Neutralizing Antibodies Against Previously Encountered Influenza Virus Strains Increase over Time: A Longitudinal Analysis

Miller, Matthew S.; Gardner, Thomas J.; Krammer, Florian; Aguado, Lauren C.; Tortorella, Domenico; Basler, Christopher F.; Palese, Peter

doi:10.1126/scitranslmed.3006637

Cited by 167 publications

(163 citation statements)

References 37 publications

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“…These findings recall the theory of original antigenic sin by which birth cohorts may be marked by the strains to which they were exposed during childhood [2,9]. Although similar patterns have been reported [26], there exists evidence that higher HI titres may not always signal the first childhood infection [27]. The second peak in HI titres against 1977 A(H1N1), corresponding to subjects aged 34 years in 1977 according to our model, suggests a cross-reactive response with A(H1N1) viruses circulating in the 1940s [11]; however, these results should be confirmed using isolates such as PR8 or FM1 in future studies.…”

Section: Discussionsupporting

confidence: 86%

“…Significance: *P < 0·05, **P < 0·01, ***P < 0·001. The important immune responses to older A(H1N1) strains shown in our study, have also been well demonstrated in another longitudinal study [26], and may be due to boosting by continued exposure to influenza viruses [5,11]. Observation of higher serological titres to earlier strains may also be due to a diminished immune response with each subsequent infection [7].…”

Section: Discussionsupporting

confidence: 86%

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Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

et al. 2016

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SUMMARYWe explored age-dependent patterns in haemagglutination inhibition (HI) titre to seasonal [1956 A(H1N1), 1977 A(H1N1), 2007 A(H1N1)] and pandemic [A(H1N1)pdm09] influenza strains using serological data collected from an adult French influenza cohort. Subjects were recruited by their general practitioners from 2008 to 2009 and followed until 2010. We explored age-related differences between strain-specific HI titres using 1053 serological samples collected over the study period from 398 unvaccinated subjects. HI titres against the tested seasonal and pandemic strains were determined using the HI technique. Geometric mean titres (GMTs) were estimated using regression models for interval-censored data. Generalized additive mixed models were fit to log-transformed HI estimates to study the relationship between HI titre and age (age at inclusion and/or age at initial strain circulation). GMT against one strain was consistently highest in the birth cohort exposed to that strain during childhood, with peak titres observed in subjects aged 7-8 years at the time of initial strain circulation. Our results complete previous findings on influenza A(H3N2) strains and identify a strain-dependent relationship between HI titre and age at initial strain circulation.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 86%

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

et al. 2016

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“…4B), and total HK/68 NAbinding antibodies (Fig. 4C), as described previously (2,3,18). As expected, IgG antibodies from each donor were capable of inducing ADCC when added to the infected monolayer.…”

Section: Haimentioning

confidence: 99%

“…A number of studies have now firmly established that stalk-specific bnAbs, normally present in low quantities, can be boosted substantially in humans following exposure to HA subtypes with antigenically foreign head domains (2)(3)(4)(5)(6)(7)(8). Sequential vaccination of animals with chimeric HAs or with "headless" vaccine constructs have effectively recapitulated the boosting of bnAbs observed in humans after exposure to foreign HAs, and also are protective against heterologous and heterosubtypic IAV challenge (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Tan

Mullarkey

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.T he discovery and ongoing characterization of broadly neutralizing antibodies (bnAbs) that bind to the hemagglutinin (HA) stalk domain of influenza A viruses (IAVs) has galvanized promising new efforts to generate a universal influenza virus vaccine (1). A number of studies have now firmly established that stalk-specific bnAbs, normally present in low quantities, can be boosted substantially in humans following exposure to HA subtypes with antigenically foreign head domains (2-8). Sequential vaccination of animals with chimeric HAs or with "headless" vaccine constructs have effectively recapitulated the boosting of bnAbs observed in humans after exposure to foreign HAs, and also are protective against heterologous and heterosubtypic IAV challenge (9-15). These strategies are now being tested as promising "universal" influenza virus vaccine candidates (16).Whereas traditional strain-specific antibodies neutralize virus by inhibiting receptor binding, stalk-binding bnAbs neutralize virus by distinct postbinding mechanisms (17). A direct comparison of in vitro neutralization has revealed that strain-specific mAbs that inhibit receptor binding tend to be more potent at neutralizing virus compared with monoclonal stalk-binding bnAbs (18, 19); however, this difference is minimized in the context of a polyclonal response (18). In addition to virus neutralization,...

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“…Original antigenic sin might explain this result whereby increased antibody production to the older strain is produced at the expense to that of novel strains. 27,28 However, it is important to note that this phenomenon is controversial with some contradictory reports available. 29 …”

Section: Introductionmentioning

confidence: 99%

Effect of antipyretic analgesics on immune responses to vaccination

Saleh

Moody

Walter

2016

Human Vaccines & Immunotherapeutics

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While antipyretic analgesics are widely used to ameliorate vaccine adverse reactions, their use has been associated with blunted vaccine immune responses. Our objective was to review literature evaluating the effect of antipyretic analgesics on vaccine immune responses and to highlight potential underlying mechanisms. Observational studies reporting on antipyretic use around the time of immunization concluded that their use did not affect antibody responses. Only few randomized clinical trials demonstrated blunted antibody response of unknown clinical significance. This effect has only been noted following primary vaccination with novel antigens and disappears following booster immunization. The mechanism by which antipyretic analgesics reduce antibody response remains unclear and not fully explained by COX enzyme inhibition. Recent work has focused on the involvement of nuclear and subcellular signaling pathways. More detailed immunological investigations and a systems biology approach are needed to precisely define the impact and mechanism of antipyretic effects on vaccine immune responses.

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Neutralizing Antibodies Against Previously Encountered Influenza Virus Strains Increase over Time: A Longitudinal Analysis

Cited by 167 publications

References 37 publications

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

Immunity against influenza A(H1N1) infections is determined by age at the time of initial strain circulation

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Effect of antipyretic analgesics on immune responses to vaccination

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