What makes viruses like the flu and covid so tolerant of mutations compared to most other viruses?

Question

I was curious about why we benefit from yearly flu shots and apparently will also benefit from yearly covid booster shots too, whereas this doesn't seem to be the case for most other vaccines -- even if a booster or multiple booster shots are needed, it's typically a set sequence of shots, such as 3, with a month between each one.

I already know the surface level explanation is that these two virus' evolve and mutate very quickly. However that doesn't explain WHY they mutate so quickly or why such much constant mutation doesn't frequently end up being fatal to the virus or destroying its ability to reproduce, or even just do nothing helpful or harmful.

I did find this article: Why We Get Annual Flu Shots—and How Universal Vaccines Could Knock Out Viruses, which states that

flu and coronaviruses seem to be very tolerant of change. For a virus to change and still be capable of infecting a host population, the virus must maintain critical functions such as attaching to host cells. A high rate of change must be combined with great tolerance for transformation. Most viruses aren’t like that at all.

“With many viruses, when mutations crop up, they just kill the virus, and that’s the end of the show,” Hensley said. Not so with flu and coronaviruses. “Flu and SARS-CoV-2 have this uncanny ability to acquire mutations and still be able to replicate efficiently,” he said. “These viruses evolve to avoid human immunity while maintaining functions critical for viral replication.”

I don't understand why though. What makes these particular species both so fast involving and so resilient in the face of mutations?

Edit: Also, just to be clear, I understand the probabilistic nature of an organism getting a useful mutation -- that, even if most mutations would either hinder an organism's ability to reproduce (either by directly killing it off, or just making it harder to reproduce) or have no effect, given a sufficiently large number of the relevant organisms repeatedly reproduce for a sufficiently long time, it's unsurprising that a few members of the species emerge that, by chance, happen to have some mutation that increases their ability to reproduce, and they pass on the mutation to their offspring (not sure if that's the correct term when talking about asexual reproduction, especially with viruses since they can't even reproduce at all without hijacking the cellular machinery of some other organism), and so on. That's just natural selection, if I'm remembering my terminology correctly, and I understand the basic idea behind it, so I just wanted to clarify that that isn't what I'm asking about. Instead, I'm asking what specifically distinguishes flu viruses and the various variants of covid from other viruses (and even from just other RNA virus) that specifically makes them more resilient to mutation.

Answer 1

This is actually a far more complex question than it might seem on the surface. It's something that has been noted for quite some time by virologists - and it isn't just RNA viruses that do this. Almost all viruses (at least for the mammalian viruses that I know of) seem to produce mutants at some rate and many of the virions produced are non-functional for some reason.

RNA viruses mutate at high rates because it is an inherent property of the mechanism that replicates these viruses, actually it's an inherent property of all RNA replicating machinery. In most RNA viruses the mechanism is a multi-component protein known as a RNA-dependent RNA polymerase, and is inherently error-prone. You can see the details of how they work and the structures in these excellent reviews by Fodor and te Velthuis¹ for influenza and Hillen² for SARS-CoV-2. SARS-CoV-2 has some form of error checking/proofreading³ in the system, but this isn't perfect, as it isn't for DNA polymerases either, so this answer applies to most viruses.

However, what is important here is not the mutation rate as such, but the fact that these viruses are incredibly infectious. You only need a few viral particles to infect - for some influenza viruses this might be as low as about 40 particles⁴, but more typically a bit higher than that. During an infection, viruses such as influenza and SARS-CoV-2 are putting out about a billion (10⁹) and 100 billion (10¹¹) particles⁵ - that's an enormous number, even if you take an infectious unit to be 1000 particles, then you still have about a million or so of them. This also means that even if a huge chunk of that number is defective in a manner that inhibits replication, then it doesn't matter; you are still going to get infection and replication of those that are capable of it.

Viruses of this sort exist as what is known as a quasi-species - basically think of it as a cloud of viruses with similar genomes. Some of those genomes are defective at replication because they are missing significant or crucial chunks of the genome (packaging faults or problems resulting from recombination for example) or packaged with defective proteins, some are defective because they have a mutation in a critical site, and some are defective because of mutations that alter protein structure or cause premature termination of protein products. There is of course, extremely strong selection pressure for genomes with no mutations or non-critical mutations in those critical locations. How this is achieved is through the use of redundancy in the genetic code; silent mutations have no effect for example, or it might be that substitution with a similar amino-acid has little to no effect. In some viruses it is thought that the ratio of replication competent virions to defective is in the order of 1:100 (i.e. 1 replication competent:100 defective), and sometimes even higher. You can actually generate higher ratios by serial passage of undiluted virus stocks, because the defective particles are often generated faster than replication competent particles due to shorter genomes

So, you might be asking - but what about all those defective particles, what are they doing and why would they be produced? Well, some of them are indeed infectious, but not capable of producing fully replication competent virus themselves, so produce a dead-end infection. These are sometimes called things like Defective Interfering Particles. There's some debate about what they do exactly, but it seems that they are drivers of the virus-host interaction in some manner⁶. They have been found in almost all viruses and they seem to be produced consistently and not produced under certain conditions, which probably indicates that they are important for infection in some way, whether it be mopping up the immune response to allow a better chance for replication competent virus, or some other mechanism.

References:

1. Te Velthuis AJ, Fodor E. Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis. Nat Rev Microbiol. 2016 Aug;14(8):479-93. doi: https://doi.org/10.1038/nrmicro.2016.87. Epub 2016 Jul 11. PMID: 27396566; PMCID: PMC4966622.

2. Hillen HS. Structure and function of SARS-CoV-2 polymerase. Curr Opin Virol. 2021 Jun;48:82-90. doi: https://doi.org/10.1016/j.coviro.2021.03.010. Epub 2021 Apr 6. PMID: 33945951; PMCID: PMC8023233.

3. Moeller NH, Shi K, Demir Ö, Belica C, Banerjee S, Yin L, Durfee C, Amaro RE, Aihara H. Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN. Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2106379119. doi: 10.1073/pnas.2106379119. PMID: 35165203; PMCID: PMC8892293.

4. HORSFALL FL Jr. Reproduction of influenza viruses; quantitative investigations with particle enumeration procedures on the dynamics of influenza A and B virus reproduction. J Exp Med. 1955 Oct 1;102(4):441-73. doi: 10.1084/jem.102.4.441. PMID: 13263486; PMCID: PMC2136520.

5. Sender R, Bar-On YM, Gleizer S, Bernshtein B, Flamholz A, Phillips R, Milo R. The total number and mass of SARS-CoV-2 virions. Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2024815118. doi: 10.1073/pnas.2024815118. PMID: 34083352; PMCID: PMC8237675.

6. Vignuzzi M, López CB. Defective viral genomes are key drivers of the virus-host interaction. Nat Microbiol. 2019 Jul;4(7):1075-1087. doi: 10.1038/s41564-019-0465-y. Epub 2019 Jun 3. PMID: 31160826; PMCID: PMC7097797.

Answer 2

One consideration is that influenza viruses and coronaviruses are RNA viruses. While DNA viruses are generally dependent on the host's replicative enzymes, which have evolved low error rates for host fitness, RNA viruses encode their own enzymes for replication, allowing optimization for viral fitness [1]. High mutation rates allow for high population-level diversity and therefore adaptability, and RNA viruses have evolved high error rates on the order of 10^-4 to 10^-6 (compare with 10^-6 to 10^-8 for DNA viruses [2] and 10^-8 for humans [3]).

This leads to your question of how RNA viruses tolerate such high mutation rates without entering an error catastrophe in which the accumulation of deleterious mutations becomes lethal. This tolerance of error is referred to as genetic robustness, and there are several mechanisms by which RNA viruses achieve this (the following is based largely on [4]):

1. Population size - Most importantly, RNA viruses replicate very quickly and very often, leading to extremely large population sizes [5]. Even though deleterious or lethal mutations occur frequently, there are still a large number of individuals with neutral or beneficial mutations that will survive [4].
2. Multiplicity of infection - A single cell can be infected by more than one virion, allowing a non-functional protein from an allele in one genome to be complemented by a functional protein from an allele in another [4].
3. Recombination - Related to multiplicity of infection, RNA viral genomes can recombine [6] and this could potentially allow deleterious mutations to be unlinked from neutral or beneficial ones [4].

Although points 2 and 3 would also apply to other types of viruses, multiplicity is also influenced by the large population size of RNA viruses. High viral copy numbers within a cell could give a greater potential for recombinational rescue of deleteriously mutated genomes, and, since mutated copies of a viral genome can also be translated [7], they can also therefore complement one another even in cellular infections initiated by only a single virion.

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NB: Several of the Wikipedia links aren't really applicable to what is being discussed here, but I included them anyways because they're about vaguely similar concepts.

References

[1] Duffy S. 2018. Why are RNA virus mutation rates so damn high? PLoS Biol 16(8):e3000003

[2] Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R. 2010. Viral mutation rates. J Virol 84(19):9733-9748

[3] Nachman MW, Crowell SL. 2000. Estimate of the mutation rate per nucleotide in humans. Genetics 156(1):297-304

[4] Lauring AS, Frydman J, Andino R. 2013. The role of mutational robustness in RNA virus evolution. Nat Rev Microbiol 11:327-336

[5] Moya A, Elena SF, Vracho A, Miralles R, Barrio E. 2000. The evolution of RNA viruses: A population genetics view. Proc Natl Acad Sci USA 97(13):6967–6973

[6] Wang H, Cui X, Cai X, An T. 2022. Recombination in Positive-Strand RNA Viruses. Front Microbiol 13:870759

[7] Boersma S, Rabouw HH, Bruurs LJM, Pavlovič T, van Vliet ALW, Beumer J, Clevers H, van Kuppeveld FJM, Tanenbaum ME. 2020. Translation and Replication Dynamics of Single RNA Viruses. Cell 183(7):1930–1945.e23