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Review
. 2016 Apr 11:7:136.
doi: 10.3389/fimmu.2016.00136. eCollection 2016.

New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza

Priyadharshini Devarajan  1 , Bianca Bautista  1 , Allen M Vong  1 , Karl Kai McKinstry  1 , Tara M Strutt  1 , Susan L Swain  1
Affiliations
Review

New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza

Priyadharshini Devarajan et al. Front Immunol. .

Abstract

Influenza viral evolution presents a formidable challenge to vaccination due to the virus' ability to rapidly mutate to evade immune responses. Live influenza infections generate large and diverse CD4 effector T cell responses that yield highly protective, long-lasting CD4 T cell memory that can target conserved viral epitopes. We review advances in our understanding of mechanisms involved in generating CD4 T cell responses against the influenza A virus (IAV), focusing on specialized follicular helper (TFH) and CD4 cytotoxic (ThCTL) effector subsets and on CD4 T cell memory. We also discuss two recent findings in context of enhancing vaccine responses. First, helper T cells require priming with APC secreting high levels of IL-6. Second, the transition of IAV-generated effectors to memory depends on IL-2, costimulation and antigen signals, just before effectors reach peak numbers, defined as the "memory checkpoint." The need for these signals during the checkpoint could explain why many current influenza vaccines are poorly effective and elicit poor cellular immunity. We suggest that CD4 memory generation can be enhanced by re-vaccinating at this time. Our best hope lies in a universal vaccine that will not need to be formulated yearly against seasonal antigenically novel influenza strains and will also be protective against a pandemic strain. We suggest a vaccine approach that elicits a powerful T cell response, by initially inducing high levels of APC activation and later providing antigen at the memory checkpoint, may take us a step closer to such a universal influenza vaccine.

Keywords: CD4 T cells; cell-mediated immunity; influenza; late-antigen; memory checkpoint; vaccination.

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Figures

Figure 1
Figure 1
We propose a two-step vaccine approach that optimizes antigen presentation at two different phases. The first phase is the early antigen–APC interaction phase that primes T cell responses where APC activation to optimize IL-6 production is suggested. The second phase is the memory checkpoint when antigen on activated APC drives the differentiation of effectors to specialized CD4 subsets such as TFH and perhaps other specialized effector subsets and also induces optimal CD4 memory formation. For IAV infections, we suggest that providing antigen 5–7 days after priming would be a suitable timeframe for administering the second vaccine dose that would provide late-antigen.
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References

    1. Hannoun C. The evolving history of influenza viruses and influenza vaccines. Expert Rev Vaccines (2013) 12(9):1085–94.10.1586/14760584.2013.824709 - DOI - PubMed
    1. CDC. Seasonal Influenza Vaccine Effectiveness, 2005-2015. (2015). Available from: http://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm
    1. Broadbent AJ, Subbarao K. Influenza virus vaccines: lessons from the 2009 H1N1 pandemic. Curr Opin Virol (2011) 1(4):254–62.10.1016/j.coviro.2011.08.002 - DOI - PMC - PubMed
    1. Pada S, Tambyah PA. Overview/reflections on the 2009 H1N1 pandemic. Microbes Infect (2011) 13(5):470–8.10.1016/j.micinf.2011.01.009 - DOI - PubMed
    1. Eisfeld AJ, Neumann G, Kawaoka Y. At the centre: influenza A virus ribonucleoproteins. Nat Rev Microbiol (2015) 13(1):28–41.10.1038/nrmicro3367 - DOI - PMC - PubMed