FDA advisory committee votes unanimously in favor of a one-shot COVID-19 vaccine approach – 5 questions answered

The U.S. Food and Drug Administration’s key science advisory panel, the Vaccines and Related Biological Products Advisory Committee, met on Jan. 26, 2023, to chart a path forward for COVID-19 vaccine policy. During the all-day meeting, the 21-member committee discussed an array of weighty issues including the efficacy of existing vaccines, the composition of future vaccine strains and the need to match them to the circulating variants of SARS-CoV-2, the possibility of moving to an annual-shot model, the potential seasonality of the virus and much more.

But the key question at hand, and the only formal question that was voted on, following a proposal from the FDA earlier in the week, had to do with how to simplify the path to getting people vaccinated.

The Conversation asked immunologist Matthew Woodruff, who has been on the front lines of studying immune responses to COVID-19 since the early days of the pandemic, to walk us through the big questions of the day and what they mean for future COVID-19 vaccine strategies.

What exactly did the advisory committee vote on?

The question put before the committee for a vote was whether to move to one COVID-19 vaccine consisting of a single composition for all people – whether currently vaccinated or not – and away from the current model that includes one formulation given as a primary series and a separate formulation administered as a booster. Importantly, approved formulations could come from any number of vaccine manufacturers, not just those that have currently authorized vaccines.

The U.S. Centers for Disease Control and Prevention currently requires that the primary series of shots, or the first two doses of the vaccine that a patient receives, consist of the first generation of vaccine against the original strain of SARS-CoV-2, known as the “Wuhan” strain of the virus. These shots are given weeks apart, followed months later by a booster shot that was updated in August 2022 to contain a bivalent formulation of vaccine that targets both the original viral strain and newer subvariants of omicron.

The committee’s endorsement simplifies those recommendations. In a 21-to-0 vote, the advisory board recommended fully replacing, or “harmonizing,” the original formulation of the vaccine with a single shot that would consist of – at least for now – the current bivalent vaccine.

In doing so, it has signaled its belief that these new second-generation vaccines are an upgrade over their predecessors in protecting from infection and severe illness at this point in the pandemic.

If the FDA panel’s recommendation is endorsed by the CDC, only a single composition of vaccine – in this case, the updated bivalent shot – will be used for both vaccinated and unvaccinated people.

Will the single shot remain a mixed-strain, or bivalent, vaccine?

For now, the single shot will be bivalent. But this may not always be the case.

There was a general agreement that the current bivalent shot is preferable to the original vaccine targeted at the Wuhan strain of the virus by itself. But committee members debated whether that original Wuhan vaccine strain should continue to be a part of updated vaccine formulations.

There is no current data comparing a monovalent, or single-strain, vaccine that targets omicron and its subvariants against the current bivalent shot. As a result, it’s unclear how a monovalent shot against recent omicron subvariants would perform in comparison to the bivalent version.

What is immune imprinting, and how does it apply here?

A main reason for the debate over monovalent versus bivalent – or, for that matter, trivalent or tetravalent – vaccines is a lack of understanding around how best to sharpen an immune response to a slightly altered threat. This has long been a debate surrounding annual influenza vaccination strategies, where studies have shown that the immune “memory” that forms in response to a prior vaccine can actively repress a robust immune response to the next.

This phenomenon of immune imprinting, originally coined in 1960 as “original antigenic sin,” has been a topic of debate both within the advisory committee and within the broader immunological community.

Although innovative strategies are being developed to overcome potential problems with routinely updated vaccines, they are not yet ready to be tested in humans. In the meantime, it is unclear how bivalent versus monovalent vaccine choices might alter this phenomenon, and it is very clear that more study is needed.

Is the committee considering only mRNA vaccines?

While a significant portion of the discussion focused on the mRNA vaccine platform used by both Pfizer and Moderna, several committee members emphasized the need for new technologies that could provide broader immunological protection. Dr. Pamela McInnes, a now-retired longtime deputy director of the National Center for Advancing Translational Sciences, highlighted this point, saying, “I would make a plea for ongoing research on broader protection, maybe different platforms, maybe a different approach.”

A good deal of attention was also directed toward Novavax, a protein-based formulation that relies on a more traditional approach to vaccination than the mRNA-based vaccines. Although the Novavax vaccine has been authorized by the FDA for use since July 2022, it has received much less national attention – largely because of its latecomer status. Nonetheless, Novavax has boasted efficacy rates on par with its mRNA cousins, with good safety profiles and less demanding long-term storage requirements than the mRNA shots.

By simplifying the vaccine schedule to include only a single vaccine formulation, the committee reasoned, it might be easier for competing vaccination platforms to break into the market. In other words, newer vaccine contenders would not have to rely on patients’ having already received their primary series before using their products. Companies seemed ready to take advantage of that future flexibility, with researchers from Pfizer, Moderna and Novavax all revealing their companies’ exploration of a hybrid COVID-19 and flu shot at various stages of clinical trials and testing.

Would the single shot resemble flu vaccine development?

Not necessarily. Currently, the influenza vaccine is decided by committee through the World Health Organization. Because of its seasonal nature, the strains to be included in each season’s flu vaccine for the Southern and Northern hemispheres, with their opposing winters, are selected independently. The Northern Hemisphere’s selection is made in February for the following winter based on a vast network of flu monitoring stations around the globe.

Although there was broad consensus among panelists that the shots against SARS-CoV-2 should be updated regularly to more closely match the most current circulating viral strain, there was less agreement on how frequent that would be.

For instance, rapidly mutating strains of the virus in both summer and winter surges might necessitate two updated shots a year instead of just one. As Dr. Eric Rubin, an infectious disease expert from the Harvard T.H. Chan School of Public Health, noted, “It’s hard to say that it’s going to be annual at this point.” Läs mer…

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

By almost any measure, the vaccination campaign against SARS-CoV-2, the virus that causes COVID-19, has been a global success.

As of 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 vaccine availability alone. With a 95% efficacy in the prevention of severe infection and death, and better safety profiles than similar historically effective vaccines, the biomedical community hoped that a combination of vaccination and natural immunity might bring the pandemic to a relatively quick end.

But the emergence of new viral variants, particularly omicron and its array of subvariants, upended those expectations. The latest omicron strain, XBB.1.5. – dubbed “Kraken”, after a mythical sea creature – has rapidly become the dominant subvariant in the U.S. The World Health Organization is calling it the most contagious strain so far, with its success almost certainly attributable to an ability to dodge 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 reconsider its approach to COVID-19 vaccination. On Jan. 23, 2023, the agency proposed that current guidelines for a series of shots followed by a booster be replaced by an annual COVID-19 vaccine that is updated each year to combat current strains. The proposal is set to be reviewed by the FDA’s science advisory committee on Jan. 26.

Limitations of current mRNA vaccination strategies

Unfortunately, the new bivalent shots, which include components from both the original SARS-CoV-2 strain as well as a recent omicron variant, have not performed as well as some scientists had hoped. Although there is no question that the updated jabs are capable of boosting antibody levels against SARS-CoV-2 and helping to prevent severe illness and hospitalization, several studies have suggested that they are not necessarily more capable of preventing 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.

When COVID-19 vaccines were being rolled out in early 2021, immunologists began having public discussions about the potential obstacles to rapidly generating updated vaccines to emerging viral strains. At the time, there was no hard data. But researchers have known for a very long time that immunological memory, the very thing that offers continued protection against a virus long after vaccination, can sometimes negatively interfere with the development of slightly updated immune responses.

The failure of these new bivalent vaccines in widely preventing omicron infections suggests that our current approach is simply not sufficient to interrupt the viral transmission cycle driving the COVID-19 pandemic. In my view, it’s clear that innovative vaccine designs capable of producing a broader immunity are badly needed.

The latest COVID-19 subvariant, XBB.1.5, accounts for a large portion of new cases.

Vaccines are designed to generate immune memory

In simplest terms, vaccines are a way to give your immune system a sneak peek at a pathogen. There are several different ways to do this. One way is to inject inactivated versions of a virus, as has been done with polio. Another is to use noninfectious viral components, such as the proteins used for flu vaccines.

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

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

In a successful response, the immune system will not only produce antibodies that are 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 proved effective at preventing serious illness and death, but it has not prevented infections as well as scientists had hoped.
Morsa Images/DigitalVision via Getty Images

The specter of ‘original antigenic sin’

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

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

While it is possible that immune responses to updated vaccines will simply replace the old ones, that has not been true for influenza. With flu, researchers have learned that preexisting immunity to one strain can actively inhibit the ability to respond well against another.

Put in everyday language, think of a virus as a car trying to run you over. You might produce one kind of antibody against the hood, one against the bumper and one against the hubcaps that prevents the wheels from turning. You have produced three kinds of antibodies specific to the car, but it turns out that only the hubcap antibodies effectively slow it down.

Now the car mutates, like SARS-CoV-2 has. It changes the shape of the hubcaps or it 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.

In ignoring the new hubcap response, the immune system’s memory of the original car is not only obsolete, but it is also actively interfering with the response necessary to target the new car’s wheels. This is what immunologists call “original antigenic sin” – ineffective immune memory that hampers desired responses to new pathogen strains.

This sort of interference has been extremely difficult to quantify and study in humans, although it may become easier with the FDA’s proposal. A once-yearly approach to COVID-19 vaccination opens the door for more straightforward studies on how memory to each vaccine influences the next.

Multi-strain vaccinations offer hope

Simultaneously, significant efforts are being made to prioritize the pursuit of a single-shot or “universal” vaccine. One approach has been to take advantage of emerging research showing that if your immune system is presented with multiple versions of the same pathogen, it will tend to choose targets that are shared between 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. Not only would this interfere with the function of all three vehicles, but it could theoretically interfere with most road-based vehicles – or viral threats such as variants.

Researchers have begun making rapid headway using this approach with the development of complex multi-strain flu vaccines that are performing well in early clinical trials. New studies focused on SARS-CoV-2 hope to do the same. Persistent pathogens including influenza and HIV all suffer from versions of the same antibody-targeting issues. It is possible that this pandemic may serve as a crucible of innovation that leads to the next generation of infectious disease prevention.

This is an updated version of an article originally published on March 8, 2021. Läs mer…