Clinical Expectations for Better Influenza Virus Vaccines-Perspectives from the Young Investigators' Point of View

Abstract

The influenza virus is one of a few viruses that is capable of rendering an otherwise healthy person acutly bedridden for several days. This impressive knock-out effect, without prodromal symptoms, challenges our immune system. The influenza virus undergoes continuous mutations, escaping our pre-existing immunity and causing epidemics, and its segmented genome is subject to reassortment, resulting in novel viruses with pandemic potential. The personal and socieoeconomic burden from influenza is high. Vaccination is the most cost-effective countermeasure, with several vaccines that are available. The current limitations in vaccine effectivness, combined with the need for yearly updating of vaccine strains, is a driving force for research into developing new and improved influenza vaccines. The lack of public concern about influenza severity, and misleading information concerning vaccine safety contribute to low vaccination coverage even in high-risk groups. The success of future influeza vaccines will depend on an increased public awarness of the disease, and hence, the need for vaccination-aided through improved rapid diagnositics. The vaccines must be safe and broadly acting, with new, measurable correlates of protection and robust post-marketing safety studies, to improve the confidence in influenza vaccines.

Keywords: clinical; future; human; immune response; influenza; safety; vaccines.

Figure 1

Illustration of the influenza virus and currently licensed vaccines. Influenza virus (the top panel) is a RNA virus with eight segments of negative sense single strand RNA genome. Two major surface glycoproteins hemagglutinin (HA, in red) and neuraminidase (NA, in blue) are the main antigenic components in inactivated influenza vaccines (the middle panel including whole inactivated, split inactivated and subunit vaccine). Live attenuated vaccine (left in lower panel) uses HA and NA that were expressed with the backbone of cold-adapted, temperature-sensitive attenuated master donor virus to elicit a multifaceted immune response. Recombinant-HA vaccine (right, lower panel) is produced in insect cells using a baculovirus vector.

Figure 2

The immune response to influenza infection. Influenza virus infection elicits a multifaceted immune response. Live attenuated influenza vaccines activate both humoral and cellular immune responses while inactivated influenza vaccines predominantly elicit antibodies. Deeper understanding of the natural protective immune responses after influenza infection will aid in designing future influenza vaccines capable of activating both humoral and cellular immune responses covering several or possibly all influenza strains. Dendritic cells in the airway mucosa present influenza proteins both through the major histocompatibility complex classes I and II to CD4 and CD8 T-cells (Section 3). Antigen presenting cells (APCs) (Section 2) recognize the virus and the subsequent activation of pro-inflammatory cytokines occurs, inducing viral resistance in uninfected neighboring cells, as well as recruiting other immune cells (Section 1). The adaptive immune system will produce virus specific antibodies, as well as CD4 and CD8 T-cells, which are capable of destroying virus infected cells (Sections 4, 6, 7). Although slower, the adaptive immune system has memory and the capacity to recognize an unlimited number of antigens with great specificity, as opposed to the generic response of the innate immune system. Figure made in collaboration with GC Johnsen at the University of Bergen, Norway.

Figure 3

Illustration of antibody targeting next generation influenza vaccine designs. (A) Computationally optimized broadly reactive antigens (COBRA) strategy generates primary consensus hemagglutinin (HA) amino acid (aa) sequences from HAs of native circulating influenza strains, and further secondary and final consensus HA aa sequences from the primary consensus HAs based on a computational algorithm and antigenic evolving analysis. The de novo HA proteins with consensus aa sequence can be displayed on virus-like-particles or rescued influenza viruses using reverse genetics. (B) Chimeric HA. Conserved HA stalk domain from a circulating virus is combined with an irrelevant HA head domain from viruses that are absent in humans. The priming-boost-boost immunization regimen enhances immunogenicity of the subdominant HA stalk, thus elicits cross-reactive stalk specific antibodies. (C) Stable and pre-fusion Headless HA. Mini-HA proteins are engineered to have a correct-folded structure of the stable or pre-fusion stage of HA protein stalk domain. The immunogenicity of HA stalk is greatly enhanced by removing the HA head domain entirely.