H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans

Khurana, Surender; Wu, Jing; Verma, Nitin; Verma, Swati; Raghunandan, Rama; Manischewitz, Jody; King, Lisa R.; Kpamegan, Eloi; Pincus, Stephanie H.; Smith, Gale; Glenn, Gregory M.; Golding, Hana

doi:10.1128/jvi.05406-11

Cited by 89 publications

(66 citation statements)

References 54 publications

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“…2B). For calculation of the dissociation kinetics (off-rates), the SPR assay was performed with a low density of the antigen on the chip surface to provide only one epitope-paratope interaction for each intact antibody and was optimized using a MAb (bivalent IgG) and a Fab counterpart to obtain comparable kinetics (18,19,22,50). Similar results were obtained in SPR studies using mammalian rHA0.…”

Section: Resultsmentioning

confidence: 84%

“…We showed previously that it is possible to generate a functional oligomeric rHA1 domain in the absence of the HA2 stalk domain (16,20,21,22). We further analyzed the impact of the oligomeric versus monomeric H5N1 HA1 proteins on immunogenicity and protective efficacy of the globular domain and evaluated the quality of antibodies generated in ferrets.…”

Section: Discussionmentioning

confidence: 99%

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Oligomeric Recombinant H5 HA1 Vaccine Produced in Bacteria Protects Ferrets from Homologous and Heterologous Wild-Type H5N1 Influenza Challenge and Controls Viral Loads Better than Subunit H5N1 Vaccine by Eliciting High-Affinity Antibodies

Verma

Dimitrova

Munjal

et al. 2012

J Virol

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Only the oligomeric rHA1 (not the monomeric rHA1) immunogen and the SU-H5N1 vaccine provided protection against the lethality and morbidity of homologous and heterologous highly pathogenic H5N1. Oligomeric rHA1 generated more cross-neutralizing antibodies and higher levels of serum antibody binding to HA1, with stronger avidity and a better IgG/IgM ratio, than monomeric HA1 and SU-H5N1 vaccines, as determined by surface plasmon resonance (SPR). Importantly, viral loads after heterologous H5N1 challenge were more efficiently controlled in ferrets vaccinated with the oligomeric rHA1 immunogen than in SU-H5N1-vaccinated ferrets. The reduction of viral loads in the nasal washes correlated strongly with higher-avidity antibodies to oligomeric rHA1 derived from H5N1 clade 1 and clade 2.2 viruses, as measured by SPR. This is the first study to show the role of antibody avidity for the HA1 globular head domain in reduction of viral loads in the upper respiratory tract, which could significantly reduce viral transmission.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Oligomeric Recombinant H5 HA1 Vaccine Produced in Bacteria Protects Ferrets from Homologous and Heterologous Wild-Type H5N1 Influenza Challenge and Controls Viral Loads Better than Subunit H5N1 Vaccine by Eliciting High-Affinity Antibodies

Verma

Dimitrova

Munjal

et al. 2012

J Virol

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“…49,50 A large trial of 2537 young adults receiving pandemic H1N1 vaccine showed that a 15 mg (HA) formulation stimulated seroprotective responses in 64-85% of seronegative subjects after one dose. 50 Dose-related trends for increased reactogenicity for formulations from 5 to 45 mg were reported.…”

Section: Recombinant Vlp-based Influenza Vaccinesmentioning

confidence: 99%

“…Neutralizing antibody titers were correlated with preferential binding to the oligomeric (vs. monomeric) form of recombinant HA1, which may present epitopes on virion spikes absent from monomeric forms. 49 That specificity is hypothesized to be important in providing cross-clade antibody responses. Anti-NA antibodies that were mapped to epitopes near the sialic acid binding site potentially could provide a functional benefit by inhibiting viral release.…”

Section: Recombinant Vlp-based Influenza Vaccinesmentioning

confidence: 99%

New technologies for influenza vaccines

Dormitzer

Tsai

Giudice

2012

Human Vaccines & Immunotherapeutics

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“…Influenza VLP vaccines have been suggested as promising alternative vaccine candidates (18,19) and have also been tested in clinical trials (20,21). Antibody responses to hemagglutinin (HA) after vaccination are the major immune correlates conferring protection against influenza virus infections.…”

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confidence: 99%

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

Lee

et al. 2016

J Virol

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An integrin-associated protein CD47, which is a ligand for the inhibitory receptor signal regulatory protein ␣, is expressed on B and T cells, as well as on most innate immune cells. However, the roles of CD47 in the immune responses to viral infection or vaccination remain unknown. We investigated the role of CD47 in inducing humoral immune responses after intranasal infection with virus or immunization with influenza virus-like particles (VLPs). Virus infection or vaccination with VLPs containing hemagglutinin from A/PR8/34 influenza virus induced higher levels of antigen-specific IgG2c isotype dominant antibodies in CD47-deficient (CD47KO) mice than in wild-type (WT) mice. CD47KO mice with vaccination showed greater protective efficacy against lethal challenge, as evidenced by no loss in body weight and reduced lung viral titers compared to WT mice. In addition, inflammatory responses which include cytokine production, leukocyte infiltrates, and gamma interferon-producing CD4 ؉ T cells, as well as an anti-inflammatory cytokine (interleukin-10), were reduced in the lungs of vaccinated CD47KO mice after challenge with influenza virus. Analysis of lymphocytes indicated that GL7 ؉ germinal center B cells were induced at higher levels in the draining lymph nodes of CD47KO mice compared to those in WT mice. Notably, CD47KO mice exhibited significant increases in the numbers of antigen-specific memory B cells in spleens and plasma cells in bone marrow despite their lower levels of background IgG antibodies. These results suggest that CD47 plays a role as a negative regulator in inducing protective immune responses to influenza vaccination. I nfluenza viruses are common pathogens in the respiratory tract that are highly contagious and can cause pulmonary diseases. Seasonal influenza virus variants annually cause significant levels of morbidity and mortality, mostly in infants, the elderly, and sick people (1, 2). Vaccination is the most effective measure to prevent infections with a variety of pathogens, including influenza virus. Virus-like particles (VLPs) are able to effectively stimulate antigen-presenting cells (APCs), which in turn activate T and B cells (3-6). It has been demonstrated that immunization with influenza VLPs can induce protective humoral responses against seasonal and pandemic influenza virus infections (7-9). However, the mechanisms for evoking long-lasting immune responses are largely unknown.CD47 is a transmembrane protein, which is first identified as integrin ␣v␤3. CD47 that is expressed on hematopoietic and nonhematopoietic cells can interact with an inhibitory receptor signal regulatory protein ␣ (SIRP␣) (10). SIRP␣ is also expressed on dendritic cells (DCs) and macrophages, whereas SIRP␣ is barely expressed on B and T cells (11,12). It has been demonstrated that CD47/CD47 and CD47/SIRP␣ interactions are important for DC and neutrophil migration (13,14). In addition, CD11b ϩ DCs in the lungs express both CD47 and SIRP␣, but CD103 ϩ DCs express only CD47. It was also demonstrated t...

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H5N1 Virus-Like Particle Vaccine Elicits Cross-Reactive Neutralizing Antibodies That Preferentially Bind to the Oligomeric Form of Influenza Virus Hemagglutinin in Humans

Abstract: Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries

Cited by 89 publications

References 54 publications

Oligomeric Recombinant H5 HA1 Vaccine Produced in Bacteria Protects Ferrets from Homologous and Heterologous Wild-Type H5N1 Influenza Challenge and Controls Viral Loads Better than Subunit H5N1 Vaccine by Eliciting High-Affinity Antibodies

Oligomeric Recombinant H5 HA1 Vaccine Produced in Bacteria Protects Ferrets from Homologous and Heterologous Wild-Type H5N1 Influenza Challenge and Controls Viral Loads Better than Subunit H5N1 Vaccine by Eliciting High-Affinity Antibodies

New technologies for influenza vaccines

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

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