FAQs and Common Misunderstandings

What do we mean by viral “strain”?

Viruses change over time through natural mutations occurring in their DNA or RNA. Each time a new mutation appears these mutations are passed onto when the virus infects the next person. If the mutation changes the behavior of the virus, for example, it is less deadly, or more contagious, then this mutant virus is considered a new strain of the original virus.

Has something like SANE been done before?

Yes. One of the three live viral strains found in the oral polio vaccine (Strain 2) was isolated from a child with a mild case of polio. Sabin found that this natural polio strain was able to provide protection from the dangerous polio strains without causing illness. 

What we are trying to do with SARS-CoV-2 is exactly the same as what Sabin did more than 60 years ago with the oral polio vaccine, except we plan to use modern genome sequencing technology to make the search for a natural attenuated strain much easier.

Will the SANE approach work?

Only if we try. We think that a naturally occurring attenuated (mild) strain can be found. Our knowledge of coronavirus biology suggests it is only a question of screening a large enough number of people. Given the relatively small cost of implementing the SANE approach, and the huge payoffs in public health if it succeeds, it is in our opinion a viable option worth exploring and investing in. The middle of a pandemic is not a time to leave any scientifically viable options to solve this problem untried.

Can’t we just wait for a COVID-19 vaccine?

No. Apart from the time it will take to develop, trial, and mass produce a vaccine (12-18 months), it is unlikely that current vaccine efforts will be practicable in producing a lasting protection with a single dose. This is because immunity to respiratory viruses (like the novel coronavirus) doesn’t usually last longer than 6 months to 2 years with a single inactivated vaccine. We would need to keep vaccinating everyone in the world every year (or maybe every 6 months if we are unlucky). There is already a study published in Nature saying that antibodies to the novel coronavirus last only 2 to 3 months!

This just isn’t going to work in the real world (especially poor countries or conflict zones) and is one of the reasons why we don’t have a vaccine for the coronavirus strains that cause the common cold. Unless we can drive the current dangerous SARS-CoV-2 strains to extinction we are going to have a problem with this disease indefinitely.

A very interesting pre-print has been released on the natural immune response to SARS-CoV-2. Many people don’t develop much of an initial immune response (IgM antibodies) and the long term immune response (IgG antibodies) fades quickly after just two months (see figure below). While this is more of an issue for those people arguing that we should lift social isolation restrictions to allow the population to develop herd immunity (this would just kill a lot of people and any herd immunity would quickly disappear), it is also a concern for any vaccine approach that can’t drive the dangerous strain to extinction (i.e. all the other conventional vaccine proposals).

What effect would using a live attenuated vaccine have on the dangerous strains?

Giving a natural attenuated viral strain deliberately to lots of people as a vaccine would change the ecosystem for the dangerous strains of the virus. The dangerous strains would find it difficult to spread through the community as many (most) people would have already been infected (and hence immune) with the attenuated strain (i.e. have herd immunity). Over time the dangerous strains would become rarer, and the attenuated strains more common, until eventually the dangerous strains would become extinct and we would just be left with the mild version floating around. While we would not be able to get rid of this mild strain, it would just be another of the hundreds of viruses out there causing common colds, including other coronaviruses that cause common colds. This proposal at its base is really one of replacing the dangerous strains with a less dangerous strain that we can live with, similar to the common cold.

It is the ecology aspect of this proposal that makes it different to other attenuated vaccine proposals. Currently all attenuated vaccines developed in the lab are designed to just protect the person receiving the vaccine. An attenuated strain identified by screening infected people (epidemiology) will identify a strain that can still be transmitted from individual to individual. This makes the use of such a strain radically different from a conventional lab created attenuated viral vaccine.

Isn’t social distancing and quarantining solving the problem of COVID-19 infections?

Social distancing and quarantining were never intended to solve the COVID-19 infection, rather only to reduce the rate of infections so that they are manageable by our health care system. Countries like South Korea and Australia have shown that through mass screening and social distancing you can keep a lid on the disease. This approach leaves the population susceptible to a new outbreak. Singapore and Japan have recently seen this in action where they eased restrictions and found the disease came back, at which point they had to reintroduce restrictions. Extinguishing the COVID-19 infections would require that the virulent strain of SARS-CoV-2 die out – a live attenuated vaccination would go a long way in hastening that process.

How would this work in practice?

Please see our page on The SANE Approach.

What are the risks?

There are at least 14 different live attenuated vaccines given in the US and more globally. The risks for a SARS-Co-V2 vaccine with a live attenuated virus would be similar. Standard practice with live attenuated vaccines is that the patient is monitored for a stronger than normal response to the vaccine like a bigger rash at the site of injection or fever that hangs around longer. In such cases all that it means is that the patient is having a more robust immune response to the vaccine. There are challenges in quality control of vaccines and ensuring that the supply chain is not contaminated. But these challenges are there for all kinds of vaccines and medications.

How do you know an attenuated strain might be out there?

Because mutations corresponding to milder clinical outcomes have already been found

Coronaviruses like SARS-COV-2 mutate continuously (this is why it is possible to tell the geographical origin of different strains) as the molecular machinery for replicating their RNA genome makes mistakes. When you combine this with the millions of mild cases out in the world, the odds are on our side that there is at least one person infected with a strain that has a mutation that makes the virus less dangerous or even harmless (attenuated).

We just need to go and look for this strain – luckily the tools we need to use (genome sequencing) are now cheap and quick. What would have been impossible 20 years ago can now be done in a week.

Aren’t most people who have mild/asymptomatic cases infected with a dangerous strain?

Yes. A mild case does not equal a harmless strain. 

For most people the mildness of symptoms is a reflection on their excellent immune system keeping the virus in check. These people still transmit a pathogenic strain. If these strains infect a person with pre-existing conditions that hamper an effective immune response then that person runs a high risk of suffering the morbidities associated with COVID-19 and even death.

While almost all mild cases of COVID-19 are caused by a pathogenic strain of SARS-CoV-2, an attenuated strain of SARS-CoV-2 will only cause mild disease. That distinction can be made only by screening mild/asymptomatic people. You can find more information on the SANE approach here.

Why only sequence those with mild/asymptomatic cases of COVID-19 in the search stage?

If there were one aspect that gets most misunderstood by people who read about the SANE approach, it would be the reason for sequencing only mild/asymptomatic cases. This choice is purely an efficiency issue. In an ideal world we would sequence the strains from every case of COVID-19 in the world, look to see if we can find mutants with deletions, and then check what the clinical outcome was for those infected with each strain. If we find that all clinical cases of a particular mutant strain are mild/asymptomatic, and no cases ended up in hospital, then we would have our candidate strain.

Unfortunately we live in a constrained world where it is not possible to collect and sequence the virus from every single case of COVID-19. Given this, where should we look first? Since we are looking for a mutant strain that only causes mild/asymptomatic cases, we can exclude patients in a first pass who have serious symptoms

It is only when we find a good candidate attenuation strain that has the right sort of mutation (a deletion) that we then need to collect further swab samples and sequence all the cases. At this point we will need to look in the local area around where the index strain was detected (including everyone in the local hospitals), to get the full clinical picture of the strain. This approach of initially screening just the mild cases is a simple way to make the search process for an attenuated strain more efficient and practicable.

Won’t the mutations in SARS-CoV-2 make this proposal fail?

Antigenic drift due to mutations could be an issue for any and all vaccine approaches. That risk does not stop us from searching for a vaccine. This is one reason why it has been challenging to get a single vaccine for influenza.

Coronaviruses do mutate, but for an RNA virus they tend to be relatively stable genetically. The coronavirus strains that cause the common cold tend to not change much antigenically over time. Yet we catch colds repeatedly in our lifetimes. This is because our immunity to a given cold virus declines fairly rapidly (in months, not years). The result is that the same common cold strains can infect you multiple times in your life as your immunity to each one fades, rather than it needing to change antigenically so much that our immune systems no longer protect us.

A recent non-human primate study out of China using a conventional vaccine approach against SARS-CoV-2 found that the antibodies produced were neutralising for all strains found around the world. Thus it does look like we only need one attenuated strain to provide protection for all strains.

Wouldn’t the use of such an attenuated strain just be a vaccine? How would it be regulated?

Yes in one way, but it is a little more subtle. Assuming we can find an attenuated strain, then how to best use it is a separate question. The most important thing to note is that a natural attenuated virus is not a vaccine.

Of course the use of a natural attenuated strain as a vaccine would fall under the regulations for vaccines, but the mere existence of an attenuated virus does not make it a vaccine. Each regulatory authority around the world would need to weigh the evidence of safety (obtained from the epidemiology) against the risks. Some regulatory agencies may decide the rewards from using such a strain as a vaccine is worth the risk, while others may decide they are not.

Why can’t we just use the less pathogenic SARS-CoV-2 strain already identified in China?

While the ZJ01 SARS-CoV-2 strain identified in China appears to be less pathogenic, the mutations that make it so are single base changes. These can easily mutate back to the more dangerous version of the virus. The viral strain we want to find will have a deletion mutation where a section of the viral genome is removed. Deletion mutations are much more difficult to mutate back to the dangerous type since rather than just a change from one nucleotide to another (e.g. C > T), the deleted region is missing and can’t easily be recreated by mutation. Put simply, deletion mutations are more stable to back reversion.

How should an attenuated SARS-CoV-2 strain be used?

This is not a decision for us to make. Regulatory authorities like the FDA could approve the use of a natural attenuated strain on the basis of the epidemiological data collected finding the strain. While most regulatory agencies are extremely conservative and slow, they understand that using an approach with some serious unknowns might be better than the alternative of waiting for the perfect vaccine. COVID-19 is a problem with only hard choices.

Even if you think a natural attenuated strain is too dangerous to use as a vaccine, it would be extremely useful to speed up other vaccine approaches. One way it could be used is to give it as a challenge to volunteers who have received a vaccine to see if it provides protection without putting them at more risk. Knowing if a vaccine works (i.e. provides protection from the disease) is one of slowest steps in new vaccine development. If you are going to do a viral challenge with SARS-CoV-2, you really want to use a strain you know is likely to be harmless, rather than one you know could kill your volunteers. Of course to do this you first have to make the effort to find such a harmless strain.