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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    • "Importantly , vaccine-induced T cells could thus confer some protection against pandemic influenza. Moreover, vaccine induced T cells could play a role in protection against influenza in elderly individuals subject to immune exhaustion [13] [14] [15] [16]. Long-lasting cellular immunity is directed predominantly against conserved, internal viral proteins, such as nucleoprotein (NP) [17] [18]. "
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    ABSTRACT: Vaccination is at present the most efficient way of preventing influenza infections. Currently used inactivated influenza vaccines can induce virus-neutralizing antibodies that are protective against a particular influenza strain, but hamper the induction of cross-protective T-cell responses to later infections. Thus, influenza vaccines need to be updated annually in order to confer protection against circulating influenza strains. This study aims at developing an efficient vaccine that can induce broader protection against influenza. For this purpose, we have used the highly conserved nucleoprotein (NP) from an influenza A virus subtype H7N7 strain, and inserted it into a vaccine format that targets an antigen directly to relevant antigen presenting cells (APCs). The vaccine format consists of bivalent antigenic and targeting units, linked via an Ig-based dimerization unit. In this study, NP was linked to MIP-1α, a chemokine that targets the linked antigen to chemokine receptors 1, 3 and 5 expressed on various APCs. The vaccine protein was indirectly delivered by DNA. Mice were vaccinated intradermally with plasmids, in combination with electroporation to enhance cellular uptake of DNA. We found that a single DNA vaccination was sufficient for induction of both antibody and T cell responses in BALB/c mice. Targeting of nucleoprotein to chemokine receptors enhanced T cell responses but not antibody responses. Moreover, a single dose of MIP1α-NP conferred protection in BALB/c mice against a lethal challenge with an H1N1 influenza virus. The observed cross-protection was mediated by CD8(+) T cells.
    Vaccine 09/2015; DOI:10.1016/j.vaccine.2015.08.094 · 3.62 Impact Factor
    • "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.
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    • "Our study showed that a higher number of antigenic mismatches at epitope A, compared to the contemporary vaccine strains, were detected among severely ill patients. On the basis of the principle of the 'original antigenic sin' (Francis et al., 1953; Kim et al., 2009; Wilson and Cox, 1990), this suggests that the rapid introduction of antigenic differences may lead to a less effective and more delayed, specific immune response by the early, naïve B-cells, resulting in longer and more complicated illness caused by these newly drifted A/H3N2 viruses (Lambert et al., 2005). "
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    ABSTRACT: Epitopes are the main targets for specific antibodies in the host defense systems. Recent studies have shown that amino acid (aa) substitutions located within the influenza A/H3N2 hemagglutinin 1 (HA1) epitopes A-E, particularly in A and B, result in antigenic drift. Viruses with such drift mutations may have resulted in more severe influenza-related illness during influenza epidemics between late 2012 and early 2015. We sought to quantify vaccine mismatches in epitopes A-E of the HA1 protein, and correlate these with the severity of the patient's illness. The influenza A/H3N2 clinical samples were collected between April 2009 and November 2013 (n=206). Patients were clinically stratified into groups with mild, moderate, and severe influenza-like illness (ILI). The impact of the number of aa mismatches in each of epitopes A-E, gender, age groups (⩽18, 19-64, ⩾65years), and comorbidities on the likelihood that patients would suffer moderate and/or severe ILI due to influenza A/H3N2 infection were assessed. A higher number of aa mismatches in epitope A between the vaccine and locally circulating viruses correlated with more severe influenza infection, although this correlation was most significant with pre-existing comorbidities. A practical application of this finding would be to monitor patients (especially those in high-risk groups) infected with such viruses more closely, as they are at increased risk of developing more serious disease. Epidemiologically, it was of interest to note that viruses from subclade 3A of Victoria/208 strain were not detected in Singapore between 2009 and 2012. By contrast, these viruses were detected at a prevalence of up to 40% in the 2011-2012 influenza seasons in other regions of the Northern and Southern hemispheres. Such findings support the rationale for more regionally customized seasonal influenza vaccine compositions to optimize the protection of the population against locally circulating virus strains.
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