Adjuvanted H5N1 vaccine induces early CD4⁺T cell response that predicts long-term persistence of protective antibody levels

Abstract

Immune responses to vaccination are tested in clinical trials. This process usually requires years especially when immune memory and persistence are analyzed. Markers able to quickly predict the immune response would be very useful, particularly when dealing with emerging diseases that require a rapid response, such as avian influenza. To address this question we vaccinated healthy adults at days 1, 22, and 202 with plain or MF59-adjuvanted H5N1 subunit vaccines and tested both cell-mediated and antibody responses up to day 382. Only the MF59-H5N1 vaccine induced high titers of neutralizing antibodies, a large pool of memory H5N1-specific B lymphocytes, and H5-CD4 ؉ T cells broadly reactive with drifted H5. The CD4 ؉ response was dominated by IL-2 ؉ IFN-␥ ؊ IL-13 ؊ T cells. Remarkably, a 3-fold increase in the frequency of virus-specific total CD4 ؉ T cells, measurable after 1 dose, accurately predicted the rise of neutralizing antibodies after booster immunization and their maintenance 6 months later. We suggest that CD4 ؉ T cell priming might be used as an early predictor of the immunogenicity of prepandemic vaccines.H5N1 influenza vaccine ͉ MF59 adjuvant ͉ prepandemic vaccination ͉ immune memory ͉ protection

Human circulating influenza-CD4 + ICOS1 + IL-21 + T cells expand after vaccination, exert helper function, and predict antibody responses

“…The antibody response to vaccination was tested by hemagglutination inhibition (HI) at baseline and 3 wk after each vaccination. In agreement with previous studies (2,13), two doses of MF59-adjuvanted H5N1 vaccine were required to induce a significant level of HI antibodies to the H5N1 avian influenza strain, whereas only one vaccination was sufficient for a substantial increase of HI titers to seasonal H3N2 (Fig. 1).…”

“…We searched for an early immunological readout of vaccination associated with and predictive of the increase of HI titers ≥1:80, used as the correlate of protection for influenza (18,19). We have previously shown that vaccination of healthy adults with adjuvanted avian H5N1 influenza induces the rapid expansion of vaccine-specific CD4 + T cells whose frequency correlates in a predictive manner with the increase and long-term persistence of neutralizing antibodies (2). Herein, we report the identification of the T cells subset responsible for this function.…”

“…Predictors should be easy to test in large clinical trials and have a clear mechanistic relationship with the correlates or surrogates of protection taken as the study endpoint. We have previously shown that an early postvaccination increase in the number of vaccine-specific CD4 + T cells is correlated in a predictive manner with the rise and long-term maintenance of protective antibody titers to avian influenza (2). The aim of the present study was to characterize the CD4 + T cells subset responsible for this function.…”

Adjuvant solution for pandemic influenza vaccine production

“…These adjuvants stimulate local inflammatory responses at the injection site, which lead to leukocyte recruitment, antigen transport to draining lymph nodes, and APC activation (17). In preclinical models, adjuvants like MF59 appear to stimulate lymphocyte priming through a TLR-independent MyD88-dependent pathway (18) and subsequent Th2-mediated antibody responses (19), whereas the majority of helper CD4 T cells induced in people are biased to a Th0/Th1 phenotype (20,21). A separate strategy for inducing anti-viral Th1 responses involves activation of TLR4, which is unique among the TLR family in its ability to activate MyD88 and IFN production through the TRIF pathway (8).…”

B‐ and T‐cell memory elicited by a seasonal live attenuated reassortant influenza vaccine: assessment of local antibody avidity and virus‐specific memory T‐cells using trogocytosis‐based method

“…However, the goal of vaccination is not only the induction of serum antibodies, but also the generation of effective immunological memory for long‐term protection. In recent years, substantial research efforts have been devoted toward vaccine assessment methods that measure memory cell responses to a wide range of pathogens and cancers 1 , 2 , 3 , 4 , 5 . In the case of vaccines delivered to mucosal surfaces, development of fast, easy, and cost‐effective assays for the measurement of immunological memory continues to be a challenge because of the different nature of the immunity elicited by such vaccines.…”