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Universal influenza vaccine candidates provide heterosubtypic protection in mice, ferrets and non-human primates

16 Sep 2015

Two new universal influenza vaccine candidates have been tested in animal models and the studies suggest that they provide protection upon intranasal virus challenge with heterosubtypic influenza H5 viruses. The protection is based on the induction of antibody response directed against the H1 haemagglutinin-stem.

Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection [1]

Yassine HM, Boyington JC, McTamney PM, Wei CJ, Kanekiyo M, Kong WP et al. Nat Med. 2015 Sep;21(9):1065-70. doi: 10.1038/nm.3927. Epub 2015 Aug 24.
The study showed new influenza H1 haemagglutinin (HA) stabilised-stem nanoparticle (HA-SS-np) immunogens, in combination with the Sigma Adjuvant System (formerly called MPL-Ribi adjuvant), induced broadly cross-reactive antibody responses that completely protected mice and partially protected ferrets against a high lethal heterosubtypic influenza intranasal H5N1 virus (H5 2004 VN) challenge.
All immunologically naïve mice died while those immunised with H1-SS-np survived. Among the immunised ferrets, four out of six survived. Antibodies to H5 2004 VN could be detected at day 14 post-challenge in surviving ferrets, indicating that H1-SS-np was able to protect against disease while it did not prevent infection. These immunogens induced antibodies to H1, H2, H5 and H9 but interestingly had no neutralising virus activity. The authors suggest that the antibody-mediated protection observed was based on effector mechanisms other than traditional virus neutralisation. Such mechanisms could be antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent complement-mediated lysis.
The article concludes that HA-stem-based influenza vaccines may not necessarily need to be based on neutralising epitopes to induce broad protection.

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen [2]

Impagliazzo A, Milder F, Kuipers H, Wagner M, Zhu X, Hoffman RMB et al. Science. 2015 Aug 24. pii: aac7263. [Epub ahead of print] 

The study finds that new stable, soluble HA stem antigens (‘mini-HAs’) induced in mice broadly neutralising antibodies and complete protection upon intranasal virus challenge with a lethal heterologous and heterosubtypic viruses (H1N1 A/Puerto Rico/8/34 and H5N1 A/Hong Kong/156/97 H5N1) following 2-3 immunisations. The mini-HAs were engineered based on the influenza H1N1 A/Brisbane/59/2007 virus that contains a previously detected broadly neutralising antibody epitope. Furthermore, reduction of fever following a sublethal intranasal virus challenge in immunised cynomolgus monkeys was observed.

The induced antibodies recognised in vitro a wide range of HAs (H1, H3, H5, H7 and H9), they competed with human broadly neutralising antibodies for HA stem binding, neutralised H5N1 viruses and mediated antibody-dependent effector activity. The breadth and protective ability of induced antibodies progressively increased with the structural evolution of the mini-HA configuration. The best candidate had a trimeric form (compared to monomers and dimers) as shown by negative-stain electron microscopy.

The authors conclude that the identified trimeric partial HA produces broad protection against influenza in both mice and cynomolgus monkeys.

ECDC Comment:

Availability of a universal vaccine against influenza is highly desirable. Such a vaccine could significantly reduce the burden of disease caused by influenza and potentially make the currently required yearly vaccination campaigns redundant [3-4]. Although these vaccines are at early stages of clinical development, it is conceivable that they could limit the spread of future influenza pandemics or mitigate their impact and thereby improve global preparedness.
The results from three animal species all point in the same direction: it seems possible to develop influenza vaccine candidates with at least broader cross-protection and possibly universal ones using different technologies.
There are a number of clinical trials in humans for broadly protective or universal influenza vaccine candidates that will start shortly, have already started or completed phase 1 trials,  listed on  M2e-flagellin [5], multimeric-001, FP-01.1 synthetic peptide influenza A vaccine, DNA vaccine with electroporation H1 & H5.
More research is urgently needed to further characterise all available broadly protective or universal vaccine candidates, since such vaccines have the potential to overcome the shortcomings of currently used seasonal influenza vaccines that are limited by their moderate effectiveness [7] and occasional mismatch between circulating influenza strains and chosen vaccine strains.
Comments or questions on this Scientific Advance are welcome and should be addressed to:


  1. 1. Yassine HM, Boyington JC, McTamney PM, Wei CJ, Kanekiyo M, Kong WP, Gallagher JR, Wang L, Zhang Y, Joyce MG, Lingwood D, Moin SM, Andersen H, Okuno Y, Rao SS, Harris AK, Kwong PD, Mascola JR, Nabel GJ, Graham BS. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection  Nat Med. 2015 Sep;21(9):1065-70. doi: 10.1038/nm.3927. Epub 2015 Aug 24.
  2. 2. Impagliazzo A, Milder F, Kuipers H, Wagner M, Zhu X, Hoffman RMB, van Meersbergen R, Huizingh J, Wanningen P, Verspuij J, de Man M, Ding Z, Apetri A, Kükrer B, Sneekes-Vriese E, Tomkiewicz D, Laursen NS, Lee PS, Zakrzewska A, Dekking L, Tolboom J, Tettero L, van Meerten S, Yu W, Koudstaal W, Goudsmit J, Ward AB, Meijberg W, Wilson IA, Radošević K. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen Science 2015 Aug 24. pii: aac7263. [Epub ahead of print] 
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  6. 6. Francis JN, Bunce CJ, Horlock C, Watson JM, Warrington SJ, Georges B, Brown CB A novel peptide-based pan-influenza A vaccine: a double blind, randomised clinical trial of immunogenicity and safety. Vaccine 2015 Jan 3;33(2):396-402. doi: 10.1016/j.vaccine.2014.06.006. Epub 2014 Jun 10.
  7. 7. Valenciano M, Kissling E, Reuss A, Jiménez-Jorge S, Horváth JK, Donnell JM, Pitigoi D, Machado A, Pozo F; I-MOVE Multicentre Case Control Study Team. The European I-MOVE Multicentre 2013-2014 Case-Control Study. Homogeneous moderate influenza vaccine effectiveness against A(H1N1)pdm09 and heterogenous results by country against A(H3N2). Vaccine. 2015 Jun 4;33(24):2813-22. doi: 10.1016/j.vaccine.2015.04.012. Epub 2015 Apr 28.
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