tetano
Editor, Senior Moderator
J Virol. 2014 Sep 10. pii: JVI.01219-14. [Epub ahead of print]
Modified vaccinia Ankara encoding influenza virus hemagglutinin induces heterosubtypic immunity in macaques.
Florek NW1, Weinfurter JT1, Jegaskanda S2, Brewoo JN3, Powell TD3, Young GR3, Das SC3, Hatta M4, Broman KW5, Hungnes O6, Dudman SG6, Kawaoka Y4, Kent SJ2, Stinchcomb DT3, Osorio JE7, Friedrich TC8.
Author information
Abstract
Current influenza vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA based vaccines 4 weeks apart, and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs, but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza HA and/or NP had high frequencies of virus-specific CD4+ and CD8+ T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC may play a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective.
IMPORTANCE:
Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs are typically effective, but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. We therefore 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 Ankara (MVA) 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 non-neutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Antibody-dependent cellular cytotoxicity (ADCC) may therefore play a role in cross-protective immunity to influenza. Vaccines that stimulate "ADCC antibodies" may enhance protection against pandemic influenza.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25210172
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25210172
Modified vaccinia Ankara encoding influenza virus hemagglutinin induces heterosubtypic immunity in macaques.
Florek NW1, Weinfurter JT1, Jegaskanda S2, Brewoo JN3, Powell TD3, Young GR3, Das SC3, Hatta M4, Broman KW5, Hungnes O6, Dudman SG6, Kawaoka Y4, Kent SJ2, Stinchcomb DT3, Osorio JE7, Friedrich TC8.
Author information
Abstract
Current influenza vaccines primarily aim to induce neutralizing antibodies (NAbs). Modified vaccinia Ankara (MVA) is a safe and well-characterized vector for inducing both antibody and cellular immunity. We evaluated the immunogenicity and protective efficacy of MVA encoding influenza virus hemagglutinin (HA) and/or nucleoprotein (NP) in cynomolgus macaques. Animals were given 2 doses of MVA based vaccines 4 weeks apart, and were challenged with a 2009 pandemic H1N1 isolate (H1N1pdm) 8 weeks after the last vaccination. MVA-based vaccines encoding HA induced potent serum antibody responses against homologous H1 or H5 HAs, but did not stimulate strong T cell responses prior to challenge. However, animals that received MVA encoding influenza HA and/or NP had high frequencies of virus-specific CD4+ and CD8+ T cell responses within the first 7 days of H1N1pdm infection, while animals vaccinated with MVA encoding irrelevant antigens did not. We detected little or no H1N1pdm replication in animals that received vaccines encoding H1 (homologous) HA, while a vaccine encoding NP from an H5N1 isolate afforded no protection. Surprisingly, H1N1pdm viral shedding was reduced in animals vaccinated with MVA encoding HA and NP from an H5N1 isolate. This reduced shedding was associated with cross-reactive antibodies capable of mediating antibody-dependent cellular cytotoxicity (ADCC) effector functions. Our results suggest that ADCC may play a role in cross-protective immunity against influenza. Vaccines optimized to stimulate cross-reactive antibodies with ADCC function may provide an important measure of protection against emerging influenza viruses when NAbs are ineffective.
IMPORTANCE:
Current influenza vaccines are designed to elicit neutralizing antibodies (NAbs). Vaccine-induced NAbs are typically effective, but highly specific for particular virus strains. Consequently, current vaccines are poorly suited for preventing the spread of newly emerging pandemic viruses. We therefore 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 Ankara (MVA) 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 non-neutralizing antibodies that bound H1 hemagglutinin and activated natural killer cells. Antibody-dependent cellular cytotoxicity (ADCC) may therefore play a role in cross-protective immunity to influenza. Vaccines that stimulate "ADCC antibodies" may enhance protection against pandemic influenza.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
25210172
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25210172