Infectious Disease

‘Chasing variants’ may not be the optimal COVID-19 vaccination strategy

January 11, 2024

5 min read

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Last autumn, the availability of the 2023-2024 updated COVID-19 vaccines, which more closely targeted the then-dominant XBB omicron subvariant lineage, promised to restore protections that had waned over time.

However, just a few months later in December, patients and providers in the Unites States began witnessing a new subvariant emerge. More closely related to the previous BA.2.86 variant, the JN.1 subvariant now accounts for about 62% of cases in the United States as of Jan. 5, according to the CDC. And although the current vaccines are expected to protect against JN.1, it is likely that additional updates — targeting whichever variant or subvariant lineage is dominant at the time — will become available in the months and years ahead.

A pull quote of Cassandra Calabrese, DO, saying,

In light of these rapid shifts in the status quo, some experts question whether more vaccines — or rather, “chasing variants” with more vaccines — is the optimal strategy for protecting those with immune-mediated conditions.

“True to form, we are not really seeing the XBB subvariant anymore,” Cassandra Calabrese, DO, of the Cleveland Clinic departments of rheumatic and immunologic disease and infectious disease, told Healio. “It has already come and gone.”

According to Calabrese, this raises a larger question about the utility of routine or yearly COVID-19 vaccination, even among vulnerable populations.

“I am not sure that chasing variants is an optimal strategy,” she said.

Experts like Kevin L. Winthrop, MD, MPH, of the Oregon Health & Science University, expressed similar concerns.

“These things are going to come and go,” he said. “We need to see how long-term studies play out and how variants evolve.”

Kevin L. Winthrop

The FDA has approved the new COVID-19 vaccines for individuals aged 5 years and older regardless of previous vaccination status. For those aged 6 months through 4 years, an emergency use authorization stipulates that those who have previously been vaccinated may get one dose, while those who are previously unvaccinated may get three doses.

However, Calabrese said she would be reluctant to apply the updated products so broadly.

“Not everyone needs it,” she said.

According to Calabrese, one concern is that there are fewer data supporting these novel products than there were supporting their predecessors. Moreover, the data in the youngest patient groups are largely nonexistent.

“Giving a vaccine with little or no data may not be the most effective way to protect the population,” she said. “Of course, I am pro-vaccine, and in favor of protecting people. I just think it is important to follow the necessary protocols to ensure that we are doing it as safely and as effectively as possible.”

The overall goal of vaccination also needs to be considered, according to Calabrese.

“At this point, we are not trying to prevent people from getting COVID,” she said. “We are trying to prevent severe disease and hospitalizations.”

To that end, a significant proportion of the U.S. population has already been vaccinated multiple times, or has had COVID-19, or both.

“If you are a young, healthy person who has had COVID and been vaccinated, you probably do not need another dose,” Calabrese said.

However, many patients who enter a rheumatology clinic are neither young nor healthy. Understanding the parameters surrounding the updated vaccines is critical to protecting them from the virus.

In addition, vaccination may not be the only strategy. Novel monoclonal antibodies are on the horizon. How and when they factor into the conversation could provide rheumatologists with another way to protect their patients as the endemic phase of COVID-19 continues.

‘Cumulative effect over time’

Like Calabrese, Winthrop remains a “fan” of using vaccines. However, he added that he wants to ensure their effective and optimal use, particularly among patients who are immunocompromised.

“There are just not enough long-term data in patients on treatments like rituximab (Rituxan, Genentech),” Winthrop said. “I would think that those patients who have received multiple doses would have improved protection with boosters. I suspect there is a cumulative effect over time, but we just do not know as longer-term studies have not been done, to my knowledge.”

That said, Calabrese stressed that viral infections tend to linger in patients who are immunocompromised, particularly those taking B-cell depleting therapies.

“We see patients on rituximab fighting COVID for 3 or 4 months,” she said. “What happens in those cases is that this prolonged infection becomes a breeding ground for mutations.”

Rheumatologists, then, are encouraged to manage individual patients carefully in the setting of B-cell depletion and vaccination.

Regarding other treatments, like methotrexate, which the data suggest holding at the time of vaccination to improve vaccine response, Winthrop offered a similar point.

“I believe holding methotrexate for 1 to 2 weeks will assist vaccine response, at least for COVID-19 and influenza vaccines where this has been studied,” he said. “But I am not sure it makes a difference on your fourth or fifth vaccine, as it might be less important at that point as compared to when a patient is first vaccinated.”

That said, the issue is far from straightforward, particularly in terms of spreading this message to patients. Winthrop acknowledged that the rise and prevalence of vaccine hesitancy makes messaging more difficult.

“From a public health standpoint, it might be easier to communicate the idea that a yearly COVID shot is necessary, rather than a more ambiguous message depending on what the current variant is doing,” he said.

As with most questions in medicine, more data could help provide an answer.

“It will take a long-term study to find out exactly how long people are protected, and when the optimal time is for re-vaccination,” Winthrop said.

Again, the goal is not necessarily to eliminate COVID-19 infection altogether, but to minimize severity, according to Winthrop.

“What we need to be thinking about is how to protect people enough to keep them out of the hospital,” he said.

In addition to the timing of vaccination, the other main concern for rheumatologists to consider is the durability of protection.

“Many people in the general public are well-protected at this point,” Winthrop said. “A sizeable portion of the population has had four or five or more exposures, either via natural infection or vaccination, or both.”

Although some recommendations suggest vaccinating patients 2 months from the last exposure, Winthrop suggested waiting at least 6 months.

“There will be improved protection in the short-term — that is to say, several months — when antibody levels go up just after booster vaccination,” he said. “But how a fifth or sixth booster affects long-term protection and, in particular, cell-mediated responses, is unclear. Patients who are immunosuppressed and likely had sub-optimal responses to prior exposures stand the most to gain from a booster.”

The original bivalent vaccine provided significant protection that may continue, according to Winthrop. That said, if a variant emerges that “substantially escapes prior immune response,” a more regular or yearly vaccination could have utility, he said.

The hope is that protection will last long enough for the next wave of monoclonal antibodies to emerge.

New and improved Evusheld

Calabrese currently serves as a site primary investigator for a clinical trial called SUPERNOVA, which is investigating a novel monoclonal antibody preexposure prophylaxis (PrEP) product currently known as AZD3152 (AstraZeneca).

“This is for the updated version of Evusheld (tixagevimab/cilgavimab, AstraZeneca), which has been out of use since January 2023 due to lack of efficacy against new variants,” she said.

The target population for this product is high-risk and immunocompromised individuals. The company announced in December 2022 that the first patient in the phase 1/3 trial had been dosed.

“High-risk patients need this product,” Calabrese said. “The trial has been ongoing for almost a year. Immunocompromised patients need it now.”

As the study concludes and the data mature, Calabrese stated she is hopeful for patients who are immunosuppressed or immunocompromised.

“Soon, we will have a PrEP option,” she said.

In the meantime, as immunocompromised patients wait for an updated replacement for Evusheld, there are larger concerns about the rate of mutation of the COVID-19 virus.

“It is difficult to say whether this virus is mutating faster than others,” Calabrese said.

Although each COVID-19 variant has proven less virulent than the last, she acknowledged it is always possible for that to change.

“We are hopeful that will not be the case,” Calabrese said.

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Calabrese reports speaking fees from AstraZeneca and Sanofi, as well as consulting fees from AstraZeneca, Sanofi, Eli Lilly & Co. and Pfizer. In addition, AstraZeneca is the primary sponsor of the SUPERNOVA trial. Winthrop reports conducting research and consulting for GlaxoSmithKline, Moderna and Pfizer.

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