mRNA vaccine technology: industry is getting the message

Can mRNA technology take vaccine
design and development into a
post-Jennerian era?

Vaccination is second only to the provision of drinking water with respect to global public health benefit, and while  still some way short of universal  vaccine coverage, hundreds of millions of children and adults are protected each year  from formerly lethal  infections.

Vaccine development has never lacked ingenuity, but progress has arguably been evolutionary rather than revolutionary. The concept of injecting selected components of infectious agents rather than whole microorganisms would not greatly surprise Edward Jenner.

Twenty-first century vaccinology faces major challenges. Conventional manufacturing and deployment capabilities are taxed by the annual challenge of shifting influenza strains [A single shot] or in mounting a large-scale response to  “swine ‘flu”-like global pandemics; shorter development cycles are needed to tackle outbreaks of Zika and Ebola viruses, or whatever emerging pathogens tomorrow might bring; no effective vaccines exist for infections common in both developed and emerging economies, including HIV, Chlamydia, cytomegalovirus and tuberculosis.

Revolutions in vaccinology have proved elusive. The prospect of replacing expensive and complex vaccine manufacture with the injection of chemically-synthesised strands of DNA encoding one or more vaccine components has been pursued since the 1990s. Although simple in concept, and despite efforts to optimise DNA delivery, low potency and unresolved safety issues have confined DNA vaccination to a few animal health products. Synthetic peptide vaccines designed to mimic and present a desirable selection of antigenic sequences, struggle to elicit robust immune responses and confer effective protection.

High profile buy-ins by vaccine industry majors suggest that a true technological revolution might, finally, be on the horizon. Protein synthesis requires DNA code to be rewritten in the form  of another nucleic acid, messenger RNA (“mRNA”), which is then translated by ribosomes, the cell’s protein factories. That the transcription of DNA can be circumvented through direct injection of mRNA to produce the  corresponding protein has been known for decades, but the instability of mRNA,  and the complication that unmodified mRNA is itself highly immunogenic,  led to the exploration of mRNA vaccination  being sidelined by less technically demanding DNA and recombinant protein approaches.

Across the board advances in ease of delivery, chemical modification to improve stability and increased duration of protein production in vivo are rapidly making mRNA vaccination a viable proposition.  Clinical trials are underway in both infectious disease indications including influenza, Zika virus and HIV infection (the latter exploring therapeutic rather than prophylactic potential), and in solid and haematological cancers. The majority of cancer studies exploit the properties of specialised antigen-presenting cells (dendritic cells) which can be readily isolated from patients, loaded with tumour antigen encoding mRNA and then returned by infusion [Dendritic cell vaccines: back to the future].

Recent licensing agreements between mRNA vaccine developers and leading vaccine companies add to a growing list of industrial, governmental and non-for-profit collaborations aimed at leveraging  the benefits that mRNA technology might bring to infectious disease vaccination: higher immunogenicity; inherent safety and rapid, low-cost, scalable manufacture.

Pfizer’s $425 million headline collaboration with mRNA vaccine developer BioNTech is focused on building better flu vaccines which can be manufactured quickly and cheaply. Another mRNA vaccine pioneer, Translate Bio, entered in an $805 million headline agreement with Sanofi Pasteur in June covering five undisclosed infectious disease agents with the option to expand the collaboration to other pathogens. CureVac AG has infectious disease mRNA vaccine partnerships with both Sanofi Pasteur and Johnson & Johnson, while GSK and Novartis are collaborating on mRNA vaccine development.

Early clinical data obtained using directly injected flu and rabies mRNA vaccines can best be described as “modestly encouraging” and it will be several years before which, if any, of the various flavours of mRNA technology  can claim to be a viable route to cost-effective, large scale vaccination,  and/or  serve as a solution to  problem pathogens. The picture may become clearer with a second Phase I study of Moderna Therapeutics’s flu vaccine candidate and a Zika virus Phase I study due to complete before year end.

Image credit: Wikipedia (public domain image)

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