Even bivalent updated COVID-19 boosters struggle to prevent omicron subvariant transmission – an immunologist discusses why new approaches are necessary


The vaccination campaign against SARS-CoV-2, the virus that causes COVID-19, has been a global success in almost every respect.

Since January 2023, more than 12 billion vaccines against SARS-CoV-2 have been administered in an effort that has saved countless lives – more than 14 million in the first year of the vaccine’s availability alone. With an efficacy of 95% in preventing serious infection and death, and better safety profiles than comparable historically effective vaccines, the biomedical community hoped that a combination of vaccination and natural immunity could bring the pandemic to an end relatively quickly.

But the emergence of new viral variants, particularly omicron and its array of subvariants, has turned those expectations upside down. The latest omicron strain, XBB.1.5. – named “Kraken” after a mythical sea creature – has quickly become the dominant sub-variety in the US. The World Health Organization calls it the most contagious strain to date, with its success almost certainly due to its ability to evade immunity from previous vaccines or infections.

The effort to get ahead of these ever-changing variants is also, in part, what has led the Food and Drug Administration to rethink its approach to COVID-19 vaccination. On January 23, 2023, the agency proposed replacing the current guidelines for a series of injections followed by a booster with an annual COVID-19 vaccine that will be updated each year to combat current tensions. The proposal will be reviewed by the FDA’s scientific advisory committee on Jan. 26.

Limitations of current mRNA vaccination strategies

Unfortunately, the new bivalent shots, which contain components of both the original SARS-CoV-2 strain and a recent omicron variant, have not performed as well as some scientists had hoped. While there is no doubt that the updated jabs are able to increase antibody levels against SARS-CoV-2 and help prevent serious illness and hospitalisation, several studies have suggested that they are not necessarily better able to prevent omicron infections. than their predecessors.

As an immunologist who studies how the immune system selects which antibodies to produce and immune responses to COVID-19, these new results are disappointing. But they are not entirely unexpected.

As COVID-19 vaccines began rolling out in early 2021, immunologists began to engage in public discussions about the potential obstacles to quickly generating updated vaccines against emerging virus strains. There were no hard numbers back then. But researchers have long known that immunological memory, the very thing that provides lasting protection against a virus long after vaccination, can sometimes negatively affect the development of slightly updated immune responses.

The failure of these new bivalent vaccines in preventing omicron infections at scale suggests that our current approach is simply not enough to interrupt the viral transmission cycle that is driving the COVID-19 pandemic. In my opinion, it is clear that innovative vaccine designs that can produce broader immunity are badly needed.

The newest sub-variant of COVID-19, XBB.1.5, accounts for a large share of new cases.

Vaccines are designed to generate immune memory

Simply put, vaccines are a way to give your immune system a taste of a pathogen. There are several ways to do this. One way is to inject inactivated versions of a virus, as has been done with polio. Another is the use of non-infectious viral components, such as the proteins used for flu vaccines.

And most recently, scientists have found ways to provide mRNA “instructions” that tell your body how to make those non-infectious viral components. This is the approach used with the Moderna and Pfizer vaccines targeting COVID-19.

The mRNA-based vaccines all train your immune system to identify and respond to critical components of a potential invader. An important part of that response is getting your body to produce antibodies that will hopefully prevent future infections, breaking the cycle of human-to-human transmission.

With a successful response, the immune system will not only produce antibodies specific to the pathogen, but will also remember how to make them in case you encounter that same pathogen again in the future.

The existing approach to COVID-19 vaccines has proven effective in preventing serious illness and death, but it hasn’t prevented infections as well as scientists had hoped.
Morsa Images/DigitalVision via Getty Images

The specter of ‘primordial antigenic sin’

But what happens as the virus evolves and that memory becomes obsolete?

Immunologists have wondered this since the initial rollout of the COVID-19 vaccine. Recently, it has found new relevance in light of the FDA’s proposal for an updated annual COVID-19 shot.

While it’s possible that immune responses to updated vaccines simply replaced the old ones, that hasn’t been the case for flu. With flu, researchers have learned that pre-existing immunity to one strain can actively inhibit the ability to respond well to another strain.

In plain language, think of a virus as a car trying to run you over. You could produce some kind of antibody against the hood, one against the bumper and one against the hubcaps that prevent the wheels from turning. You’ve produced three types of antibodies specific to the car, but it turns out that only the hubcap antibodies effectively slow them down.

Now the car is mutating, as SARS-CoV-2 has done. It changes the shape of the hubcaps or removes them altogether. Your immune system still recognizes the car, but not the hubcaps. The system doesn’t know that the hubcap was the only effective target, so it ignores the hubcaps and ramps up its attack on the hood and bumper.

By ignoring the new hubcap response, the immune system’s memory of the original car is not only obsolete, but it actively disrupts the response needed to hit the new car’s wheels. This is what immunologists call “primordial antigenic sin”: ineffective immune memory that hinders desirable responses to new pathogen strains.

This kind of interference is extremely difficult to quantify and study in humans, although it could be made easier with the FDA’s proposal. An annual approach to COVID-19 vaccination opens the door to more straightforward studies of how remembering each vaccine affects the next.

Multi-strain vaccinations offer hope

At the same time, significant efforts are being made to prioritize the pursuit of a single or “universal” vaccine. One approach has been to take advantage of emerging research showing that if your immune system gets multiple versions of the same pathogen, it will tend to choose targets that are shared by them.

Presented with a Model T, Ford F-150, and electric Mustang all at once, your immune system will often choose to ignore differences like the hubcaps in favor of similarities like the shape and rubber on the tires. This would not only disrupt the operation of all three vehicles, but could theoretically disrupt most road vehicles – or viral threats such as variants.

Researchers have begun to make rapid progress using this approach with the development of complex multi-strain flu vaccines that perform well in early clinical trials. New studies targeting SARS-CoV-2 hope to do the same. Persistent pathogens, including flu and HIV, all suffer from versions of the same antibody-targeting problems. It is possible that this pandemic can serve as a crucible of innovation leading to the next generation of infectious disease prevention.

This is an updated version of an article originally published March 8, 2021.

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