22 Nov 2021
Issue #84: Viruses, Vaccines and COVID-19: arming up
Written by Nobel Laureate Professor Peter Doherty
Currently, the only COVID-19 vaccines available to anyone across the planet require one or two ‘jabs’ that are generally given into the upper arm. The high pressure exerted on the syringe plunger drives some of the inoculum into the deltoid muscle, while a lot discharges straight into the extracellular, or interstitial space. There, it may be taken up by specialised antigen presenting cells, the dendritic cells (DCs) which, along with any free vaccine material in the extracellular fluid, then travel via our other (than the blood) circulation system, the lymph (#9), to enter the regional axillary lymph nodes (ALNs) via the fine tubules of the afferent lymphatics. Many of us know the ALNs as the ‘glands’ in our armpits.
If anyone has had their ALNs excised (stripped) for cancer surgery, it might be better to ask that the vaccine be injected into the region of the gluteus maximus, what the Americans refer to as ‘the butt’. Why? the lymph nodes are both the ‘filter stations’ of the lymphatic system that drains our bodily tissues and the ‘organised’ environments where primary immune responses occur (#40, #41, #42). The DCs hang-up there while the clear, fluid lymph exits via the efferent lymphatics that, in turn, join the ‘main line’ of the thoracic duct to flow back into the venous circulation and be pumped back around the body in the blood.
Enveloped in a drop of protective lipid (fat), the factory-made mRNA (#44) in the Pfizer and Moderna vaccines is, when injected into the arm and then ‘eaten’ by a DC, released into the cytoplasm to serve as the instructional template for making the SAR-CoV-2-spike protein. The makers of the AstraZeneca (AZ) vaccine copy (using an enzyme called reverse transcriptase) the RNA coding for the SARS-CoV-2 spike to DNA and incorporate that into a ‘viral vector’, a replication-defective adenovirus (Ad). Protected by the surrounding Ad proteins, the SARS-CoV-2 DNA sneaks into the DC in its Ad shell. Accessing the nucleus, the DNA serves as the template for synthesising the mRNA which, back in the cytoplasm, makes the spike protein.
The coronaviruses have no known molecular strategy for persisting in those who are immunologically competent, though we do wonder if they might be ‘hiding out’ somewhere in people with Long COVID. And, unless manipulated in a lab dish, there is no mechanism for the integration (into the human genome) of SARS-CoV-2 viral, or vaccine, mRNA, RNA or DNA (AZ). These are not oncogenic (cancer) viruses. The retroviruses, like HIV and human T cell leukemia virus (HTLV-1), carry their own reverse transcriptase and HIV is certainly copied back into our DNA. That’s one of the reasons that it has been impossible to make vaccines to prevent HIV.
In the not too distant future, Australians who have medical issues re possible side effects of the mRNA and AZ vaccines should be able to access Novovax, a more conventional, recombinant spike protein product grown in a moth cell line. After being cleaned up for human use, the spike is mixed with the Matrix-M adjuvant, saponin from the Chilean soap bark tree. As with any adjuvant, the role of Matrix-M is to induce the production of the ‘innate response’ molecules that ‘set-up’ our lymph nodes to generate the optimal recruitment, then clonal expansion of SARS-CoV-2 spike specific T cells and B cells (#18, #19, #41).
Novovax has evidently satisfied the US FDA approval process after completing Phase III clinical trials (#59) and is now being evaluated by Australia’s TGA regulator. Beyond Novovax, the Vaxine company led by Flinders University’s Nikolai Petrovsky has been developing the recombinant spike protein COVAX-19 vaccine. As it is now going into a Phase III trial, we should expect to hear more of COVAX-19 in 2022.
Prominent early on in the Australian vaccination strategy, the ‘protein clamp’ vaccine developed by Paul Young’s group at the University of Queensland used part of the HIV gp41 protein to ‘clamp’ the base of the SARS-CoV-2 spike in a conformation designed to induce a ‘best fit’ antibody response. Unfortunately, it was abandoned because there was also some antibody response to the HIV component, which had the potential to cause confusion in HIV screening assays. That has now been corrected using a different clamp, so we may yet see the UQ strategy re-emerge.
An unfortunate consequence was that the mention of HIV led to propaganda that this particular vaccine could cause AIDS, a misinterpretation that soon spilled over to other vaccines! Such is the ‘information’ (or disinformation) world we live in. For the record, none of the vaccines discussed here can infect other people, or even other cells in our own body. And there is no evidence that anything that is injected in the vaccine formulation persists for more than a week or two. What does endure, perhaps with the help of regular boosting, are the protective immune responses they induce.