There’s no question that the next version of the COVID-19 vaccine in the US will contain components of Omicron subvariant XBB.1.5.
What’s still up in the air, though, is who should get the shot when it debuts this fall.
On June 15, members of the US Food and Drug Administration’s (FDA) Vaccine and Related Biological Products Advisory Committee (VRBPAC) voted unanimously to recommend updating the COVID-19 vaccine composition to a monovalent XBB lineage.
On June 16, the FDA announced that it had advised manufacturers planning to update their COVID-19 vaccines that they should specifically target XBB.1.5. Scientists from Moderna, Novavax, and Pfizer had told the FDA and its advisory committee that their XBB.1.5 monovalent vaccines could be ready to inject into arms by late July or early fall.
Although the FDA decides what antigens the COVID-19 vaccines should include, the US Centers for Disease Control and Prevention (CDC) is responsible for deciding who should get them and when. As soon as the FDA greenlights an XBB.1.5 vaccine, “I’m sure the ACIP will have a specially called meeting” to decide how it should be used, William Schaffner, MD, chair of the department of preventive medicine at the Vanderbilt University School of Medicine, said in an interview.
ACIP stands for the CDC’s Advisory Committee on Immunization Practices, on which Schaffner serves as the liaison representing the National Foundation for Infectious Diseases, where he is medical director. At the ACIP meeting on an XBB.1.5 vaccine, “I think there will be a rather elaborate discussion on who will receive this vaccine,” Schaffner predicted.
The Whats of an XBB.1.5 Vaccine
Current bivalent COVID-19 vaccines take aim at the ancestral SARS-CoV-2 strain, first identified in December 2019 and targeted by the original monovalent vaccines, and the BA.4 and BA.5 Omicron subvariants, whose spike proteins are identical.
Even before the bivalent vaccines became available last September, though, the ancestral SARS-CoV-2 strain had disappeared, edged out by a Greek alphabet of variants leading up to Omicron and its offspring.
“The virus has continued to evolve…really since the beginning of the pandemic,” CDC scientist Natalie Thornburg, PhD, noted at the VRBPAC meeting.
However, given that the original monovalent vaccines still protected against severe illness and death and that the virus’ trajectory was unpredictable, the VRBPAC and the FDA in June 2022 concluded that it would be wise to keep targeting the ancestral strain as well as the newer Omicron subvariants in a bivalent vaccine.
But less than a year after the bivalent vaccine debuted, BA.4 and BA.5 also dropped out of circulation among humans, and chances are those subvariants are never coming back, Kanta Subbarao, MD, MPH, director of the World Health Organization’s (WHO) Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia, told the advisory committee members.
Meanwhile, she said, research has shown that among people who received 3 doses of the original monovalent vaccine against ancestral SARS-CoV-2, only those who also received the bivalent vaccine or became infected with the Omicron variant produced protective antibodies against XBB subvariants. Even so, the levels of protective antibodies induced by the bivalent vaccine were lower against XBB subvariants than against other Omicron subvariants, she noted.
The T-cell response also factors in, though. It’s thought to be responsible for longer-lasting protection against serious illness and death from COVID-19. “We all acknowledge that neutralizing antibody is a very important correlate of protection, but it doesn’t tell the whole story,” Subbarao noted at the VRBPAC meeting.
However, FDA scientist Jerry Weir, PhD, told committee members, higher levels of neutralizing antibodies correlated with higher levels of protection with all spike-based COVID-19 vaccines.
“This is still the strongest marker that we have that is useful for evaluating vaccine selection,” he said. “I would love to be standing here next year telling you we have more information about T-cell responses and what correlates with protection.”
But, he reminded the group, studying the T-cell response is more challenging than studying the antibody response generated by the vaccines.
Preclinical data for XBB monovalent vaccines developed by Moderna, Novavax, and Pfizer suggest that including the ancestral SARS-CoV-2 is unlikely to enhance the immune response to currently circulating subvariants, Weir said.
Because the ancestral virus and antigenically closely related variants no longer circulate in humans, the WHO’s Technical Advisory Group on COVID-19 Vaccine Composition, which Subbarao chairs, in May recommended moving away from including the original SARS-CoV-2 in vaccine formulations. Instead, the group advised that new COVID-19 vaccines should induce neutralizing antibodies against XBB subvariants.
Back in March and the first half of April, XBB.1.5 represented more than 80% of circulating SARS-CoV-2 in the US, according to CDC estimates. Its dominance began to slip in late April, and as of late June, XBB.1.5 represented little more than a quarter of circulating SARS-CoV-2 variants. By then, though, XBB.1.5 and 9 other XBB subvariants together accounted for a total of 96% of circulating SARS-CoV-2 in the US. Fortunately, members of the XBB family of subvariants are antigenically similar to each other, so a vaccine against XBB.1.5 should protect against the rest of them as well, the WHO committee noted.
Eliminating ancestral SARS-CoV-2 from COVID-19 vaccines increases the concentration of antigens for the new subvariants, possibly raising the magnitude of the humoral response, which leads to antibody production, the WHO committee pointed out.
Another benefit of moving on from the bivalent vaccine: repeated exposure to the ancestral SARS-CoV-2 spike through vaccination may reduce immune responses to new target antigens, an effect called immune imprinting. While there is in vitro evidence of immune imprinting, its clinical impact remains unclear, Subbarao told the FDA advisory committee members.
The Whos of an XBB.1.5 Vaccine
What a difference 3 years and a few months make.
“We’ve really seen a changing landscape in the immune history of our population,” the CDC’s Thornburg noted at the VRBPAC meeting.
In slides presented at ACIP’s June meeting, held a week after the VRBPAC endorsed an XBB monovalent vaccine, CDC medical epidemiologist Jefferson Jones, MD, MPH, pointed out that the proportion of people with immunity from infection or a combination of infection and vaccination has increased over time.
The combination, known as hybrid immunity, likely protects better against infection and severe disease from Omicron than either vaccination or previous infection alone, Jones concluded.
“There are data [showing] that hybrid immunity is better, but why it’s better is still up for grabs,” VRBPAC member Mark Sawyer, MD, said in an interview.
By the third quarter of 2022, an estimated 96.4% of approximately 143 000 blood donors in a nationwide, longitudinal cohort had SARS-CoV-2 antibodies from previous infection or vaccination or both, according to an analysis published in June in Morbidity and Mortality Weekly Report.
Or, as Sawyer told JAMA, “[t]he whole US has had this virus in one form or another.”
Because of the high prevalence of SARS-CoV-2 antibodies in the population, Paul Offit, MD, in an interview predicted “a focused recommendation by the CDC” regarding who should receive the XBB.1.5 vaccine.
The US was the only country last year to recommend COVID-19 boosters for everyone 6 months or older, pointed out Offit, who is a VRBPAC member, a coinventor of the rotavirus vaccine, and chair of vaccinology at the University of Pennsylvania’s Perelman School of Medicine.
Offit said he expects that the CDC will recommend the new monovalent XBB.1.5 vaccine for groups at the greatest risk for severe disease, reflected in continuing hospitalizations for COVID-19. Those groups likely would include people who are 75 years or older, people with severely compromised immune systems, and pregnant people, Offit said.
The Whens of an XBB.1.5 Vaccine
At their June 15 meeting, some VRBPAC members questioned the FDA’s use of such terms as “periodic updated COVID-19 vaccines” and “the 2023-2024 vaccination campaign” when describing the discussion topic. Such language suggested that COVID-19 is a seasonal respiratory virus like influenza, necessitating a dose of vaccine every year, the panelists pointed out.
Sawyer, professor of pediatrics at the University of California, San Diego, and Rady Children’s Hospital, was one of them. “To me, it was a little premature to jump to seasonal” to describe COVID-19, he explained.
True, he said, “other coronaviruses are generally seasonal with a peak in the winter, as are most respiratory viruses.” And, he noted, COVID-19 “was more active this past winter and early spring than…it is right now.”
But only time will tell if SARS-CoV-2 is seasonal, Sawyer said. “This virus has behaved very differently from anything we’ve ever experienced before,” he noted. “Any predictions are a little bit squishy.”
Although it’s clear that “COVID is not nearly as seasonal as influenza,” Schaffner said, he recognizes that the FDA would like to make getting a COVID-19 shot as routine as getting a flu shot.
At least for people 60 years or older, the fall vaccine situation will be more complicated than it was a year earlier, Schaffner noted. That’s because at its regular monthly meeting in June, ACIP voted to recommend that this age group have the option of being vaccinated against respiratory syncytial virus (RSV) after consulting with their physician or pharmacist.
The FDA approved the first 2 RSV vaccines for older adults in May. Like influenza, RSV is seasonal, and manufacturer GSK told ACIP members that its RSV vaccine, called Arexvy, provided protection over 2 RSV seasons in a phase 3 trial, suggesting that older adults would need to be vaccinated every other year instead of annually.
“This is a population that is more accepting of vaccines,” Schaffner acknowledged. For example, people 65 years or older were more likely to get the bivalent COVID-19 vaccine than younger individuals, according to the CDC, which posted its last update on vaccine uptake May 11, the day the federal COVID-19 public health emergency ended. At that point, 43.3% of those 65 years or older had received a bivalent shot compared with only 17% of all eligible people.
“Nonetheless, 3 vaccines this fall? That is going to be a huge challenge,” Schaffner said. One likely reason that ACIP didn’t make a blanket recommendation for everyone 60 years or older to get an RSV shot this fall was because more data are needed about administering it with other vaccines, he said.
In slides presented at the ACIP meeting, CDC medical officers noted that clinical trial data are available only for coadministration of RSV and influenza vaccines. Data are lacking on coadministration of RSV with other vaccines recommended for older adults, including COVID-19 vaccines.
At the VRBPAC meeting, Peter Marks, MD, MPH, director of the FDA’s Center for Biologics Evaluation and Research, seemed to suggest that relatively few people opted to get the bivalent vaccines because the agency had authorized them only for emergency use and not fully licensed them.
Despite the end of the public health emergency, the FDA can still authorize emergency use of vaccines and treatment, Marks noted. However, he added, “[w]e do understand that having licensed products increases public confidence,” so “it is our intent to move many of these to licensed products.”
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