Saturday, 14 November 2020

Vaccine update. Bio-technology to the rescue?

SUMMARY

  • Pfizers new mRNA vaccine trial is the first to analyse results with Russia's Sputnik 5 vaccine is hot on its heels
  • Early analysis suggest 90% protection - what the results show
  • What mRNA is and how mRNA vaccines work is explained together with their potential for future pandemics and treatment of cancer.
  • More results on other vaccines will be rolling in soon, but a vaccine for 2021 is looking more likely. 
  • Imperfections of Vaccine trials explained
  • It remains important to stay mentally and physical healthy (COVID19 ready)
  • The causes and consequences of the pandemic mean a fundamental green revolution to restore habitats is more critical than ever

Pfizer's first

After what might have seemed a quiet summer in the vaccine front, results from phase 3 trials are beginning to come in with the Pfizer/ BioNTech mRNA vaccine the first to announce preliminary results. This has been widely welcomed as a major leap forward and demonstrates that a vaccine can be made which is effective, at least in the short term. 

Pfizer is an American drug company founded in 1849 by Karl Pfizer who, like the founder of most drug companies was German. It made its mark by understanding how to make citric acid by fermentation, which proved critical in the mass manufacture of penicillin after World War 2.  It's blockbusters since includes cholesterol lowering drugs, antibiotics and viagra.

Karl Pfizer
(1824-1906)

The vaccine itself was developed by BioNTech, a much smaller and perhaps more clever German company in a symbiotic relationship between research, innovation and mass production clout. For anyone interested in biology and health, it is an incredibly powerful and for many, exciting development. For others it is scary. I hope this post will help you understand what the vaccines are about. 

So far, in Pfizers trial of 43,000 people, given the vaccine and a booster 21 days later. 94 have developed symptoms of COVID19, 90% of whom were in the placebo arm, which was an exciting early result. This level of protection was way beyond what might have been reasonably hoped for. This has been announced by Pfizer and are yet to be published by peer reviewed journals, but is still very good news. After many uncertainties, the results show that a vaccine is possible. 

Hot on the heels of this announcement is the news that Russia has declared its vaccine "Sputnik5" to be 93% effective. 

Both trials were blinded, so no one knew who was getting the vaccine or the placebo. Once enough cases were generated, unblinding revealed how many cases of COVID were in the treatment or placebo groups. The short answer is 90% were in the placebo group. Put another way, the vaccine prevented 90% of infections. The blinded trials have now resumed and Pfizer will announce more results towards the end of November, particularly those related to safety.

Sputnik 5

Sputnik, rather like its name, uses a more established vaccine technology. It was rushed into phase 3 trials without the usual level of scrutiny and was thus the first to be widely trialled. Its novel aspect is that it used two different human adenoviruses to carry the S protein of the viral spike in each of the two jabs given three weeks apart, in the hope if increasing its effectiveness.

They claim 92% effectiveness against developing symptoms of COVID19 based on early data from their phase three trials. There were just 20 cases of COVID in 16,000 volunteers. Small numbers and again yet to be formally published for scrutiny. It seems to me they have published too early with what must be 18 cases in the placebo and just and two in the treatment arm.

Their vaccine is delivered by 'vectors', as the modified human viruses carrying the spike protein are called. They are non-replicating adenoviruses; that is they have no genes responsible for reproduction and so can't cause infections themselves. 

The idea is that exposure to the foreign COVID19 protein they carry stimulates the production of antibodies and possibly T Cells against COVID. Adenoviruses are responsible for colds and would cause infections if the were able to reproduce.

Clever though traditional stuff. The new kid on the block is the mRNA vaccine - so what is mRNA and how does it work?

What is mRNA? m is for Messenger.

Everyone had heard of DNA. Indeed, "Its in my DNA!" has become an annoying expression to convey any notion from the desire to win a football match to just about any characteristic you wish to describe as being a fundamental part of your nature. DNA's totality is described as our Genome, genetic blueprint, or construction manual. 

Messenger RNA

mRNA is a part of the hidden molecular machinery that makes you and I what and who we are. If you like, it "reads" the information in DNA, takes it to the protein making machinery located in the ribosomes and wonderful Golgi Apparatus, a structure within every cell which knocked me sideways when I first saw its amazing structure under a microscope. 

mRNA is like that worker with a clipboard  taking instructions from the design department (genes) to the factory floor, (  and Golgi)and then ensuring the product (protein) is accurately created.

Your wonderful Golgi apparatus!

In reality DNA unzips its double strand to reveal its sequences of amino acids. This sequence is copied by mRNA, (m=messenger) creating a single stranded mirror of the code, and transported to where the information acts as a template for the construction of proteins which are also made of amino acids, and which are the building bricks of structures from the hair on top of your head to your toenails and just about everything in between. 

Proteins also include the cascades of antibodies, cytokines and the multitude of other molecules floating around inside and outside every cell in our body which keep us ticking along and healthy. They control of our immune system. 

This process is usually controlled by the processes within the cell which decides which bit of DNA to unwrap and read, they study of which is called Epigenetic. This whole process is by-passed by mRNA vaccines. It's fair to say in summary that the mRNA injected into our arm utilises our own capability to manufacture our own vaccine.

Interstingly and thankfully, they seemed to produce an appropriate immune resonse in both the young and the old, essential for the vaccine to work in the real world.

Simple? No! Absolutely amazing? Yes. I have captivated by the wonder and beauty of all things beyond our vision since a young boy with a microscope. I used to escape from day to day life to go on safari in those vast spaces contained within any drop of pond water or other gloop I could find. Single celled creatures are wonderful to behold, yet the invisible complexity the inner molecular machinery is simply astonishing in its intricate beauty. 

In the working of DNA and how it assembles amino acids into what becomes you and me, I can see back to the primordial soup, where amino acids were first formed from their own atomic building bricks, started copying each other and so laid the foundation for every living thing we see on earth and probably in the universe.

I kid you not, understanding DNA and mRNA is to understand our world and how it came about. Apologies there for getting lost in my own sense of wonder, but how our immune system actually works continues to be a source of incredulity and astonishment. The complexity of life is humbling.

So, in essence, mRNA can make molecules, and the molecule this vaccine makes is the receptor site protein of COVID19's spike protein. How?

How does an mRNA vaccine work?

mRNA is injected into the muscle of the arm, enclosed within tiny fat nano-envelopes. It is then taken up by the cell and then to the protein making machinery to make the receptor site protein of COVID's spike, which is then released into the bloodstream where it's recognised as foreign by the immune system. 

Lipid nanoparticle
 "envelopes"

We then produce antibodies to the spike protein which cling to it, destroy it using activated T Cells, and remember it in the form of B cells to produce antibodies and memory T Cells to kill COVID19 when you come across the real thing. Putting it another way, we have recorded the biological 'number plate' of COVID19 and will recognise it when spotted again.

Normal viral RNA not only contains codes for the proteins to make its daughters, but also genes to make DNA out of its RNA (called reverse transcriptase) and others for insertion into the DNA of the host cell(called integrase). There are other genes to control processes in the host cell. 

A topical example of this being COVID19's genes for the production of proteins which switch off production of interferon, one of our first line defences against infection. This is akin to switching off the burglar alarm. These genes are behind the incredible prolific reproduction which defines viruses success and the ability of COVID19 to spread before symptoms develop.

Vaccine mRNA is different. It's important to know that the mRNA in vaccines cannot replicate like viral RNA as they do not include the genes to do this. The cannot integrate into our genome as they lack to genes to make that happen. 

Understanding of this basic science might reduce some of the worries about "having genes inserted into your body" and other fears which fuels those who are not keen on the whole notion of vaccination. Remember as well, that viruses are continually inserting their genetic information into ours, and always have been.

Consider that most of our DNA is not even of vertebral origin - it is viral. We have been having our Genome added to by viruses since time began, oiling the wheels of evolution. For example, the delicate membranous interface between maternal and foetal sides of our placenta is created by genes of viral origin. Yes, without the insertion of viral genes into our genome, we would not even be placental animals. 

Mitochondrial DNA is not of vertebral origin either, in this case bacterial. In that sense, mRNA vaccination can be seen as an adaptation of a natural process to our modern world whose  industries and systems are not at all designed for human health.

The mRNA vaccine does not replicate, once it makes the protein is codes for, it is destroyed and does not insert itself into the genome as it lacks the tools (enzymes) to make this happen. This is why is it theoretically considered safe, indeed more safe than conventional vaccines. We shall have to wait for more data to see this hope play out in the real world.

It's you again!!

In summary, the mRNA makes us manufacture spike receptor proteins which do not harm us directly. We learn to destroy them and remember how to do it for next time. The inserted non replicating mRNA will not last forever, is not inserted into our DNA and it will degrade.

 The memory cells will then be on the lookout for the viral number plate again and so you will have a milder infection, or no infection at all when you again come across COVID19.

Other horses in the race

Hot on the heels of this news will be the early results from other trials on more conventionally produced vaccines using harmless viruses modified to have those COVID19 protein "number plates" attached in order to pre-arm the immune system for the real thing. 

Adenovirus

Results from the Oxford vaccine will also soon be available so there seems there will be choice available as we trundle into 2021. That the mRNA vaccines need to be stored at minus 70deg C during transport is a major stumbling block in global terms and an administrative though not insuperable nightmare as it can be kept in a normal fridge for 5 days before administration.  Different vaccines might not only suit some individuals, but also some nations, environments and economies.

There are agreements designed to ensure availability to all nations which will now be tested, as well as the economic implications which make the science look so simple.

I have listened to experts who feel the mRNA vaccine by-passes many of the safety concerns regarding vaccines for the immunocompromised and other at risk groups. It is not clear from the study if these groups have been included in the trials. 

Further, the speed at which RNA vaccines can be developed might well be used for the next pandemic, early enough and targeted enough to make the next pandemic experience totally different. That's another story.

Vaccination trials in an imperfect world?

So the data is preliminary, but it shows that COVID19 infection rates can be be hugely reduced. The trials do not have end points of hospital admission or death. This might seem surprising, after all this is what we are after, but such trials would involve millions of people costing many billions and taking far longer. That means that the pragmatic end points are symptoms and positive tests for COVID19 in the assumption that you wont develop more serious disease if you don't get infected. 

It may surprise you that we still have no hard data on whether influenza vaccine reduces death from flu, but again, if you don't get the infection, you wont get the complications. Influenza vaccination is now part of the culture and for many of us makes sense, even without what could be called ideal trial data. In my GP day's I certainly noticed reduced deaths in the elderly after vaccination, particularly in care homes.

We have to wait for safety data and further results so while I do think some of the hype is premature, availability of a vaccine next year is looking far more likely. Some of these results will be available later in November, so this continues to be a hot topic. 

The future of mRNA vaccines - I feel optimistic not only about the potential for controlling this pandemic, but also for rapid responses to further pandemics and indeed, vaccines for cancer (where our knowledge of mRNA vaccines comes from) which will be able to target antigen producing tumours and so revolutionise management of certain cancers.

In the meantime..

It remains to stay as healthy as possible. The virus is very infective and continues to spread, with big impacts on our ability to care for the unwell.

For many, staying, or getting healthy is not helped by restrictions which have huge health impacts of their own. Poverty, inequality, poor diet, low levels of Vitamin D and structural racial discrimination all play a big part in the toll of illness and death from COVID19.

We already have incredible immune systems at our disposal and for the majority of people this is enough to deal with COVID19. For those at risk or caring for those at risk, there is a new optimism that this and other pandemics will be better controlled and far less damaging in terms of their direct and indirect effects. 

The immune system is fine tuned by having all the raw materials it needs to function well, including the right food, sunlight and Vitamin D, being as physically fit as possible, and a mind under as much control from the ravages of anxiety and depression as it can be. It's not always easy.

Vaccines will not let us off the hook

A hint of regret, fear even, coloured my emotional response to this latest triumph of science and caused me to reflect why.

The underlying causes of the pandemic continue to operate - bad farming generates the spillover infections from the shrinking natural world. We are proceeding recklessly towards the terrifying conclusion of this latest global mass extinction event. Low level endemic infections in bats, primates and others are spilling over to humanity as habitats shrink and the wild animals immunity is reduced by lack of food and space. 

A dangerous interface
The low quality food produced by agribusiness damages our personal and collective ability to respond to infection. Global mass transport of goods, humans and thus viruses is an irresponsible, immoral mess. The pandemic might has paused climate change, just a tiny tiny bit, but business as usual would means it roars on and our response remains inadequate.

Any early triumphalism of "science" versus "nature' is not only wholly inappropriate, it's ill informed - genuinely stupid. The brilliance of the science sector has shown itself to be way ahead of "politics" and "business' establishments in terms of rising to challenges. 

The lessons of the pandemic must not be swept under the beautiful carpet of science. If it doesn't mean the end of poorly regulated capitalism and traditional conservative thinking, then the future continues to look uniquely grim. 

We keep hearing about "Building Back Better' and if this rebuild does not revolve around redesigning society for a low energy, far more locally orientated, low pollution, land and habitat restoring future then COVID19 might well be looked back as a minor blip. A warning from nature erased by a vaccine and ignored.

Biology, the study of life, is telling us in no uncertain terms that we are no longer adapted to the world in which we live. The vaccine has the potential to save many lives, but in terms of our long term survival species, it is a sticking plaster. 

Getting back to business as usual, ignoring the causes of this latest but not the last pandemic, will be the greatest disaster of all.  











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