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author:("Feng, jingli")
1.  Individual antibody and T cell responses to vaccination and infection with the 2009 pandemic swine-origin H1N1 influenza virus 
Journal of clinical immunology  2011;31(5):900-912.
The 2009 swine origin H1N1 influenza virus (swH1N1) provided an opportunity to study immune responses to a new influenza strain in the context of seasonal influenza vaccination. Our goals were: to assess whether analyzing multiple parameters of immune responsiveness to influenza has an advantage over evaluating hemagglutination inhibition (HAI) titer alone, to determine whether vaccination with the seasonal vaccine induced cross-reactive immunity to swH1N1 in some individuals, and to determine whether the immune response against swH1N1 is higher after infection than vaccination.
Antibody and T cell responses were studied in ten subjects who were first immunized with the 2009-10 seasonal influenza subunit vaccine, then six weeks later with the swH1N1 monovalent subunit vaccine. The amount of antibody against native virus glycoproteins, overall avidity of these antibodies, and HAI titer were measured. T cells were evaluated for proliferation and IFNγ secretion in response to the vaccine in vitro. Individuals with influenza-like illness were also evaluated, adding a microplate neuraminidase-inhibition (NAI) test.
The immune response to influenza was highly variable and immune parameters did not increase in parallel. The seasonal vaccine induced antibodies recognizing the pandemic virus in 50% of subjects. Antibody affinity and NAI activity to swH1N1 were higher after natural infection than vaccination.
Evaluation of several immune parameters gives a more complete measure of immune responsiveness to influenza infection or vaccination than the HAI test alone.
PMCID: PMC3197711  PMID: 21732013
pandemic 2009 H1N1 influenza; vaccine response; antibodies and T cells after infection
2.  Antibody quantity versus quality after influenza vaccination 
Vaccine  2009;27(45):6358-6362.
The correlates for protection against influenza infection are incompletely characterized. We have applied an ELISA strategy that distinguishes antibodies against native viral surface antigens (potentially neutralizing) from antibodies directed against internal and denatured viral proteins (not neutralizing) to three groups of vaccinated subjects: (1) participants in a study of repeated annual vaccination (2) elderly subjects and (3) patients with Systemic Lupus Erythematosus compared to control subjects. Antibody increase after vaccination was inversely related to the level of pre-existing antibodies in all groups; most subjects had significant initial antibody levels and showed little increase in amount of antibody after vaccination, but the avidity of their serum antibodies tended to increase. Antibodies against denatured virus proteins varied with vaccine formulation; vaccines that are more recent have less total protein for the same amount of native hemagglutinin. We propose an index consisting of rank order of antibody level plus antibody avidity, both measured against native virus, plus hemagglutination-inhibition antibody titer, as a useful measure of immunity against influenza.
PMCID: PMC2765411  PMID: 19840673
3.  Influenza A virus infection engenders a poor antibody response against the ectodomain of matrix protein 2 
Virology Journal  2006;3:102.
Matrix protein 2 (M2) is an integral tetrameric membrane protein of influenza A virus (IAV). Its ectodomain (M2e) shows remarkably little diversity amongst human IAV strains. As M2e-specific antibodies (Abs) have been shown to reduce the severity of infection in animals, M2e is being studied for its capability of providing protection against a broad range of IAV strains. Presently, there is little information about the concentration of M2e-specific Abs in humans. Two previous studies made use of ELISA and Western blot against M2e peptides and recombinant M2 protein as immunosorbents, respectively, and reported Ab titers to be low or undetectable. An important caveat is that these assays may not have detected all Abs capable of binding to native tetrameric M2e. Therefore, we developed an assay likely to detect all M2e tetramer-specific Abs.
We generated a HeLa cell line that expressed full length tetrameric M2 (HeLa-M2) or empty vector (HeLa-C10) under the control of the tetracycline response element. These cell lines were then used in parallel as immunosorbents in ELISA. The assay was standardized and M2e-specific Ab titers quantified by means of purified murine or chimeric (mouse variable regions, human constant regions) M2e-specific Abs in the analysis of mouse and human sera, respectively. We found that the cell-based ELISA was substantially more effective than immobilized M2e peptide in detecting M2e-specific Abs in sera of mice that had recovered from repetitive IAV infections. Still, titers remained low (< 5 μg/ml) even after two consecutive infections but increased to ~50 μg/ml after the third infection. Competition with free M2e peptide indicated that ~20% of M2e-specific Abs engendered by infection reacted with M2e peptide. In humans presenting with naturally acquired influenza virus infection, 11 of 24 paired sera showed a ≥ 4-fold increase in M2e-specific Ab titer. The Ab response appeared to be of short duration as titers were very low (average 0.2 μg/ml) in all patients at onset of infection and in controls, in spite of evidence for previous exposure to IAV.
The results provide convincing evidence that M2e-specific Ab-mediated protection is currently lacking or suboptimal in humans.
PMCID: PMC1702354  PMID: 17150104
4.  Roles of CD4+ T-Cell-Independent and -Dependent Antibody Responses in the Control of Influenza Virus Infection: Evidence for Noncognate CD4+ T-Cell Activities That Enhance the Therapeutic Activity of Antiviral Antibodies 
Journal of Virology  2005;79(10):5943-5951.
Previous studies have indicated that B cells make a significant contribution to the resolution of influenza virus infection. To determine how B cells participate in the control of the infection, we transferred intact, major histocompatibility complex class II (MHC-II)-negative or B-cell receptor (BCR)-transgenic spleen cells into B-cell-deficient and CD8+ T-cell-depleted μMT mice, termed μMT(−8), and tested them for ability to recover from infection. μMT(−8) mice that received no spleen cells invariably succumbed to the infection within 20 days, indicating that CD4+ T-cell activities had no significant therapeutic activity on their own; in fact, they were harmful and decreased survival time. Interestingly, however, they became beneficial in the presence of antiviral antibody (Ab). Injection of MHC-II(−/−) spleen cells, which can provide CD4+ T-cell-independent (TI) but not T-cell-dependent (TD) activities, delayed mortality but only rarely resulted in clearance of the infection. By contrast, 80% of μMT(−8) mice injected with normal spleen cells survived and resolved the infection. Transfer of BCR-transgenic spleen cells, which contained ∼10 times fewer virus-specific precursor B cells than normal spleen cells, had no significant impact on the course of the infection. Taken together, the results suggest that B cells contribute to the control of the infection mainly through production of virus-specific Abs and that the TD Ab response is therapeutically more effective than the TI response. In addition, CD4+ T cells appear to contribute, apart from promoting the TD Ab response, by improving the therapeutic activity of Ab-mediated effector mechanisms.
PMCID: PMC1091716  PMID: 15857980
5.  Influenza Type A Virus Escape Mutants Emerge In Vivo in the Presence of Antibodies to the Ectodomain of Matrix Protein 2 
Journal of Virology  2005;79(11):6644-6654.
The ectodomain of matrix protein 2 (M2e) of human influenza type A virus strains has remained remarkably conserved since 1918. Because M2e-specific immunity has been shown to decrease morbidity and mortality associated with influenza virus infection in several animal models and because natural infection and current vaccines do not appear to induce a good M2e-specific antibody (Ab) response, M2e has been considered as potential vaccine for inducing cross-reactive protection against influenza type A viruses. The high degree of structural conservation of M2e could in part be the consequence of a poor M2e-specific Ab response and thus the absence of pressure for change. To assess this possibility, we studied the course of infection in SCID mice in the presence or absence of passive M2e-specific monoclonal Abs (MAbs). We found that virus mutants with antigenic changes in M2e emerged in 65% of virus-infected mice treated with M2e-specific but not control MAbs. However, the diversity of escape mutants was highly restricted since only two types were isolated from 22 mice, one with a proline-to-leucine and the other with a proline-to-histidine interchange at amino acid position 10 of M2e. The implications of these findings for the use of M2e as a broadly protective vaccine are discussed.
PMCID: PMC1112148  PMID: 15890902
6.  Virus-Neutralizing Activity Mediated by the Fab Fragment of a Hemagglutinin-Specific Antibody Is Sufficient for the Resolution of Influenza Virus Infection in SCID Mice 
Journal of Virology  2003;77(15):8322-8328.
Antibodies (Abs) contribute to the control of influenza virus infection in vivo by reducing progeny virus yield from infected cells (yield reduction [YR]) and by inhibiting progeny virus from spreading the infection to new host cells (virus neutralization [VN]). Previous studies showed that the infection could be resolved in severe combined immunodeficiency (SCID) mice by treatment with hemagglutinin (HA)-specific monoclonal antibodies (MAbs) that exhibit both VN and YR activities but not by MAbs that exhibited only YR activity. To determine whether virus clearance requires both activities, we measured the therapeutic activity of an HA-specific MAb (VN and YR) and its Fab fragment (VN) by intranasal (i.n.) administration to infected SCID mice. Immunoglobulin G (IgG) and Fab cleared the infection with i.n. 50% effective doses (ED50s) of 16 and 90 pmol, respectively. To resolve an established infection solely by VN activity, Fab must be present in the respiratory tract at an effective threshold concentration until all infected cells have died and production of virus has ceased. Because IgG and Fab had different half-lives in the respiratory tract (22 and 8 h, respectively) and assuming that both operated mainly or solely by VN, it could be estimated that clearance was achieved 24 h after Ab treatment when both reagents were present in the respiratory tract at ∼10 pmol. This dose was ∼200 times larger than the respiratory tract-associated Ab dose resulting from administration of the intraperitoneal ED50 (270 pmol) of IgG. This indicated that our procedure of i.n. administration of Ab did not make optimal use of the Ab's therapeutic activity.
PMCID: PMC165237  PMID: 12857901

Results 1-6 (6)