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Vaccination with ADCC activating HA peptide epitopes provides partial protection from influenza infection.

ABSTRACT: Influenza-specific antibody dependent cellular cytotoxicity (ADCC) antibodies have a broad cross reactivity and potential as an immune correlate for universal vaccines. Peptide-mapping for ADCC reactivity of H1-HA and H7-HA proteins from human serum samples identified high ADCC-inducing peptides in both the HA1 and HA2 regions. Vaccination of mice with single ADCC-peptides induced ADCC activity leading to partial protection from lethal influenza challenge, with increased survival, reduced viral loads, and reduced activation of NK cells in the lungs. Targeted vaccination strategies to elicit ADCC responses may provide an approach for universal vaccines.

SUBMITTER: Kavian N

PROVIDER: S-EPMC7524583 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Vaccination with ADCC activating HA peptide epitopes provides partial protection from influenza infection.

Kavian Niloufar N Hachim Asmaa A Poon Leo L M LLM Valkenburg Sophie A SA

Vaccine 20200725 37

Influenza-specific antibody dependent cellular cytotoxicity (ADCC) antibodies have a broad cross reactivity and potential as an immune correlate for universal vaccines. Peptide-mapping for ADCC reactivity of H1-HA and H7-HA proteins from human serum samples identified high ADCC-inducing peptides in both the HA1 and HA2 regions. Vaccination of mice with single ADCC-peptides induced ADCC activity leading to partial protection from lethal influenza challenge, with increased survival, reduced viral ...[more]

PMID: 32718818

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Project description:BackgroundInfluenza infection could be more effectively controlled if a multi-purpose vaccine with the ability to induce responses against most, or all, influenza A subtypes could be generated. Conserved viral proteins are a promising basis for the creation of a broadly protective vaccine. In the present study, the immunogenicity and protective properties of three recombinant proteins (vaccine candidates), comprising conserved viral proteins fused with bacterial flagellin, were compared.MethodsBalb/c mice were immunized intranasally with recombinant proteins comprising either one viral protein (the ectodomain of the M2 protein, 'M2e') or two viral proteins (M2e and the hemagglutinin second subunit 'HA2' epitope) genetically fused with flagellin. Further, two different consensus variants of HA2 were used. Therefore, three experimental positives were used in addition to the negative control (Flg-his). The mucosal, humoral, and T-cell immune responses to these constructs were evaluated.ResultWe have demonstrated that insertion of the HA2 consensus polypeptide (aa 76-130), derived from either the first (HA2-1) or second (HA2-2) virus phylogenetic group, into the recombinant Flg4M2e protein significantly enhanced its immunogenicity and protective properties. Intranasal administration of the vaccine candidates (Flg-HA2-2-4M2e or Flg-HA2-1-4M2e) induced considerable mucosal and systemic responses directed at both the M2e-protein and, in general, the influenza A virus. However, the immune response elicited by the Flg-HA2-1-4M2e protein was weaker than the one generated by Flg-HA2-2-4M2e. These recombinant proteins containing both viral peptides provide complete protection from lethal challenge with various influenza viruses: A/H3N2; A/H2N2; and A/H5N1.ConclusionThis study demonstrates that the intranasal administration of Flg-HA2-2-4M2e recombinant protein induces a strong immune response which provides broad protection against various influenza viruses. This construct is therefore a strong candidate for development as a universal vaccine.

Project description:The H7N9 subtype influenza A viruses pose a serious threat to public health, and there is still a lack of vaccines or drugs for humans against H7N9 influenza viruses. In this study, we screened two monoclonal antibodies (MAbs), 4H1E8 and 7H9A6, that specifically recognize the hemagglutinin (HA) protein of H7N9 influenza virus and display highly neutralizing activity against H7N9 virus. The epitopes recognized by two MAbs are nearly all conserved within all known H7 subtypes. Characteristic identification showed that two MAbs have high avidity for the HA protein but no hemagglutinin inhibition activity or antibody-dependent cellular cytotoxicity. Mechanistically, the 4H1E8 and 7H9A6 antibodies inhibit the pH-dependent conformational change of HA and block the HA-mediated membrane fusion. More importantly, 4H1E8 and 7H9A6 exhibit promising prophylactic and therapeutic effects against lethal challenge with H7N9 virus. Moreover, 4H1E8- and 7H9A6-treated mice displayed inhibition of pulmonary viral replication and reduced lung lesions after viral challenge. Together, these findings indicate that antibodies 4H1E8 and 7H9A6 recognize unique epitopes in the HA protein and possess the neutralizing activity and protective efficacy against the H7N9 influenza A viruses. IMPORTANCE In 2013, H7N9 influenza viruses appeared in China and other countries resulting in more than 1,500 individual infections or death. There are still limited studies on vaccines or drugs for humans against H7N9 influenza viruses. Alternative approaches against H7N9 virus infection need to be developed. Here, we identified two monoclonal antibodies (4H1E8 and 7H9A6) that possess neutralizing activity by blocking the pH-dependent HA-mediated membrane fusion. Additionally, the two monoclonal antibodies protect mice against the H7N9 virus challenge prophylactically or therapeutically. Therefore, our study demonstrates that 4H1E8 and 7H9A6 could be used for the prevention and treatment of the H7N9 influenza virus, and the conserved epitopes we identified may contribute to the development of a broad H7N9 vaccine and provide insights into unique antiviral approaches.

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Vaccination with ADCC activating HA peptide epitopes provides partial protection from influenza infection.

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Vaccination with ADCC activating HA peptide epitopes provides partial protection from influenza infection.

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