Therese Raphael

Why You'll Probably Get Covid (Again) Soon

The question used to be: “Have you had Covid?” Now it’s: “How many times have you had it?”

Both of us have had a Covid (re)infection in recent months. Many of us know people currently sick with Covid or recently recovered. In the week ending June 24, an estimated 1 in 30 people in the UK (some 2.3 million people) were infected with Covid, up 32% from the previous week.

That largely reflects the changing virus. The UK’s Health Security Agency reckons omicron’s more highly transmissible subvariants BA.4/5 make up more than half of new infections. The Centers for Disease Control in the US came to a similar conclusion there.

While people are still hospitalized with Covid, and there are still Covid deaths (especially among the more vulnerable or unvaccinated), the vast majority of vaccinated people soon recover, though the illness can still be rough for many. “In terms of its kind of lethality, the picture now is much, much, much closer to seasonal flu than it was when [coronavirus] first emerged,” Jonathan Van-Tam, formerly England’s deputy chief medical officer told the BBC recently.

That leaves the question of how to manage the virus through the coming winter. On one hand, countries with high levels of vaccination should have higher resilience and therefore fewer restrictions. On the other, the virus’s ability to mutate means high infection levels pose risks. We discuss what lies ahead for booster shots and other strategies for containing the pandemic.

Therese Raphael: Both Pfizer Inc. and Moderna Inc. have announced that their candidate vaccines that target omicron provide more potent and potentially durable immune responses. The FDA’s advisory panel recommended Tuesday that updated Covid-19 booster shots include an omicron component. Do you think it’s right to go ahead with an omicron-specific booster?

Sam Fazeli: There was some uncertainty among FDA panel members about whether omicron shots would beat the current vaccine, but the majority believed that a vaccine that includes an omicron sequence has a good chance of being beneficial against omicron while also providing a defense against other variants. Still, when you look at the data that the companies presented, they both marginally failed to show statistical superiority of their new vaccines against BA.1 compared to the currently available shots.

TR: So what gives the panel confidence they will be superior then?

SF: The shots still showed improved antibody responses to BA.1, the original omicron variant. But the panel stated that they want a BA.4/5 omicron shot, and I think regulators are going to ask the companies to update their vaccines yet again. The data on shots based on omicron BA.1 induced three times less neutralization against BA.4 and BA.5 than against BA.1. My math suggests they will be about 50% effective against BA.4 and BA.5 infections after three to four months.

Pfizer has already started work on a vaccine to counter BA.4 and BA.5, and they showed some promising data at the meeting looking at neutralization in mice. If those findings carry through to humans, it will make for a better vaccine than one based on BA.1.

TR: That’s good, since it seems most of us having reinfections are getting the later subvariants. It’s hardly summer here, but thinking ahead, do we need to do something different this winter? Especially with flu potentially more prevalent than it has been the previous two years? Or will levels of natural immunity do the work of booster shots?

SF: Neither vaccines nor prior infection is going to stop reinfections. I tested positive two weeks ago having been fully vaccinated and having had a delta infection last October. Vaccination may delay it by a few months, but infections will eventually happen, even if Moderna is right that the bivalent vaccine (treating both omicron and previous variants) may induce longer-lived antibodies.

The concept of herd immunity as regards infection is dead really. What we need to do is to make sure we have protected the most vulnerable segments of the population against severe disease, which was also noted several times by the FDA panel. Whether this is people aged over 65 or 60 or 50, we will see what the FDA says.

TR: We were told that mRNA technology could be easily adapted to fit emerging virus strands so it’s surprising that we don’t even have a booster shot for BA.1 on the market yet. Why not?

SF: Well let’s not forget that this is the first time we are updating the vaccines and the virus is changing very fast. Still, Pfizer noted at the meeting that it could have high-volume production of a BA.4/5 shot by September, and Moderna by October or November. This is assuming the FDA does not require large human trials with a couple of months of safety data. Both companies are still adamant that they can get to a manufactured product within 90 to 100 days.

TR: There are two things that concern most vaccinated people these days when they think about new Covid variants. One is the risk of serious illness and the other is Long Covid. Have those risks changed in light of BA.4/5?

SF: Data from South Africa and Portugal does not suggest a major change in severity with BA.4/5 compared with BA.1. But don’t forget that this is on the background of many people having been infected with BA.1 in the first omicron wave, so it’s not easy to compare.

It’s worth mentioning a recent study showing much higher severity after reinfections, which included the omicron variant. The problem is that this study was done on patient data from the US Department of Veterans Affairs electronic health records, with most subjects being over the age of 60 and having comorbidities that increase the risk of severe disease. It’s also notable that a majority of those included in the analysis were unvaccinated.

But its biggest flaw is what we call “ascertainment bias,” which arises when some members of a target population are less likely to be included than others. For example, if most people don’t bother getting officially tested if they have mild symptoms due to reinfection, the data become skewed to more severe disease which leads to an overestimate.

As regards Long Covid, a recent study showed that omicron seems to lead to fewer Long Covid cases than previous variants. Note, this was in the UK, where a large majority of people are triple-vaccinated.

TR: It sounds like many of us face reinfections this winter. Does that make it more likely we’ll see another significant mutation with greater ability to evade immunity? Will the updated vaccines be able to protect us against new variants?

SF: The problem is that we don’t know what the next variant will look like. Everyone thought any new variant would be based on the delta variant — instead it came from left field with a host of mutations that few expected. Using a bivalent vaccine may already be the first step towards a polyvalent shot. But, we must not forget that a large majority of people have either been vaccinated or infected, so these booster shots are on top of pre-existing immunity. That leads to immune imprinting, where the body keeps getting pushed into making the same antibodies.

As regards new mutations, it’s not background immunity which has so far led to big mutational jumps like omicron but long-term infections in immunocompromised people.

If there are major shifts again in omicron or a totally new variant turns up, we may have to develop yet another variant vaccine. But, if immune imprinting is not a problem, each successive infection or immunization with updated vaccines will broaden the immune response and further reduce the risk of severe illness. Alas, as antibody levels fall within a few months of every infection or vaccine shot, the chances of getting reinfected and developing mild disease returns.