Photo: Jeremy Bezanger / Unsplash

There’s been much chatter lately regarding the BA.2 variant. Also, “what about the next big variant? When will it come?” These questions are being posted as the United States and many other nations around the world are curtailing Covid-19 restrictions. So, is the pandemic over? What’s next?

First off, sorry to disappoint but BA.2 is not going to drive an explosive new wave of Covid-19 cases in the United States. It is slowly replacing BA.1 & BA.1.1. But this is happening as overall cases are declining. What BA.2 will do is drag out the tail of the omicron wave here (it’s important to remember BA.2 is still part of the omicron lineage).

As for the next big variant, we really don’t know what’s next. Anyone who thinks they do is more likely to be wrong than right. Could the pandemic be “done” after omicron? This is unlikely. But the next big variant is likely to (i) be antigenically distinct from omicron, and (ii) will surprise us. It’s almost certainly not going to be a derivative of omicron. And if it turns out to be a derivative of delta or alpha or other variant of concern (VOC), its spike will look massively different from the way its parent’s did.

The next “big one” — when and if it emerges, will likely escape a key subset of broadly neutralizing antibodies that can hit most if not all previous variants — including omicron and delta. One of the key questions, at least for me, is how constrained are the sites where broadly neutralizing antibodies bind on spike? Can the virus mutate to escape those without sacrificing fitness? If not, good news. If yes, buckle your seat belt.

To hedge a bit, there is a plausible, albeit low, likelihood scenario in which the next big wave is driven by a derivative of omicron. But this exception to “the next big variant always comes out of left field” rule would not apply to previous variants of concern because unlike previous variants, in which spike kept getting more & more “open,” omicron evolved a more “closed” spike, meaning it hides its receptor binding domains from antibodies, just as the late Michael G. Rossmann’s canyon hypothesis would predict.

Yes, you could even say omicron’s fashion sensibilities take a Victorian-era slant. Omicron definitely has a more chaste spike. That said, when an omicron spike does open one of its three receptor binding domains (RBDs) and finds an ACE2 receptor, it latches on much more tightly than previous variants. You can read more about this, and how the spike has been evolving, here.

Michael G. Rossmann’s ‘Canyon Hypothesis’ applied to zoonotic spillover. During circulation in populations with high rates of humoral immunity, viral entry proteins favor predominantly closed receptor-binding domain (RBD) configurations. Immediately after spillover into a population that lacks immunity, the newly emergent virus remains closely related to its ancestor and, hence favors closed RBD configurations. During sustained transmission between seronegative individuals, large viral population sizes and wide transmission bottlenecks facilitate the rapid emergence of variants that favor open RBD configurations to spread rapidly between hosts. Over time, the evolutionary entanglement between viral entry proteins and humoral immunity gradually leads to a return to closed RBDs as repeat exposures facilitate the affinity maturation of expansive antibody repertoires that are disproportionately costly to open RBD configurations. Figure was generated with biorender.com; excerpted from Wolf, Kwan, and Kamil (2022). https://doi.org/10.1128/mbio.02030-21

But instead of taking the rapid “surface” / “early” entry route where spike fuses at the plasma membrane, as all earlier variants did, omicron gets in via a slower route, it hitches a ride in a bubble of membrane called an “endosome.” In other words, it uses what the professional coronavirologist Tom Gallagher calls the “late entry” route.

Early versus Late entry. MERS coronavirus cell entry model. In some producer cell types, MERS-CoV S proteins are cleaved by furin/proprotein convertases in the exocytic pathway. Cleaved MERS-CoV S proteins change their conformations rapidly after receptor binding, exposing subsequent proteolytic cleavage sites, which are processed by proteases (that is, TMPRs, found at or near cell surfaces). Early cell-surface entry is achieved when several adjacent S proteins are processed. In other producer cell types, MERS-CoV S proteins are not cleaved. UncleavedMERS-CoV S proteins slowly change their conformations after receptor binding. MERS-CoVs having uncleaved S proteins traffic to the late endosomes/lysosomes and late endosomal entry is achieved when several adjacent S proteins are eventually processed by cathepsins. Figure from Park et. al. (2016). Proc. Natl. Acad. Sci., U.S.A. https://doi.org/10.1073/pnas.1608147113

The reliance on this slower cell entry route has important evolutionary implications because omicron is using a “structure-function” mechanism to hide from antibodies: instead of only mutating antibody binding sites on spike as earlier variants did, omicron also hides the parts of the spike that bind to our ACE2 receptors. Its more “closed” or “chaste” spike resembles how the spikes of “endemic” coronaviruses behave, and so this shift in how the spike functions could continue to influence the trajectory for emergence of new variants. So, perhaps omicron could mutate enough to drive a new “big wave” simply by escaping a few of the major types of antibody responses that are “broadly” neutralizing. In my opinion, the next big variant is still most likely again come out of left field, but maybe it’s not impossible for omicron to buy itself a new pandemic wave by mutating the sites where the most common “broadly neutralizing” antibodies bind.

Another important note, Marc Johnson’s group (Twitter @SolidEvidence) and their collaborators have found evidence in U.S. wastewater of independently emergent variants with omicron-like mutations. This means a new variant “out of left field” might still have a more “closed” spike. So, “closed” spikes were likely on track to evolve in here in the U.S., and elsewhere — even if the virus had been magically eliminated from the African continent. In essence, the same selection pressures that led to omicron’s emergence were causing the virus to convergently evolve similar features on multiple continents.

Therefore, we really don’t know what’s next in SARS-CoV-2 evolution, other than to say the virus is likely to keep coming up with ways to crack the code and get past our neutralizing antibody defenses. And why do I keep emphasizing neutralizing antibodies? “Why not T-cells?” Even though other facets of immunity are important to contain and limit coronavirus disease, neutralizing antibodies are — as far as I know, the only surefire way to entirely block infection and hence, prevent transmission.

We know that SARS-CoV-2 emerged out of bats already well-equipped to broadly mute mammalian interferon responses & limit pro-inflammatory alarm signals long enough to delay recruitment of immune cell “clean up crews,” enabling it to efficiently spread from host to host. So for these reasons, neutralizing antibodies represent a critical selection pressure on this virus, and for respiratory viruses in general. Viruses that come up with new ways to escape neutralizing antibodies are going to be hugely rewarded. As to what happens next during the Covid-19 pandemic, my crystal ball is cloudy as everyone else’s. We will just have to wait and see.