Wide Prevalence of Heterosubtypic Broadly Neutralizing Human Anti-Influenza A Antibodies

Sui, Jianhua; Sheehan, Jared; Hwang, William C.; Bankston, Laurie A.; Burchett, Sandra; Huang, Chiung Yu; Liddington, Robert; Beigel, John H.; Marasco, Wayne A.

doi:10.1093/cid/cir121

Cited by 121 publications

(117 citation statements)

References 24 publications

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“…These findings corroborate previous findings made by biochemical analysis of a limited number of samples [4,8]. We have found that vaccination not only enhanced antibody responses to subtypes that are currently circulating, and are therefore included in the vaccine, but also augmented binding and neutralizing antibody titers to Reference age: 0-40 years.…”

Section: Discussionsupporting

confidence: 91%

“…Heterosubtypic antibodies-that is, antibodies recognizing HAs from different subtypes-are rare [4]: In human prevaccination sera, only 0.01% of total serum immunoglobulin G has been described to have heterosubtypic binding activity, one-tenth of which is specific for the HA stem epitope [4][5][6]. To establish the prevalence and predictors for heterosubtypic antibody responses, serum from 305 human immunodeficiency virus-negative volunteers was collected in October 2009.…”

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confidence: 99%

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Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Kohler¹,

Scherrer²,

Zagordi³

et al. 2014

Clinical Infectious Diseases

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Background. The effectiveness of trivalent influenza vaccination has been confirmed in several studies. To date, it is not known whether repeated exposure and vaccination to influenza promote production of cross-reactive antibodies. Furthermore, how strains encountered earlier in life imprint the immune response is currently poorly understood.Methods. To determine the prevalence for human homo-and heterosubtypic antibody responses, we scrutinized serum samples from 305 healthy volunteers for hemagglutinin-binding and -neutralizing antibodies against several strains and subtypes of influenza A. Statistical analyses were then performed to establish the association of measured values with potential predictors.Results. It was found that vaccination not only promoted higher binding and neutralizing antibody titers to homosubtypic influenza isolates but also increased heterosubtypic human immune responses. Both binding and neutralizing antibody titers in relation with age of the donors mirrored the course of the different influenza strain circulation during the last century. Advanced age appeared to be of advantage for both binding and neutralizing titers to most subtypes. In contrast, the first virus subtype encountered was found to imprint to some degree subsequent antibody responses. Antibodies to recent strains, however, primarily seemed to be promoted by vaccination.Conclusions. We provide evidence that vaccinations stimulate both homo-and heterosubtypic immune responses in young and middle-aged as well as more senior individuals. Our analyses suggest that influenza vaccinations not only prevent infection against currently circulating strains but can also stimulate broader humoral immune responses that potentially attenuate infections with zoonotic or antigenically shifted strains.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Kohler¹,

Scherrer²,

Zagordi³

et al. 2014

Clinical Infectious Diseases

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“…Although these antibodies can be found in humans who have been exposed to influenza viruses via either vaccination or infection (3,14,15), they do seem to be rare in nature, and in vivo levels of these antibodies are likely too low to afford protection. Vaccines able to boost the levels of these broadly neutralizing stalk reactive antibodies could lead to universal protection against circulating human influenza virus strains, as well as potential pandemic avian viruses like the emerging Chinese H7N9 strain (10).…”

Section: Discussionmentioning

confidence: 99%

“…These antibodies inhibit receptor binding and thus have hemagglutination inhibition (HI) activity, which is generally strain specific. The stalk domain of the HA is relatively well conserved; however, it is far less immunogenic and, under normal conditions, antibodies against this domain occur only at a low frequency (14,15). Recently, broadly neutralizing antibodies against this domain of the HA have been isolated (16)(17)(18)(19)(20)(21)(22), suggesting that a vaccine based on the induction of such antibodies would protect from infection with divergent strains within a subtype and also against strains from other subtypes that have similar stalk structures.…”

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confidence: 99%

Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

Margine

Krammer

Hai

et al. 2013

J Virol

183

161

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f Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.

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“…49 Interestingly, variation between individuals in the levels of broadly neutralizing antibodies against hemagglutinin of H5N1 strains from serum of prevaccinees was recently observed, suggesting a role for inter-individual IGHV gene germline polymorphisms. 63 Briefly expanding beyond this specific gene, antibodies using IGHV genes other than IGHV1-69 have also recently been identified from individuals infected with the 2009 H1N1 influenza virus (IGHV4-31, IGHV4-30-4, IGHV4-39, IGHV3-21, IGHV3-30). 64 Importantly, four of these five germline IGHV genes contributing to these antibodies are known to vary in copy number.…”

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confidence: 99%

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

2012

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The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual's highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

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Wide Prevalence of Heterosubtypic Broadly Neutralizing Human Anti-Influenza A Antibodies

Cited by 121 publications

References 24 publications

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

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