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Human CD4+ T Helper Cell Responses after Tick-Borne Encephalitis Vaccination and Infection.

ABSTRACT: Tick-borne encephalitis virus (TBEV) is a human-pathogenic flavivirus that is endemic in large parts of Europe and Asia and causes severe neuroinvasive illness. A formalin-inactivated vaccine induces strong neutralizing antibody responses and confers protection from TBE disease. CD4+ T cell responses are essential for neutralizing antibody production, but data on the functionalities of TBEV-specific CD4+ T cells in response to vaccination or infection are lacking. This study provides a comprehensive analysis of the cytokine patterns of CD4+ T cell responses in 20 humans after TBE vaccination in comparison to those in 18 patients with TBEV infection. Specifically, Th1-specific cytokines (IFN-γ, IL-2, TNF-α), CD40 ligand and the Th1 lineage-specifying transcription factor Tbet were determined upon stimulation with peptides covering the TBEV structural proteins contained in the vaccine (C-capsid, prM/M-membrane and E-envelope). We show that TBEV-specific CD4+ T cell responses are polyfunctional, but the cytokine patterns after vaccination differed from those after infection. TBE vaccine responses were characterized by lower IFN-γ responses and high proportions of TNF-α+IL-2+ cells. In vaccine-induced responses-consistent with the reduced IFN-γ expression patterns-less than 50% of TBEV peptides were detected by IFN-γ+ cells as compared to 96% detected by IL-2+ cells, indicating that the single use of IFN-γ as a read-out strongly underestimates the magnitude and breadth of such responses. The results provide important insights into the functionalities of CD4+ T cells that coordinate vaccine responses and have direct implications for future studies that address epitope specificity and breadth of these responses.

SUBMITTER: Aberle JH

PROVIDER: S-EPMC4605778 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UNLABELLED:Tick-borne encephalitis (TBE) virus is an important human-pathogenic flavivirus endemic in large parts of Europe and Central and Eastern Asia. Neutralizing antibodies specific for the viral envelope protein E are believed to mediate long-lasting protection after natural infection and vaccination. To study the specificity and individual variation of human antibody responses, we developed immunoassays with recombinant antigens representing viral surface protein domains and domain combinations. These allowed us to dissect and quantify antibody populations of different fine specificities in sera of TBE patients and vaccinees. Postinfection and postvaccination sera both displayed strong individual variation of antibody titers as well as the relative proportions of antibodies to different domains of E, indicating that the immunodominance patterns observed were strongly influenced by individual-specific factors. The contributions of these antibody populations to virus neutralization were quantified by serum depletion analyses and revealed a significantly biased pattern. Antibodies to domain III, in contrast to what was found in mouse immunization studies with TBE and other flaviviruses, did not play any role in the human neutralizing antibody response, which was dominated by antibodies to domains I and II. Importantly, most of the neutralizing activity could be depleted from sera by a dimeric soluble form of the E protein, which is the building block of the icosahedral herringbone-like shell of flaviviruses, suggesting that antibodies to more complex quaternary epitopes involving residues from adjacent dimers play only a minor role in the total response to natural infection and vaccination in humans. IMPORTANCE:Tick-borne encephalitis (TBE) virus is a close relative of yellow fever, dengue, Japanese encephalitis, and West Nile viruses and distributed in large parts of Europe and Central and Eastern Asia. Antibodies to the viral envelope protein E prevent viral attachment and entry into cells and thus mediate virus neutralization and protection from disease. However, the fine specificity and individual variation of neutralizing antibody responses are currently not known. We have therefore developed new in vitro assays for dissecting the antibody populations present in blood serum and determining their contribution to virus neutralization. In our analysis of human postinfection and postvaccination sera, we found an extensive variation of the antibody populations present in sera, indicating substantial influences of individual-specific factors that control the specificity of the antibody response. Our study provides new insights into the immune response to an important human pathogen that is of relevance for the design of novel vaccines.

Project description:Obesity has dramatically increased over the last 30 years and reaches according to World Health Organization dimensions of a global epidemic. The obesity-associated chronic low-level inflammation contributes to severe comorbidities and directly affects many immune cells leading to immune dysfunction and increased susceptibility to infections. Thus, prophylaxis against vaccine-preventable diseases is crucial, yet the responsiveness to several vaccines is unclear under obesity. In order to assess the responsiveness to tick-borne encephalitis (TBE) vaccine, we revaccinated 37 obese individuals and 36 normal-weight controls with a licensed TBE vaccine. Metabolic, hormonal, and immunologic profiles along with vaccine-specific humoral and cellular immune responses were evaluated in sera and peripheral blood mononuclear cells (PBMCs) before, 1 week, 4 weeks, and 6 months after TBE booster. Obese adults had significantly increased metabolic (triglycerides, cholesterol ratios, leptin, insulin) and proinflammatory (C-reactive protein) parameters. They showed stronger initial increase of TBE-specific Ab titers (d7_d28) followed by a significantly faster decline after 6 months, which correlated with high body mass index and leptin and insulin levels. The fold increase of Ab-titer levels was significantly higher in obese compared to control males and linked to reduced testosterone levels. Obesity also affected cellular responses: PBMCs of the obese vaccinees had elevated interleukin 2 and interferon γ levels upon antigen stimulation, indicating a leptin-dependent proinflammatory TH1 polarization. The expansion of total and naive B cells in obese might explain the initial increase of Ab titers, whereas the reduced B-memory cell and plasma blast generation could be related to fast Ab decline with a limited maintenance of titers. Among T follicular helper cell (Tfh) cells, the Tfh17 subset was significantly expanded particularly in obese males, where we observed a strong initial Ab increase. Systemic but not local vaccine side effects were more frequent in obese subjects as a possible consequence of their low-grade proinflammatory state. In summary, TBE booster vaccination was effective in obese individuals, yet the faster Ab decline could result in a reduced long-term protection. The sex-based differences in vaccine responses indicate a complex interplay of the endocrine, metabolic, and immune system during obesity. Further studies on the long-term protection after vaccination are ongoing, and also evaluation of primary vaccination against TBE in obese individuals is planned. Clinical Trial Registration: NCT04017052; https://clinicaltrials.gov/ct2/show/NCT04017052.

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Human CD4+ T Helper Cell Responses after Tick-Borne Encephalitis Vaccination and Infection.

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