Random variation is an essential component of all living things. It drives diversity, and it is why there are so many different species. Viruses are no exception. Most viruses are experts at changing genomes to adapt to their environment. We now have evidence that the virus that causes Covid, SARS-CoV-2, not only changes, but changes in ways that are significant. This is the third part of a series of articles on how the virus changes and what that means for humanity. Read the first two parts here and here.

Let’s recap what we’ve learned so far.

Tiny, random alterations in viral RNA allow SARS-CoV-2 to change over time. Most of these mutations have next to no effect on the virus and some are even corrected using a special proofreading mechanism, slowing the speed of their natural selection. But a large population size—as in, the nearly 100 million people and counting who have caught Covid-19 worldwide—increases the odds that some mutations will end up giving the virus an evolutionary edge, one that benefits SARS-CoV-2 at great cost to us.

I discussed in my last piece the risk that new variants of SARS-CoV-2, whether already emergent or soon to come, might develop a propensity for immune escape. Now comes a question that has been top of mind for most since variants like B.1.1.7 and 501.V2 were first identified: what does this possibility mean for our efforts to vaccinate millions, if not billions, of people?

A recently published preprint attempted to answer this question, at least for the lucky few who have received a dose of the vaccine created by Pfizer and BioNTech. Based on blood samples taken from 20 already inoculated individuals, the study suggests that antibodies generated by the Pfizer vaccine held strong against variants containing the mutation N501Y, an alteration to the spike protein that is also the defining feature of B.1.1.7. But these results, while reassuring, barely scratch the surface of what genomic databases like GISAID have proven to be a much deeper pool.

Though most mutations ultimately do little to increase the survival prospects of SARS-CoV-2, there are dozens that can. Some, like N501Y, help the virus become more transmissible by increasing its affinity for our cellular receptors, making it easier for it to latch on tight and force entry. Other mutations could increase viral load, pushing the number of infectious particles that overrun the body to explosive new heights. And others still—arguably the most dangerous of the bunch—might allow the virus to evade or overcome our immune defenses, even if they’re bolstered by vaccines.

While it’s highly unlikely a variant will arise that renders current vaccines totally useless, mutations that encourage immune escape could make them less effective. One mutation experts fear will fall into this category is the substitution E484K, which like N501Y is located on the spike protein and has appeared in variants currently circulating in South Africa, Brazil, Japan, and several other countries. E484K appears to give SARS-CoV-2 an element of disguise, making it less recognizable to the antibodies a vaccine trains to eliminate it. Another preprint study found, after mapping the specific ways in which antibodies in several preparations of convalescent plasma were impacted by spike mutations, that E484—more than any other region—had the biggest and most adverse impact on antibody neutralization. In some participants, E484-related mutations reduced the potency of antibodies more than tenfold. And in Brazil, at least one woman who recovered from Covid-19 once before has not only been reinfected with a variant containing the E484K mutation, but also experienced worse symptoms the second time around.

Other naturally occurring mutations have been found, either in laboratory experiments or clinical case studies, that have even more profound effects on escape from neutralization by convalescent plasma. The H69-V70 deletion, which I described in my last piece, might be one. Most of the research conducted so far has concentrated on the receptor binding domain, but clearly other viral proteins could assist in escape and thus deserve our attention.

Immune escape isn’t the only development that could prove challenging for mass vaccination efforts. In the coming months and even years, so long as infections around the globe continue to rise or reoccur steadily, SARS-CoV-2 will become more efficient at the very task of evolving. Much as the virus has been mutating and experimenting all this time, it has done so clumsily, through aimless and repetitious trial and error alone. Given its lack of sentience, as the virus evolves it will continue to be none the wiser. But that doesn’t mean it can’t get wilier, using each advantageous variation as a stepping stone to the fittest and fiercest version of itself.

To avoid being crushed by the incoming tide, we’ll need to do two things. First, vaccinate as many people as possible—and fast. The snail’s crawl at which vaccine rollout is proceeding in the United States simply won’t cut it, especially now that researchers at Ohio State University have reported the discovery of a new SARS-CoV-2 variant in Columbus, Ohio. People must be vaccinated not just to prevent them from getting sick, but to reduce the number of opportunities SARS-CoV-2 has to experiment, mutate, and evolve new means of surpassing our defenses. These new properties are ones we cannot anticipate—only observe and react to.

Second, expand current efforts to sequence and survey new variants. We need to be prospecting the entirety of the genome, as well as the entirety of the biosphere, for alterations that encourage immune modulation. And we need to be prepared to adapt our vaccines to an adapting virus, as we do with seasonal flu. Over the course of the pandemic, not nearly enough emphasis has been placed on thinking longer term about the bigger picture. That has cost us dearly. We can’t afford to make the same mistake with these variants. Not when we know exactly what to do to protect ourselves against them.

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