A non-neutralizing antibody broadly protects against influenza virus infection by engaging effector cells

Ko, Young-Chai; Yu, Yueh‐Hsiang; Wu, Yen-Fei; Tseng, Yeu-Yang; Chen, Chia-Lin; Goh, King-Siang; Liao, Hsin-Kai; Chen, Ting-Hua; Cheng, Ting‐Jen R.; Yang, An‐Suei; Wong, Chi‐Huey; Ma, Che; Lin, Kuo‐I

doi:10.1371/journal.ppat.1009724

Cited by 19 publications

(15 citation statements)

References 54 publications

(75 reference statements)

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“…A large portion of specific IgG antibodies detected in 293T cell-expressed H5+N6 protein antisera may be the non-neutralizing antibody. Although non-neutralizing antibody is not able to prevent viral infection, it may still contribute to antiviral protection through other antibody-mediated effects, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or antibody-mediated complement-dependent cytotoxicity (CDC) [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of Avian Influenza H5N6 Virus-like Particles as a Broad-Spectrum Vaccine Candidate against H5Nx Viruses

Tai

Cheng

Wang

et al. 2022

Viruses

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Highly pathogenic avian influenza (HPAI) clade 2.3.4.4 viruses have been reported to be the source of infections in several outbreaks in the past decades. In a previous study, we screened out a broad-spectrum virus strain, H5N6-Sichuan subtype, by using a lentiviral pseudovirus system. In this project, we aimed to investigate the potential of H5N6 virus-like particles (VLPs) serving as a broad-spectrum vaccine candidate against H5Nx viruses. We cloned the full-length M1 gene and H5, N6 genes derived from the H5N6-Sichuan into pFASTBac vector and generated the VLPs using the baculovirus-insect cell system. H5N6 VLPs were purified by sucrose gradient centrifugation, and the presence of H5, N6 and M1 proteins was verified by Western blot and SDS-PAGE. The hemagglutination titer of H5N6 VLPs after purification reached 5120 and the particle structure remained as viewed by electron microscopy. The H5N6 VLPs and 293T mammalian cell-expressed H5+N6 proteins were sent for mice immunization. Antisera against the H5+N6 protein showed 80 to 320 neutralizing antibody titers to various H5Nx pseudoviruses. In contrast, H5N6 VLPs not only elicited higher neutralizing antibody titers, ranging from 640 to 1280, but also induced higher IL-2, IL-4, IL-5, IFN-γ and TNF production, thus indicating that H5N6 VLPs may be a potential vaccine candidate for broad-spectrum H5Nx avian influenza vaccines.

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Section: Discussionmentioning

confidence: 99%

Investigation of Avian Influenza H5N6 Virus-like Particles as a Broad-Spectrum Vaccine Candidate against H5Nx Viruses

Tai

Cheng

Wang

et al. 2022

Viruses

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“…In contrast to the neutralization antibodies, the nonneutralizing antibodies against the influenza virus also have demonstrated that they play a key role in protection according to their Fc-mediated responses (102,103). Indeed, a large number of non-neutralizing antibodies can broadly cross-react with coronaviruses (104).…”

Section: Omicron Variant: Good News Exists Beyond "Neutralization"mentioning

confidence: 99%

SARS-CoV-2 Omicron Variant: Epidemiological Features, Biological Characteristics, and Clinical Significance

et al. 2022

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The SARS-CoV-2 Omicron (B.1.1529) variant was designated as a variant of concern (VOC) by the World Health Organization (WHO) on November 26, 2021. Within two months, it had replaced the Delta variant and had become the dominant circulating variant around the world. The Omicron variant possesses an unprecedented number of mutations, especially in the spike protein, which may be influencing its biological and clinical aspects. Preliminary studies have suggested that increased transmissibility and the reduced protective effects of neutralizing antibodies have contributed to the rapid spread of this variant, posing a significant challenge to control the coronavirus disease 2019 (COVID-19) pandemic. There is, however, a silver lining for this wave of the Omicron variant. A lower risk of hospitalization and mortality has been observed in prevailing countries. Booster vaccination also has ameliorated a significant reduction in neutralization. Antiviral drugs are minimally influenced. Moreover, the functions of Fc-mediated and T-cell immunity have been retained to a great extent, both of which play a key role in preventing severe disease.

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“…In addition to binding via the antigen-binding fragment (Fab) region of the antibodies, the crystallizable fragment (Fc) region of antibodies plays a key role in recruitment of complement and activation of cellular effector mechanisms, most notably via ADCP by FcγR2a [ 34 ] and ADCC by FcγR3a [ 35 – 37 ]. Increased interactions of WPV-induced antigen-specific antibodies with these receptors suggests that apart from direct inhibition of viral entry in the event of infection, these antibodies also have the potential to engage Fc receptors on effector cells to facilitate cytolysis of virally-infected cells [ 38 ] and phagocytosis of opsonized material by cells expressing these receptors [ 34 ], thus can contribute to overall protection against infection and disease severity [ 39 ]. The engineering of low affinity FcγR ectodomains as a linked dimer confers avid binding only by pairs of IgG that occupy closely spaced (“near-neighbor”) epitopes [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Immunization with inactivated whole virus particle influenza virus vaccines improves the humoral response landscape in cynomolgus macaques

et al. 2022

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Although antibody-inducing split virus vaccines (SV) are currently the most effective way to combat seasonal influenza, their efficacy can be modest, especially in immunologically-naïve individuals. We investigated immune responses towards inactivated whole influenza virus particle vaccine (WPV) formulations, predicated to be more immunogenic, in a non-human primate model, as an important step towards clinical testing in humans. Comprehensive analyses were used to capture 46 immune parameters to profile how WPV-induced responses differed to those elicited by antigenically-similar SV formulations. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV consistently induced stronger antibody responses and hemagglutination inhibition (HI) antibody titres against vaccine-matched viruses compared to SV formulations, while acute reactogenic effects were similar. Responses in WPV-primed animals were further increased by boosting with the same formulation, conversely to modest responses after priming and boosting with SV. 28-parameter multiplex bead array defined key antibody features and showed that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV increased IgG responses against A/H1N1 hemagglutinin (HA) and HA-Stem, and higher IgA responses to A/H1N1-HA after each vaccine dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were also present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. Furthermore, WPV-enhanced antibody responses were associated with higher frequencies of HA-specific B-cells and IFN-γ-producing CD4+ T-cell responses. Our data additionally demonstrate stronger boosting of HI titres by WPV following prior infection and support WPV administered as a priming dose irrespective of the follow up vaccine for the second dose. Our findings thus show that compared to SV vaccination, WPV-induced humoral responses are significantly increased in scope and magnitude, advocating WPV vaccination regimens for priming immunologically-naïve individuals and also in the event of a pandemic outbreak.

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A non-neutralizing antibody broadly protects against influenza virus infection by engaging effector cells

Cited by 19 publications

References 54 publications

Investigation of Avian Influenza H5N6 Virus-like Particles as a Broad-Spectrum Vaccine Candidate against H5Nx Viruses

Investigation of Avian Influenza H5N6 Virus-like Particles as a Broad-Spectrum Vaccine Candidate against H5Nx Viruses

SARS-CoV-2 Omicron Variant: Epidemiological Features, Biological Characteristics, and Clinical Significance

Immunization with inactivated whole virus particle influenza virus vaccines improves the humoral response landscape in cynomolgus macaques

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