1. Universal influenza virus vaccines and therapeutic antibodies
R. Nachbagauer, F. Krammer 
Clinical Microbiology and Infection 
Volume 23, Issue 4, Pages (April 2017)
DOI: /j.cmi
Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions

2. Fig. 1
Influenza virus circulation. (a) Two subtypes of influenza A, H1N1 (group 1, blue) and H3N2 (group 2, red) are currently circulating alongside influenza B viruses in the human population. In documented history, there have only been three subtypes of haemagglutinin (HA) (H1, H2, H3) and two subtypes of neuraminidase (NA) (N1, N2) that caused pandemics and established themselves as human seasonal influenza viruses. Interestingly, viruses of the same HA group do generally not circulate at the same time in the human population. A newly introduced pandemic virus usually replaces the previous seasonal virus of the same group (as seen in 1957 with H1N1 and H2N2 and in 2009 with H1N1 and pandemic H1N1). (b) A large number of different subtypes of influenza viruses have been discovered in animals (mainly avian species). This graph shows viruses with documented human zoonotic cases (purple) and viruses of concern that widely circulate in animal reservoirs (teal). The bars are shown in colour for times when human cases or outbreaks were reported. If a virus disappeared from surveillance, the bar is shown in grey. (c) Overview of the benefits of vaccines and biological agents for influenza virus infection prophylaxis and therapy.
Clinical Microbiology and Infection  , DOI: ( /j.cmi )
Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions

3. Fig. 2
Targets for universal influenza virus vaccines. (a) The haemagglutinin (HA) head domain is the main target of currently licensed influenza virus vaccines. This domain is highly variable and antibodies elicited by the vaccine are generally neutralizing, but strain specific. Novel universal influenza virus vaccines target the HA stalk domain instead. This domain is highly conserved and antibodies against the stalk are generally broadly cross-reactive and often neutralizing. In addition, these antibodies can use additional Fc-mediated effector functions like antibody-dependent cell-mediated cytotoxicity to mediate protection. (b) The ectodomain of the M2 ion channel is highly conserved, which made an ideal target for some of the earliest universal vaccine approaches. Antibodies against this domain are generally non-neutralizing and mediate their protective effects through antibody-dependent cell-mediated cytotoxicity. (c) The M1 matrix protein is conserved within influenza A viruses. Since M1 is an internal protein that is generally not exposed on the outside of virus particles, the focus has been on eliciting cytotoxic T-cell responses. These vaccines would be infection permissive (i.e. non-neutralizing), but could protect from severe infection. (d) The nuclear protein (NP) is highly conserved within influenza A viruses. Because it is an internal viral protein it is being used as a target for cytotoxic T cells that could protect individuals from severe infection.
Clinical Microbiology and Infection  , DOI: ( /j.cmi )
Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions

4. Fig. 3
Universal influenza virus vaccination approaches. (a) Two approaches are in late-stage preclinical development to target the haemagglutinin (HA) stalk domain. One vaccination strategy is based on the use of chimeric haemagglutinins (cHAs) that express exotic head domains in combination with the conserved stalk domain. Repeated exposure to cHAs with different head domains can re-focus the antibody response towards the stalk. Another approach uses headless HAs that can specifically elicit antibodies against the stalk domain. (b) Vaccination strategies for M2e are largely focused on eliciting a potent response by presenting the M2 ectodomain as part of virus-like particles (e.g. made from hepatitis B core proteins) or linked to bacterial flagellins. Another approach is the use of DNA vectors that will lead to protein expression in large amounts on the cell surface and offer a good target for B cells. (c) matrix protein 1 (M1) and nucleoprotein (NP) are often targeted in combination approaches with virus vectors (e.g. modified vaccinia virus Ankara vector based) that will express the proteins in infected cells. Peptides will be presented on MHC receptors on the cell surface and facilitate the induction of T-cell responses. A similar approach for NP is the use of DNA vectors that leads to protein expression in the cells and presentation of peptides on the cell surface. (d) Another approach to elicit T-cell responses are peptide vaccines. Peptide pools that consist mainly of M1 and NP, but often also include peptides from other influenza virus proteins, are given individually or in combination with conventional seasonal influenza virus vaccines to elicit broadly protective T-cell responses.
Clinical Microbiology and Infection  , DOI: ( /j.cmi )
Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases Terms and Conditions