scholarly journals Direct Administration in the Respiratory Tract Improves Efficacy of Broadly Neutralizing Anti-Influenza Virus Monoclonal Antibodies

2015 ◽  
Vol 59 (7) ◽  
pp. 4162-4172 ◽  
Author(s):  
Victor H. Leyva-Grado ◽  
Gene S. Tan ◽  
Paul E. Leon ◽  
Mark Yondola ◽  
Peter Palese
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Therapeutic Agent ◽  
Influenza Infection ◽  
Virus Challenge ◽  
Routes Of Administration ◽  
Neutralizing Monoclonal Antibody ◽  
Direct Administration ◽  
Virus Strains ◽  
Potential Use

ABSTRACTThe emergence of influenza virus strains resistant to approved neuraminidase inhibitors and the time constrains after infection when these drugs can be effective constitute major drawbacks for this class of drugs. This highlights a critical need to discover new therapeutic agents that can be used for the treatment of influenza virus-infected patients. The use of broadly neutralizing anti-influenza monoclonal antibodies (MAbs) has been sought as an alternative immunotherapy against influenza infection. Here, we tested in mice previously characterized broadly neutralizing anti-hemagglutinin (HA) stalk MAbs prophylactically and therapeutically using different routes of administration. The efficacy of treatment against an influenza H1N1 pandemic virus challenge was compared between two systemic routes of administration, intraperitoneal (i.p.) and intravenous (i.v.), and two local routes, intranasal (i.n.) and aerosol (a.e.). The dose of MAb required for prophylactic protection was reduced by 10-fold in animals treated locally (i.n. or a.e.) compared with those treated systemically (i.p. or i.v.). Improved therapeutic protection was observed in animals treated i.n. on day 5 postinfection (60% survival) compared with those treated via the i.p. route (20% survival). An increase in therapeutic efficacy against other influenza virus subtypes (H5N1) was also observed when a local route of administration was used. Our findings demonstrate that local administration significantly decreases the amount of broadly neutralizing monoclonal antibody required for protection against influenza, which highlights the potential use of MAbs as a therapeutic agent for influenza-associated disease.

scholarly journals Construction and Immunogenicity of a Novel Multivalent Vaccine Prototype Based on Conserved Influenza Virus Antigens

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 197 ◽  
Author(s):  
Anna Kirsteina ◽  
Inara Akopjana ◽  
Janis Bogans ◽  
Ilva Lieknina ◽  
Juris Jansons ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Matrix Protein ◽  
Influenza Infection ◽  
Alpha Helix ◽  
H1n1 Influenza ◽  
Dimensional Structure ◽  
Effective Vaccine ◽  
High Dose ◽  
Virus Challenge ◽  
Practical Applications

Influenza, an acute, highly contagious respiratory disease, remains a significant threat to public health. More effective vaccination strategies aimed at inducing broad cross-protection not only against seasonal influenza variants, but also zoonotic and emerging pandemic influenza strains are urgently needed. A number of conserved protein targets to elicit such cross-protective immunity have been under investigation, with long alpha-helix (LAH) from hemagglutinin stalk and ectodomain of matrix protein 2 ion channel (M2e) being the most studied ones. Recently, we have reported the three-dimensional structure and some practical applications of LAH expressed in Escherichia coli system (referred to as tri-stalk protein). In the present study, we investigated the immunogenicity and efficacy of a panel of broadly protective influenza vaccine prototypes based on both influenza tri-stalk and triple M2e (3M2e) antigens integrated into phage AP205 virus-like particles (VLPs). While VLPs containing the 3M2e alone induced protection against standard homologous and heterologous virus challenge in mice, only the combination of both conserved influenza antigens into a single VLP fully protected mice from a high-dose homologous H1N1 influenza infection. We propose that a combination of genetic fusion and chemical coupling techniques to expose two different foreign influenza antigens on a single particle is a perspective approach for generation of a broadly-effective vaccine candidate that could protect against the constantly emerging influenza virus strains.

scholarly journals The analysis of the monoclonal immune response to influenza virus. II. The antigenicity of the viral hemagglutinin.

1976 ◽  
Vol 144 (4) ◽  
pp. 985-995 ◽  
Author(s):  
W Gerhard
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Influenza Viruses ◽  
Antigenic Determinants ◽  
Humoral Immune ◽  
Viral Hemagglutinin ◽  
Or Groups ◽  
Virus Strains

The antigenicity of the hemagglutinins (HA) of five influenza viruses of the A0 and A1 subtypes has been analyzed by means of monoclonal antibodies of murine origin produced in vitro. Secondary monoclonal anti-HA(PR8) antibodies were able to differentiate 14 antigenic determinants (or groups of determinants) on the HA of five influenza virus strains of the A0 and A1 subtypes. Taking into account that certain pairs of determinants delineated on heterologous HA may reflect the heterogeneity of the humoral immune response to a single homologous determinant, the presence of at least eight determinants (host cell-derived determinants not included) on the homologous HA of PR8 and probably on the HA of influenza viruses in general is postulated. Three types of HA-determinants of A0 and A1 influenza virus strains could be distinguished: strain-specific, partially shared, and determinant(s) common to all five virus strains tested. Roughly 40, 55, and 5%, respectively, of the secondary anti-PR8 antibodies of BALB/c mice were directed against determinants belonging to either of the three types.

scholarly journals Recombinant Vesicular Stomatitis Virus Expressing Influenza Nucleoprotein Induces CD8 T-Cell Responses That Enhance Antibody-Mediated Protection after Lethal Challenge with Influenza Virus

2009 ◽  
Vol 16 (4) ◽  
pp. 488-498 ◽  
Author(s):  
Brice E. Barefoot ◽  
Christopher J. Sample ◽  
Elizabeth A. Ramsburg
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cd8 T Cells ◽  
Influenza Infection ◽  
Clinical Signs ◽  
Lethal Challenge ◽  
Live Attenuated Vaccine ◽  
Virus Challenge ◽  
Vesicular Stomatitis

ABSTRACT Live attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSVs) expressing foreign antigens are highly effective vaccines in animal models. In this study, we report that an rVSV expressing influenza nucleoprotein (VSV NP) from the first position of the VSV genome induces robust anti-NP CD8 T cells in immunized mice. These CD8 T cells are phenotypically similar to those induced by natural influenza infection and are cytotoxic in vivo. Animals immunized with an rVSV expressing the influenza hemagglutinin (rVSV HA) were protected but still exhibited considerable morbidity after challenge. Animals receiving a cocktail vaccine of rVSV NP and rVSV HA had reduced pulmonary viral loads, less weight loss, and reduced clinical signs of illness after influenza virus challenge, relative to those vaccinated with rVSV HA alone. Influenza NP is a highly conserved antigen, and induction of protective anti-NP responses may be a productive strategy for generating heterologous protection against divergent influenza strains.

scholarly journals The study of neuraminidase immunity in protection against secondary bacterial pneumonia induced by S. aureus after influenza infection in mice

2021 ◽  
Vol 97 (6) ◽  
pp. 564-577
Author(s):  
I. A. Leneva ◽  
I. N. Falynskova ◽  
N. P. Kartashova ◽  
E. A. Glubokova ◽  
A. V. Poddubikov ◽  
...  
Keyword(s):  
Weight Loss ◽  
Influenza Virus ◽  
Bacterial Pneumonia ◽  
Bacterial Infections ◽  
Influenza Infection ◽  
H1n1 Influenza ◽  
H1n1 Influenza Virus ◽  
Virus Challenge ◽  
Influenza Outbreaks ◽  
Secondary Bacterial Pneumonia

Introduction. Pneumonia often occurs secondary to influenza infection and accounts for a large proportion of the morbidity and mortality associated with seasonal and pandemic influenza outbreaks. We previously have shown that vaccination with Virus-like particles (VLPs) containing hemagglutinin (HA) of influenza virus reduces mortality caused by bacterial infections after an influenza infections in mice.The aim of this work is to study whether this protective effect may be potentiated by supplementing the HA preparation with the influenza neuraminidase (NA).Materials and methods. We studied the effect of Gag-VLPs with the influenza HA or NA from А/PR/8/34 alone or in combination, in a lethal BALB/c mouse model of S. aureus infection after vaccine-matched or mismatched influenza virus challenge.Results. A cocktail of HA-Gag and NA-Gag-VLPs fully protected from weight loss, mortality and viral replication and significantly reduced the bacterial burden in the lungs of А/PR/8/34 infected animals. Immunization with this cocktail HA-Gag-VLPs 100 ng + NA-Gag-VLPs 20 ng also protected 60% of animals from mortality associated with secondary bacterial S. aureus infection following a heterologous H1N1 influenza virus challenge, and led to the significant protection from weight loss and pulmonary pathogen replication even in the absence of HA-inhibition and NA-inhibition antibodies.Conclusion. Our results indicate that influenza vaccination may improve the outcome of a secondary bacterial pneumonia induced by S. aureus after influenza even when the virus is antigenically different from the vaccine strain. At the same time, in our model, the significance of the immunity to influenza virus HA was prevalent.

scholarly journals Infection of influenza virus neuraminidase-vaccinated mice with homologous influenza virus leads to strong protection against heterologous influenza viruses

2014 ◽  
Vol 95 (12) ◽  
pp. 2627-2637 ◽  
Author(s):  
Biao He ◽  
Haiyan Chang ◽  
Zhihua Liu ◽  
Chaoyang Huang ◽  
Xueying Liu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Infection ◽  
Lethal Dose ◽  
Influenza Viruses ◽  
Virus Challenge ◽  
Influenza Pandemics ◽  
Homologous Virus ◽  
Major Antigen ◽  
Influenza Virus Neuraminidase ◽  
Antibody Levels

Vaccination is the best measure to prevent influenza pandemics. Here, we studied the protective effect against heterologous influenza viruses, including A/reassortant/NYMC X-179A (pH1N1), A/Chicken/Henan/12/2004 (H5N1), A/Chicken/Jiangsu/7/2002 (H9N2) and A/Guizhou/54/89×A/PR/8/34 (A/Guizhou-X) (H3N2), in mice first vaccinated with a DNA vaccine of haemagglutinin (HA) or neuraminidase (NA) of A/PR/8/34 (PR8) and then infected with the homologous virus. We showed that PR8 HA or NA vaccination both protected mice against a lethal dose of the homologous virus; PR8 HA or NA DNA vaccination and then PR8 infection in mice offered poor or excellent protection, respectively, against a second, heterologous influenza virus challenge. In addition, before the second heterologous influenza infection, the highest antibody level against nucleoprotein (NP) and matrix (M1 and M2) proteins was found in the PR8 NA-vaccinated and PR8-infected group. The level of induced cellular immunity against NP and M1 showed a trend consistent with that seen in antibody levels. However, PR8 HA+NA vaccination and then PR8 infection resulted in limited protection against heterologous influenza virus challenge. Results of the present study demonstrated that infection of the homologous influenza virus in mice already immunized with a NA vaccine could provide excellent protection against subsequent infection of a heterologous influenza virus. These findings suggested that NA, a major antigen of influenza virus, could be an important candidate antigen for universal influenza vaccines.

scholarly journals Anti-Influenza Hyperimmune Immunoglobulin Enhances Fc-Functional Antibody Immunity During Human Influenza Infection

2018 ◽  
Vol 218 (9) ◽  
pp. 1383-1393 ◽  
Author(s):  
Hillary A Vanderven ◽  
Kathleen Wragg ◽  
Fernanda Ana-Sosa-Batiz ◽  
Anne B Kristensen ◽  
Sinthujan Jegaskanda ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Infection ◽  
Intravenous Immunoglobulins ◽  
Human Influenza ◽  
Functional Antibodies ◽  
Virus Strains

Anti-influenza hyperimmune immunoglobulin (Flu-IVIG) generally contained higher concentrations of influenza-specific Fc-functional antibodies than standard intravenous immunoglobulins against an array of influenza virus strains and subtypes. Passive infusion of Flu-IVIG into influenza-infected patients transiently boosted Fc-functional antibodies early after infusion.

Therapeutic Monoclonal Antibodies in Clinical Practice against Cancer

2020 ◽  
Vol 20 (16) ◽  
pp. 1895-1907
Author(s):  
Navgeet Kaur ◽  
Anju Goyal ◽  
Rakesh K. Sindhu
Keyword(s):  
Monoclonal Antibody ◽  
Monoclonal Antibodies ◽  
Clinical Practice ◽  
Therapeutic Agent ◽  
Hematologic Malignancies ◽  
Immune Checkpoints ◽  
Malignant Cells ◽  
Main Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Cancerous Cells

The importance of monoclonal antibodies in oncology has increased drastically following the discovery of Milstein and Kohler. Since the first approval of the monoclonal antibody, i.e. Rituximab in 1997 by the FDA, there was a decline in further applications but this number has significantly increased over the last three decades for various therapeutic applications due to the lesser side effects in comparison to the traditional chemotherapy methods. Presently, numerous monoclonal antibodies have been approved and many are in queue for approval as a strong therapeutic agent for treating hematologic malignancies and solid tumors. The main target checkpoints for the monoclonal antibodies against cancer cells include EGFR, VEGF, CD and tyrosine kinase which are overexpressed in malignant cells. Other immune checkpoints like CTLA-4, PD-1 and PD-1 receptors targeted by the recently developed antibodies increase the capability of the immune system in destroying the cancerous cells. Here, in this review, the mechanism of action, uses and target points of the approved mAbs against cancer have been summarized.

scholarly journals Effective use of monoclonal antibodies for treatment of persistent COVID-19 infection in a patient on rituximab

2021 ◽  
Vol 14 (8) ◽  
pp. e243469
Author(s):  
Carlos X Rabascall ◽  
Becky X Lou ◽  
Brianne Navetta-Modrov ◽  
Stella S Hahn
Keyword(s):  
Monoclonal Antibodies ◽  
Symptom Onset ◽  
Severe Disease ◽  
Therapeutic Window ◽  
Immunosuppressed Patient ◽  
Unique Case ◽  
Risk Of Progression ◽  
Immunosuppressed Patients ◽  
Effective Use ◽  
Potential Use

As we are over a year into the COVID-19 pandemic, we have made many forward strides in therapeutics. These treatments, such as monoclonal antibodies, have help mitigate the detrimental and often fatal consequences of COVID-19. The current indication for the use of monoclonal antibodies is mild to moderate COVID-19 infection within 10 days of symptom onset in those who are at high risk of progression to severe disease. However, their role in patients with prolonged symptoms is not clear. We present a unique case of monoclonal antibodies use after 54 days of symptom onset in an immunosuppressed patient with persistent COVID-19 infection despite standard treatment. This case illustrates the potential use of monoclonal antibodies outside of the current recommended therapeutic window in immunosuppressed patients, who may have difficulty with viral clearance.

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