Coronavirus Mutations, Variants, Epitopes, and Vaccine Efficacy

This article provides an overview of virus mutations, the current variants from the UK and South Africa, how the immune system works on pathogen proteins, and whether all this has implications on the efficacy of the current vaccines.

Mutations

Mutations are a fact of life for all living beings. Viruses, due to many reasons (generation rate in hours, infecting millions of cells, ...), have a very fast mutation rate. That is just what goes on.

The problem is not mutations, but rather mutations that are selected for, and change behaviour. That is, evading immune system, more infectiousness, more virulence, and so on ...

Mutation Rate

HIV is the fastest mutating human infecting virus. That is why a vaccine is near impossible, and that is why those infected have to take a combination of several drugs together, because the fast mutating virus will quickly accumulate mutations that make one or two drugs useless.

Influenza is the next fastest virus. It mutates every year, and people get it every year, and vaccines have to be developed every year.

Some other viruses do not significantly mutate at all and therefore vaccines developed for them continue to work even after 70 years (e.g. polio, smallpox, ...etc.). This is because mutations affect its infectiousness that they are selected out.

Coronavirus is slower to mutate than the HIV or the flu. Why? Because Coronaviruses, are RNA viruses, and RNA has a very high error rate (i.e. more mutations). However, Coronaviruses have in their genetic code an error correcting mechanism (the RNA-Dependent RNA Polymerase, or RdRp) that corrects copying error, thus reducing the error rate inherent in RNA viruses, unlike the flu for example. This mechanism also allows the Coronavirus family to have the largest genome for an RNA virus known.

Think of the 4 viruses that cause ~ 15% or so of the common cold. People get reinfected every other year or every third year. So the mutation rate is not as high as the flu.

There was also a study that looked at one of these Human CoV common cold Coronavirus blood samples from back in the 80s, and how long they neutralized antibodies, and the 1984 strain was being neutralized by blood of infected people for up to 8 years, and after that, it was ineffective. The efficacy decreased as the years progressed. Listen to virologists discussing this paper on TWiV. More on how this works below.

Epitopes

Important parts of the immune system, specifically T-cells which holds immune memory, does not work on whole proteins (e.g. Spike), because they are simply too large for the antibodies. Instead, the immune system works on multiple subsets of the protein known as epitopes. Epitopes are relatively short peptide sequences (up to ~ 15 amino acids), rather than the whole spike protein, which has several hundreds of amino acids.

For a large protein like Coronavirus spike (1273 amino acids), if a handful of these peptide sequences have a change because of mutations, then there are plenty of other epitopes left for the spike protein (at least 16 of them per a study that lists them as vaccine candidates, and I have seen up to 20 epitopes).

And that is exactly what we are seeing: if a mutation disrupts the peptide sequence in an epitope or two, the others will still work, but efficacy will be less. As more mutations accumulate, efficiacy decreases.

Vaccine Efficacy Against Variants

The Pfizer/BioNTech vaccine was shown to be still effective against the B.1.1.7 variant (further research.

Moderna tests took this further, testing more variants.

Some of what they say is alarming, in isolation:

A six-fold reduction in neutralizing titers was observed with the B.1.351 variant relative to prior variants.

But then you see the overall conclusion:

Despite this reduction, neutralizing titer levels with B.1.351 remain above levels that are expected to be protective.

Because both companies use the mRNA technology, they said that they can modify the genetic code for their vaccines to make a future vaccine (or booster shot) for the variant of concern.

More Infections = More Mutations

As more infections cause trillions of generations more, there are much more chances for mutations. This is simple genetics, and the number of generations increase with a known mutation rate, so the number of mutations will increase.

Most countries are not controlling the pandemic enough to prevent this. Be that incompetence, non-cooperation from the populace, conspiracy theories, non-trust of government, ... etc.

As I said above: what matters is the whether mutations accumulate enough to change the behaviour of the virus (e.g. infectivity, immune evasion, virulence).

Shadows Of South Africa AIDS Pandemic

We saw this in HIV, and also in South Africa: where the virus ran rampant out of control, because of the intersection with poverty, political turmoil, inefficient public health ...etc. and it seems to be happening again in the same country, and there is already decreased efficacy of vaccines for it. That means that it can be selected for (by infecting more people), and accumulating more immune evasion mutations.

There is also concern about the P.1 variant in Brazil.

But the rate for Coronaviruses is not as fast as the flu or HIV (thankfully, witness the Human CoV study above).

What will happen? Anyone's guess as of now ...

Hopefully, with mRNA being easy to develop, there can be a booster shot for emerging variables that are concerning due to immune evasion. They still have to be tested though, and not sure how many months will that take, and we can be in a whack-a-mole situation with variants emerging faster than vaccines can be rolled out ...