Issue #50: COVID-19 vaccines and influenza vaccines: Part 4 – the future and other formulations

Written by Nobel Laureate Professor Peter Doherty

As summarised last week (#49) the new era vaccines – including the PfizerBioNTech (BP) mRNA and AstraZeneca (AZ) adenovirus-vectored product (#43, #44) being deployed in Australia – to limit the prevalence of severe COVID-19 disease caused by SARS-CoV-2 - seem to be more effective than the more traditional ‘killed’ whole virus, viral subunit or live attenuated products (#46) used to reduce the toll of that old plague, influenza. That’s not to decry the importance of being vaccinated against influenza, particularly for the elderly (also at major risk from COVID-19) and the very young (relatively spared by COVID-19) as many lives have been saved over the decades. And there’s also the caveat that a COVID-19 vaccine is targeting only one, relatively stable virus, while the flu vaccine is asked to deal with three or four influenza A or B strains each of which mutates at a much higher rate than SARS-CoV-2. Still, even if we limit the discussion to one flu strain, we don’t see 90 per cent efficacy for flu vaccines.

Could the difference be in the vaccine formulation? There’s great interest in the possibility of using mRNA vaccines to combat the flu and early results that are still in the experimental phase are looking very promising. In fact, the mRNA strategy (#44), apart from giving high level, quality neutralising antibody (Immunoglobulin, Ig) response (#21), also has the advantage of rapid development and production with the capacity to switch fast as mutant strains emerge. As with SARS-CoV-2, vaccine developers just need to know the relevant gene sequence and don’t, for example, have to isolate live virus and adapt it to grow in chick embryos or human cell lines.

Back during the H5N1 bird flu scare in the first decade of this century, development of a protective vaccine was delayed because the virus was too lethal for the chick embryo (#47) production system. Then there’s also the issue that, if high-path H5N1 virus had got into the poultry populations of countries where such vaccines were being produced, where would the eggs have come from? That led to an increase in targeted research funding under US President GW Bush’s administration, which greatly sped up the development of vaccines produced from viruses grown in tissue culture. Now, both the eggs and the cell cultures could potentially be displaced by the mRNA strategy. The SARS-CoV-2 adenovirus-vectored approach has, though, no past or obvious future with influenza. The reason is that circulating Igs (#21) specific for the adenovirus proteins could lead to poor vaccine efficacy if the same adenovirus were to be used for the repeat, annual vaccinations required to deal with variant influenza strains. The adenovirus strategy has, however, been used to make a ‘one-off’ vaccine to protect against infection with the hideous Ebola virus in Africa.

There are, though, other adenovirus-vectored COVID-19 vaccines that could be used for mix and match prime boost applications that avoid using the same carrier twice. Such strategies would, however, require separate clinical trials (hopefully small) before approval. The Johnson and Johnson (J&J) COVID-19 vaccine that was recently approved by the US Food and Drug Administration (FDA) delivers the genetic information to make the SARS-CoV-2 spike protein in much the same way as the AZ product, by encasing it in a replication defective human adenovirus, Ad5. The J&J and AZ vaccines seem to be about equivalent in efficacy. Again, as with the AZ but with the additional concern that pre-existing antibodies to Ad5 could modify the way the immunising dose is processed by our antigen presenting cells (APCs) following injection (#45), it’s been gratifying to see that the J&J vaccine works so well. The original intent was to give just a single J&J dose, which would have made it ideal for use in remote areas and in countries that have less well-developed public health systems, but the clinical trials were done using the usual two dose prime and boost strategy.

Then there’s the ‘Sputnik V’ vaccine from Russia’s Gamalayev Institute that uses a human Ad26 (pre-existing antibody levels to Ad26 are generally very low) to deliver the first dose of the SARS-CoV-2 spike and Ad5 to provide the second. The Gamalayev has a long history of making good vaccines, and Sputnik V is said to give 90% protection. And an Italian company (RiThera) is evidently moving forward with clinical trials of a vaccine that uses a gorilla adenovirus.

Though these various adenovirus vectors could, in principle, be used to make influenza vaccines, this would seem to be a cumbersome approach when compared with the mRNA possibility. Their one relative advantage at the moment might seem to be cost and ease of delivery, but the mRNA field is moving very quickly and newer strategies are emerging that allow the use of a much lower dose – which should make the vaccine much cheaper – in a formulation that can survive well at refrigerator, and even ambient, temperatures. There are also implications here for different vaccine delivery systems that go beyond needles (#45) and puffers (#48), but we’ll wait a bit to address that as we see how these progress during 2021. Next week, I’ll conclude this discussion of COVID-19 and influenza vaccines with some speculation on how they interface with the pathogenesis of these two infections as they do the job of protecting us.