Influenza: the quest for a universal vaccine
Influenza virus infections are a major public health concern. Each year, the influenza virus causes 3–5 million cases of serious illness, resulting in 250–500 thousand deaths worldwide.1 Furthermore, pandemics have the potential to claim millions of human lives.2 Influenza has made headline news across the world in 2017/18, with reports of three times more people dying from flu in the UK than last winter, and widespread virus activity in every state in the continental US. European Centre for Disease Prevention and Control surveillance data published in February 2018 shows that, among individuals sampled that presented with an influenza-like illness (ILI) or acute respiratory infection to primary care centres, around 51% tested positive for influenza viruses.3 The World Health Organisation (WHO) has reported rising cases of ILI and the highest level of outpatient visits for ILI since the previous peak in 2011.4
The main factor responsible for the severity of this year’s influenza season has been the circulation of H3N2, a particularly aggressive strain that is only targeted by vaccines in about 30% of cases.4 Influenza viruses evade human adaptive immune responses through an accumulation of point mutations that constantly change their surface glycoproteins. This makes it necessary to re-formulate and re-administer current seasonal influenza vaccines on an annual basis.5 The existing seasonal trivalent or quadrivalent influenza vaccines provide protection against three or four strains, which are defined every 6 months by the WHO for the northern and the southern hemispheres, respectively. Accurately predicting and selecting virus strains is challenging, since mismatches between virus strains and circulating strains substantially decrease vaccine efficacy.6 For example, during the 2014/15 influenza season in the US, more than 80% of the circulating influenza A (H3N2) viruses differed from the vaccine virus, and vaccine effectiveness was only 13% against H3N2.4 Since current methods of vaccine production take around 6 months, it is impossible to provide adequate protection from an influenza pandemic resulting from antigenic changes in circulating strains.7 There is an urgent need for new vaccine constructs that induce broad or even universal influenza virus protection in all age groups.8
Recently, new vaccines that target specific epitopes of the virus have entered clinical and preclinical development. Several of these new approaches focus on the surface receptor-binding glycoprotein of the influenza virus, haemagglutinin (HA), which is comprised of globular head and stem (or stalk) regions. Antibodies against influenza are typically directed at the head but the HA stem does not undergo antigenic changes and therefore has become a target for vaccine development.
A chimeric HA-based vaccine is in development by GlaxoSmothKline. This presents novel globular head domains to the immune system but with a common stem backbone. In preclinical ferret studies, the vaccine gave protection against pandemic H1N1 infections.9 The vaccine is now entering phase I clinical studies.
Sanofi-Pasteur are investigating another approach that aims to overcome the high variability of the HA head by generating computationally optimized broadly reactive antigens (COBRAs) for the influenza HA. This approach is attractive since it maximises the breadth of antibody recognition against all strains of influenza in a subtype with a single ‘cocktail’ of COBRA HA;10 however, development is still at the preclinical stage.
The Multimeric-001 (M-001) vaccine being developed by BiondVax Pharmaceuticals Ltd contains nine common influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. The vaccine has provided multi-season and multi-strain protection in phase I and II clinical trials11 and a phase III study is about to begin. However, M-001 is not able to elicit HA inhibition antibodies, therefore administration of M-001 will require boosting with seasonal or pandemic strain specific vaccines.12
It is unlikely that a ‘one shot’ vaccine will become available in the near future, and there will remain a need for epidemiological surveillance. However, a number of candidate vaccines are now being evaluated for long-lasting and broad protection against influenza viruses, raising the possibility of a universal vaccine within the next decade.
1. World Health Organization (WHO). Influenza (seasonal) fact sheet. Available at: www.who.int/mediacentre/factsheets/fs211/en/ (accessed 21 February 2018).
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3. European Centre for Disease Prevention and Control (ECDC). Weekly influenza update, week 6, February 2018. Available at: https://ecdc.europa.eu/en/publications-data/weekly-influenza-update-week-6-february-2018 (accessed 21 February 2018).
4. Centers for Disease Control and Prevention (CDC). Influenza (flu). Available at: www.cdc.gov/flu/index.htm (accessed 21 February 2018).
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10. Carter DM, Darby CA, Lefoley BC, et al. Design and characterization of a computationally optimized broadly reactive hemagglutinin vaccine for H1N1 influenza viruses. J Virol. 2016;90:4720–34.
11. van Doorn E, Liu H, Ben-Yedidia T, et al. Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: phase IIb study protocol. Medicine (Baltimore). 2017;96:e6339.
12. Atsmon J, Caraco Y, Ziv-Sefer S, et al. Priming by a novel universal influenza vaccine (Multimeric-001) - a gateway for improving immune response in the elderly population. Vaccine. 2014;32:5816–23.