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Tuesday 24 March 2020

COVID-19 vaccine clinical development gets off the mark


Vaccine development has never lacked for innovation, although as a necessarily conservative industry, only a small number of evolutionary technologies have so far been exploited in large-scale “routine” childhood and adult vaccines.

This wealth of background ingenuity, along with experience gained in earlier pandemics (SARS, MERS) and the ongoing quest for better influenza vaccines, has allowed COVID-19 vaccine development to get off to a flying start, with an impressive number of candidates incorporating both established and novel technologies now under laboratory evaluation, and with a few in, or very close to, first in human studies.

A high-profile front runner is Moderna’s mRNA-1273, comprising synthetic mRNA encoding COVID-19 S (“spike”) protein, delivered in a lipid formulation which assists in getting the mRNA into cells and to ribosomes, where it’s translated into immunising protein. Dosing is now underway in healthy adults, with safety and immunogenicity read-out anticipated by mid-June next year[1]

However, on the 23rd March, Moderna raised the possibility of being able to make the vaccine available to essential healthcare personnel before year end under an emergency provision.[2] 

Another mRNA player, CureVac, encouraged by early results from an mRNA rabies vaccine study, plans to enter its own COVID-19 mRNA candidate into trials by mid-year.  CureVac hopes that the vaccine might achieve useful responses at the same very low doses used in the rabies study, allowing it to meet early demand from its existing manufacturing capability. Several other mRNA vaccine candidates under development within academia and industry (from BioNTech, Arcturus, Fosun and Pfizer) are at earlier stages of preclinical development and include a nasally administered vaccine encoding highly conserved COVID-19 proteins (eTheRNA consortium) [3].

A Chinese developed non-replicating viral vector vaccine, Ad5-nCoV (CanSino Biological and the Beijing Institute of Biotechnology) will shortly enter the clinic[4]. This exploits an engineered adenovirus (the workhorse of gene therapy) to deliver DNA encoding coronavirus proteins. The technology has a track record, being the same as used in the first Ebola vaccine to receive regulatory approval.

Adenovirus-based vaccines are not without their problems, but as a relatively well-understood platform, it’s no surprise that several companies and institutes are pursuing non-replicating adenovirus candidate vaccines, including J&J, GeoVax, Altimmune, Greffex and Vaccitech. An arguably riskier route is the use of replicating viral vectors such as measles (Institute Pasteur) and horsepox viruses (Tonix Pharma).

DNA delivery does not require a living carrier, replicating or otherwise. Inovio is applying its electroporation to push COVID-19 protein encoding DNA through the skin. Zydus Cadilla is also looking at a DNA, although has not disclosed how the encoding plasmid might be delivered.

Protein subunit vaccines are well-understood, with several candidates developed in response to the SARS pandemic. Importantly, the manufacture of protein subunit vaccines is well-established and can be accomplished to high yields in in standard bacteria and yeast expression systems, although several COVID-19 candidates involve insect cell (Sanofi, ExpreS2ion) or plant-based manufacture (IBio/CC Farming).

And, in the midst of all this experimental vaccine tech, let’s not ignore the old school approaches of formalin-inactivated virus (Sinovac) and attenuated live vaccines (Codagenix/Serum Institute of India) which have proved their worth in existing viral vaccines.

Nor should we ignore the slog ahead. The correlates of protection for COVID-19, that is what should we be looking for with respect to the quality and magnitude of a neutralising antibody response, are unknown: analysis of the immune response from recovering (and infected but asymptomatic) individuals may shed much needed light.  The phenomenon of “antibody dependent enhancement” (ADE), where the virus hijacks the host antibody response to infect certain cell types has been observed in both  non-SARS human and animal coronavirus infection. Early SARS vaccine development pointed up a potential risk of severe hypersensitivity reactions in immunised animals when challenged with virus.  

Despite the pressing need to at least be able to protect those on the front line, history dictates caution[5]. A possible silver lining of the pandemic is that revolutionary approaches such as mRNA vaccination may prove their worth much earlier than would normally be the case.  Vaccine development failures, and there will be many, will, at hte very least, will add to preparedness for the next pandemic by eliminating blind alleys. 

With a fair wind, we might see limited release of a vaccine within 18 months. Until then, and with the gradual development of what will hopefully be protective natural immunity, we all need to accept that lockdown and social distancing save lives and takes some of the pressure off our healthcare systems.





[1] Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to Prevent SARS-CoV-2 Infection https://tinyurl.com/vnvl7wd
[2] Moderna: Virus Vaccine May Be Available to Aid Workers by Fall, Wider Provision in 12-18 Months https://tinyurl.com/s3tm6as
[3]eTheRNA Launches an International Consortium and Starts Development of Cross-strain Protective CoV-2 mRNA Vaccine for High Risk Populations https://tinyurl.com/wdmkk6d
[4] A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) https://tinyurl.com/vqemt6u
[5] h Don’t rush to deploy COVID-19 vaccines and drugs without sufficient safety guarantees https://tinyurl.com/swybbya

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