Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion

Abstract

Background Influenza related morbidity and mortality disproportionately impacts older adults. The serologic response to vaccine is diminished in older adults; however, high dose inactivated influenza vaccine (HD IIV) has shown improved rates of seroconversion compared to standard dose (SD IIV). We hypothesize this may be due to the superior ability of high dose vaccine to activate T follicular helper (Tfh) cells and provide B cell dependent T cell help. Methods We measured peripheral Tfh (pTfh) activation in 50 community dwelling adults 65 years or older who were randomly assigned to receive either the HD IIV or SD IIV. Results The HD vaccination elicited significantly higher levels of ICOS expression on pTfh cells, at day 7 compared to SD vaccination (p= 0.02). The magnitude of the increase in ICOS+ pTfh cells from baseline to day 7 was predictive of seroconversion for both influenza A and B vaccination. Conclusion Strong Tfh activation in response to influenza vaccination forecasts successful seroconversion in older adults, and HD IIV elicits greater Tfh activation than SD IIV. Future vaccine studies should focus on ways to further optimize the Tfh response.

Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage

“…Low dose influenza peptides favour a Th1 response, and at very high concentrations favour Th2/T follicular helper (T FH ) cell response (Brown et al, 2009; Pompano et al, 2014). The relationship between T FH and antigen dose corresponds to a recent study founding a greater frequency of (peripheral) pT FH post-vaccination in those receiving HD compared to SD vaccine (Pilkinton et al, 2017). It has also been shown that the frequency of activated pT FH cells following vaccination is correlated with antibody responses to vaccination (Bentebibel et al, 2013; Spensieri et al, 2013; Herati et al, 2014), consistent with that observed with HD vaccination.…”

With a Little Help from T Follicular Helper Friends: Humoral Immunity to Influenza Vaccination

“…These PD1 + ICOS + cTFh1 cells peaked at day 7 following IIV before returning to baseline by day 14. This observation was subsequently verified by several other groups in the settings of IIV immunization (17,23,29,30). It is now well known that IIV-induced cTfh cells express activation markers PD-1, ICOS, CD38, and Ki-67 (17,22,23,30), and most importantly, the emergence of activated cTfh1 cells in peripheral blood on day 7 after IIV correlates with the emergence of ASCs and increased levels of serum Ab titers (17,22,23,29).…”

“…The age-dependent decline in IAVspecific T cell and B cell responsiveness can reflect both immune dysfunction and "repertoire holes" from the loss of IAV-specific lymphocytes (35,36). Recent reports provide consistent data that the elderly adults also have reduced frequency of cTfh cells at steady-state but higher expression of ICOS, but not CD38 or Ki-67, as compared with young adults (29,30). Importantly, cTfh cells from elderly adults have decreased helper capacity toward naive B cells, as measured by IgG and IgM production after T and B cell cocultures (29).…”

Signals that drive T follicular helper cell formation

“…Experimental strategies to prolong antigen presentation by DC leads to increased numbers of Tfh cells in mice . In humans, use of high antigen dose vaccines also results in increased antibody levels and circulating Tfh‐like cells . In autoimmune settings, chronic antigen exposure correlates with increased numbers of Tfh cells .…”

“…13,14 In humans, use of high antigen dose vaccines also results in increased antibody levels and circulating Tfh-like cells. [15][16][17] In autoimmune settings, chronic antigen exposure correlates with increased numbers of Tfh cells. [18][19][20][21] Likewise, increased proximal TCR signalling (e.g.…”