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Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs.

ABSTRACT: Despite the ability to induce a broad range of cross protection, M2e5x virus-like particles (VLPs) alone provide limited vaccine efficacy and confer low efficacy of protection against highly pathogenic avian influenza virus (HPAIV) infection in chickens. Avian influenza hemagglutinin (HA) has been a major antigenic target that enhances humoral immunity, but the efficacy of avian HA-based vaccines against HPAIV needs to be further improved. In this study, we evaluated the vaccine efficacy induced by combination of conserved tandem repeat M2e5x VLPs and HA VLPs against an avian influenza virus. We found that combinatorial vaccine elicited higher levels of reassortant H5N1 (rgH5N1) virus-specific IgG, IgG1, IgG2a and IgA antibody responses compared to M2e5x VLPs in sera and lungs of mice. Combinatorial VLPs vaccination induced higher levels of CD8+ T cell and germinal center B cell responses in lung and spleen compared to M2e5x VLPs. Combinatorial VLPs vaccination showed significantly reduced inflammatory responses and lung viral loads upon rgH5N1 virus challenge infection, resulting in less body weight loss compared to M2e5x VLPs alone. These results indicate that immune responses to both M2e and HA might provide a strategy of vaccination inducing enhanced protection against avian influenza virus.

SUBMITTER: Kang HJ

PROVIDER: S-EPMC6597044 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs.

Kang Hae-Ji HJ Chu Ki-Back KB Lee Dong-Hun DH Lee Su-Hwa SH Park Bo Ryoung BR Kim Min-Chul MC Kang Sang-Moo SM Quan Fu-Shi FS

PloS one 20190627 6

Despite the ability to induce a broad range of cross protection, M2e5x virus-like particles (VLPs) alone provide limited vaccine efficacy and confer low efficacy of protection against highly pathogenic avian influenza virus (HPAIV) infection in chickens. Avian influenza hemagglutinin (HA) has been a major antigenic target that enhances humoral immunity, but the efficacy of avian HA-based vaccines against HPAIV needs to be further improved. In this study, we evaluated the vaccine efficacy induced ...[more]

PMID: 31246961

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Project description:BackgroundCurrent vaccines to avian influenzae virus (AIV), a highly contagious disease of birds, need to be constantly updated due to the high level of variation in the target antigens. Therefore, a vaccine that could induce broad cross protection against AIV is required. The M2 membrane protein is structurally conserved amongst AIV subtypes but tends in induce a poor immune response, whereas C3d has been shown in many species to enhance immunogenicity. In this study, we investigated the potential of M2-avian C3d fusion proteins to provide effective immunity.ResultsWe fused chicken complement C3d to sM2 (M2 protein with the transmembrane region deleted) of AIV and expressed four fusion proteins, GST (Glutathione S-transferase tagged proteins in pGEX expression vector) -C3d-sM2, GST-C3d-L2-sM2, GST-C3d-L1-C3d-sM2 and GST-C3d-L1-C3d-L2-sM2 were used to immunize mice. In addition, Specific pathogen free (SPF) chickens were inoculated with the plasmids pcDNA-sM2, pcDNA-C3d-L1-C3d-L2-sM2, GST-sM2 and GST-C3d-L1-C3d-L2-sM2. The immune response was monitored by an enzyme-linked immunosorbent assay (ELISA) for sM2 antibody, and all the test animals were challenged with A/chicken/Bei Jing/WD9/98 (H9N2) virus. Results revealed that the anti-sM2 antibody in mice and chickens vaccinated with these proteins was higher than the nonfused forms of sM2, the GST-C3d-L1-C3d-L2-sM2 groups have conferred the highest 30% and 20% protection ratio in mice and chickens respectively. In addition, the pcDNA-C3d-L1-C3d-L2-sM2 also enhances the antibody responses to sM2 compared to pcDNA-sM2 in chickens, and acquired 13.3% protection ratio.ConclusionThese results indicated that chicken C3d enhanced the humoral immunity against AIV M2 protein either fused proteins expressed by the prokaryotic system or with the DNA vaccine. Nevertheless, in view of the poor protection ratio for these animals, we speculated that this is not a worthy developing of vaccine in these constructs.

Project description:H6N6 viruses are commonly isolated from domestic ducks, and avian-to-swine transmissions of H6N6 viruses have been detected in China. Whether subsequent adaptation of H6N6 viruses in mammals would increase their pathogenicity toward humans is not known. To address this, we generated a mouse-adapted (MA) swine influenza H6N6 virus (A/swine/Guangdong/K6/2010 [GDK6-MA]) which exhibited greater virulence than the wild-type virus (GDK6). Amino acid substitutions in PB2 (E627K), PA (I38M), and hemagglutinin ([HA] L111F, H156N, and S263R) occurred in GDK6-MA. HA with the H156N mutation [HA(H156N)] resulted in enlarged plaque sizes on MDCK cells and enhanced early-stage viral replication in mammalian cells. PA(I38M) raised polymerase activity in vitro but did not change virus replication in either mammalian cells or mice. These single substitutions had only limited effects on virulence; however, a combination of HA(H156N S263R) with PA(I38M) in the GDK6 backbone led to a significantly more virulent variant. This suggests that these substitutions can compensate for the lack of PB2(627K) and modulate virulence, revealing a new determinant of pathogenicity for H6N6 viruses in mice, which might also pose a threat to human health.Avian H6N6 influenza viruses are enzootic in domestic ducks and have been detected in swine in China. Infections of mammals by H6N6 viruses raise the possibility of viral adaptation and increasing pathogenicity in the new hosts. To examine the molecular mechanisms of adaptation, a mouse-adapted avian-origin swine influenza H6N6 virus (GDK6-MA), which had higher virulence than its parental virus, was generated. Specific mutations were found in PB2 (E627K), PA (I38M), and HA (L111F, H156N, and S263R) and were assessed for their virulence in mice. The combination of HA(H156N S263R) and PA(I38M) compensated for the lack of PB2(627K) and showed increased pathogenicity in mice, revealing a novel mechanism that can affect the virulence of influenza viruses. H6N6 viruses should be monitored in the field for more virulent forms that could threaten human health.

Dataset Information

Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs.

Publications

Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs.

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