Issue #44: Virus and vaccine - Part 2

Written by Nobel Laureate Professor Peter Doherty

Last week we looked a little at the SARS-CoV-2 virus and at the mRNA BioNTech/Pfizer (BP) and the Oxford/AstraZeneca (AZ) ChAd9 virus-vectored vaccines that will soon be going into the arms of Australians (#43). In countries where the pandemic is raging, two identical, sequential shots of these vaccines have already been given – generally three to four weeks apart – to large numbers of people. We can be reassured that it all looks good so far, though those who are highly allergic and have to carry an epinephrine-loaded Epipen will likely be directed to the AZ product.

The aim here is to give a bit more detail on what the virus does while drawing a parallel with how these vaccines work. Once the SARS-CoV-2 virion is in the cell, it dissociates to release its ‘bad news’ the viral RNA (#6) into the cytoplasm. The first thing that happens is that the single copy of virus-introduced positive strand (+ve) RNA carrying the 11 SARS-CoV-2 genes is exposed and serves as the template for making a whole bunch of little proteins that are required to make the complementary RNA negative (-ve) strand.

Think of those little proteins as the ‘tools’ an art forger uses as he pours plaster (or moulds rubber) around an ancient bronze head of Hygieia (+ve strand), then carefully cuts that away, removes the original, sticks the mould (- ve strand) back together and fills it with a hot metal to cast new bronzes (+ve strand) for later, artificial ‘ageing’. In the antiques trade, fake ageing is called ‘distressing’. Distressing and accelerated ageing can certainly go together for COVID-19! And Hygieia was the Greek Goddess of sanitation and hygiene.

The -ve strand RNA ‘mould’ acts as the template for producing multiple new, full length copies of the +ve strand SARS-CoV-2 genome, the ‘bad news’ component of the numerous progeny virions that will ultimately leave the infected ‘factory cell’. Some of these virus particles will be coughed and spluttered into the atmosphere to infect other people. Others are carried in our mucus or blood to invade and set-up more virus-producing cell factories, and ramp-up the magnitude of virus-induced damage within us.

The other function of the -ve strand RNA mould is to be the template for the multiple, smaller +ve strand mRNAs that, translated by the ribosomal ‘machine, assemble the amino acids in sequence to make the new proteins essential for the manufacture of progeny SARS-CoV-2 virions. Additional to the four structural proteins that actually form the virion (the spike, envelope, membrane protein and nucleocapsid) the mRNAs also specify a whole bunch of non-structural proteins (NSPs) that do all sorts of jobs. That includes switching off normal functions in the host factory cell: the degradation of host mRNA, for instance, means that the cell essentially becomes dysfunctional and ‘dead to us’. Other NSPs are involved in facilitating virus assembly and cell exit mechanisms.

So, let’s reflect a little on the antibody response to infectious virus (#23, #24). Only one of the virion proteins, the spike, is, so far as we know, of any significance as a target for protective, neutralising antibody (#22). Yet, if newly made virus – and it’s pretty normal for many virus particles to be damaged – is taken in and processed by an antigen presenting cell (APC), we will make irrelevant antibodies specific for those other virion structural proteins (#41, #42). Then, when the infected ‘factory cells’ cells die and fragment, that ‘useless antibody response equation’ is potentially applicable to all the NSPs.

True, some of the tiny peptides (p, each coded by less than 40 nucleic acid bases in a 30,000 base genome #6) from any virus protein made within an infected cell may form the virus+ self (pMHC1, #36, #37) complexes that target the CD8+ ‘killer’ T cells. And, while the recall of that response from memory will never give us sterilising immunity, it may help diminish disease longevity and severity. The BP and AZ vaccines are clearly missing any immunogenic peptides that come from viral proteins other than the spike, but there are strategies for adding a few peptides and not the proteins to a second or third generation vaccine. There’s currently a lot of basic discovery work going on to identify the most important peptides.

The injected BP or AZ product likely ends up in the cytoplasm of any cell it runs into, with some of those being APCs that will carry it in lymph to the regional node (#41, #42). The BP mRNA stays in the cytoplasm, while the DNA of the AZ product goes into the nucleus where it is transcribed to make mRNA, which then goes into the cytoplasm. Any ‘irrelevant’ cells that interiorise the SARS-CoV-2 spike protein mRNA or DNA will also make protein that could potentially be picked up by APCs, perhaps after being secreted back into the extracellular fluid and lymph (#9). The BP vaccine will drive only the production of antibodies specific for the SARS-CoV-2 spike, while the AZ vaccine will, in addition, stimulate antibody production to the ChAd adenovirus shell proteins. Both products could, of course, also provide any spike protein peptides that might target a killer T cell response (#36). Enough for now, more next week.