syncytiaux/administration et posologie , Souris , Anticorps antiviraux/immunologie , Infections à virus respiratoire syncytial/prévention et contrôle , Infections à virus respiratoire syncytial/immunologie , Anticorps neutralisants/immunologie , Antigènes viraux/immunologie , Antigènes viraux/génétique , Mutation , Épitopes/immunologie , Épitopes/génétique , Virus respiratoire syncytial humain/immunologie , Virus respiratoire syncytial humain/génétique , Souris de lignée BALB C , Virus respiratoires syncytiaux/immunologie , Virus respiratoires syncytiaux/génétiqueRÉSUMÉ
Human Respiratory Syncytial Virus (hRSV), a prevalent respiratory pathogen affecting various age groups, can trigger prolonged and intense inflammation in humans. The severity and outcome of hRSV infection correlate with elevated levels of pro-inflammatory agents, yet the underlying reasons for this immune system overstimulation remain elusive. We focused on the impact of hRSV non-structural proteins, NS1 and NS2, on immune response within epithelial cells. Available data indicates that these proteins impair the interferon pathway. We reinforce that NS1 and NS2 induce heightened secretion of the pro-inflammatory cytokines IL-6 and CXCL8. We also indicate that hRSV non-structural proteins provoke differential gene expression of human host FosB and long non-coding RNAs (MALAT1, RP11-510N19.5). It suggests an impact of NS molecules beyond IFN pathways. Thus, new light is shed on the interplay between hRSV and host cells, uncovering unexplored avenues of viral interference, especially the NS2 role in cytokine expression and immune modulation.
Sujet(s)
Cytokines , ARN long non codant , Virus respiratoire syncytial humain , Protéines virales non structurales , Humains , ARN long non codant/génétique , ARN long non codant/métabolisme , Virus respiratoire syncytial humain/génétique , Virus respiratoire syncytial humain/immunologie , Protéines virales non structurales/génétique , Protéines virales non structurales/métabolisme , Cytokines/métabolisme , Cytokines/génétique , Infections à virus respiratoire syncytial/virologie , Infections à virus respiratoire syncytial/immunologie , Infections à virus respiratoire syncytial/métabolisme , Infections à virus respiratoire syncytial/génétique , Interactions hôte-pathogène/immunologie , Cellules épithéliales/virologie , Cellules épithéliales/métabolisme , Cellules épithéliales/immunologie , Régulation de l'expression des gènes , Interleukine-6/génétique , Interleukine-6/métabolismeRÉSUMÉ
In the post-COVID-19 era, the co-circulation of respiratory viruses, including influenza, SARS-CoV-2, and respiratory syncytial virus (RSV), continues to have significant health impacts and presents ongoing public health challenges. Vaccination remains the most effective measure for preventing viral infections. To address the concurrent circulation of these respiratory viruses, extensive efforts have been dedicated to the development of combined vaccines. These vaccines utilize a range of platforms, including mRNA-based vaccines, viral vector vaccines, and subunit vaccines, providing opportunities in addressing multiple pathogens at once. This review delves into the major advancements in the field of combined vaccine research, underscoring the strategic use of various platforms to tackle the simultaneous circulation of respiratory viruses effectively.