scholarly journals Recombinant Respiratory Syncytial Virus That Does Not Express the NS1 or M2-2 Protein Is Highly Attenuated and Immunogenic in Chimpanzees

2000 ◽  
Vol 74 (19) ◽  
pp. 9317-9321 ◽  
Author(s):  
Michael N. Teng ◽  
Stephen S. Whitehead ◽  
Alison Bermingham ◽  
Marisa St. Claire ◽  
William R. Elkins ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Target Population ◽  
Large Deletion ◽  
Upper Respiratory Tract ◽  
Wild Type ◽  
Upper Respiratory ◽  
Syncytial Virus

ABSTRACT Mutant recombinant respiratory syncytial viruses (RSV) which cannot express the NS1 and M2-2 proteins, designated rA2ΔNS1 and rA2ΔM2-2, respectively, were evaluated as live-attenuated RSV vaccines. The rA2ΔNS1 virus contains a large deletion that should have the advantageous property of genetic stability during replication in vitro and in vivo. In vitro, rA2ΔNS1 replicated approximately 10-fold less well than wild-type recombinant RSV (rA2), while rA2ΔM2-2 had delayed growth kinetics but reached a final titer similar to that of rA2. Each virus was administered to the respiratory tracts of RSV-seronegative chimpanzees to assess replication, immunogenicity, and protective efficacy. The rA2ΔNS1 and rA2ΔM2-2 viruses were 2,200- to 55,000-fold restricted in replication in the upper and lower respiratory tracts but induced a level of RSV-neutralizing antibody in serum that was only slightly reduced compared to the level induced by wild-type RSV. The replication of wild-type RSV in immunized chimpanzees after challenge was reduced more than 10,000-fold at each site. Importantly, rA2ΔNS1 and rA2ΔM2-2 were 10-fold more restricted in replication in the upper respiratory tract than was thecpts248/404 virus, a vaccine candidate that retained mild reactogenicity in the upper respiratory tracts of 1-month-old infants. Thus, either rA2ΔNS1 or rA2ΔM2-2 might be appropriately attenuated for this age group, which is the major target population for an RSV vaccine. In addition, these results show that neither NS1 nor M2-2 is essential for RSV replication in vivo, although each is important for efficient replication.

scholarly journals Discovery of a Prefusion Respiratory Syncytial Virus F-Specific Monoclonal Antibody That Provides Greater In Vivo Protection than the Murine Precursor of Palivizumab

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Min Zhao ◽  
Zi-Zheng Zheng ◽  
Man Chen ◽  
Kayvon Modjarrad ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Antigenic Site ◽  
Neutralizing Antibody ◽  
Binding Affinities ◽  
High Potency ◽  
F Protein ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Palivizumab, a humanized murine monoclonal antibody that recognizes antigenic site II on both the prefusion (pre-F) and postfusion (post-F) conformations of the respiratory syncytial virus (RSV) F glycoprotein, is the only prophylactic agent approved for use for the treatment of RSV infection. However, its relatively low neutralizing potency and high cost have limited its use to a restricted population of infants at high risk of severe disease. Previously, we isolated a high-potency neutralizing antibody, 5C4, that specifically recognizes antigenic site Ø at the apex of the pre-F protein trimer. We compared in vitro and in vivo the potency and protective efficacy of 5C4 and the murine precursor of palivizumab, antibody 1129. Both antibodies were synthesized on identical murine backbones as either an IgG1 or IgG2a subclass and evaluated for binding to multiple F protein conformations, in vitro inhibition of RSV infection and propagation, and protective efficacy in mice. Although 1129 and 5C4 had similar pre-F protein binding affinities, the 5C4 neutralizing activity was nearly 50-fold greater than that of 1129 in vitro. In BALB/c mice, 5C4 reduced the peak titers of RSV 1,000-fold more than 1129 did in both the upper and lower respiratory tracts. These data indicate that antibodies specific for antigenic site Ø are more efficacious at preventing RSV infection than antibodies specific for antigenic site II. Our data also suggest that site Ø-specific antibodies may be useful for the prevention or treatment of RSV infection and support the use of the pre-F protein as a vaccine antigen. IMPORTANCE There is no vaccine yet available to prevent RSV infection. The use of the licensed antibody palivizumab, which recognizes site II on both the pre-F and post-F proteins, is restricted to prophylaxis in neonates at high risk of severe RSV disease. Recommendations for using passive immunization in the general population or for therapy in immunocompromised persons with persistent infection is limited because of cost, determined from the high doses needed to compensate for its relatively low neutralizing potency. Prior efforts to improve the in vitro potency of site II-specific antibodies did not translate to significant in vivo dose sparing. We isolated a pre-F protein-specific, high-potency neutralizing antibody (5C4) that recognizes antigenic site Ø and compared its efficacy to that of the murine precursor of palivizumab (antibody 1129) matched for isotype and pre-F protein binding affinities. Our findings demonstrate that epitope specificity is an important determinant of antibody neutralizing potency, and defining the mechanisms of neutralization has the potential to identify improved products for the prevention and treatment of RSV infection.

scholarly journals Immunogenicity and efficacy of one and two doses of Ad26.COV2.S COVID vaccine in adult and aged NHP

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Laura Solforosi ◽  
Harmjan Kuipers ◽  
Mandy Jongeneelen ◽  
Sietske K. Rosendahl Huber ◽  
Joan E.M. van der Lubbe ◽  
...  
Keyword(s):  
Single Dose ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
T Helper ◽  
Th Cell ◽  
Upper Respiratory ◽  
Early Indication ◽  
Dose Vaccine

Safe and effective coronavirus disease–19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged nonhuman primates (NHPs). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared with a single dose. In one-dose regimens, neutralizing antibody responses were stable for at least 14 wk, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and T helper cell (Th cell) 1–skewed cellular responses in aged NHPs that were comparable to those in adult animals. Aged Ad26.COV2.S-vaccinated animals challenged 3 mo after dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. Neutralization of variants of concern by NHP sera was reduced for B.1.351 lineages while maintained for the B.1.1.7 lineage independent of Ad26.COV2.S vaccine regimen.

scholarly journals Infectious Laryngotracheitis Virus Viral Chemokine-Binding Protein Glycoprotein G Alters Transcription of Key Inflammatory Mediators In Vitro and In Vivo

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Mauricio J. C. Coppo ◽  
Joanne M. Devlin ◽  
Alistair R. Legione ◽  
Paola K. Vaz ◽  
Sang-Won Lee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Binding Protein ◽  
Upper Respiratory Tract ◽  
Infectious Laryngotracheitis Virus ◽  
Glycoprotein G ◽  
Infectious Laryngotracheitis ◽  
Upper Respiratory ◽  
Laryngotracheitis Virus

ABSTRACTInfectious laryngotracheitis virus (ILTV) is an alphaherpesvirus that infects chickens, causing upper respiratory tract disease and significant losses to poultry industries worldwide. Glycoprotein G (gG) is a broad-range viral chemokine-binding protein conserved among most alphaherpesviruses, including ILTV. A number of studies comparing the immunological parameters between infection with gG-expressing and gG-deficient ILTV strains have demonstrated that expression of gG is associated with increased virulence, modification of the amount and the composition of the inflammatory response, and modulation of the immune responses toward antibody production and away from cell-mediated immune responses. The aims of the current study were to examine the establishment of infection and inflammation by ILTV and determine how gG influences that response to infection.In vitroinfection studies using tracheal organ tissue specimen cultures and blood-derived monocytes andin vivoinfection studies in specific-pathogen-free chickens showed that leukocyte recruitment to the site of infection is an important component of the induced pathology and that this is influenced by the expression of ILTV gG and changes in the transcription of the chicken orthologues of mammalian CXC chemokine ligand 8 (CXCL8), chicken CXCLi1 and chicken CXCLi2, among other cytokines and chemokines. The results from this study demonstrate that ILTV gG interferes with chemokine and cytokine transcription at different steps of the inflammatory cascade, thus altering inflammation, virulence, and the balance of the immune response to infection.IMPORTANCEInfectious laryngotracheitis virus is an alphaherpesvirus that expresses gG, a conserved broad-range viral chemokine-binding protein known to interfere with host immune responses. However, little is known about how gG modifies virulence and influences the inflammatory signaling cascade associated with infection. Here, data fromin vitroandin vivoinfection studies are presented. These data show that gG has a direct impact on the transcription of cytokines and chemokine ligandsin vitro(such as chicken CXCL8 orthologues, among others), which explains the altered balance of the inflammatory response that is associated with gG during ILTV infection of the upper respiratory tract of chickens. This is the first report to associate gG with the dysregulation of cytokine transcription at different stages of the inflammatory cascade triggered by ILTV infection of the natural host.

scholarly journals Case Report: Infection With SARS-CoV-2 in the Presence of High Levels of Vaccine-Induced Neutralizing Antibody Responses

2021 ◽  
Vol 8 ◽  
Author(s):  
Bianca Schulte ◽  
Benjamin Marx ◽  
Marek Korencak ◽  
Dorian Emmert ◽  
Souhaib Aldabbagh ◽  
...  
Keyword(s):  
Case Report ◽  
Respiratory Tract ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
Protective Measures ◽  
Specific Antibodies ◽  
Household Members ◽  
Upper Respiratory

We present a case of SARS-CoV-2 B.1. 525 infection in a healthcare worker despite the presence of highly neutralizing, multivariant-specific antibodies 7 weeks after full vaccination with the mRNA vaccine BNT162b2. We show that the virus replicated to high levels in the upper respiratory tract over the course of several days in the presence of strong antibody responses. The virus was readily propagatable in vitro, demonstrating the potential to transmit to others, bolstered by the fact that several household members were equally infected. This highlights the importance of protective measures even in vaccinated individuals.

Antiviral Properties of Food Plants Could Help to Reduce Contagion and Severity in SARS-CoV-2 Infections

2021 ◽  
Vol 07 ◽  
Author(s):  
Betina Cardoso
Keyword(s):  
Respiratory Tract ◽  
Literature Search ◽  
Food Plants ◽  
Upper Respiratory Tract ◽  
Site Specific ◽  
In Vivo Experiments ◽  
Upper Respiratory ◽  
Novel Coronavirus

Introduction: The importance of an immediate tool to help patients and prevent viral diffusion of new pneumonia caused by 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) that causes the disease COVID-19 becomes evident. Recent articles have reported on body site-specific SARS-CoV-2 infection, showing very active replication in the throat and upper respiratory tract when symptoms were still mild, and thus being efficient in viral transmission in sputum. Material and Methods: An alternative that may be feasible is to resort to scientific studies that demonstrate the antiviral potential of medicinal plants species through in-vitro and in-vivo experiments to alleviate symptoms and prevent the spread of contagion. A literature search in Scopus and PubMed on herbs and foods with antiviral properties was performed. Results: Herbs and foods with demonstrated antiviral potential have been identified, which could limit SARS-CoV-2 spreading by interfering on ACE2 protein on infection sites. The analysis of transdisciplinary knowledge allows us to connect previous research on the action of common plants and foods on viruses to limit the replication of SARS-CoV-2 in the throat and upper respiratory tract. Conclusions: Herbs and foods with demonstrated antiviral potential have been identified, which could limit SARS-CoV-2 spreading by interfering on ACE2 protein on infection sites. The analysis of transdisciplinary knowledge allows us to connect previous research on the action of common plants and foods on viruses to limit the replication of SARS-CoV-2 in the throat and upper respiratory tract.

A Review of Topical Povidone-iodine to Decrease Viral Load of COViD-19

2021 ◽  
Vol 36 (5) ◽  
pp. 238-241
Author(s):  
Katherine M. Benson ◽  
Amalia A. Mancini ◽  
Michael R. Brodeur
Keyword(s):  
Viral Load ◽  
Respiratory Tract Infections ◽  
Povidone Iodine ◽  
Preventive Measure ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Clinical Trial Results ◽  
Tract Infections

Topical povidone-iodine (PVP-I) is currently being considered as a potential preventive measure against the spread of COVID-19. Diluted PVP-I solutions have been historically used in Asia to treat upper respiratory tract infections (URTIs) by decreasing the bacterial and viral load on oropharyngeal mucosa to decrease the transmission of diseases. Efficacy of gargling 0.23% PVP-I mouthwash in Japan demonstrated to be efficacious in lowering the prevalence of URTIs when compared with placebo. The 0.23% concentration was used in vitro on severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, which produced undetectable results after 30 seconds of exposure. Additionally, a recent study in 2020 proved the efficacy of PVP-I 0.45%-10% in reducing COVID-19 (SARS-CoV 2) viral load in vitro. Numerous clinical trials are being conducted to determine if there is a decrease in viral load, and thus transmission, when using oral or nasal topical PVP-I in COVID-19 patients. Because of the current lack of evidence for the use of PVP-I in vivo with COVID-19, it is recommended to await the clinical trial results before initiating this practice.

A rat nasal epithelial model for predicting upper respiratory tract toxicity: in vivo–in vitro correlations

Toxicology ◽  
2000 ◽  
Vol 145 (1) ◽  
pp. 39-49 ◽  
Author(s):  
J.D Kilgour ◽  
S.A Simpson ◽  
D.J Alexander ◽  
C.J Reed
Keyword(s):  
Respiratory Tract ◽  
Upper Respiratory Tract ◽  
Upper Respiratory

scholarly journals Inhibition of AIM2 inflammasome-mediated pyroptosis by Andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Jian Gao ◽  
Shuang Peng ◽  
Xinni Shan ◽  
Guoliang Deng ◽  
Lihong Shen ◽  
...  
Keyword(s):  
Late Phase ◽  
Chemotherapeutic Agents ◽  
Protective Agent ◽  
Upper Respiratory Tract ◽  
Effective Interventions ◽  
Radiation Induced ◽  
Upper Respiratory ◽  
Lung Tissue Damage

AbstractRadiation-induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy, whereas no effective interventions are available. Andrographolide, an active component extracted from Andrographis paniculate, is prescribed as a treatment for upper respiratory tract infection. Here we report the potential radioprotective effect and mechanism of Andrographolide on RILI. C57BL/6 mice were exposed to 18 Gy of whole thorax irradiation, followed by intraperitoneal injection of Andrographolide every other day for 4 weeks. Andrographolide significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, and pro-inflammatory cytokine release in the early phase and progressive fibrosis in the late phase. Moreover, Andrographolide markedly hampered radiation-induced activation of the AIM2 inflammasome and pyroptosis in vivo. Furthermore, bone marrow-derived macrophages (BMDMs) were exposed to 8 Gy of X-ray radiation in vitro and Andrographolide significantly inhibited AIM2 inflammasome mediated-pyroptosis in BMDMs. Mechanistically, Andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation or chemotherapeutic agents in BMDMs. Taken together, Andrographolide ameliorates RILI by suppressing AIM2 inflammasome mediated-pyroptosis in macrophage, identifying Andrographolide as a novel potential protective agent for RILI.

scholarly journals Increased Chain Length Promotes Pneumococcal Adherence and Colonization

2012 ◽  
Vol 80 (10) ◽  
pp. 3454-3459 ◽  
Author(s):  
Jesse L. Rodriguez ◽  
Ankur B. Dalia ◽  
Jeffrey N. Weiser
Keyword(s):  
Parental Strain ◽  
A549 Cells ◽  
Invasive Disease ◽  
Upper Respiratory Tract ◽  
Epithelial Surface ◽  
Content Type ◽  
Morphological Heterogeneity ◽  
Upper Respiratory

ABSTRACTStreptococcus pneumoniaeis a mucosal pathogen that grows in chains of variable lengths. Short-chain forms are less likely to activate complement, and as a consequence they evade opsonophagocytic clearance more effectively during invasive disease. When grown in human nasal airway surface fluid, pneumococci exhibited both short- and long-chain forms. Here, we determined whether longer chains provide an advantage during colonization when the organism is attached to the epithelial surface. Chain-forming mutants and the parental strain grown under conditions to promote chain formation showed increased adherence to human epithelial cells (A549 cells)in vitro. Additionally, adherence to A549 cells selected for longer chains within the wild-type strain.In vivoin a murine model of colonization, chain-forming mutants outcompeted the parental strain. Together, our results demonstrate that morphological heterogeneity in the pneumococcus may promote colonization of the upper respiratory tract by enhancing the ability of the organism to bind to the epithelial surface.

scholarly journals Effect of Coexpression of Interleukin-2 by Recombinant Respiratory Syncytial Virus on Virus Replication, Immunogenicity, and Production of Other Cytokines

2000 ◽  
Vol 74 (15) ◽  
pp. 7151-7157 ◽  
Author(s):  
Alexander Bukreyev ◽  
Stephen S. Whitehead ◽  
Calman Prussin ◽  
Brian R. Murphy ◽  
Peter L. Collins
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mononuclear Cells ◽  
Protective Efficacy ◽  
Interleukin 2 ◽  
Cytokine Mrna ◽  
Virus Growth ◽  
Ifn Γ ◽  
Syncytial Virus

ABSTRACT We constructed rRSV/mIL-2, a recombinant respiratory syncytial virus (rRSV) containing the coding sequence of murine interleukin-2 (mIL-2) in a transcription cassette inserted into the G-F intergenic region. The recovered virus (rRSV/mIL-2) expressed high levels (up to 2.8 μg/ml) of mIL-2 in cell culture. Replication of rRSV/mIL-2 in vitro was reduced up to 13.6-fold from that of wild-type (wt) rRSV, an effect that was due to the presence of the foreign insert but was not specific to mIL-2. Replication of the rRSV/mIL-2 virus in the upper and lower respiratory tracts of BALB/c mice was reduced up to 6.3-fold, an effect that was specific to mIL-2. The antibody response, including the levels of RSV-specific serum immunoglobulin G1 (IgG1), IgG2a, IgA, and total IgG, and the level of protective efficacy against wt RSV challenge were not significantly different from those of wt rRSV. Analysis of total pulmonary cytokine mRNA isolated 1 and 4 days following infection with rRSV/mIL-2 revealed elevated levels of mRNA for IL-2, gamma interferon (IFN-γ), IL-4, IL-5, IL-6, IL-10, IL-13, and IL-12 p40 compared to those for wt rRSV. Flow cytometry of total pulmonary mononuclear cells isolated 10 days following infection with rRSV/mIL-2 revealed increased levels of CD4+ T lymphocytes expressing either IFN-γ or IL-4 compared to those of wt rRSV. These elevations in cytokine mRNA or cytokine-expressing CD4+cells relative to those of wt rRSV-primed animals were not observed following challenge with wt RSV on day 28. Thus, the expression of mIL-2 by rRSV was associated with a modest attenuation of virus growth in vivo, induction of serum antibodies at levels comparable to that of wt rRSV, and transient increases in both the Th1 and Th2 CD4+ lymphocytes and cytokine mRNAs compared to those of wt rRSV.

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