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 forma 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)
BioNTech Signs Collaboration Agreement with Pfizer to Develop mRNA-based Vaccines for Prevention of Influenza. Company press release online 16th August 2018. http://tinyurl.com/y88mfkr7.
Translate Bio Announces Closing of Collaboration and Licensing Agreement with Sanofi Pasteur to Develop mRNA Vaccines for Infectious Diseases. Company press release online 9th July 2018. http://tinyurl.com/ycha48vp.
Moderna Therapeutics clinical trials (accessed 23rd August 2018). http://tinyurl.com/ybspttrm