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: 4.92). 08/2009; 183(5):3294-301. DOI: 10.4049/jimmunol.0900398
Source: PubMed


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.

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    • "However, 277 there are different opinions on the effect of the inoculation dose on OAS. Kim et al. 278 demonstrated that induction of OAS was independent of the dose of live viruses 279 (0.01 or 0.1 LD50) in BALB/c mice (Kim et al., 2009). On the other hand, Fazekas 280 and Webster showed that irrespective of the primary vaccine dose in rabbits, both 281 cross-reactive and specific antibodies to the secondary antigen are produced when a 282 large dose (500 HA units) is used as second inoculum; while a low dose of 283 secondary antigen (31.6 HA units) induced more cross-reactive antibodies (Fazekas 284 de St. Groth & Webster, 1966). "
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    ABSTRACT: Human bocavirus (HBoV) 1 is a widespread parvovirus causing acute respiratory disease in young children. HBoV2 rather occurs in the gastrointestinal tract potentially associating with gastroenteritis, while HBoV3 and -4 infections are less frequent and not yet linked with human disease. Due to HBoV1-DNA persistence in the nasopharynx, serology has been advocated as a better alternative for diagnosing acute infections. In constitutionally healthy children, we have earlier noticed that pre-existing HBoV2 immunity in a subsequent HBoV1 infection typically resulted in low or non-existent HBoV1-specific antibody responses. A phenomenon describing such immunologic events among related viruses has been known since the 1950s as "original antigenic sin" (OAS). The aim of this study was to characterize this putative OAS phenomenon in a more controlled setting. Follow-up sera of 10 rabbit pairs, inoculated twice by HBoV1-4 virus-like particles (VLPs) or control antigens, in various combinations, were analysed with HBoV1-4 IgG EIAs with and without depletion of heterotypic HBoV antibodies. There were no significant IgG boosts after the second inoculation in either the heterologously or the homologously HBoV-inoculated rabbits, but a clear increase in cross-reactivity was seen with time. We could, however, distinguish a distinct OAS pattern from plain cross-reactivity: half the heterologously inoculated rabbits showed IgG patterns representative of the OAS hypothesis, in line with our prior results with naturally infected children.HBoVs are the first parvoviruses to show the possible existence of OAS. Our findings provide new information on HBoV1-4 immunity and emphasize the complexity of human bocavirus diagnosis.
    Journal of General Virology 07/2015; DOI:10.1099/jgv.0.000253 · 3.18 Impact Factor
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    • "Secondly, most of the adult patients were poultry workers or visitors who had prolonged exposure to the H7N9 virus in a larger dose. Moreover, researchers found that older adults have a higher risk of comorbid illnesses and a weaker immune response toward the H7N9 virus due to the immunological phenomenon of 'original antigenic sin' (Kim et al., 2009; Skowronski et al., 2013). However, population immunity toward this novel H7N9 virus is low as it only emerged recently. "
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    ABSTRACT: The novel avian influenza A H7N9 virus which caused the first human infection in Shanghai, China; was reported on the 31st of March 2013 before spreading rapidly to other Chinese provinces and municipal cities. This is the first time the low pathogenic avian influenza A virus has caused human infections and deaths; with cases of severe respiratory disease with pneumonia being reported. There were 440 confirmed cases with 122 fatalities by 16 May 2014; with a fatality risk of ∼28%.The median age of patients was 61 years with a male-to-female ratio of 2.4:1. The main source of infection was identified as exposure to poultry and there is so far no definitive evidence of sustained person-to-person transmission. The neuraminidase inhibitors, namely oseltamivir, zanamivir, and peramivir; have shown good efficacy in the management of the novel H7N9 virus. Treatment is recommended for all hospitalized patients, and for confirmed and probable outpatient cases; and should ideally be initiated within 48 h of the onset of illness for the best outcome. Phylogenetic analysis found that the novel H7N9 virus is avian in origin and evolved from multiple reassortments of at least four origins. Indeed the novel H7N9 virus acquired human adaptation via mutations in its eight RNA gene segments. Enhanced surveillance and effective global control are essential to prevent pandemic outbreaks of the novel H7N9 virus.
    Frontiers in Microbiology 03/2015; 6(140):1-11. DOI:10.3389/fmicb.2015.00140 · 3.99 Impact Factor
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    • "Although we found that SphB1 and Vag8 were both expressed during infection in naïve mice, antibodies against these (recombinant) antigens were undetectable in convalescent pertussis patients (data not shown). Although it is possible that these proteins have poor intrinsic immunogenicity in humans during natural infection, another explanation may be that vaccinated individuals who are subsequently infected with B. pertussis preferentially respond to only a limited number of immunodominant vaccine antigens, also known as original antigenic sin [37]. "
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    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 08/2014; 9(8):e105011. DOI:10.1371/journal.pone.0105011 · 3.23 Impact Factor
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