A single shot

Each year, healthcare agencies undertake the crucial task of choosing which particular influenza virus strains will be included in vaccines to be manufactured and deployed in time for the next flu season. Selection is assisted by history and epidemiological surveillance but, as in this, the 2017-2018 flu season, mismatching of vaccine composition and the actual infecting strains greatly reduces the impact of vaccination.

That flu viruses regularly undergo changes that render vaccines ineffective has been known since the introduction of large scale flu immunization campaigns in the 1950s, leading to the World Health Organization setting up a global influenza surveillance and response system.

Seasonal flu infection is largely due to influenza Type A, and to a lesser extent, the generally less severe influenza Type B. Type C influenza strains cause only mild and sporadic infection. New “pandemic” strains, to which there is no widespread immunity, can pop up with devastating effect. The “Spanish Flu” of 1918-1919 may have caused 20-50 million deaths (more than in the Great War), while the 2009 “swine flu” pandemic may have caused more than half a million deaths.

Flu vaccines work by inducing a neutralising antibody response to haemagglutinin (HA), a protein expressed on the surface of the virus essential for infection and spread. HA can, unfortunately, undergo regular “antigenic shift”, necessitating annual adaption of seasonal flu vaccine composition to match the characteristics of the infecting strains.  

The logistical challenge of getting the right vaccine ready at the right time (a task still almost completely dependent on growing the selected virus strains in hen’s eggs), along with the need to be better able to deal with future flu pandemics, are powerful incentives to develop so-called “universal” flu vaccines, capable of inducing long-lasting or even lifelong protective immunity which is not compromised by the mutability of the HA protein. Moreover, recombinant protein vaccines would simplify large-scale manufacture and speed up vaccine availability in the face of a pandemic. 

Government and industrially funded research is pursuing a variety of routes towards a universal vaccine. A leading contender being developed by Vaccitech, an Oxford University spin-out (backed in part by Google’s venture fund), combines two highly-conserved core proteins (nuclear protein and matrix protein 1) that are naturally expressed by influenza A strains. A Phase II clinical study, which aims to eventually recruit over 2000 subjects aged over 65, is now underway, with recruitment of the initial tranche of volunteers announced earlier this month. It’s hoped that the vaccine will elicit both antibody and cellular immune responses to generate long-lasting protection.

A not dissimilar approach is being pursued by BiondVax. Various antigenic sequences (“epitopes”) present in HA, nuclear protein and matrix protein have been selected for their ability to elicit both antibody and cellular responses and knitted together in a single recombinant protein. The company hopes to initiate a Phase III study in Europe later this year, involving 7,700 subjects aged 50 years or older older, with at least half of participants being over 65 years of age.

Promising pre-clinical candidates include synthetic nanoparticles incorporating multiple copies of a conserved matrix protein developed at Georgia State University, while another Georgia group (in collaboration with Sanofi Pasteur) has used computational analysis to cherry-pick and combine different epitopes from HA proteins to induce antibodies broadly protective against one particularly important flu strain and its variants.

DNA vaccination, in which a piece of flu virus DNA is injected and then expressed as an immunising protein by the subject’s own cells, has been shown to reduce the effects of flu infection in primates. An advantage of DNA vaccination is that the “immunising” strand can encode several different conserved flu proteins to give broad protection. On the other hand, despite the wide optimism over the utility of DNA vaccination expressed during the last 25 years, only a handful of veterinary DNA vaccines have obtained regulatory approval.

"All done. See you again in five years"

While there’s no shortage of ingenuity and endeavour, a truly “universal” flu vaccine remains a good way off. Progress has so far been largely confined to influenza A viruses and the ideal universal vaccine will need to provide protection against influenza B (and ideally, pandemic strains and those of animal origin).

Science is only one barrier. As with other vaccines, large scale studies will be required to establish efficacy over conventional vaccines and safety, particularly in those at most risk from flu infection (young children and the elderly). Meaningful evaluation and deployment of a universal flu vaccine is likely outside the capacity of industry or national agencies and will require regional, if not global, co-operation and co-ordination if we are to finally attain adequate protection against “la grippe”.

Photo credit: CDC and Doug Jordan, M.A

Update added 3rd February 2018

The vaccine deployed in the US for this flu season does contain virus types corresponding to the most commonly reported infecting strain, H3N2, but vaccine strains are known to have low efficacy against H3N2. 

Flu vaccine Study Recruits First Participants. Vaccitech company press release online 19^th January 2018. http://tinyurl.com/y9xe7agv

BiondVax plans Phase 3 clinical trial following receipt of scientific advice from the European Medicines Agency (EMA). Company press release online 27^th December 2017. http://tinyurl.com/yaxzh48u

Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses. Deng, L et al. Nature Communications. Nature Communications. 2018 9:359. http://tinyurl.com/y9rn3dby

COBRA HA elicits hemagglutination-inhibition antibodies against a panel of H3N2 influenza virus co-circulating variants. Wong, TM et al. Virol. J VI.01581-17; online 4th October 2017.

Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates. Koday, MT et al. PLOS One, published online 21^st December 2017, https://doi.org/10.1371/journal.pone.0189780