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Protein transduction domain-mediated influenza NP subunit vaccine generates a potent immune response and protection against influenza virus in mice.

ABSTRACT: The nucleoprotein (NP) is a highly conserved internal protein of the influenza virus, a major target for universal influenza vaccine. Our previous studies have proven NP-based subunit vaccine can provide partial protection in mice. It is reported that the protein transduction domain (PTD) TAT protein from human immunodeficiency virus-1 (HIV-1) is able to penetrate cells when added exogenous protein and could effectively enhance the immune response induced by the exogenous protein. In present study, the recombinant protein TAT-NP, a fusion of TAT and NP was effectively expressed in Escherichia coli and purified as a candidate component for an influenza vaccine. We evaluated the immunogenicity and protective efficacy of recombinant influenza TAT-NP vaccine by intranasal immunization. In vitro experiments showed that TAT-NP could efficiently penetrate into cells. Animal results showed that mice vaccinated with TAT-NP could not only induce higher levels of IgG and mucosal IgA, but also elicit a robust cellular immune response. Moreover, the TAT-NP fusion protein could significantly increase the protection of mice against lethal doses of homologous influenza virus PR8 and could also provide mice protection against a lethal dose challenge against heterosubtypic H9N2 and H3N2 influenza virus. In conclusion, the recombinant TAT-NP might be a universal vaccine candidate against influenza virus.

SUBMITTER: Yin Y

PROVIDER: S-EPMC8284974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8(+) T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity.The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative.

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Protein transduction domain-mediated influenza NP subunit vaccine generates a potent immune response and protection against influenza virus in mice.

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