Mechanism of Protection against Influenza A Virus by DNA Vaccine Encoding the Hemagglutinin Gene

Publisher： Karger

E-ISSN： 1423-0100|43|4-6|322-330

ISSN： 0300-5526

Source： Intervirology, Vol.43, Iss.4-6, 2001-02, pp. : 322-330

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Abstract

Influenza A virus with its two major antigenic surface proteins hemagglutinin (HA) and neuraminidase (NA) is a widely used model to study DNA immunizations in mice and other animals. Natural protection against influenza A virus infection is mediated by antibodies, which mostly are not protective against antigenic shift or drift variants of the original virus. Therefore, it would be a major task to induce a protective cellular immune re- sponse to more conserved proteins or epitopes. Injection of plasmid encoding a viral antigen is known to induce cellular as well as humoral immunity. In this study we investigate the mechanism of protection after intramuscular vaccination of C57Bl/6 mice with a DNA vaccine encoding HA of influenza A/PR/8/34. After a single injection, only a small percentage of mice survive the lethal challenge with homologous virus. The amount of protection can be doubled by applying a booster injection. Furthermore, by coinjection of plasmids encoding cytokines GM-CSF and IL-12, respectively, nearly all of the mice are protected. Mice with specific defects in the cellular immune response [perforin knockout (P^–/–) mice] and in the humoral immune response [IgD/IgM knockout (µMT) mice], respectively, have been immunized with HA DNA with or without cytokine DNA. Protection could only be induced in P^–/– mice, whereas µMT mice succumbed to the infection. Moreover, when µMT mice were infected with only 0.75 ×50% lethal dose they died all the same, whereby mice that had been depleted of CD8+ T cells before infection showed an even greater progression of illness. Altogether these results demonstrate that antibodies mediate protection after immunization with plasmid coding for HA of influenza A virus, and that booster immunizations and coinjection of plasmids encoding GM-CSF or IL-12 can improve this protection.