How would a search for a natural attenuated SARS-CoV-2 strain work in practice?

My previous post on a possible solution to COVID-19 has attracted quite a bit of interest on Twitter and Hacker News, but I have noticed that many people are having difficulty understand how it might work in practice.

So how exactly would we go about looking for a naturally attenuated (weakened) SARS-CoV-2? The answer is there are many good ways, but I thought I would describe one approach. It is very likely there will be better approaches, but for the purpose of illustrating how you could go about doing this, what follows should help.

Step 1. Obtain 50,000 swab samples collected from people known to have only mild/asymptomatic cases of COVID-19.

We would request swabs from known positive COVID-19 cases from around the world with the aim of sampling from the widest number of locations. The aim here is to cover as much of the SARS-CoV-2 genetic diversity out there in the world. In practice, most of the samples will come from rich countries purely because that is where most of the testing is being done, but we do want to make an effort to cast the net as wide as possible. A map of the current genetic diversity of SARS-CoV-2 found around the world is shown below.

Phylogenetic network analysis of SARS-CoV-2 genomes

Phylogenetic network analysis of SARS-CoV-2 genomes

Step 2. DNA sequence the genomes of all 50,000 SARS-CoV-2 strains.

We would perform conventional next-gen genome sequencing on the samples. While this seems laborious and expensive, with modern genome DNA sequencing instruments you can sequence all 50,000 viral genomes in a single run. The genome of SARS-CoV-2 is approximately 30,000 nucleotides long. To sequence each nucleotide 20 times for all 50,000 samples will require 30 billion bases (nucleotides) of raw sequencing. With a modern genome sequencer like the Illumina NextSeq 2000 can sequence 300 billion bases in 48 hours – more than 10x the capacity we need. The cost of all this sequencing is low – in the thousands, not hundreds of thousands dollar range.

Illumina NextSeq 2000

Illumina NextSeq 2000

Step 3. Analyse the raw genome sequence data for deletion mutants.

This step involves assembling the raw data collected from the DNA sequencer to generate the genome sequence of each viral sample. Each genome would be aligned (matched up) to the reference genome (i.e. the dangerous strain) to look for regions of the genome that are deleted (missing) from the genome.

What we are looking for is regions of more than 30 nucleotides that have been deleted from one of the strains. These strains with gene deletions will be our putative attenuated strains.

What such a sequence alignment looks like is shown below – regions of deletions are shown with a dash (-) (technical note. This is actually an alignment of the translated amino acid sequences, not DNA sequences).

Multiple sequence alignment of coronavirus spike protein S2

Multiple sequence alignment of coronavirus spike protein S2

Step 4. Develop a rapid test for the deletion mutant strains.

We will need to develop a rapid test for the gene deletion mutant strains. This is one of the easier tasks as it just involves designing different primers for use with the current SARS-CoV-2 RT-PCR test kits.

Step 5. Screen for additional COVID-19 cases in the local area where each putative attenuated strain was isolated.

The first four steps are relatively cheap and quick, the next few steps are more difficult. Once we have identified one (or more) putative attenuated strains we need to find more clinical cases resulting from infection with these strain(s) to ensure they are true attenuated strains.

This step will require going into the community where the person who provided the original sample lives (the index case) and taking nasal swabs from people and testing them for SARS-CoV-2 infection. We will need to collect many thousands of swabs from the local area (using an expanding ring approach) to find as many additional cases of COVID-19 caused by these strains as possible. The COVID-19 patients in the local hospitals will also need to be checked to make sure the strain is not making people seriously ill.

Step 6. Monitor the clinical outcome of infection by the putative attenuated strain(s).

Any positive cases of infection by the putative attenuated strains will need to be monitored for at least a couple of weeks to determine the final clinical outcome. While this is occurring, we will need to collect additional swabs from the close contacts of those identified as being infected with the putative attenuated strains. What we want to find is that all the people infected with a putative attenuated strain only get mild or no symptoms and none end up in hospital. If we can identify a large number of infection cases then we will have strong epidemiological evidence that the putative attenuated strain is actually attenuated and unlikely to cause serious illness or death.

We will also want to take blood samples (serology) to check that the attenuated strain can still create a strong immune response to the virus and that will cross-protect with the dangerous strains. My estimate (which may be wrong) is the first five steps will take 2 to 3 months if we make a serious effort.

Step 6a. Scaling up production of the attenuate virus.

This step is complex, but conventional. It is not hard to grow large volumes of virus at an industrial scale in cell culture. We have been doing this since the 1950s when the polio vaccine was first created. The only major issue is to make sure that the process is efficient as possible and not a point of delay. I would advise that this step be started as soon as we identify a putative attenuated strain so that when (if) we have a attenuated strain we don’t need waste time in the scale up process.

Industrial Cell Culture Plant

Industrial Cell Culture Plant


Step 7. Using the attenuated strain.

Assuming steps 1-6 have gone well and we have identified and mass produced an attenuated (deletion) strain of SARS-CoV-2 that doesn’t appear to cause serious illness, then we have reached the point of choosing how and when to use this strain as a live attenuated vaccine. This will be a political and regulatory decision that will need to balance the risks and rewards of using it at scale. While this won’t be an easy decision, it will allow us to at least have a discussion rather than just waiting for another vaccine that may never arrive.

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5 comments on “How would a search for a natural attenuated SARS-CoV-2 strain work in practice?
  1. Since this attenuated strain is already propagating in the community and we have determined it to be safe (reaching step #6 as per your article), can’t we just host coronavirus parties and obtain the infection naturally and skip step #6a (ramping up production) to go straight to step #7?

    If social distancing measures can bring the R0 below 1, then well planned “coronavirus parties” theoretically can increase the standard R0 in multiples and you can use this exponential growth to immunise an entire nation within a few months without spending billions on vaccines.

  2. Yes you could host coronavirus parties to spread an attenuated strain and it would work, but I don’t think this is the best way to go. It would be better to produce the virus in a controlled way and release it under regulatory approval.

  3. I was confirmed positive for Sars-CoV-2 back in mid June in Australia. I would describe my symptoms as extremely mild (if any at all) to non-existent….I’m assuming I was/am asymptomatic. I got tested not due to symptoms (I lied at the testing station about. amino cough) but because I was intrigued by the process – stupidly – or maybe not.

    None of my close contacts (2) including my partner in same house (I did isolate in spare bedroom, own bathroom etc) tested positive.

    One thing that has been interesting is that there is no follow-up what-so-ever on my progress or any post infection data collection such as antibody analysis etc.

    I’d happily volunteer my time/blood to help build a picture but I have no idea how I’d go about it.

    Any ideas?

  4. I am glad you had a mild case. I am not really able to help in regards you helping. From what I can see the authorities don’t seem to have much idea of what to do.

  5. Your logic and method is brilliant!

    Locking down the whole nation, like Italy did, actually increased more deaths, caused more injuries and harmful damage for it, not to mention the billions of euros loss in the economy and the additional debts in billions more to afford vaccinations here.

    Wearing face mask interferes with spreading the natural cure, just as imposing social distancing does too. In fact, if you think about it more, all these things were imposed by the communist who controlled the World Health Organization narratives.

    Remember, proactive and democratic Taiwan only had 7 deaths compared to reactive Italy 60,000+ in comparison. Italy waited for the deadly strain to enter and spread around and even then told infectious patients to go home until you develop a more serious condition to get treatment later on! A perfect storm brewing.

    If the governments had a clue, they would NEVER accept how China lied, covered up, censored about to them. They would had banned ALL international commercial flights leaving China. As China failed to contain their outbreak and continues to deny the whole world (every country) any right to investigate the emergence and origins of the outbreak in China!

    Next, the world should had gone into China, fully investigating the emergence and origins of SARS-CoV-2 strains. From here virologist and scientists could detect and find a natural attenuated SARS-CoV-2 strain for the rest of the world to build immunity for possible further outbreaks from China that may include more deadly strains of SARS-CoV-2 strains.

    None of this cost much money, no vaccine is required, because nature had already given the antidote to humanity, if they would had just let it spread around. Obviously, how this spreads around is not as simple or ensured, as further RNA mutations would continue given one by one exposures, instead of a more controlled regulated method of using the same natural attenuated SARS-CoV-2 strain to everyone simultaneously all at once.

    Furthermore, those who are asymptomatic should be allowed to spread the natural attenuated SARS-CoV-2 strain, but anyone with actual symptoms should be controlled to limit exposure to other people, by going to get treatment or quarantine so those more deadly strains don’t get the opportunity for further spreading or reduced exposure to society.

    If that wasn’t all, anyone with a more serious condition with a SARS-CoV-2 strain should boost their immune system, as in most cases this is why they had more serious conditions for having a weaker immune system. Strengthening the immune system can be as simple as not consuming refined sugar, but at the same time insuring sufficient levels of vitamin D (+80ng/ml), NAD+ levels, zinc, vitamin c, the things that your body requires to not just function, but at an optimum level.

    Taking a vaccine even if it confers some immunity, will only work for that 1 disease. Whereas, boosting your health so your natural immunity is optimum will better protect you from many more diseases, but sadly not ignorance.

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