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 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 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.

Influenza virus H1N1 activates platelets through FcγRIIA signaling and thrombin generation

Blood ◽  
2014 ◽  
Vol 123 (18) ◽  
pp. 2854-2863 ◽  
Author(s):  
Eric Boilard ◽  
Guillaume Paré ◽  
Matthieu Rousseau ◽  
Nathalie Cloutier ◽  
Isabelle Dubuc ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Complexes ◽  
Thrombin Generation ◽  
Influenza Infection ◽  
H1n1 Influenza ◽  
Virus H1n1 ◽  
H1n1 Influenza Virus ◽  
Key Points

Key PointsIn influenza-immune subjects, H1N1 influenza virus–containing immune complexes can activate platelets through FcγRIIA. H1N1 can also activate platelets through thrombin, independently of FcγRIIA, pointing to a role of coagulation in influenza infection.

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 New Onset Refractory Status Epilepticus in a Young Man with H1N1 Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-3 ◽  
Author(s):  
Faisal Ibrahim ◽  
Naim Haddad
Keyword(s):  
Status Epilepticus ◽  
Influenza Infection ◽  
H1n1 Influenza ◽  
Neurological Complications ◽  
Refractory Status Epilepticus ◽  
Clonic Seizure ◽  
High Dose ◽  
H1n1 Infection ◽  
Refractory Status ◽  
Sedative Drugs

Objective. To report a case of refractory status epilepticus (SE) as an unusual early manifestation of H1N1 influenza infection.Introduction. H1N1 neurological complications have been reported and consist mainly of seizures or encephalopathy occurring in children. However, we only found a single report of an adult developing complex partial SE with H1N1 infection.Case Report. A 21-year-old previously healthy man was brought to the emergency room (ER) after a witnessed generalized tonic clonic seizure (GTCS). He was fully alert and afebrile upon ER arrival, but a second GTCS prompted treatment with Lorazepam and Fosphenytoin. The initial EEG showed diffuse slowing, but a repeat one requested as the patient failed to regain consciousness revealed recurrent focal seizures of independent bihemispheric origin, fulfilling the criteria for nonconvulsive SE. Chest X-ray, followed by chest CT scan, showed a left upper lobe consolidation. H1N1 infection was confirmed with PCR on bronchoalveolar lavage material. Despite aggressive treatment with Midazolam, Propofol, and multiple high dose antiepileptic drugs, the electrographic seizures recurred at every attempt to reduce the intravenous sedative drugs. The patient died two weeks after his initial presentation.Conclusion. H1N1 should be added to the list of rare causes of refractory SE, regardless of the patient’s age.

scholarly journals Universal Live-Attenuated Influenza Vaccine Candidates Expressing Multiple M2e Epitopes Protect Ferrets against a High-Dose Heterologous Virus Challenge

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1280
Author(s):  
Daria Mezhenskaya ◽  
Irina Isakova-Sivak ◽  
Victoria Matyushenko ◽  
Svetlana Donina ◽  
Andrey Rekstin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
High Dose ◽  
Virus Challenge ◽  
Consensus Sequences ◽  
Degree Of Protection ◽  
Live Attenuated Influenza Vaccine ◽  
Universal Influenza Vaccine

The development of an influenza vaccine with broad protection and durability remains an attractive idea due to the high mutation rate of the influenza virus. An extracellular domain of Matrix 2 protein (M2e) is among the most attractive target for the universal influenza vaccine owing to its high conservancy rate. Here, we generated two recombinant live attenuated influenza vaccine (LAIV) candidates encoding four M2e epitopes representing consensus sequences of human, avian and swine influenza viruses, and studied them in a preclinical ferret model. Both LAIV+4M2e viruses induced higher levels of M2e-specific antibodies compared to the control LAIV strain, with the LAIV/HA+4M2e candidate being significantly more immunogenic than the LAIV/NS+4M2e counterpart. A high-dose heterosubtypic influenza virus challenge revealed the highest degree of protection after immunization with LAIV/HA+4M2e strain, followed by the NS-modified LAIV and the classical LAIV virus. Furthermore, only the immune sera from the LAIV/HA+4M2e-immunized ferrets protected mice from a panel of lethal influenza viruses encoding M genes of various origins. These data suggest that the improved cross-protection of the LAIV/HA+4M2e universal influenza vaccine candidate was mediated by the M2e-targeted antibodies. Taking into account the safety profile and improved cross-protective potential, the LAIV/HA+4M2e vaccine warrants its further evaluation in a phase I clinical trial.

scholarly journals Neuraminidase in Virus-Like Particles Contributes to the Protection against High Dose of Avian Influenza Virus Challenge Infection

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1291
Author(s):  
Hae-Ji Kang ◽  
Ki-Back Chu ◽  
Keon-Woong Yoon ◽  
Gi-Deok Eom ◽  
Jie Mao ◽  
...  
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Critical Role ◽  
Protective Role ◽  
Challenge Infection ◽  
High Dose ◽  
Post Challenge ◽  
Virus Challenge

Neuraminidase is an important target for influenza vaccination. In this study, we generated avian influenza VLPs, expressing hemagglutinin (HA), neuraminidase (NA), HA and NA co-expressed (HANA), to evaluate the protective role of NA against a high (10LD50) and low (2LD50) dose of avian influenza virus challenge infections. A single immunization with HANA VLPs elicited the highest level of virus-specific IgG, IgG1, and IgG2a responses from the sera post-vaccination and the lungs post-challenge-infection. Potent antibody-secreting cell responses were observed from the spleens and lungs of HANA-VLP-immunized mice post-challenge-infection. HANA VLPs induced the highest CD4+ T cell, CD8+ T cell, and germinal center B cells, while strongly limiting inflammatory cytokine production in the lungs compared to other VLP immunization groups. In correlation with these findings, the lowest bodyweight losses and lung virus titers were observed from HANA VLP immunization, and all of the immunized mice survived irrespective of the challenge dose. Contrastingly, VLPs expressing either HA or NA alone failed to elicit complete protection. These results indicated that NA in VLPs played a critical role in inducing protection against a high dose of the challenge infection.

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 Virus-Like Particle Vaccine Induces Protective Immunity against Homologous and Heterologous Strains of Influenza Virus

2007 ◽  
Vol 81 (7) ◽  
pp. 3514-3524 ◽  
Author(s):  
Fu-Shi Quan ◽  
Chunzi Huang ◽  
Richard W. Compans ◽  
Sang-Moo Kang
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Protective Immunity ◽  
Protective Efficacy ◽  
High Serum ◽  
Influenza Viruses ◽  
Effective Vaccine ◽  
Lethal Challenge ◽  
Virus Challenge ◽  
Vaccine Approach

ABSTRACT Recurrent outbreaks of highly pathogenic avian influenza virus pose the threat of pandemic spread of lethal disease and make it a priority to develop safe and effective vaccines. Influenza virus-like particles (VLPs) have been suggested to be a promising vaccine approach. However, VLP-induced immune responses, and their roles in inducing memory immune responses and cross-protective immunity have not been investigated. In this study, we developed VLPs containing influenza virus A/PR8/34 (H1N1) hemagglutinin (HA) and matrix (M1) proteins and investigated their immunogenicity, long-term cross-protective efficacy, and effects on lung proinflammatory cytokines in mice. Intranasal immunization with VLPs containing HA induced high serum and mucosal antibody titers and neutralizing activity against PR8 and A/WSN/33 (H1N1) viruses. Mice immunized with VLPs containing HA showed little or no proinflammatory lung cytokines and were protected from a lethal challenge with mouse-adapted PR8 or WSN viruses even 5 months postimmunization. Influenza VLPs induced mucosal immunoglobulin G and cellular immune responses, which were reactivated rapidly upon virus challenge. Long-lived antibody-secreting cells were detected in the bone marrow of immunized mice. Immune sera administered intranasally were able to confer 100% protection from a lethal challenge with PR8 or WSN, which provides further evidence that anti-HA antibodies are primarily responsible for preventing infection. Taken together, these results indicate that nonreplicating influenza VLPs represent a promising strategy for the development of a safe and effective vaccine to control the spread of lethal influenza viruses.

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