CD4+ T-Cell Expansion Predicts Neutralizing Antibody Responses to Monovalent, Inactivated 2009 Pandemic Influenza A(H1N1) Virus Subtype H1N1 Vaccine

Department of Pediatrics, Division of Infectious Diseases, University of Rochester Medical Center, 601 Elmwood Ave, Box 690, Rochester, NY 14642, Phone: 585-275-5944, Fax: 585-273-1104.
The Journal of Infectious Diseases (Impact Factor: 6). 11/2012; 207(2). DOI: 10.1093/infdis/jis684
Source: PubMed


The ability of influenza vaccines to elicit CD4(+) T cells and the relationship between induction of CD4(+) T cells and vaccine-induced neutralizing antibody responses has been controversial. The emergence of swine-origin 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) provided a unique opportunity to examine responses to an influenza vaccine composed of both novel and previously encountered antigens and to probe the relationship between B-cell and T-cell responses to vaccination.

We tracked CD4(+) T-cell and antibody responses of human subjects vaccinated with monovalent subunit A(H1N1)pdm09 vaccine. The specificity and magnitude of the CD4(+) T-cell response was evaluated using cytokine enzyme-linked immunosorbent spot assays in conjugation with peptide pools representing distinct influenza virus proteins.

Our studies revealed that vaccination induced readily detectable CD4(+) T cells specific for conserved portions of hemagglutinin (HA) and the internal viral proteins. Interestingly, expansion of HA-specific CD4(+) T cells was most tightly correlated with the antibody response.

These results indicate that CD4(+) T-cell expansion may be a limiting factor in development of neutralizing antibody responses to pandemic influenza vaccines and suggest that approaches to facilitate CD4(+) T-cell recruitment may increase the neutralizing antibody produced in response to vaccines against novel influenza strains.

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    • "Magnitude, quality and localization of primary T helper (Th) cell responses are of fundamental importance for the evaluation of novel vaccine candidates. T-cell priming can be evaluated as a target for improving and modulating the immune response during vaccination [5], and as an early predictor of the vaccine immunogenicity [6] [7]. CD4 + T-cell priming has been studied to characterize the mechanism of action of a broad range of adjuvants such as alum [8], CpG ODN [9], lipopolysaccharide [10], cholera toxin [11] or its B subunit (CTB) [12]. "
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    ABSTRACT: CD4(+) T-cell priming is an essential step in vaccination due to the key role of T helper cells in driving both effector and memory immune responses. Here we have characterized in C57BL/6 mice the T helper subtype differentiation among tetramer-specific CD4(+) T cells primed by subcutaneous immunization with the tuberculosis vaccine antigen H56 plus the adjuvant CAF01. Peptide-specific population identified by the MHC class II tetramers differentiated into several T helper subtypes upon antigen encounter, and the frequency of subpopulations differed according to their localization. Th1 (CXCR3(+)T-bet(+)), Tfh (CXCR5(+)PD-1(+)Bcl-6(+)) and RORγt(+) cells were induced in the lymph nodes draining the immunization site (dLN), while Th1 cells were the predominant subtype in the spleen. In addition, CD4(+) T cells co-expressing multiple T-cell lineage-specifying transcription factors were also detected. In the lungs, most of the tetramer-binding T cells were RORγt(+), while Tfh and Th1 cells were absent. After boosting, a higher frequency of tetramer-binding cells co-expressing the markers CD44 and CD127 was detected compared to primed cells, and Tet(+) T cells showed a prevalent Th1 phenotype in both dLN and spleens, while Tfh cells were significantly reduced. In conclusion, these data demonstrate that parenteral immunization with H56 and CAF01 elicits a distribution of antigen-specific CD4(+) T cells in both lymphoid tissues and lungs, and gives rise to multiple T helper subtypes, that differ depending on localization and following reactivation.
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    • "Recent studies in young subjects indicate a substantial cross-reactivity of CD4 T cell responses for different strains of influenza virus [9], consistent with better sequence conservation outside of NAb determinants. In addition, expansion of CD4 T cell responses following vaccination correlates with NAb responses in young subjects [10,11] suggesting that vaccine-mediated boosting of CD4 T cell responses may be important not only for generating Th1-like memory that can be directly protective [5,12], but also for generating CD4 T cells that can provide help for other components of the immune response. "
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