In mid-August, the Centers for Disease Control and Prevention (CDC) released new, streamlined public health guidelines for managing the COVID-19 pandemic, relaxing some previous guidance and signaling a shift in the pandemic.
With the help of vaccines, boosters, immunity from infection, and the availability of effective antivirals such as Paxlovid, the CDC reasons that the virus no longer poses a high risk of severe illness, hospitalization, and death for most people. The change in guidance places more emphasis on personal risk assessment and individual behavior modification, including staying up to date on vaccination, wearing a high-quality mask, and using prescription therapeutics if infected.
“This guidance acknowledges that the pandemic is not over, but also helps us move to a point where COVID-19 no longer severely disrupts our daily lives,” said Greta Massetti, PhD, MPH, a CDC epidemiologist, in a press release.
The current dominant COVID-19 subvariant in the United States, BA.5, may have proved less deadly than its predecessors, but it continues to spread wildly, infecting many, killing hundreds each day, and increasing the likelihood of new mutations.
AAMCNews spoke with infectious disease experts about this latest phase of the pandemic, the BA.5 subvariant, Paxlovid and “Paxlovid rebound,” newly formulated vaccines expected to arrive in September or October, and the threat of future mutations.
How is BA.5 different from previous variants?
This subvariant of omicron is the most transmissible version of the virus that causes COVID-19 yet, according to the CDC. It can also evade the immunity created by both the vaccines and previous infection due to a mutation in the spike protein. That’s the part of the virus that latches onto cells and is the target of most of the existing vaccines.
The good news, however, is that, despite the increase in infections (many of which are not recorded because of the prevalence of at-home testing), hospitalizations and deaths have remained low compared to during previous waves. In mid-August, less than two per million people in the United States died of COVID-19 each day, compared with more than seven per million when the original omicron peaked in February and 10 per million in January 2021 when the original virus was dominant, according to Our World in Data.
“This is what is referred to as uncoupling of death rate with infection rate,” says Alessandro Sette, Dr.Biol.Sci, an immunologist and professor at La Jolla Institute for Immunology in California. “It’s a sign of a building of walls of immunity in the general population.”
Even though BA.5 can evade some of the protection provided by neutralizing antibodies created by vaccination or prior infection, the immune system also has another line of defense known as cellular immunity. Once a virus has infected a cell, the body’s T-cells can recognize the infected cell and destroy it, preventing the infection from spreading and causing more serious disease.
“Almost everybody has some underlying immunity to COVID, either from vaccination or infection,” explains Anna Durbin, MD, a professor at Johns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health in Baltimore who specializes in infectious disease and vaccines. “This provides protection against more severe outcomes.”
However, a significant portion of the population remains vulnerable to severe disease and death if they are unvaccinated, older, or have compromised immune systems or other health conditions that put them at higher risk. An average of nearly 500 people a day were dying of COVID-19 as of mid-August.
Does the original vaccine still work against BA.5? Who should get a booster now?
The two mRNA vaccines produced by Moderna and Pfizer-BioNTech using the original SARS-CoV-2 virus have proved to be effective at reducing severe disease, even against omicron.
“The existing vaccines are doing an absolutely terrific job of keeping people out of hospital, out of ICU, and alive,” says Sten Vermund, MD, PhD, an infectious disease epidemiologist, and professor at the Yale School of Public Health and a pediatrician at Yale School of Medicine in New Haven, Connecticut.
While the effectiveness of the primary series (the first two shots) of the vaccines has dropped over time and with the emergence of new variants, the CDC has found that protection against hospitalization increased with each of the third and fourth doses in eligible populations, specifically those over the age of 50 or with health conditions putting them at higher risk of severe disease.
They’ve also proved to be very safe.
“By and large, they have not been associated with severe reactions,” says Kathryn Edwards, MD, a vaccinologist and professor of pediatrics at Vanderbilt University School of Medicine in Nashville, Tennessee. She leads the CDC-funded Clinical Immunization Safety Assessment unit, which is responsible for monitoring and reporting adverse reactions to the vaccines.
Edwards says that there were some instances of inflammation of the heart after vaccination, particularly in young men, but that the occurrence was less often seen as a result of vaccination than it was as a result of illness from COVID-19.
Though boosters have proved both safe and effective, many people in the United States have not gotten all the shots for which they are eligible.
While 92% of people over the age of 65 have gotten their primary vaccine series, only 70% have gotten a single booster and 40% have gotten a second booster, according to the CDC.
“Nobody should wait to take a booster if they are eligible,” Vermund says.
How will the updated vaccine work?
Under the direction of the Food and Drug Administration (FDA), Pfizer-BioNTech and Moderna have started clinical trials of bivalent vaccines targeting BA.4 and BA.5, which have nearly identical spike proteins. This means that the vaccine will be a mixture of the original vaccine and one that has been reformulated to target the mutated spike proteins of the now-dominant subvariants.
Without the inclusion of the original vaccine in these latest booster formulations, experts worried that earlier versions of the virus that are no longer dominant could resurface and once again drive up severe disease, Edwards explains. The tweaked formulation will likely also elicit the production of neutralizing antibodies that will more readily recognize and root out the BA.4 and BA.5 subvariants. Pfizer-BioNTech released data in June showing that a previous bivalent formulation targeting the omicron BA.1 subvariant increased neutralizing antibodies against that subvariant 10-fold compared to pre-booster levels, but found those antibodies were three times less effective against BA.4 and BA.5. Both companies are testing bivalent vaccines targeting BA.4 and BA.5 while simultaneously manufacturing millions of doses in anticipation of the FDA issuing emergency use authorization this fall. The U.S. government has agreed to purchase an initial 171 million doses, enough to vaccinate a little more than half the country’s population, with the option to purchase up to 600 million doses.
Vermund anticipates the new formulations to be more effective, not only at further reducing severe disease in high-risk patients, but also in lessening symptomatic illness for those infected.
“I’m very optimistic as to the biology [of the vaccine],” he says. “Where I’m less optimistic is whether people will take the vaccine. If you look at people 50 and over, more than a third have not even gotten a single booster.”
The U.S. Department of Health and Human Services has said that the new boosters could be available in early fall, though BioNTech more recently said October was the earliest deliveries could start.
Since it’s still unclear exactly when the new formulations will be available, and whether they will be rolled out in phases, Sette recommends eligible people get a third or fourth booster of the original vaccines if it’s been six months or more since their last shot or infection, rather than waiting for the new vaccines.
What is Paxlovid and who should take it?
Paxlovid is an oral antiviral that is approved under an FDA emergency use authorization to treat COVID-19 in people at high risk for severe illness, including those over the age of 65 and anyone with a serious medical condition. In its initial clinical trials, Paxlovid reduced the risk of hospitalization by 89% for high risk, unvaccinated patients.
The medication is available for free by prescription, should be taken within five days of developing symptoms, and is given in a five-day regimen. It works by inhibiting an enzyme the virus needs in order to replicate, preventing it from spreading and infecting more cells.
“Paxlovid is a very beneficial drug to decrease the severity of disease and reduce the length of time that someone is viremic,” Vermund says. “It’s an excellent tool for people at high risk.”
Those who qualify for the antiviral should get it as soon as possible, even if only experiencing mild symptoms — but younger and low-risk patients often don’t need it, he adds.
A small percentage of people who take Paxlovid initially recover but then have a “rebound” and test positive again. This is what happened to President Joseph R. Biden when he was recently infected with COVID-19 and took Paxlovid. While patients are contagious during the reemergence of the virus, symptoms often are mild, according to the CDC. One study that looked at electronic health records found that less than 6% of those who took Paxlovid had a rebound infection or symptoms. However, Paxlovid reacts badly with several common medications and can have unpleasant side effects, including impaired taste, nausea, and high blood pressure.
Keeping up with the virus
The virus that causes COVID-19 has mutated faster than many experts anticipated. Omicron is the 15th variant that the World Health Organization has recognized, and in the nine months since it was first identified it has yielded at least five subvariants. Already, another subvariant, BA.2.75 has taken hold in India, though it seems to be similar to BA.5 in its severity and ability to evade immunity.
This quick evolution has made vaccine development complicated. Because it takes time to develop, test, manufacture, and distribute a vaccine, the virus might mutate again by the time the vaccine is widely available.
“There was an updated vaccine including delta that had been developed and tested,” Sette says. “That has been scratched because delta is gone.”
While scientists work hard to map out the most likely evolutions to come, the process still involves a lot of guesswork, Edwards says.
And as the virus continues to mutate, it’s likely that new boosters will be needed every couple of years or whenever there is a new variant that is particularly problematic, Vermund says.
For now, Sette is hopeful that the updated vaccine will provide a broad enough immune response that it will hold up against even the next variant to emerge. He also says the virus seems to be evolving in a direction that is likely to make it more like a common cold.
“But this situation could change in the blink of an eye if there is a new variant,” he adds.
“As with all things COVID, we don’t want to get ahead of ourselves,” Durbin says.
The key at this stage of the pandemic, she says, is to be aware of personal risk and take appropriate protective measures.
She personally feels safe traveling, but continues to wear a mask in the airport, on planes, and in any crowded, public place.
And even for those at low risk of severe disease, staying up to date with vaccine coverage is important to controlling the pandemic long term by reducing transmission and maintaining the wall of immunity that is keeping people out of the hospital.
The new vaccines “are another brick in the wall,” Sette says.