How Will It All End?
Goo: So how will this epidemic end? How are we going to win?
Dr Xxxxx : There are 4 main known paths for this epidemic to progress to a satisfactory end. And then we’re going to propose a new path we have developed of our own. A 5th option.
One. We develop an anti-viral medication. We actually do have one called Remdesivir. This is a nucleotide analog drug. As the virus replicates, it builds into its structure bits of DNA (nucleotides). Remdesivir is a false nucleotide. It builds into the growing RNA/DNA strands. It does not allow the RA/DNA strands to build properly. Commonly this is because the shape of the new strand incorporating remdesivir has a wrong shape – which the RNA polymerase/DNA polymerase cannot process. This causes chain termination. The new strands stop being replicated. The polymerase becomes jammed. Viral replication stops.
Remdesivir: Molecular Structure
There is also some evidence that the HIV antiviral has some usefulness due to partial homology (of the order of 60-70%) with HIV protease. It is not a great drug as it will probably only reduce viral replication by say 20-40%, not very high in the scheme of things.
Erasmus :Yes but I can see how it were started early in infected patients according to a scaled risk protocol it could indeed make a difference.
Dr Xxxxx : Exactly what research has shown. There is evidence that it has produced a 50% mortality drop if used as early treatment in clinically significantly infected patients. It has made no difference to mortality if started late, and too many people have looked at this statistic and dismissed the drug. I think, reducing mortality and morbidity is the name of the game, especially where ventilator use can be curtailed.
But it is a drug probably unnecessary in the bulk of clinically asymptomatic infections. And this is the problem. How can you use it early in infections that begin as mild but then deteriorate without wasting time, effort and resources using it in people who will get better without injury anyway.
Goo : It's obvious you would need some method of predicting the odds of a bad outcome, to improve the efficient use of you medication stockpiles.
Dr Xxxxx : True.
Erasmus : I think there are a few other problems with the concept of antiviral medications in the CoVid Scenario. I remember seeing a press release saying this drug had been discovered in the last few weeks. Doesn’t it take a lot of time for new drugs to come to market?
Dr Xxxxx : Absolutely! New drugs go through trials to make sure they are safe to use in the general population.
Firstly there are tests on animals. We use animal models which are hopefully in many ways similar to human beings. This allows us to identify potential problems such as mutation, chemical injury or death before inflicting these en human test subjects.
Then there are small-scale trials on human beings. These trials aim to discover efficacy, dosage, side effects and complications, and other difficulties with the use of the drug, (such as how much of the drug is absorbed when it is swallowed or taken with or without food).
Then there are large-scale trials for proof of concept. Then there are usually trials to show superiority to drugs in existence in the market. And then finally the drug makes its way to market.
Erasmus : But surely in a crisis such as this we would hurry a drug to market to help save people’s lives.
Dr Xxxxx : You might think so but when you think about it, it is obvious you would not.
Imagine if you would that the drug kills .1% of its users in some distinctive fashion. I think you would guarantee that within 3 years – at which point the epidemic is over and the memory of the danger, mortality threatening from the epidemic is dimming – anybody who suffers an adverse effect from the use of the drug – no matter what the circumstance, would be keen to litigate against the company who produced and distributed the drug, no matter how good the intentions of the company may have been at the time.
Any company foolish enough to market and distribute a drug without extensive trials could well be left facing $100 billion of legal actions within a few years of the epidemic being over.
This process takes a lot of time. Consequently, most drugs once they are declared in a patent, can take up to 10 years to come to market. Even then governments drag their feet, not wanting to pay for new and potentially expensive drugs. This makes it difficult for the companies to recoup their investment in the 10 or 15 years remaining in a typically 25 year patent life.
In short, I believe we are not going to control the coronavirus epidemic with a new drug even if we have it available to us. The legal ramifications and legal dangers arising from early usage and causing injury to people, limit the speed at which a new product can be brought to market.
Developing new drugs is not going to save us in the short term.
Erasmus : So what about the 2nd option for ending the epidemic?
Dr Xxxxx : The 2nd option is for us to develop a new vaccine. Currently we don’t have one. So we need to develop one from scratch. Again this process takes time. Having very little experience with vaccines for the coronavirus (as opposed to vaccines for the influenza virus), means that much of the vaccine technology needs to be developed De Novo.
The Vaccine : a promise
Which protein or which antigen should be the target of the vaccine? How many antigens should be present in the vaccine?? Should we simply target one antigen? Does a vaccine incorporating a number of antigens give us enhanced immunity and longer life? How can you make the vaccine more immunogenic (getting a better immune response) and more durable? (For example currently we are focusing on protein vaccines as opposed to polysaccharide vaccines for much of our childhood humanization program. Protein antigens produce far more durable immunity than polysaccharide antigens, but are harder to develop.)
So we need to develop the vaccine. Then do trials to assess efficacy, dosage, side effects and complications, and other difficulties with the use of the new vaccine. Then the process progresses much the same as for a new drug.
We use animal models which are hopefully in many ways similar to human beings. This allows us to identify potential problems such as mutation, chemical injury or death before inflicting these en human test subjects.
The promised vaccine.
Then there are small-scale trials on humans human beings. These trials aim to discover efficacy, dosage, side effects and complications, and other difficulties with the use of the vaccine, (such as how much of the drug is handled by the immune system when it is introduced into the body).
Then there are large-scale trials for proof of concept.
Then there are usually trials to show superiority to other clinical courses of action such as – not doing anything. And then finally the vaccine makes its way to market.
Erasmus : I see a problem with our vaccine developmental strategy. We develop narrow spectrum vaccines delivering a narrow group of critical antigens. This gives us the possibility of amplifying the immune response and giving us great statistics for immunisation. It is likely to give poor coverage of variants of the virus developing through mutation and poor immunity for distant viral relatives in the next pandemic.
We may be better using multiple antigens in a vaccine. In the long term, our short term statistics would not improve much over an optomised antigen- specific vaccine. However our long term statistics are more likely to show us decimating the risk of a new viral class such as CoVid resurrecting itself again and again through antigenic drift and more importantly antigenic shift. ( Antigenic shift relates to mixing events where multiple viruses co-incubate in a host, giving rise to whole substantially different or new viruses recurrently emerging with pandemic after pandemic as a result.
Kinkajou: Then the final obvious problem is how do you produce 2 billion doses of a vaccine. It would take incredible capital investment to set up the infrastructure to mass produce this viral vaccine. Then what do you do with all the machinery when the vaccine run is over. At least the influenza virus has the economic decency to come back each year, necessitating a new vaccine using all the same vaccine production machinery each year. It would give a very long term return on investment.
Erasmus :So I can see that there are just as many problems bringing a new vaccine to market as there are to bring a new drug to market.
It takes just as much time and there are just as many difficulties. There are just as many impediments to releasing a new vaccine to the market as there is to release a new drug to the market. And if you get it wrong, in 3 years’ time – long after the epidemic is over – no one is likely to thank you for releasing something “harmful” in a Just hurry.
Erasmus : So what is the 3rd option in controlling the coronavirus epidemic?
Dr Xxxxx : Let it rip. People catch the infection. People recover from infection. As herd immunity rises, the virus cannot find new people to infect because so many of the people it contacts have immunity to the virus which killed it when it attempts to colonize a new victim.
This is probably what is happening at the moment. I believe that we cannot recognise the process as we are blind to the existence of subclinical coronavirus infection. In short, a lot more people have been infected by the coronavirus and have recovered from the disease – than the PCR evidence of coronavirus infection tells us.
Erasmus : This is the usual infection process. Each year with the flu virus – people either gain immunity through vaccination or through catching illness. All these people become immune. The virus can spread. The virus proceeds to die out – perhaps lurking in tiny pockets of humanity. Its existence only sustained by antigenic drift – the slow mutational change in antigens in the virus forcing the immune systems of millions of people to play catch up with virus after virus, viral survival only half a step ahead of extermination.
Erasmus : And the 4th option?
Dr Xxxxx : The 4th option for the end of The Epidemic arises from the antigenic drift to which we have just referred. As the virus undergoes the occasional change, evolution favours the survival of less aggressive and less pathogenic viruses which survive longer in each person with less symptoms, creating longer infective windows – enabling more people to be exposed to an infection by the virus, simply because they have fewer symptoms and it is less obvious that they are sick with an illness.
Sick people generally stay out of the way and stop spreading illness once they are sick. But human beings when they are not very sick; they tend to go about their business –
Kinkajou: Spreading disease with the greatest of ease.
Social distancing in public places.
Erasmus : So antigenic drift and mutation favour the development of new more infectious antigenic strains and of hopefully less aggressive viruses able to persist longer and infect more people due to their lower symptom burden.
Coronaviruses are capable of adapting quickly to new hosts through the processes of genetic recombination and mutation in vivo. As RNA viruses, coronaviruses rely on RNA-dependent RNA 5 polymerase to replicate the virus genome. The intrinsic error rate of this polymerase is approximately 1,000,000 mutation/site/replication, resulting in continuous point mutations. Point mutations alone are not sufficient to create a new virus. However, when a single person is simultaneously infected with two coronavirus strains, recombination of the viral strains within an affected cell can occur. One coronavirus can gain a genomic fragment of hundreds or thousands base-pairs from another CoVid strain when the two co-infect the same host.
Such antigenic “shift”, enables the virus to increase its ecological niche or to make the leap to a new species.
Phylogeny of coronaviruses. Phylogenetic tree of 50 coronaviruses constructed by the neighbour-joining method using partial nucleotide sequences of RNA-dependent RNA polymerase. The scale bar lines indicate the estimated number of substitutions per 20 nucleotides.
Viral Evolution Phylogeny
This type of evolution is already occurring amongst the CoVid 19 isolates. There is some evidence that the Australian CoVid strain is less pathogenic than some of the overseas e.g. Italian strains.