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Ali H. Ellebedy Florian Krammer Gui-Mei Li Matthew S. Miller Christopher Chiu Jens Wrammert Cathy Y. Chang Carl W. Davis Megan McCausland Rivka Elbein Srilatha Edupuganti Paul Spearman Sarah F. Andrews Patrick C. Wilson Adolfo García-Sastre Mark J. Mulligan Aneesh K. Mehta Peter Palese Rafi Ahmed 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(36):13133-13138
The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.The emergence of novel influenza virus strains poses a continuous public health threat (1, 2). The World Health Organization estimates that influenza viruses infect one-billion people annually, with three- to five-million cases of severe illness, and up to 500,000 deaths worldwide (3). Following influenza virus infection, humoral immune responses against the viral hemagglutinin (HA) protein may persist for decades in humans (4). These anti-HA responses correlate strongly with protection against influenza infection (5). Serological memory is maintained by antibody-secreting long-lived plasma cells and reinforced by memory B cells, which can rapidly differentiate into antibody-secreting cells upon antigen reexposure (6).Influenza vaccine efficacy is constantly undermined by antigenic variation in the circulating viral strains, particularly in the HA and neuraminidase (NA) proteins. Current influenza vaccination strategies rely on changing the HA and NA components of the annual human vaccine to ensure that they antigenically match circulating influenza strains (7, 8). Developing an influenza vaccine that is capable of providing broad and long-lasting protective antibody responses remains the central challenge for influenza virus research.HA is a trimer, with each monomer comprised of two subunits: HA1, which includes the HA globular head, and HA2, whose ectodomain together with the N- and C-terminal parts of HA1 constitute the HA stem region (9). Phylogenetically, the 18 HA subtypes characterized so far are divided into two groups. Among strains that have recently caused disease in humans, H1 and H5 HAs belong to group 1, whereas H3 and H7 HAs belong to group 2 (10). Conventional anti-HA neutralizing antibodies primarily target a few immunodominant epitopes located in proximity to the receptor-binding domain within the globular head region of the molecule (11, 12). Although these antibodies are potentially protective, they are strain-specific because of the high variability of such epitopes, and thus lack, in general, the much-desired broad neutralizing activity. Recently, broadly neutralizing human (13–18) and murine (19) monoclonal antibodies (mAbs) directed against distinct epitopes within the HA stem region have been extensively characterized. These mAbs were shown to interfere with the influenza viruses’ life cycle in different ways (20). By generating monoclonal antibodies from plasmablasts isolated ex vivo, we demonstrated that these broadly neutralizing antibodies could be retrieved from patients infected with or vaccinated against the pandemic H1N1 2009 influenza virus (18, 21). Recent observations that HA stem epitopes are accessible on the majority of HA trimers on intact virions (22), and that a stable HA stem protein that is immunologically intact could be produced (23), provided further hope for the feasibility of a stem-based universal influenza vaccine (24).Notably, HA stem-specific mAbs isolated from humans showed a high degree of affinity maturation, suggesting a memory B-cell origin. These results raised two important questions that we address in the current study. First, what are the baseline levels of broadly cross-reactive stem-binding antibodies and memory B cells? Second, using current influenza vaccines, to what extent can HA stem-specific responses be boosted in comparison with those directed against the HA globular head?Structural studies have clearly demonstrated that the main neutralizing antibody epitopes within the HA stem region are conformation-dependent, and that the integrity of these epitopes requires the presence of the HA1 subunit in addition to the HA2 subunit, which constitute the bulk of the HA stem (16, 17). To be able to directly measure HA stem-reactive antibodies and memory B cells, we used a chimeric HA molecule that expresses the globular head of H9 HA on H1 backbone (25). Our data demonstrate that post-2009 trivalent inactivated vaccines (TIV) induced minimal stem-specific responses in comparison with head-specific responses. On the other hand, immunization with H5N1 generated relatively strong anti-HA stem responses, demonstrating that it is feasible to elicit broadly neutralizing responses in humans given the right immunogen design. 相似文献
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Li GM Chiu C Wrammert J McCausland M Andrews SF Zheng NY Lee JH Huang M Qu X Edupuganti S Mulligan M Das SR Yewdell JW Mehta AK Wilson PC Ahmed R 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(23):9047-9052
We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection. 相似文献
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McCausland AM McCausland VM 《Obstetrics and gynecology》2008,111(4):992, author reply 992-992, author reply 993
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Prevention of diabetes-induced albuminuria in transgenic rats overexpressing human aldose reductase 总被引:2,自引:0,他引:2
Ng DP Hardy CL Burns WC Muggli EE Kerr N McCausland J Alcorn D Adams TE Zajac JD Larkins RG Dunlop ME 《Endocrine》2002,18(1):47-56
Studies using pharmacologic inhibitors have implicated the enzyme aldose reductase in the pathogenesis of albuminuria and
diabetic renal disease. However, a clear conclusion is not easily drawn from such studies since these pharmacologic inhibitors
have nonspecific properties. To examine further the role of aldose reductase, we have overexpressed the human enzyme in a
transgenic rat model. Transgene expression in the kidney was predominantly localized to the outer stripe of the outer medulla,
compatible with the histotopography of the straight (S3) proximal tubule. The effect of enzyme overexpression on diabetes-induced
renal function and structure was then investigated. Contrary to what may have been anticipated from the previous enzyme inhibition
studies, diabetes-induced albuminuria was completely prevented by the overexpression of aldose reductase. No effect of overexpression
of aldose reductase on renal structure nor on urinary excretion of β2-microglobulin and N-acetyl-β-d-glucosaminidase was observed in this transgenic rat model. In conclusion, our study strongly suggests that multiple roles
for aldose reductase may give it a more complex place in diabetic nephropathy than is currently recognized. 相似文献
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Designing a leadership development program for nurse managers: an evidence-driven approach 总被引:4,自引:0,他引:4
The authors describe an evidence-driven approach used in designing a leadership development program targeted for nurses in middle management positions in an academically affiliated integrated healthcare system. A qualitative study was conducted to investigate leadership development needs and experiences of nurse managers across the health system. Study findings were used to inform educational programs and organizational initiatives responsive to needs of both novice and expert nurse managers across diverse clinical settings. 相似文献