Universal influenza virus vaccines and therapeutic antibodies

Abstract

Background: Current influenza virus vaccines are effective when well matched to the circulating strains. Unfortunately, antigenic drift and the high diversity of potential emerging zoonotic and pandemic viruses make it difficult to select the right strains for vaccine production. This problem causes vaccine mismatches, which lead to sharp drops in vaccine effectiveness and long response times to manufacture matched vaccines in case of novel pandemic viruses.

Aims: To provide an overview of universal influenza virus vaccines and therapeutic antibodies in preclinical and clinical development.

Sources: PubMed and clinicaltrials.gov were used as sources for this review.

Content: Universal influenza virus vaccines that target conserved regions of the influenza virus including the haemagglutinin stalk domain, the ectodomain of the M2 ion channel or the internal matrix and nucleoproteins are in late preclinical and clinical development. These vaccines could confer broad protection against all influenza A and B viruses including drift variants and thereby abolish the need for annual re-formulation and re-administration of influenza virus vaccines. In addition, these novel vaccines would enhance preparedness against emerging influenza virus pandemics. Finally, novel therapeutic antibodies against the same conserved targets are in clinical development and could become valuable tools in the fight against influenza virus infection.

Implications: Both universal influenza virus vaccines and therapeutic antibodies are potential future options for the control of human influenza infections.

Keywords: Influenza vaccine; Monoclonal antibody therapeutics; Pandemic influenza; Seasonal influenza; Universal influenza virus vaccine; Zoonotic influenza.

Figure 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 HA (H1, H2, H3) and two subtypes of NA (N1, N2) that caused pandemics and established themselves as human seasonal influenza viruses. Interestingly, viruses of the same HA group do usually 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 with occasional human contact (teal). The bars are shown in color for times when human cases or outbreaks were reported. If a virus disappeared from surveillance, the bar is shown in grey. H7N2 and H5N1 are good examples for viruses that might not be detected in surveillance efforts, but still circulate in their respective animal reservoirs. Both of these viruses infected humans, disappeared and then re-appeared to infect humans years later. C) Overview of the benefits of vaccines and biologicals for influenza virus infection prophylaxis and therapy.

Figure 2. Targets for universal influenza virus vaccines

A) The HA head domain is the main target of currently licensed influenza virus vaccines. This domain is very variable and antibodies elicited by the vaccine are generally neutralizing, but highly 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 utilize additional Fc-mediated effector functions like ADCC. 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 via ADCC. 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.

Figure 3. Universal influenza virus vaccination approaches

A) Two approaches are in late stage pre-clinical development to target the HA stalk domain. One vaccination strategy is based on the use of chimeric hemagglutinins (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) M1 and NP are often targeted in combination approaches with either virus vectors (e.g. MVA 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, similar to virus vectors 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.