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[JAMA医学新闻]:决定是否以及何时更新疫苗以保护新冠病毒变异株感染所面临的挑战
2022年08月11日 研究点评, 进展交流 暂无评论

Medical News & Perspectives 

June 1, 2022

Challenges of Deciding Whether and How to Update COVID-19 Vaccines to Protect Against Variants

Rita Rubin

JAMA. Published online June 1, 2022. doi:10.1001/jama.2022.9367

Seasonal influenza vaccines are updated every year, depending on what strains are circulating globally, leaving many people—especially those who still contracted COVID-19 after 2 booster shots—wondering why vaccines against SARS-CoV-2 haven’t changed as variants have come and gone.

Currently available COVID-19 vaccines are based on the spike protein of Wuhan-Hu-1, the prototype SARS-CoV-2 virus. But the virus has changed significantly since Wuhan-Hu-1 was sequenced in January 2020, with variants of concern ranging from Alpha to Omicron.

Omicron, and especially its subvariants, is so different from Wuhan-Hu-1 that it is most adept at evading the immune response generated by current vaccines. Even so, studies have shown that the prototype COVID-19 vaccines still reduce the risk of serious illness and death from Omicron.

Updating COVID-19 vaccines is easier said than done, and some observers question whether it’s the best way to tackle the unpredictable, ever-changing virus. To help sort out the matter, the US Food and Drug Administration (FDA) convened its Vaccines and Related Biological Products Advisory Committee (VRBPAC) on April 6 to examine general considerations for future COVID-19 vaccine boosters and has scheduled a follow-up meeting on June 28 to discuss the possibility of changing the composition of SARS-CoV-2 vaccines to better protect against variants.

“I don’t think it’s as simple as: ‘There’s a new variant so let’s make a new vaccine,’” Kanta Subbarao, MBBS, MPH, director of the World Health Organization’s (WHO’s) Collaborating Centre for Reference and Research on Influenza in Melbourne, said in an interview.

In a May 2 JAMA Viewpoint, FDA officials called circulating SARS-CoV-2 “the new normal,” likely requiring consideration of annual updates of COVID-19 vaccines, as is done with influenza vaccines. “[A] greater depth and duration of protection might be achieved with a vaccine covering currently circulating variants,” wrote coauthors Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research (CBER); Principal Deputy Commissioner Janet Woodcock, MD; and Commissioner Robert Califf, MD.

But influenza viruses were first isolated in the 1930s, and the first influenza vaccines were licensed in the 1940s, so scientists, vaccine manufacturers, and regulatory agencies have had decades to figure out the immunization strategy for that disease.

“The challenge is we don’t know the rules of how this virus [SARS-CoV-2] behaves. For seasonal flu, we know the rules,” John Beigel, MD, associate director for clinical research in the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), explained in an interview. “Omicron kind of came out of nowhere. A year ago, we wouldn’t have predicted something like Omicron.”

One thing for sure, VRBPAC member Paul Offit, MD, said in an interview, boosting people every 6 months “is not a reasonable public health strategy.” Indeed, as of May 22, only 20% of US adults 50 years of age or older, for whom second boosters are recommended, had received one, according to the US Centers for Disease Control and Prevention (CDC).

COVID-19 Is Not the Flu

The WHO conducts influenza surveillance 24/7 year-round.

Twice annually, in February for the Northern Hemisphere and in September for the Southern Hemisphere, the WHO convenes a panel of experts to review the surveillance data to see whether new influenza strains are circulating and infecting people.

If so, the panel must decide whether current vaccines protect against the new circulating strains and, if not, whether the vaccines need to be updated with antigens that are a better match. About a week after that decision is made, the FDA convenes VRBPAC to make recommendations for the composition of US vaccines for the upcoming flu season.

Determining the composition of the vaccine must be done months in advance of flu season to give manufacturers enough time to produce tens of millions of doses.

When the vaccine is well-matched to circulating viruses, it is approximately 60% effective for the overall population, the FDA’s Jerry Weir, PhD, director of the Division of Viral Products in CBER’s Office of Vaccine Research and Review, told VRBPAC panelists at their April meeting.

Sometimes the vaccine isn’t well-matched, though. For example, preliminary, interim estimates for the 2021-2022 flu season show that the vaccine didn’t reduce the risk of mild or moderate illness from influenza A viruses, according to the CDC.

Reasons vary for why the flu vaccine might not be well-matched, Weir explained at the VRBPAC meeting. Sometimes antigenically distinct viruses emerge after the vaccine composition has been decided, such as the 2009 H1N1 pandemic virus, which required development of a supplemental vaccine against the pandemic strain. Sometimes manufacturing issues can’t be resolved in time to produce a well-matched vaccine, Weir said.

And that’s with a vaccine against a virus that has a long track record.

Updating vaccines against SARS-CoV-2 presents special challenges, Weir noted at the VRBPAC meeting. While most influenza vaccines have similar platforms with similar time frames needed for updating them, that’s not the case with COVID-19 vaccines, he pointed out. Not only do COVID-19 vaccine platforms differ from each other, but there’s been no coordination among manufacturers, who are at various stages in clinical trials with updated vaccines of varying compositions, Weir said.

Although some manufacturers are considering a combination annual vaccine against both COVID-19 and seasonal influenza, “it’s premature to combine them,” Subbarao told JAMA. “We don’t know how often we’ll have to vaccinate against COVID.” Plus, she said, whether SARS-CoV-2 follows the same seasonal pattern as influenza isn’t yet clear. Although transmission has appeared to be greatest during the winter in temperate climates, that could be due to people spending more time indoors, not because more virus is circulating, Subbarao said.

Subbarao chairs the WHO’s recently assembled 18-member Technical Advisory Group on COVID-19 Vaccine Composition; her vice chair is David Wentworth, PhD, chief of the Virology, Surveillance, and Diagnosis Branch of the CDC’s Influenza Division.

The advisory group will recommend methods to assess the impact of variants of concern on COVID-19 vaccines, interpret available evidence on the effects of those variants on vaccines, and provide guidance on whether vaccine composition should be adjusted to protect against variants of concern, Subbarao told VRBPAC members at their April 6 meeting.

If the FDA decides to grant Emergency Use Authorization (EUA) of investigational vaccines that contain antigenic material from SARS-CoV-2 variants, manufacturers may be hard-pressed to manufacture enough doses to meet demand by the fall. (Given the relatively low number of people who’ve received a second booster, just what the demand might be for a third one represents another as-yet unanswered question.)

“It’s not hard to change it,” Beigel said of current COVID-19 vaccines. “It’s hard to scale it and deliver 100 million doses.”

Asking Too Much?

Although he’s 71 and, therefore, eligible for a second booster shot, Offit, chair of vaccinology at the University of Pennsylvania’s Perelman School of Medicine, hasn’t yet opted to get one. He’s healthy, and research has clearly shown that 3 doses would reduce the risk of serious illness if he were to contract COVID-19, he explained.

Offit, citing a lack of evidence showing that an Omicron-based booster would provide more protection than the prototype vaccines do, said, “I don’t understand the thinking behind it.”

By adding a booster against variants to the vaccine arsenal, “What are you really doing for the pandemic: Protecting people who are already protected?” Offit asked. A wiser investment would be to ship the prototype vaccines overseas to vaccinate the unvaccinated, he said.

Protection against serious illness isn’t enough for many people, Offit acknowledged. Concerned about the possibility of long COVID, many people don’t want to get infected with SARS-CoV-2, period, he said, adding that he’d like to see more rigor in defining long COVID.

Offit questioned whether preventing infection completely was an attainable goal for vaccines against SARS-CoV-2.

“Is it realistic to expect that we can protect against all illness with this virus?” Offit asked. “I feel like this is much ado about little. This is not flu. You get a flu vaccine every year because you’re still not protected against serious disease” even if vaccinated the previous year. If the goal is to prevent all SARS-CoV-2 infections, even the mild ones, “I think we’re going to drive ourselves a little crazy,” he said.

Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, is the coinventor of a vaccine to protect against rotavirus, a common cause of severe diarrhea, vomiting, fever, and abdominal pain in infants. Like SARS-CoV-2, rotavirus is a mucosal infection with a short incubation period, giving vaccine-generated immunity a relatively brief window of opportunity to completely block infection.

Infants vaccinated against rotavirus still sometimes get mild disease, just as people vaccinated against SARS-CoV-2 can still get sick with COVID-19, Offit explained. In contrast, measles is a viral infection with an average incubation period of 11 or 12 days—more than twice that of SARS-CoV-2. On top of that, there’s only 1 antigenic type of measles, which has barely changed over time, so vaccine-induced immunity against it is thought to be lifelong.

By expecting the same from COVID-19 vaccines as from measles vaccines, “we’re setting [COVID-19] vaccine up for failure,” Offit said. The wording used to describe SARS-CoV-2 infections in vaccinated and boosted individuals hasn’t helped lower expectations for COVID-19, he added. “We damned it when we used the term ‘breakthrough infection.’”

Still, Subbarao—echoing a March 8 statement from her WHO vaccine composition committee—told VRBPAC members at their April 6 meeting, “We do need to encourage the development of COVID-19 vaccines that will have an impact on prevention of infection and transmission, in addition to protecting against severe illness and death.”

SARS-CoV-2 Vaccine 2.0

Developing variant-based injectable vaccines might seem like a game of whack-a-mole.

Targeting Omicron with a vaccine assumes that there will be an Omicron resurgence, but by the time such a vaccine is ready to be used, the circulating variant could be Beta or Delta, both significantly different from Omicron and Alpha, Beigel told VRBPAC members.

A multivalent COVID-19 vaccine, containing antigens from multiple SARS-CoV-2 variants of concern, would be the next step after a monovalent vaccine, but, as with the quadrivalent seasonal flu vaccines, manufacturers would have to prove that antigens from multiple variants combined were just as immunogenic as each alone, Subbarao said.

To cover as many bases as possible, vaccine makers have set their sights on multivalent COVID-19 vaccines, Robert Johnson, PhD, director of Medical Countermeasure Programs at the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), said in an interview. (BARDA has partnered with companies and funded manufacturing, development, and procurement of 6 COVID-19 vaccines, including the 3 available in the US.)

Multivalent vaccines against numerous varieties of a virus aren’t unprecedented, he noted; human papillomavirus (HPV) vaccines contain antigenic material for multiple HPV strains (for example, human papillomavirus 9-valent vaccine, recombinant, marketed as Gardasil, targets 9 disease-causing HPV strains). However, Johnson pointed out at the April 6 VRBPAC meeting, it will take manufacturers longer to produce a multivalent vaccine than a monovalent vaccine.

Meanwhile, the NIAID is conducting a phase 2 trial, the COVID-19 Variant Immunologic Landscape (COVAIL) study, to compare different vaccine regimens in adults who’ve already received their primary COVID-19 vaccination and a booster.

The open-label COVAIL trial began enrolling participants in early April. As of mid-May, it consisted of 12 groups that are testing, singly and combined, Moderna’s and Pfizer-BioNTech’s prototype messenger RNA vaccines and the companies’ Beta, Delta, and Omicron variant–based investigational vaccines. Researchers will compare the innate, cellular, and humoral immune responses of each group to help figure out how best to cover new variants as they emerge.

The Road Not Taken

Instead of trying to smack down 1 variant just as another pops up, researchers and funders should prioritize creating nasal vaccines and pan–SARS-CoV-2 or even pan-sarbecovirus (the viral subgenus that contains SARS-CoV-2 and SARS-CoV) vaccines, some scientists say. Both types of vaccines are in early clinical trials.

A nasal vaccine could stop SARS-CoV-2 in its tracks, and a pan–SARS-CoV-2 or pan-sarbecovirus vaccine could generate an immune response to current SARS-CoV-2 variants and those yet to come.

“The enemy has evolved, and the world needs next-generation vaccines to respond,” Yale School of Medicine immunology professor Akiko Iwasaki, PhD, who is working on a COVID-19 nasal vaccine, wrote May 16 in the New York Times.

Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine and codirector of the Texas Children’s Hospital Center for Vaccine Development, tweeted May 22 that he has asked the White House COVID-19 team “to explore alternative strategies or technologies to provide longer-lasting protection for years” because, he explained, he thinks public acceptance of another booster in the fall will be “quite low.” (Hotez’s lab developed the technology, which is owned by Baylor, for Corbevax, a low-cost protein subunit COVID-19 vaccine that has received EUA in India.)

Omicron-based boosters are a “done deal,” though, because Moderna and Pfizer-BioNTech have already invested heavily in them, Eric Topol, MD, founder and director of the Scripps Research Translational Institute, said in an email. And yet, he pointed out in a May 15 online column, those boosters are directed against BA.1, the original flavor of Omicron, and might not be as effective against newer Omicron subvariants or other SARS-CoV-2 variants yet to come.

“Before that effort was launched,” Topol told JAMA, referring to the development of Omicron-based boosters, “I do believe strong consideration and priority should have been given to nasal/oral and pan-betacoronavirus vaccines.

“We’ve learned that the time it takes to get a new bivalent vaccine tested and an EUA, no less the resources expended, might, in the future, be directed to variant-proof efforts that are in our reach.”

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