Impact of preexisting memory to seasonal A/H1N1 influenza virus on the immune response following vaccination against avian A/H5N1 virus

Abstract

Cross-protection against divergent strains of influenza virus is an objective of various vaccination approaches. B cells cross-neutralizing several influenza A heterosubtypes have been isolated from cultured human memory B cells (MBCs) and plasmablasts early after influenza vaccination or infection.However, a systematic assessment of the frequency of MBCs and plasmablasts in the blood of healthy individuals is lacking. Here, we show that under resting conditions about 45% of human adults never vaccinated nor exposed to avian A/H5N1 influenza have detectable circulating MBCs cross-reacting with H5N1. This proportion rises to 63.3% among subjects with a large pool of MBCs specific for seasonal H1N1 (i.e. frequency ≥1% of total IgG MBCs). Moreover, subjects with high baseline frequencies of H1N1-specific MBCs had an expansion of H5N1-specific MBCs producing H5-neutralizing antibodies already after the first dose of an MF59-adjuvanted H5N1 vaccine. These results suggest that H1N1-specific MBCs contain a subset of cells cross-reacting to H5. We propose that a proportion of human adults have a pool of H5/H1 cross-reactive MBCs that contribute to the rapid rise of the antibody response to divergent influenza strains. This may have implications on vaccination strategies aimed at counteracting future influenza pandemics. Keywords:Cross-reactive antibodies r H5N1 r Influenza r Memory B cells r Vaccination Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe influenza A virus surface proteins hemagglutinin (HA) and neuraminidase (NA) are highly susceptible to mutations that favor the selection of variants able to escape neutralizing antibodies. This phenomenon, known as antigenic drift, necessitates the proCorrespondence: Dr. Oretta Finco e-mail: oretta.finco@novartis.com duction of new influenza vaccines every year. More rarely, reassortment of genome segments from animal and human viruses might also occur, leading to the emergence of new viruses to which the human population is immunologically naïve (antigenic shift). These viruses, like avian H5N1, have the potential to cause pandemics [1][2][3].The immunological naivety of the human population to H5N1 is inferred by the low proportion of adults with hemagglutinationinhibiting antibodies to H5N1 virus [4]. In addition, clinical trials with H5N1 and H9N2 vaccines have shown that two doses of C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 642Francesca Buricchi et al. Eur. J. Immunol. 2013. 43: 641-648 adjuvanted vaccine are needed in order to increase neutralizing antibody titers to potentially protective levels [5][6][7][8][9][10]. In spite of this, it has been observed that vaccination with seasonal strains or natural influenza infection can transiently induce antibodies neutralizing the H5N1 virus [11,12]. Heterosubtypic monoclonal antibodies able to cross-react across group 1 or group 2 influenza virus subtypes have been isolated from MBCs and plasma cells of adults e...

Intranasal Live Influenza Vaccine Priming Elicits Localized B Cell Responses in Mediastinal Lymph Nodes

“…1b). The moderate frequency of H5-specific memory B cells in subjects who were not exposed to H5N1 viruses or vaccines is likely a consequence of prior seasonal influenza vaccination and/or infection (18,19). Notably, at this time point there was no significant difference in the frequencies of H5-specific memory B cells between the H5N1 pLAIVprimed and unprimed or between the H5N1 pLAIV-primed and H7N3 pLAIV-primed subjects (P Ͼ 0.05, separate Mann-Whitney U tests) ( Fig.…”

Selection of therapeutic H5N1 monoclonal antibodies following IgVH repertoire analysis in mice

“…Normally, the frequency of broadly neutralizing Abs that recognize highly conserved epitopes within the HA2 domain of the protein is very low and has been estimated to occur in only one in 100,000 HA-specific plasma cells (Corti et al, 2011). However, several studies have shown that these types of antibodies can be induced following heterologous primeboost vaccination and by using vaccine adjuvants that broaden heterosubtypic Ab responses (Buricchi et al, 2013; Chiu et al, 2013; Li et al, 2013). Thus, to enrich for cross-reactive Abs, mice were immunized with rHA isolated from 2 Group 1 HA viruses, VN1203 and CA07 virus, in the presence of the TLR4 adjuvant GLA-SE, which increases antibody repertoire diversity and enhances protection against heterosubtypic strains of H5N1 virus in mice and ferrets (Clegg et al, 2014; Clegg et al, 2012; Wiley et al, 2011).…”

Populations at Risk for Severe or Complicated Avian Influenza H5N1: A Systematic Review and Meta-Analysis

“…One can hypothesize that previous exposure to other subtypes may have offered protection against H5N1 [32].…”