Virus World

President Biden cautioned that the immunocompromised are at heightened risk this winter and should talk to their physician about precautions.

• Omicron subvariants are reducing the effectiveness of antibody treatments that have played a crucial role in keeping people with weak immune systems safe.
• President Joe Biden cautioned the immunocompromised that they are at heightened risk this winter and should talk to their physician about what precautions to take.
• Dr. Ashish Jha, head of the White House Covid task force, said treatment options are dwindling for the vulnerable because Congress failed to pass more funding.

Emerging omicron subvariants are resistant to key antibody treatments for HIV patients, kidney transplant recipients and other immunocompromised people, making them particularly vulnerable to Covid this winter, the White House warned this week. “With some of the new subvariants that are emerging, some of the main tools we’ve had to protect the immunocompromised like Evusheld may not work moving forward. And that’s a huge challenge,” Dr. Ashish Jha, head of the White House Covid task force, told reporters on Tuesday.  President Joe Biden on Tuesday cautioned the estimated 7 million adults in the U.S. who have compromised immune systems that they are particularly at risk, but he could offer little in the way of reassurance other than telling them to consult their physician about what precautions to take. “New variants may make some existing protections ineffective for the immunocompromised,” the president said before getting his booster Tuesday. “Sadly, this means you may be at a special risk this winter. I urge you to consult your doctors on the right steps to protect yourself, take extra precautions.” The message clashes with repeated White House assurances that the U.S. has all the vaccines and treatments it needs to fight Covid this winter as public health officials are expecting another surge. While this may be true for the general population, it is not the case for people with weak immune systems. They include those with cancer, those who have had organ transplants, people living with HIV and individuals who are taking medicine for autoimmune diseases.

Evusheld is an antibody cocktail authorized by the Food and Drug Administration to prevent Covid in people ages 12 and older who have moderately or severely compromised immune systems. The drug is administered as two injections, prior to infection, every six months. Evusheld, made by AstraZeneca, has helped fill a gap in protection for those with weak immune systems who cannot mount a strong response to the vaccines. The drug, plus several rounds of vaccination, has led to significant declines in hospitalization among this cohort over the past several months, according Camille Kotton, an infectious disease expert who specializes in treating people with weak immune systems.

“We’ve been in a sweet spot for maybe several months now as far as immunocompromised patients having good protection and then good treatment options,” said Kotton, a physician at Massachusetts General Hospital and a member of the Centers for Disease Control and Prevention’s independent vaccine advisory committee. But more immune evasive omicron subvariants such as BA.4.6, BA.2.75.2, BF.7, BQ.1 and BQ.1.1 are resistant to Evusheld, according to the National Institutes of Health. Scientists at Columbia University, for example, found Evusheld had completely lost its effectiveness against BA.4.6. And BQ.1 and BQ.1.1 are likely resistant to bebtelovimab, the monoclonal antibody developed by Eli Lily to prevent people with compromised immune systems who catch Covid from developing severe disease, according to NIH. That leaves people with compromised immune systems increasingly vulnerable as these subvariants increase in circulation in the U.S. As omicron BA.5 declines, this swarm of newer subvariants collectively make up about 38% of infections in the U.S., according to CDC data. Although Pfizer’s antiviral Paxlovid remains effective against the omicron subvariants, people who have had organ transplants often can’t take the pill because of the way it interacts with other drugs they need, Kotton said. “I’m concerned that the near future will be a challenging time for immunocompromised patients,” said Kotton. “The monoclonal antibodies in Evusheld are going to provide less protection and bebtelovimab is going to provide ineffective treatment for several of the emerging variants.”

And help is not on the way at the moment. Kotton said she’s not aware of any monoclonal antibodies that are ready to replace the ones the subvariants are chipping away at. Jha acknowledged at the White House on Tuesday that the U.S. has dwindling treatment and prevention options for people with weak immune systems as Covid evolves. He blamed Congress for failing to pass $22.5 billion in funding for the nation’s Covid response due to Republican opposition. “We had hoped that over time as the pandemic went along, as our fight against this virus went along, we would be expanding our medicine cabinet,” Jha told reporters. “Because of lack of congressional funding that medicine cabinet has actually shrunk and that does put vulnerable people at risk.” Andrew Pekosz, a virologist at Johns Hopkins University, said finding ways to protect people with compromised immune systems is the most critical issue of the pandemic right now and it needs to be addressed quickly. “What we need to really work on is getting new antibody treatments out of the lab and into clinics,” Pekosz said. “In the lab, scientists know what next-generation monoclonal antibodies look like.” Kotton said people with compromised immune systems should stay up to date on their vaccines, which means getting the new booster that targets omicron BA.5. Those who have stayed up to date throughout the pandemic have received six shots by now. Those starting from scratch would receive a three-dose primary series of Moderna or Pfizer with the older generation shots and then a new booster that targets omicron, according to CDC guidelines.

People with compromised immune systems should continue to exercise caution this winter, because the immune-resistant omicron subvariants could pick up in circulation as people gather for the holidays, Kotton said. But she noted that the group has been more diligent in wearing masks and practicing mitigation measures to avoid the virus than the rest of the population. The bigger problem is that the general population has largely moved on and is no longer taking basic precautions that could reduce transmissions and protect the vulnerable — such as wearing masks, Kotton said. “If we all were to mask more in public venues that would enhance the safety for them and allow them to have a higher likelihood of a safer return to many activities,” she said. Jha was asked by NBC News on Tuesday whether Biden telling people with weak immune systems to consult their physicians about precautions is an indication that the burden of responsibility has shifted to the individuals instead of the broader community. “As a society — as a caring society, we care about all Americans, particularly the most vulnerable Americans,” Jha said.  “So it remains, I think, a collective responsibility for all of us to care about our fellow Americans who are immunocompromised.” The CDC recommends that people in communities where the Covid risk level is moderate to self test and wear a high-quality mask before meeting indoors with someone who is at high risk of getting sick. Those who are at high risk should wear a high-quality mask when indoors in public. When the Covid level is high, people in general should consider wearing high-quality masks and the vulnerable should consider avoiding indoor activities in public that aren’t essential, according to CDC. You can check your county’s Covid level at the CDC’s website.

The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has splintered into multiple subvariants with increased transmissibility and immune escape.1 At the time of this report, omicron subvariant BA.5 is the dominant global virus and has shown substantial immune escape as compared with previous omicron subvariants.2-5 BA.4.6 is a sublineage of BA.4 with two additional mutations in the spike protein (R346T and N658S) (Figure 1A) and has recently increased in prevalence in certain regions currently dominated by BA.5, including in the United States. The ability of BA.4.6 to evade neutralizing antibodies that were induced by infection or vaccination remains to be determined.  We evaluated neutralizing antibody titers against five SARS-CoV-2 strains — WA1/2020 and omicron subvariants BA.1, BA.2, BA.4–BA.5, and BA.4.6 — in 19 participants who had been recently infected with the omicron BA.1 or BA.2 subvariant and in 16 participants who had been vaccinated and boosted with the original mRNA-1273 vaccine (Moderna) (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In the cohort with previous omicron infection, all the participants except for one had been vaccinated; samples were obtained a median of 21 days after diagnosis of omicron infection. In this cohort, the median pseudovirus neutralizing antibody titer was 42,067 against WA1/2020, 6352 against BA.1, 3854 against BA.2, 1673 against BA.4–BA.5, and 630 against BA.4.6 (Figure 1B). The median neutralizing antibody titers against BA.4.6 were lower than the median titers against WA1/2020 by a factor of 67, against BA.1 by a factor of 10, against BA.2 by a factor of 6, and against BA.4–BA.5 by a factor of 2.7.

In the mRNA-1273 vaccine cohort, participants were excluded if they had a known history of SARS-CoV-2 infection or positive results on nucleocapsid serologic analysis or if they had received immunosuppressive medications or other vaccines against SARS-CoV-2. Six months after the initial two mRNA-1273 immunizations, the median neutralizing antibody titer was 951 against WA1/2020, 28 against BA.2, 30 against BA.4–BA.5, and 23 against BA.4.6 (Figure 1C). At a median of 17 days after the first booster dose, the median neutralizing antibody titer was 16,011 against WA1/2020, 802 against BA.2, 449 against BA.4–BA.5, and 225 against BA.4.6. The median neutralizing antibody titer against BA.4.6 was lower than that against WA1/2020 by a factor of 71, against BA.2 by a factor of 4, and against BA.4–BA.5 by a factor of 2. Our data show that the BA.4.6 omicron subvariant markedly escaped neutralizing antibodies induced by infection or vaccination, with values that were lower than BA.5 titers by a factor of 2 to 2.7, which suggests continued evolution of SARS-CoV-2. These findings provide immunologic context for the increasing prevalence of BA.4.6 in populations in which BA.5 is currently dominant. Moreover, the R346T mutation had also recently been observed in other omicron subvariants, including BA.2.75 and BA.5, which suggests the biologic relevance of this mutation. The potential effect of the emergence of the BA.4.6 subvariant on vaccine boosters containing BA.5 immunogens or on infection with BA.5 remains to be determined.

Published in NEJM (Oct. 19, 2022):

https://doi.org/10.1056/NEJMc2212117 

Continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ. 1.1, BA.4.6, BF.7 and BA.2.75.2. Here we examine the neutralization resistance of these subvariants, as well as their ancestral BA.4/5, BA.2.75 and D614G variants, against sera from 3-dose vaccinated health care workers, hospitalized BA.1-wave patients, and BA.5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially the BQ.1 and BQ.1.1 subvariants driven by a key N460K mutation, and to a lesser extent, R346T and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation.

The BQ.1 and BQ.1.1 subvariants also exhibited enhanced fusogenicity and S processing dictated by the N460K mutation. Interestingly, the BA.2.75.2 subvariant saw an enhancement by the F486S mutation and a reduction by the D1199N mutation to its fusogenicity and S processing, resulting in minimal overall change. Molecular modelling revealed the mechanisms of receptor-binding and non-receptor binding monoclonal antibody-mediated immune evasion by R346T, K444T, F486S and D1199N mutations. Altogether, these findings shed light on the concerning evolution of newly emerging SARS-CoV-2 Omicron subvariants.

Preprint available in bioRxiv (October 20, 2022):

https://doi.org/10.1101/2022.10.19.512891