Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes

Lee, Andrew Chak-Yiu; Zhu, Hua; Zhang, Anna Jinxia; Li, Can; Wang, Pui; Li, Chuangen; Chen, Honglin; Hung, Ivan Fan-Ngai; To, Kelvin Kai-Wang; Yuen, Kwok‐Yung

doi:10.1128/cvi.00443-15

Cited by 14 publications

(12 citation statements)

References 34 publications

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“…The NP positive cells were examined under fluorescence microscope, and counted for 20 microscopic fields under 200 × magnification from each well using ImageJ software. Percentages of reduction of NP positive cell number were calculated against the virus only control, which was set at 100 ( 20 , 21 ).…”

Section: Methodsmentioning

confidence: 99%

Co-stimulation With TLR7 Agonist Imiquimod and Inactivated Influenza Virus Particles Promotes Mouse B Cell Activation, Differentiation, and Accelerated Antigen Specific Antibody Production

Zhang

et al. 2018

Front. Immunol.

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Current influenza vaccines have relatively low effectiveness, especially against antigenically drifted strains, the effectiveness is even lower in the elderly and immunosuppressed individuals. We have previously shown in a randomized clinical trial that the topical application of a toll-like receptor 7 agonist, imiquimod, just before intradermal influenza vaccine could expedite and augment antibody response, including to antigenically-drifted strains. However, the mechanism of this vaccine and imiquimod combination approach is poorly understood. Here, we demonstrated that imiquimod alone directly activated purified mouse peritoneal B cells. When combined with inactivated H1N1/415742Md influenza virus particle (VP) as vaccine, co-stimulation of mouse peritoneal B cells in vitro induced stronger activation, proliferation, and production of virus-antigen specific IgM and IgG. Intraperitoneal injection of a combination of VP and imiquimod (VCI) was associated with an increased number of activated B cells with enhanced expression of CD86 in the mesenteric draining lymph nodes (mesLN) and the spleen at 18 h after injection. Three days after immunization with VCI, mouse spleen showed significantly more IgM and IgG secreting cells upon in vitro re-stimulation with inactivated virus, mouse sera were detected with viral neutralizing antibody. Transfer of these spleen B cells to naïve mice improved survival after lethal dose of H1N1/415742Md challenge. More importantly, the functional response of VCI-induced B cell activation was demonstrated by early challenge with a lethal dose of H1N1/415742Md influenza virus at 3 days after immunization. The spleen and mediastinal lymph nodes (mdLN) in mice immunized with VCI had germinal center formation, and significantly higher number of plasmablasts, plasma cells, and virus-antigen specific IgM and IgG secreting cells at only 3–4 days post virus challenge, compared with those of mice that have received imiquimod, inactivated virus alone or PBS. Serum virus-specific IgG2a, IgG2b, and IgG1 and bronchoalveolar lavage fluid (BALF) virus-specific IgA at 3 or 4 days post challenge were significantly higher in mice immunized with VCI, which had significantly reduced lung viral load and 100% survival. These findings suggested that imiquimod accelerates the vaccine-induced antibody production via inducing rapid differentiation of naïve B cells into antigen-specific antibody producing cells.

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Section: Methodsmentioning

confidence: 99%

Co-stimulation With TLR7 Agonist Imiquimod and Inactivated Influenza Virus Particles Promotes Mouse B Cell Activation, Differentiation, and Accelerated Antigen Specific Antibody Production

Zhang

et al. 2018

Front. Immunol.

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“…First, a poor microneutralization titer may be related to the effect of internal genes on host humoral immune response. In our previous mice model with A(H7N9) virus infection, microneutralization antibodies were not detected despite the presence of hemagglutination inhibition antibody titer 27 . Experiments with reassortant viruses showed that the internal genes of the A(H7N9) virus was responsible for the lower microneutralization titer.…”

Section: Discussionmentioning

confidence: 66%

Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017

Zhu

Lee

et al. 2018

Emerging Microbes & Infections

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The 2017 Hong Kong influenza A(H3N2) summer season was unexpectedly severe. However, antigenic characterization of the 2017 circulating A(H3N2) viruses using ferret antisera did not show significant antigenic drift. We analyzed the hemagglutinin amino acid sequences of A(H3N2) virus circulating in Hong Kong in 2017, and found that viruses with hemagglutinin N121K substitution, which was rare before 2017, emerged rapidly and dominated in 2017 (52.4% of A[H3N2] virus in 2017 contains N121K substitution). Microneutralization assay using archived human sera collected from mid-2017 showed that the geometric mean microneutralization titer was 3.6-fold lower against a 2017 cell culture-grown circulating A(H3N2)-N121K virus (3391/2017 virus) than that against the cell culture-grown 2016–2017 A(H3N2) seasonal influenza vaccine-like vaccine virus (4801/2014 virus) (13.4 vs 41.8, P < 0.0001). Significantly fewer serum specimens had a microneutralization titer of 40 or above against 3391/2017 virus than that against 4801/2014 virus (26.4% vs 60.0%, P < 0.0001). Conversely, the geometric mean hemagglutination inhibition titer was slightly higher against 3391/2017 virus than that against the 4801/2014 virus (96.9 vs 55.4, P < 0.0001). Moreover, 59.1% of specimens had a significantly lower microneutralization antibody titer (≥4-fold) against 3391/2017 virus than that against 4801/2014 virus, but none for hemagglutination titer (P < 0.0001). Similar results of microneutralization and hemagglutination titers were observed for day 21-post-vaccination sera. Hence, the 2017 A(H3N2) summer peak in Hong Kong was associated with a low-microneutralization titer against the circulating virus. Our results support the use of microneutralization assay with human serum in assessing population susceptibility and antigenic changes of A(H3N2) virus. Novel and available immunization approach, such as topical imiquimod followed by intradermal vaccination, to broaden the neutralizing antibody response of influenza vaccine should be considered.

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“…Furthermore, one ferret showed a quite different disease outcome, in which the ferret presented an escalation of clinical signs and was euthanised for ethical reasons at day 6 post-infection. Other studies have previously shown clinical variation between strains of H7N9 ( 15 ), however most studies with A /Anhui/1/2013 (H7N9) show ferrets presenting only mild clinical signs ( 1 , 4 , 33 ). To our knowledge, this is the first reported result showing variable disease outcome in an animal study using a single low pathogenicity H7N9 strain, in which one ferret showed severe clinical outcomes.…”

Section: Discussionmentioning

confidence: 96%

“…While hypercytokinemia is common amongst many AI virus infections, H7N9 strains such as the human infecting A/Anhui/1/2013 virus have been associated with dampened IFN responses in humans ( 13 , 14 ). Furthermore, they have previously been associated with an attenuated humoral immune response in the mouse model ( 15 ). These studies demonstrate the unpredictable nature and wide spectrum of pathogenicity of AI viruses.…”

Section: Introductionmentioning

confidence: 99%

The Dynamics of the Ferret Immune Response During H7N9 Influenza Virus Infection

et al. 2020

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As the recent outbreak of SARS-CoV-2 has highlighted, the threat of a pandemic event from zoonotic viruses, such as the deadly influenza A/H7N9 virus subtype, continues to be a major global health concern. H7N9 virus strains appear to exhibit greater disease severity in mammalian hosts compared to natural avian hosts, though the exact mechanisms underlying this are somewhat unclear. Knowledge of the H7N9 host-pathogen interactions have mainly been constrained to natural sporadic human infections. To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. Intriguingly, we observed variable disease outcomes when ferrets were inoculated with the A/Anhui/1/2013 (H7N9) strain. We observed relatively reduced antigen-presenting cell activation in lymphoid tissues which may be correlative with increased disease severity. Additionally, depletions in CD8 + T cells were not apparent in sick animals. This study provides further insight into the ways that lymphocytes maturate and traffic in response to H7N9 infection in the ferret model.

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Suboptimal Humoral Immune Response against Influenza A(H7N9) Virus Is Related to Its Internal Genes

Cited by 14 publications

References 34 publications

Co-stimulation With TLR7 Agonist Imiquimod and Inactivated Influenza Virus Particles Promotes Mouse B Cell Activation, Differentiation, and Accelerated Antigen Specific Antibody Production

Co-stimulation With TLR7 Agonist Imiquimod and Inactivated Influenza Virus Particles Promotes Mouse B Cell Activation, Differentiation, and Accelerated Antigen Specific Antibody Production

Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017

The Dynamics of the Ferret Immune Response During H7N9 Influenza Virus Infection

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