This post will attempt to answer the following questions:

  1. What are viral variants and what do they do?
  2. What are the SARS CoV2 variants of concern?
  3. What is the difference between the UK and South African variants?
  4. Are the vaccines effective against the new strains?
  5. How do we know?

I was late. It was an early class and it was the furthest distance across campus and I was late for the first day of organic chemistry. The class was notorious for its brutality and I didn’t want to start behind, but behind I was. The auditorium had a few hundred seats and the decor made me feel as if I had traveled back in time 100 years with its wood paneling and musty aroma. The professor was a small woman dwarfed by the 10 oversized chalkboards that spread 30 feet a across and slid up and down like a dust covered guillotine. She had already started scribbling illegible hieroglyphics that I should have been paying attention to but I was more focused on where I was going to sit. There was not an empty seat in the room which was teeming with eager pre-meds with clean, unused notebooks and sharp cornered overpriced textbooks. I ended up sitting on the steps at the top of the aisle.

I was not late again after that, but it turned out not to matter. After every exam there were more and more empty seats as the course chewed up and spit out students turning countless premeds into future lawyers, accountants, and bankers. By the end of the year, instead of two full classes with a couple of hundred students each, there was one class with plenty of room for all of our tattered notebooks and dog-eared, mangled textbooks. In this case, those of us that liked the class, or at least could do well enough on the exams to stay afloat, were the mutant strains.

It is an imperfect metaphor for natural selection but I have grown tired of telling stories of the sick and dying from COVID-19. I still see them every day and there are now concerns of pandemics within a pandemic as new mutant viral strains have developed that are of growing concern worldwide. It is clear that these variants are going to be vital in determining how the things progress over the next several months but how that all goes is still a big unknown. The news media is filling our heads with their usual alarmist cacophony and the scientific literature is inaccessible and difficult to understand. My goal is to bridge that gap and clarify the issue for myself as much as for you. Here’s the breakdown:

What are they?

The “goal” of every virus, if a proteinaceous bag full of genetic material can be said to have a goal, is essentially the same, to get inside your cells and make more of itself. That’s it. It wants to take its string of RNA or DNA, hijack your cells to make more copies of said RNA and DNA, and move on to infect more cells. The viruses are very good at this but they are not perfect. With a certain regularity, errors are made in the copying process leading to a new virus that has a slightly different genetic makeup (aka a mutation). In the context of a virus these mutations can do one of three things:

  1. They can alter the virus in such a way that it makes it less effective.
  2. They can alter the virus in a way that makes no difference.
  3. They can alter the virus in such a way that it makes it more effective.

For obvious reasons, option three is the one to worry about. We don’t want viruses getting better at their job. When they do get better they do so in one or a combination of three ways:

  1. They get better at spreading.
  2. They get better at making us sick.
  3. They get better at evading our immune response – either from prior infection or vaccination.

Something that happens once in a blue moon is no big deal unless you have several hundred million blue moons.

Since the pandemic began there have been many variants discovered. Fortunately, the vast majority fall into category one or two from the first list and are interesting only to virologists, but there are many others which are concerning to everyone and are aptly referred to as variants of concern (VOCs). SARS-CoV2 happens to mutate relatively infrequently compared to other RNA viruses which begs the question: If it mutates infrequently, why are there so many different variants? This is because of the sheer number of infections. Something that happens once in a blue moon is no big deal unless you have a several hundred million blue moons. First, let’s break down the most concerning VOCs, then we can get to the most important question: Will they impact the effectiveness of vaccines.

The VOCs

B.1.1.7

The one that has received the most attention in the US (because it has the most documented cases) is called B.1.1.7 aka the UK variant. The British are coming the British are coming! As an aside, the country of origin is not necessarily where it originated from but where it was first discovered so don’t hate the British invasion. All you need is love. This strain has been associated with increased transmissibility but as of yet has not been associated with increased severity of illness. It is already present in the US and is doubling every 10 days. This number is not fully reliable as there has not been adequate tracking of different strains and the spike could be from more testing. For all we know, this could already be the dominant strain driving the spike in cases over the past couple months. If it isn’t already, there are real concerns that this will become the dominant strain in the US by March.

B.1.351

This one is called the South African or African variant. It has been associated with more transmissibility but not more severity. This strain has many more genetic changes than the UK variant and these changes are more worrisome because they are located in or close to the part of the virus that vaccines and antibodies target. This immediately raises concerns that it may affect how vaccines work and research has shown reduced efficiency of mRNA vaccine-induced antibodies ability to neutralize virus in the laboratory (more on this later).

P.1

This is an isolate that was first discovered in Northwest Brazil. What is concerning about this variant is that it affected a community there called Manaus. This community had >70% rates of infection early in the pandemic which was the presumed threshold for herd immunity. This should mean that this community was protected from new infections. Unfortunately this community had a spike in cases in January from this new strain indicating it evades the immune protection from earlier infections.

CAL.20C

This is a more transmissible variant now circulating in southern California that has a sequence change that is thought to act similarly to the UK variant. Its sensitivity to vaccine remains to be determined.

Will the vaccines work against the VOCs?

There is currently evidence that the mRNA vaccines from Moderna and Pfizer will work against the UK and South African variant. This was not the case for the AztraZeneca-Oxford vaccine which South Africa stopped using after evidence emerged that it might not work well against their hometown variant. The Johnson and Johnson vaccine’s efficacy rate dropped from 72 percent in the United States to 57 percent in South Africa. Most of these reports of decreased efficacy need to be interpreted with caution as it is very difficult to clearly measure how effective a vaccine will be against a different strain. You could do studies where you expose vaccinated individuals to the different strains and see if they get sick but this has the ethical and logistical problems I discussed in my last post (Do I need to wear a mask if I’m vaccinated?). You can also compare how the vaccine did in different locations but you are then limited to the large trials which are not necessarily nimble enough to respond to new variants and have numerous complicating issues. As an example the results from the Johnson and Johnson and Novavax trials in South Africa did not account for those with prior infection or immunocompromise which may have skewed the results.

When these studies show resistance to a vaccine they suggest the possibility of vaccine resistance but do not confirm it.

Because of the difficulties in answering the questions, scientists use a surrogate way of guessing whether a variant will be neutralized by a vaccine or by a prior infection called correlates of protection. The most common way this is done is by taking the serum of people who have recovered from infection or have been vaccinated and exposing the virus to this serum. The scientists can then measure how much serum is necessary to neutralize the mutant strain and compare it to how much is necessary to neutralize the normal strain. This is fast and easy but it is only a surrogate. When these studies show resistance to a vaccine they suggest the possibility of vaccine resistance but do not confirm it. Here’s why.

To begin with, human serum contains only the antibodies. Antibodies are an essential part of the immune responsive to SARS-CoV2 but they are not the one. There are many other parts of the immune system that are important. This is important for example, because vaccines from Pfizer and Moderna induce virus-specific helper T cells and cytotoxic T cells, both of which might be involved in protection against infection and are not present in serum. We also have memory cells that remain dormant until woken up by the virus. These other parts of the immune system could be activated to clear an infection but, since they are not present in the serum of vaccinated individuals, the serum may not be adequate to neutralize the virus in the lab. This would mean the vaccine works in real life even if the correlate of protection suggested it didn’t.

Even if the serum antibodies are the primary factor that determines immunity we don’t know the threshold of protection. Imagine if a vaccinated person’s serum is half as good at neutralizing the mutant virus compared to a regular virus. This sounds scary but what if the vaccine induces 10x the number antibodies needed to block true infection or transmission. In that case, the vaccine will still have 5x as much antibody needed and there will be no change in real life effectiveness even though it is half as effective in the lab. The mRNA vaccines, in particular, induce such a strong antibody response that there could be enough “spare capacity” to deal with reductions in the sensitivity of the variant to neutralizing antibodies.

Why we should be optimistic about the vaccines…

  • Aside form the real world data of the AztraZeneca-Oxford, Johnson and Johnson, and Novavax vaccines in South Africa, most of the research on decreased effectiveness comes from serum tests which have the limitations discussed above.
  • Further, while any drop in efficacy is not a good thing, it may not be that bad. After the results from the Pfizer and Moderna trials, we have come to expect efficacy rates nearing 100%. Very few vaccines in history have achieved this level of success. The vaccines we use every day for other viruses are still good enough to prevent pandemics even if they are not quite as good as the Pfizer and Moderna vaccines are. As a crude analogy, if your goal is to get around town safely, a Mercedes is nice but a Toyota or Honda is just fine.
  • We take for granted now the great scientific advances behind these vaccines, especially the mRNA platforms. Because of this, the processes are now in place to change the vaccines to accommodate the new mutations and new vaccines can be made easily and rapidly. This could create a situation similar to seasonal flu where public health surveillance identifies new strains and the vaccine production is adjusted to accommodate the genetic changes.
  • Mutations happen at a consistent rate per number of replications. This means that the more virus that is replicating, the more mutations will happen, and the more likely one will develop that makes the virus nastier. If the number of people infected is cut in half, the risk of a dangerous mutation developing also is cut in half. The fewer the cases, the lower the risk of future mutations developing and the less the mutant strains will circulate in the population.
  • Wearing masks, physical distancing, and applying common sense still protect you, no matter what the mutation is.

Vaccination can’t help us in the short term

It is clear that vaccination is still the only way out of this mess and, based on all the reasons I listed above, there is good reason to be confident that they will get the job done. The biggest problem we now have is between now and the time when enough people are immune. The president is targeting 150 million doses given in 100 days. This is a noble and important goal but it still means only 75 million people will receive both doses by April. Even if you include those who have natural immunity from a prior infection, it will not be enough for herd immunity for several months. The number needed to have protection for immunity gets higher if the mutant strains make the vaccines and prior infection less effective at protection.

Getting to herd immunity is the goal and everyone should continue to get vaccinated but until then our population is vulnerable. We could still have enough infections to cripple the healthcare system and lead to significant debility and loss of life. It’s the last few miles of the marathon and we’re all cramping up but we have to push through to the finish. When the vaccination numbers go up and the case and hospitalization numbers go way down we’ll know we’re at the finish line. Until then, we push on.

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