Immunological assessment of influenza vaccines and immune correlates of protection

Abstract

Influenza vaccines remain the primary public health tool in reducing the ever-present burden of influenza and its complications. In seeking more immunogenic, more effective and more broadly cross-protective influenza vaccines, the landscape of influenza vaccines is rapidly expanding, both in near-term advances and next-generation vaccine design. Although the first influenza vaccines were licensed over 60 years ago, the hemagglutination-inhibition antibody titer is currently the only universally accepted immune correlate of protection against influenza. However, hemagglutination-inhibition titers appear to be less effective at predicting protection in populations at high risk for severe influenza disease; older adults, young children and those with certain medical conditions. The lack of knowledge and validated methods to measure alternate immune markers of protection against influenza remain a substantial barrier to the development of more immunogenic, broadly cross-reactive and effective influenza vaccines. Here, the authors review the knowledge of immune effectors of protection against influenza and discuss assessment methods for a broader range of immunological parameters that could be considered in the evaluation of traditional or new-generation influenza vaccines.

Figure 1.. Assessment of immune responses to influenza.

(A) Antibody titers measured by the hemagglutination-inhibition assay are the gold-standard immune marker correlated with protection against influenza. However, there are limitations to the generalizability of the currently accepted hemagglutination-inhibition titer criteria, particularly in populations at high risk for severe influenza disease, and for the assessment of nontraditional influenza vaccines. Single radial hemolysis is also a recognized correlate of protection for influenza and is used by the EU for vaccine licensure. (B) A variety of serological assays are currently used to assess antibodies; some of these have the potential to identify alternative correlates of protection for both traditional and nontraditional influenza vaccines. Virus neutralization assays are becoming more widely used, but standardized methods and criteria for evaluation of titers associated with protection are lacking. Standardized assays that detect responses to M2 and neuraminidase are also needed. (C) T cells target viral epitopes primarily derived from internal proteins that have been shown to be highly conserved across viral strains. While assays assessing cell-mediated immune responses to influenza vaccination are becoming more commonplace, identification of key, qualified assays are needed to develop cellular immune markers that may correlate with protection against influenza. ELISpot: Enzyme-linked immunosorbent spot.