Modified Vaccinia Virus Ankara Encoding Influenza Virus Hemagglutinin Induces Heterosubtypic Immunity in Macaques

Abstract

Current influenza virus vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia virus IMPORTANCECurrent influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs typically are effective but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. Therefore, we evaluated a vaccine strategy designed to induce both antibody and T cell responses, which may provide more broadly cross-protective immunity against influenza. Here, we show in a translational primate model that vaccination with a modified vaccinia virus Ankara encoding hemagglutinin from a heterosubtypic H5N1 virus was associated with reduced shedding of a pandemic H1N1 virus challenge, while vaccination with MVA encoding nucleoprotein, an internal viral protein, was not. Unexpectedly, this reduced shedding was associated with nonneutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Therefore, antibody-dependent cellular cytotoxicity (ADCC) may play a role in cross-protective immunity to influenza virus. Vaccines that stimulate ADCC antibodies may enhance protection against pandemic influenza virus.

Mosaic H5 Hemagglutinin Provides Broad Humoral and Cellular Immune Responses against Influenza Viruses

“…Heterosubtypic protection against influenza viruses by vaccination has been linked to CD8 ϩ T cells, anti-stalk HA antibodies, and ADCC responses (17,19,21,22). MVA-H5M provided heterosubtypic protection against H1N1 virus without detectable neutralizing antibodies (12).…”

“…3C). In addition, the anti-HA stalk antibody has been shown to contribute to heterosubtypic protection against influenza virus (17). Plaque reduction neutralization tests (PRNTs) have been used to identify the existence of anti-stalk HA (17).…”

“…MVA has been widely used as a vaccine vector due to its ability to induce strong Th1, Th2, and innate immune responses (17,18). To examine the role of the MVA vector on the broad protection conferred by the mosaic H5 vaccine, the H5M gene was cloned and expressed in a DNA vaccine vector (pCMV-H5M).…”

Vaccine approaches conferring cross-protection against influenza viruses

“…Immunization of mice with purified NP of H3N2 influenza A virus (X31) resulted in significant cross-protection against lethal challenge with a heterosubtypic H1N1 influenza virus, A/PR/8/34[59–63]. Co-administration of ferrets with a DNA-based vaccine encoding HA from A/Hawaii/01/91 (H3N2) and NP and M1 from A/Beijing/353/89 (H3N2) was shown to provide better protection against challenge with antigenic drift variants A/Georgia/03/93 (H3N2) or A/Johannesburg/33/94 (H3N2) compared to an inactivated vaccine produced for the 1992–93 influenza season[64]. Immunization of mice with a DNA vaccine encoding the NP and matrix protein of A/PR/8/34 (H1N1) virus was shown to reduce replication of A/Hong Kong/483/97 (H5N1) and conferred protection against a lethal challenge with A/Hong Kong/156/97 (H5N1)[63].…”

Heterosubtypic immunity to H7N9 influenza virus in isogenic guinea pigs after infection with pandemic H1N1 virus

“…Heterosubtypic immunity has been demonstrated in several species including mice [7,8], macaques [9,10], ferrets [11], pigs [12,13], ducks [14,15], chickens [16,17], cotton-rats [18], and has also been confirmed following natural infection in humans [19]. Previous infection with H3N2 has been shown to have an effect on viral transmission of pandemic H1N1 virus in outbred guinea pigs [20] but to date, the existence of heterosubtypic immunity has not been ascertained in isogenic guinea pigs and, although it has been speculated that prior infection with H1N1pdm09 would provide a certain degree of protection against H7N9 infection [21], this combination of viruses has never been studied in an animal model.…”