Article

Original antigenic sin responses to influenza viruses.

Department of Microbiology and Immunology, Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA.
The Journal of Immunology (Impact Factor: 5.52). 08/2009; 183(5):3294-301. DOI: 10.4049/jimmunol.0900398
Source: PubMed

ABSTRACT Most immune responses follow Burnet's rule in that Ag recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of "original antigenic sin" stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce Abs against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. This blind spot of the immune system and the redirection of responses to the "original Ag" rather than to novel epitopes were described fifty years ago. Recent reports have questioned the existence of this phenomenon. Hence, we revisited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we show that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we show that sequential infection of mice with two live influenza virus strains leads to almost exclusive Ab responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.

0 Bookmarks
 · 
86 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The implications of sequential prime and challenge with mismatched influenza A viruses is a concern in mammals, including humans. We evaluated the ability of pigs affected with vaccine-associated enhanced respiratory disease (VAERD) to generate a humoral immune response against the heterologous challenge virus inciting the VAERD. Vaccinated and challenged (V/C) pigs were administered an inactivated swine δ-cluster H1N2 (MN08) vaccine with an HA similar to pre-2009 seasonal human viruses and challenged with heterologous A(H1N1) pandemic 2009 (H1N1pdm09). Vaccination induced MN08-specific hemagglutination inhibition (HI) antibody but not cross-reacting H1N1pdm09 HI antibody. However, vaccinated pigs demonstrated significantly higher post-challenge anti-H1N1pdm09 serum neutralizing (SN) antibodies at 14 and 21 days post inoculation (dpi) compared to nonvaccinated, challenged pigs (NV/C), indicating a priming effect of the vaccine. Serum and lung whole virus anti-H1N1pdm09 IgG ELISA antibodies in the vaccinated group were significantly higher than the challenge only pigs at all-time points evaluated. Lung IgA ELISA antibodies to both antigens were detected at 2, 5, and 21 dpi in vaccine-primed pigs, contrasted against mucosal ELISA antibody responses detected only at 21 dpi in the naïve-challenged group. Collectively, vaccine-primed pigs demonstrated a robust humoral immune response and elevated local adaptive cytokine levels, indicating VAERD does not adversely affect the induction of an immune response to challenge with heterologous virus despite the severe clinical disease and underlying lung pathology. Thus, original antigenic sin does not appear to be a component of VAERD.
    Viral immunology 09/2013; · 1.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pertussis is a highly infectious respiratory disease of humans caused by the bacterium Bordetella pertussis. Despite high vaccination coverage, pertussis has re-emerged globally. Causes for the re-emergence of pertussis include limited duration of protection conferred by acellular pertussis vaccines (aP) and pathogen adaptation. Pathogen adaptations involve antigenic divergence with vaccine strains, the emergence of strains which show enhanced in vitro expression of a number of virulence-associated genes and of strains that do not express pertactin, an important aP component. Clearly, the identification of more effective B. pertussis vaccine antigens is of utmost importance. To identify novel antigens, we used proteomics to identify B. pertussis proteins regulated by the master virulence regulatory system BvgAS in vitro. Five candidates proteins were selected and it was confirmed that they were also expressed in the lungs of naïve mice seven days after infection. The five proteins were expressed in recombinant form, adjuvanted with alum and used to immunize mice as stand-alone antigens. Subsequent respiratory challenge showed that immunization with the autotransporters Vag8 and SphB1 significantly reduced bacterial load in the lungs. Whilst these antigens induced strong opsonizing antibody responses, we found that none of the tested alum-adjuvanted vaccines - including a three-component aP - reduced bacterial load in the nasopharynx, suggesting that alternative immunological responses may be required for efficient bacterial clearance from the nasopharynx.
    PLoS ONE 01/2014; 9(8):e105011. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. We report a follow up clinical and serological investigation of 274 children receiving seasonal influenza vaccine (TIV) one year after receipt of either AS03B-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV. Method and Findings. Vaccine responses were analysed using Haemagglutination Inhibition (HAI) assays. In individuals under 3 years of age, previous receipt of adjuvanted vaccine resulted in higher HAI antibody responses to H3N2 and B strains compared to non-adjuvanted vaccine (fold change 16.8 vs 4.3 for H3N2 and 7.0 vs 1.6 for B). In older children, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken pre- and post pandemic vaccine were also analysed by HAI with A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03B-adjuvanted vaccine but only 1.4% in the non-adjuvanted group had a 4-fold rise to A/Perth/16/2009. Conculsion. AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in <3-year-old children one year later.
    Clinical Infectious Diseases 10/2013; · 9.37 Impact Factor