Covid: Reinfections amid ‘complex mix of immunity’

Variants of the original version of SARS-CoV-2, the virus that causes Covid, first made headlines in December 2020. It was a sign that SARS-CoV-2 is more volatile than initially expected.

Then in November 2021, Omicron became the fifth variant of concern in circulation — after Alpha, Beta, Delta and Gamma before it. Now, Omicron’s numerous spinoffs have complicated the picture even further.

SA abandoned its remaining regulations — like mask wearing indoors and gathering restrictions — as the fifth wave caseload dropped in June. This wave was driven by sublineages of Omicron called BA.4 and BA.5, the same variants which are causing spikes of infections around the world.

Why are they taking off at such a fast pace? Because each variant is rapidly evolving to outsmart the last.

Evolving to survive

Omicron was the most drastically different variant that had been discovered, with more than 50 changes to its genetic structure when compared to the first version of SARS-CoV-2 that kicked off the pandemic. Mutations are errors that appear in the coding of the virus as it is making copies of itself.

Not all errors will stick around and those that are detrimental will naturally phase out. But those that can give the virus an edge and help it survive will eventually become the dominant form of the bug that’s spreading.

“The naming system doesn’t dictate how the virus behaves,” says Dr Richard Lessells, an infectious disease specialist at the University of KwaZulu-Natal. “The virus will continue to evolve in a way that allows it to continue spreading from human to human.”

People typically develop protection against a germ once they have been exposed to it. This can happen through natural infection, when someone gets sick, or through vaccination. But immunity is less straightforward when the germ in question keeps changing shape and the protection is imperfect.

“The immune landscape in SA is very complex,” says Lessells. “Because we’ve had these five waves of infection and we’ve got vaccines, we’ve got this kind of complex mix of immunity.”

We know that most people in SA have some kind of immunity to Covid by now. After two years and five waves, there have been almost 4-million confirmed cases. But this only represents people who have been tested. The National Institute for Communicable Diseases (NICD) estimates that this is less than 10% of the actual number of Covid infections in the country. This means that over two-thirds of the population could have some level of natural immunity to SARS-CoV-2.

Just over half of SA’s adults have received at least one dose of a Covid vaccine, according to the national rollout dashboard. The percentages for those fully vaccinated according to initial definitions and fully up-to-date with recommended boosters are lower. Blood donor data published in a May preprint estimates that as many as 98% of people in SA had SARS-CoV-2 antibodies. One in 10 of these were people who had protection solely through vaccination and no previous infection.

“In terms of SA and the kind of selection pressure for this virus now, any virus that’s going to gain an advantage in this context is going to be able to escape at least the immunity against infection,” explains Lessells.

The rise of BA.4

There is a mix of different types of immunity for the virus to contend with — from each of the previous variants that people were exposed to as well as vaccination. To become the dominant form of the virus that is spreading, each new variant has to learn how to outdo its predecessors.

In SA, the variant that’s currently doing that the most successfully is BA.4. This sublineage of Omicron accounted for two-thirds of infections in June.

The spread of Omicron and its sublineages since November 2021 has been astounding. During the fourth wave, just over half of infections were caused by BA.1, and by February BA.2 had taken over — making up 86% of cases. But by April, the newest sublineages BA.4 and BA.5 had become dominant and as of June together they drove 96% of infections — effectively pushing out all other forms of the virus from circulation.

Lessells says: “For BA.4 and BA.5 to spread in the way that they have, they had to have a property that allowed them to gain an advantage in the population. And that property was that they were a bit better at getting around the immunity in the population — particularly, they were a bit better at getting around the immunity that had been acquired from a BA.1 infection. So that’s what allowed them to gain ground.”

Two lines of defence

In making sense of the impact of new variants on immunity, it helps to distinguish between antibody and T-cell immunity. (What follows is of course a gross simplification — immunity is complicated.)

The virus might be thought of as a spy trying on different disguises in an attempt to get past security guards to infiltrate a highly secure building. That building is your body — and the security guards are your immune system. These security guards are trying to protect you from getting sick and your cells will try different types of attacks to keep you safe. One part of the response is antibodies. These work to stop the virus from attaching itself to your cells and getting inside or spreading. In a sense, the antibodies are blocking the door to prevent the bug from entering.

SARS-CoV-2 has been learning along the way how to get past this line of defence and new ways to sneak inside. The most recognisable part of the virus is the spike protein, a mushroom-shaped molecule that sits on the surface of SARS-CoV-2.

By trying on different outfits and altering its appearance, the virus can learn what changes will help it get past the guards. The guards can get wise to one disguise, so the germ will change again and try a new look to hide behind.

“Omicron had so many mutations and changes to its structure that essentially many of the antibodies that had been triggered by previous infection just didn’t recognise it,” says Prof Penny Moore, SA Research Chair of Virus-Host Dynamics at Wits University and the NICD. “It was like Omicron was wearing a different coat altogether.”

But just as the virus learns, so do the guards. With each new disguise, antibodies also get smarter to fight off the invading germ. Because of this dynamic, however, the antibodies are on a bit of a back foot, says Moore. It makes it harder to block off the virus completely and leaves people vulnerable to infection.

That’s where the second line of defence comes in, with the next arm of the immune system stepping in. While antibodies aim to prevent infection by heading off the virus, your T-cells are much more ruthless in their approach to completely destroy the bug. Killer T-cells do this with the intention of annihilating cells that have already been infected with the virus. In this way, this part of the immune system can stop you from falling severely ill but can’t stop the germ from entering your body.

“You have this cat-and-mouse game where both the virus and the antibodies are changing,” Moore explains. “The antibodies are changing and getting better. The T-cells are hanging on for dear life and they’re also applying pressure to the virus. And so the virus is also changing as a consequence of all the population immune pressure that it’s been subjected to.”

Reinfection: once, twice, thrice?

Omicron is the wiliest of the variants discovered to date and has become a master of disguise in managing to get past existing defences blocking its path. A March paper published in Science showed that this version of the virus was reinfecting more people than any other waves seen in SA to date. This cements the idea that people can now get Covid more than once, especially as the virus continues to evolve.

Even though BA.4 and BA.5 appear to have stemmed from the original Omicron that was circulating in SA, they still behave like completely a different virus — and should be treated as such, says Lessells.

Both subvariants have similar changes in their spike protein evolved in similar ways that help them get past immunity from both previous infection as well as vaccination, according to new research shared in the New England Journal of Medicine.

While the Omicron variants behind SA’s fourth wave were already proving quite a challenge, the BA.4 and BA.5 sublineages are even trickier. The July data shows that there was a threefold reduction in the antibodies that bind to these forms of the virus and stop them from spreading, as compared to the earlier versions of Omicron.

“We probably only pick up 10% of the infections that are happening and with Omicron it’s probably even less than that,” says Lessells. He estimates less than 5% of Covid cases during the last wave were actually picked up.

“So that’s why we have this false kind of understanding that reinfections are relatively rare, because diagnosed reinfections may still be relatively rare. But if we think about what we miss, then it’s very clear that most of the infections happening now are reinfections,” Lessells explains.

Earlier research from June shared in Nature showed that BA.1 infection would offer little protection against other sublineages of Omicron. The paper found that while the immune system had generated a response to fight off this earlier form of the variant, its newer versions (BA.2, BA.4 and BA.5) had changed in such a way that they could avoid even these newer antibodies.

A July preview of a paper in Nature had similar findings indicating that the latest Omicron sublineages were four times more resistant to antibodies in people who had been fully vaccinated — making it more likely that a person could still get sick even if they have received their Covid jabs.

All of this means that these emerging subvariants can get past defences built up against vaccination or infection, even if the person was exposed to an earlier type of Omicron.

Still changing

But the virus is continuing to change, even now, and there’s no telling what it could look like. While we can’t predict exactly what the next variant will be, it’s highly likely that it’s going to continue along this pattern of outsmarting the immune system, warns Lessells.

“The virus is going to be able to reinfect a large proportion of the population again,” he says. “We have already seen that lots of people in SA have [had] multiple infections and we’re going to continue to see people having repeat infections.”

These findings highlight the importance of developing new vaccines targeted specifically at a later form of Omicron in an attempt to help the immune system stay one step ahead of the virus, says Moore.

“The approach to next-generation vaccines is a little bit different,” she explains. “There are gaps in what immunity is covering, whether it’s from infection or vaccination. These next-generation vaccines will be trying to get enough overlap in the immune response to start filling in the gaps.”

* This article first appeared in Spotlight