Wrammert, J. et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J. Exp. Med. 208, 181-193

Emory Vaccine Center, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2011; 208(1):181-93. DOI: 10.1084/jem.20101352
Source: PubMed


The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates.

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Available from: Aneesh K Mehta, Oct 10, 2015
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    • "Recent studies aiming to characterize conserved epitopes of influenza virus revealed that specific regions in the HA stalk domain are highly preserved both in the structure and the sequence among various subtypes of viruses. It has been discovered that neutralizing antibodies to the HA stalk domain can be found after influenza infection (Wrammert et al., 2011) and vaccination (Corti et al., 2010). These anti-stalk antibodies demonstrate cross-reactivity between HAs of many strains from group 1 as well as from group 2 and it has been shown * e-mail: "
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    ABSTRACT: Influenza A virus infections are the major public health concern and cause significant morbidity and mortality each year worldwide. Vaccination is the main strategy of influenza epidemic prevention. However, seasonal vaccines induce strain-specific immunity and must be reformulated annually based on prediction of the strains that will circulate in the next season. Thus, it is essential to develop vaccines that would induce broad and persistent immunity to influenza viruses. Hemagglutinin is the major surface antigen of the influenza virus. Recent studies revealed the importance of HA stalk-specific antibodies in neutralization of different influenza virus strains. Therefore, it is important to design an immunogen that would focus the immune response on the HA stalk domain in order to elicit neutralizing antibodies. In the present study, we report characterization of a conserved truncated protein, potentially a universal influenza virus antigen from the H5N1 Highly Pathogenic Avian Influenza A virus strain. Our results indicate that exposure of the HA stalk domain containing conserved epitopes results in cross reactivity with different antibodies (against group 1 and 2 HAs). Additionally, we conclude that HA stalk domain contains not only conformational epitopes recognized by universal FI6 antibody, but also linear epitopes recognized by other antibodies.
    Acta biochimica Polonica 09/2014; 61(3). · 1.15 Impact Factor
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    • "Most adults will have been infected or vaccinated with influenza multiple times, and secondary responses are therefore the most commonly examined. During natural infection with influenza A(H1N1)pdm09, virus-specific plasmablasts are readily detected at a frequency of approximately 1,000 IgG-secreting cells per million PBMCs using B cell ELISpot assay at 7–10 days after symptom onset (Wrammert et al. 2011; Lee et al. 2011). The kinetics of these responses have been studied in more detail in the experimental human challenge model, where infection with seasonal influenza H1N1 A/Brisbane/59/07 led to an expansion of ASCs peaking at an average of 166 IgG+ ASCs per million PBMCs around 7 days postinoculation , correlating with viral shedding and symptoms (Huang et al. 2014). "
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    ABSTRACT: Although vaccinesVaccines against influenza are widely available, control of the disease remains elusive. In part, this is due to the inability of current vaccines to induce durable, broadly protective immune responses. Prevention of influenza depends primarily on effective antibodyAntibody responses that block virus entry. Following infection, high-affinity IgAAntibody IgA antibodies are generated in the respiratory tract that lead to immune exclusion, while IgGAntibody IgG prevents systemic spread. These are effective and long-lasting but also exert immune pressure. Mutation of the antigenic determinants of influenza therefore rapidly leads to emergence of novel variants that evade previously generated protective responses. Not only do vaccines suffer from this strain-specific limitation, but also they are suboptimal in their ability to induce durable immunity. However, recent evidence has demonstrated the possibility of inducing broadly cross-reactive antibodyAntibody broadly cross-reactive antibody responses. Further understanding of the ways in which high-titer, long-lived antibody responses directed against such cross-reactive epitopes can be induced would lead to the development of novel vaccines that may remove the requirement for recurrent vaccination.
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    • "As their epitopes are highly conserved among various influenza virus subtypes, these stem-binding antibodies have heterosubtypic neutralizing activity. Studies conducted after the initial identification of these broadly neutralizing antibodies (bnAbs) have shown that they are less rare than initially believed [13] and that infection with the 2009 pandemic H1N1 virus frequently elicited B cells producing stem-reactive antibodies [14]–[16]. Importantly, various reports indicate that B cells producing bnAbs were also induced in humans following vaccination with the 2009 pandemic H1N1 influenza vaccine [15], [17]–[20], which supports the possibility of designing vaccines that elicit bnAbs and provide broad protection against influenza. Various approaches to the design of such ‘universal’ vaccines are being explored, such as the creation of ‘headless’ HA immunogens [21], [22] and novel immunization strategies [23], [24]. "
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