Virus World

The 20-month-long infection is the longest known and highlights how prolonged infections enable the pandemic virus to accumulate genetic changes—potentially spawning new variants of concern. A Covid-19 patient with a weakened immune system incubated a highly mutated novel strain over 613 days before succumbing to an underlying illness, researchers in the Netherlands found. The patient, a 72-year-old man with a blood disorder, failed to mount a strong immune response to multiple Covid shots before catching the omicron variant in February 2022. Detailed analysis of specimens collected from more than two dozen nose and throat swabs found the coronavirus developed resistance to sotrovimab, a Covid antibody treatment, within a few weeks, scientists at the University of Amsterdam’s Centre for Experimental and Molecular Medicine said. It later acquired over 50 mutations, including some that suggested an enhanced ability to evade immune defenses, they said.

The 20-month-long SARS-CoV-2 infection is the longest known, according to the researchers, who are presenting the case at a medical meeting in Barcelona next week. While his mutant virus wasn’t known to have infected other people, it highlights how prolonged infections enable the pandemic virus to accumulate genetic changes, potentially spawning new variants of concern. “This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals,” the authors said. “We emphasize the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections.” Scientists studying genomic data collected from wastewater samples have reported evidence of individuals in the community shedding heavily mutated coronaviruses for more than four years. Such persistent infections may also be causing patients to experience long Covid symptoms, research suggests.

Analysis of hundreds of mpox patients suggests it is “a different disease” in those with compromised immune systems. In June 2022, a young man in his 30s severely sick with mpox, the viral disease formerly known as monkeypox, was admitted to the Salvador Zubirán National Institute of Health Sciences and Nutrition hospital in Mexico City. Tests showed the patient was also HIV-positive, which he had not known, and that his blood had few CD4 cells, critical immune cells that HIV attacks. The man’s immune system was so weak it could not keep mpox in check and painful lesions kept spreading across his body, eating away at, or necrotizing, the flesh, according to HIV researcher Brenda Crabtree Ramirez, who was on his care team. Then the virus spread to his lungs, too. “He just kept getting worse and worse and worse,” she says. With no treatments available, his doctors got the hospital’s ethics board to approve a desperate plan: They would transfer blood plasma from a colleague who had been vaccinated in the United States against mpox to the patient, in the hope that the antibodies from the donation might help fight his infection with the poxvirus. The experimental therapy failed—the man died 2 weeks later, one of the first deaths from the disease in Mexico. Although mpox cases have plummeted globally since then, the outbreak still simmers in Latin America and other locations. The World Health Organization (WHO) last week reaffirmed that the disease remains a global emergency. And a grim report today in The Lancet and being presented at a conference in Seattle, which analyzes the death last summer in Mexico and the cases of 381 other mpox patients who also had advanced HIV infections, makes clear the disease poses an enormous risk to those living with uncontrolled HIV. Of the 179 patients with less than 200 CD4 cells per microliter—more than 500 is considered normal—27 died.

Mpox isn’t just more severe in these immunocompromised patients, says Oriol Mitjà, an infectious disease researcher at the Germans Trias i Pujol University Hospital in Barcelona and one of the study authors. “It’s like a different disease.” In the cases where people had few CD4 cells, mpox’s normally small skin lesions grew into large necrotizing patches and their infection sometimes spread to the lungs or caused severe secondary infections with bacteria. Mitjà, Crabtree Ramirez, and their colleagues argue this disseminated form of mpox should be added to the list of AIDS-defining conditions, opportunistic secondary infections that are a typical sign of advanced HIV infection. That might alert physicians to test mpox patients for HIV to be able to prioritize them for any possible treatments. Health authorities should also prioritize people living with HIV for mpox vaccination, Mitjà says. But the Lancet report also contained a warning for physicians: Starting coinfected patients on antiretrovirals for their HIV infection could worsen their mpox. The data presented in the Lancet report are compelling and WHO plans to assemble a group to consider the research team’s recommendation to make mpox an AIDS-defining condition, says Meg Doherty, who heads the program for HIV and other sexually transmitted infections at the agency. In some ways the world may have been lucky with the strain of mpox virus that has been spreading globally. The two types previously known from cases in Africa were thought to kill 10% and 1% of patients, respectively.

The current outbreak strain has infected more than 85,000 people globally, predominantly affecting gay men and their sexual networks, and caused fewer than 100 deaths, or a mortality rate of about 0.1%. A paper published last week in the Proceedings of the National Academy of Sciences found that in a particular strain of laboratory mice, this virus, known as clade IIb, is far less deadly than its relatives. “We were unable to cause the mice to be sick even at 100 times the lethal dose [for the current strain],” says Bernard Moss, a poxvirus researcher at the U.S. National Institute of Allergy and Infectious Diseases and one of that study’s authors. But the Lancet paper, which covers more than one-quarter of all known mpox deaths for the clade IIb strain, shows the virus can still cause devastating disease in a particularly vulnerable group of people. Men who have sex with men are much more likely to acquire an HIV infection, but are also less likely in most parts of the world to have access to HIV testing and treatment, notes Gregg Gonsalves, a Yale School of Public Health epidemiologist and former HIV activist. “This creates a dangerous situation, in which our failures to address the AIDS epidemic among this population now may create new risks” for this group, he says. The Lancet report also revealed an important dilemma for physicians caring for these coinfected people. When those with untreated HIV were given antiretrovirals, one-quarter of them seemed to develop a condition in which the recovering immune system responds to the opportunistic infection—mpox in this case—with an overzealous inflammatory response. More than half the patients suspected to have this overreaction, known as immune reconstitution inflammatory syndrome, died. “We are grappling with these scenarios and clinicians do not know what the best approach is at this time,” says Boghuma Titanji, a virologist at Emory University who was not involved with the study.

The milder clinical manifestations of Omicron infection relative to pre-Omicron SARS-CoV-2 raises the possibility that extensive evolution results in reduced pathogenicity. To test this hypothesis, we quantified induction of cell fusion and cell death in SARS-CoV-2 evolved from ancestral virus during long-term infection. Both cell fusion and death were reduced in Omicron BA.1 infection relative to ancestral virus. Evolved virus was isolated at different times during a 6-month infection in an immunosuppressed individual with advanced HIV disease. The virus isolated 16 days post-reported symptom onset induced fusogenicity and cell death at levels similar to BA.1. However, fusogenicity was increased in virus isolated at 6 months post-symptoms to levels intermediate between BA.1 and ancestral SARS-CoV-2. Similarly, infected cell death showed a graded increase from earlier to later isolates. These results may indicate that, at least by the cellular measures used here, evolution in long-term infection does not necessarily attenuate the virus.

Preprint available at medRxiv (Nov. 24, 2022):

 https://doi.org/10.1101/2022.11.23.22282673 

Reports of myocarditis, penile necrosis, and atypical/persistent rash requiring amputation.  Be alert for potentially severe manifestations of monkeypox in patients who are immunocompromised or co-infected with HIV, the CDC told healthcare workers on Thursday. "People who are immunocompromised due to HIV or other conditions are at higher risk for severe manifestations of monkeypox than people who are immunocompetent," the agency said in a health advisory to its Health Alert Network, adding that "the HIV status of all sexually active adults and adolescents with suspected or confirmed monkeypox should be determined."  Of the patients with severe manifestations "for whom CDC has been consulted," the majority had HIV with CD4 counts below 200 cells/mL, indicating "substantial immunosuppression," the agency noted. These severe manifestations have included cases involving atypical or persistent rash requiring amputation of an extremity; secondary bacterial or fungal infections; lesions in sensitive areas resulting in severe pain or urethral or bowel strictures; and comorbidities involving organ systems, including myocarditis, transverse myelitis, bowel lesions, penile necrosis, and others. The news arrives as the U.S. records its third known monkeypox-associated death in Ohio. To date, over 25,000 monkeypox cases have been reported in the U.S., 38% of which involved patients co-infected with HIV. Researchers have highlighted monkeypox severity and outcomes in people with HIV before.

For example, a study in The Lancet about a 2017-2018 monkeypox outbreak in Nigeria reported seven deaths in a population of 122 patients, with four of the seven co-infected with HIV.  More recently, papers on the current outbreak have reported conflicting results about the association between monkeypox severity and HIV co-infection. CDC data involving more than 1,300 monkeypox patients showed a higher rate of hospitalizations for those with HIV (8% vs 3% for those without HIV), with higher rates for those whose HIV was not virally suppressed. Conversely, German researchers reported that the clinical characteristics in HIV-infected versus non-infected monkeypox patients were largely similar. The new CDC advisory recommends that monkeypox treatment include optimization of immune function for people with immunocompromising conditions, such as limiting the use of immunosuppressive medications when "not otherwise clinically indicated," and offering antiretroviral therapy for those living with HIV. 

Severe immunocompromising conditions can including those with autoimmune disease where immunodeficiency is a clinical component; leukemia or lymphoma, transplant recipients; and those treated with high-dose steroids, alkylating agents, antimetabolites, radiation, or tumor necrosis factor (TNF) inhibitors.  On a case-by-case basis, medications such as oral and intravenous tecovirimat (Tpoxx), cidofovir or brincidofovir, and vaccinia immune globulin intravenous should be considered, "although there are no data on effectiveness in treating human monkeypox with these medical countermeasures," according to the CDC. Clinicians should gather repeat lesion swabs in patients with persistent monkeypox DNA, and continue tecovirimat beyond 14 days (but not more than 90 days), "until there is clinical improvement," the advisory stated. Modifications to the dose, frequency, and duration of tecovirimat may be necessary, depending on the patient's clinical condition, disease progression, or therapeutic response. The advisory encouraged clinicians to consult with the CDC Monkeypox Response Clinical Escalations team when appropriate.  The following severe manifestations seen in monkeypox patients were reported to the CDC, although the advisory did not include information about HIV status:

• Atypical or persistent rash with coalescing or necrotic lesions, or both, some of which have required extensive surgical debridement or amputation of an affected extremity

• Lesions on a significant proportion of the total body surface area, which may be associated with edema and secondary bacterial or fungal infections among other complications

• Lesions in sensitive areas (including mucosal surfaces such as the oropharynx, urethra, rectum, and vagina) resulting in severe pain that interferes with activities of daily living

• Bowel lesions that are exudative or cause significant tissue edema, leading to obstruction

• Severe lymphadenopathy that can be necrotizing or obstructing (such as in airways)

• Lesions leading to stricture and scar formation resulting in significant morbidity such as urethral and bowel strictures, phimosis, and facial scarring

The CDC advisory also noted reports of individuals with severe monkeypox involving multiple organ systems and associated comorbidities, including oropharyngeal lesions inhibiting oral intake; pulmonary involvement with nodular lesions; neurologic conditions, including encephalitis and transverse myelitis; cardiac complications, including myocarditis and pericardial disease; ocular conditions including severe conjunctivitis; sight-threatening corneal ulcerations; and urologic involvement including urethritis and penile necrosis. The advisory also urged healthcare providers and public health jurisdictions to encourage patients to enroll in the AIDS Clinical Trials Group STOMP trial to evaluate the efficacy of tecovirimat for monkeypox.

CDC Health Advisory published September 29, 2022:

https://emergency.cdc.gov/han/2022/han00475.asp 

Long-term SARS-CoV-2 infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COG-UK dataset. The spike gene receptor binding domain (RBD) and N-terminal domains (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, - T30I was determined to be the most recurrent frequently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation. There is an apparent selective pressure for mutations which aid intra-host transmission or persistence which are often different to mutations which aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted.

Preprint available in medRxiv (March 2, 2022):

 https://doi.org/10.1101/2022.03.02.22271697 

Cele et al. examine a SARS-CoV-2 infection persisting over 6 months, starting as ancestral virus but evolving various mutations found in Omicron and other variants. The evolved virus substantially but incompletely escaped BNT162b2-elicited immunity as well as neutralization by self-plasma and showed extensive escape from neutralization elicited by Delta infections.

Characterizing SARS-CoV-2 evolution in specific geographies may help predict properties of variants coming from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa, infected prior to emergence of the Beta and Delta variants. We longitudinally tracked the evolved virus and tested it against self-plasma and convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral but evolved a multitude of mutations found in Omicron and other variants. It showed substantial but incomplete Pfizer BNT162b2 escape, weak neutralization by self-plasma, and despite pre-dating Delta, extensive escape of Delta infection-elicited neutralization. This example is consistent with the notion SARS-CoV-2 evolving in individual immune-compromised hosts, including those with advanced HIV disease, may gain immune escape of vaccines and enhanced escape of Delta immunity, with implications for vaccine breakthrough and reinfections.

Published in Cell and Host Microbe (Jan. 13, 2022):

https://doi.org/10.1016/j.chom.2022.01.005 

The "mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine," the CDC wrote in updated guidance. The Centers for Disease Control and Prevention (CDC) issued new COVID-19 vaccine guidance, which indicates that those with preexisting medical conditions should receive the vaccine. "Adults of any age with certain underlying medical conditions are at increased risk for severe illness from the virus that causes COVID-19," the CDC wrote in updated guidance on December 26, adding that "mRNA COVID-19 vaccines may be administered to people with underlying medical conditions provided they have not had a severe allergic reaction to any of the ingredients in the vaccine." The two different vaccines that are currently being administered to Americans use mRNA technology, which tells the body to create antibodies to combat the virus, instead of using a weakened version of the virus. The two vaccines include one developed by Pfizer and German biotech company, BioNTech and the other developed by Moderna.  The CDC's COVID-19 vaccine update provides guidance for those with several different preexisting medical conditions including weakened immune systems, autoimmune conditions, Guillain-Barre syndrome and Bell's palsy.

As the CDC notes, people with HIV and weakened immune systems "due to other illnesses or medication might be at increased risk for severe COVID-19." The CDC states that these people should receive a COVID-19 vaccine but notes that "information about the safety of mRNA COVID-19 vaccines" for this group is not yet available. "People living with HIV were included in clinical trials, though safety data specific to this group are not yet available at this time," the CDC said.  The CDC provides similar guidance for those with autoimmune conditions, stating that this group should receive a COVID-19 vaccine but adds that "they should be aware that no data are currently available on the safety of mRNA COVID-19 vaccines for them." According to the CDC, to date, there have been no reported cases of Guillain-Barre syndrome after a person received a COVID-19 vaccine during clinical trials and people who previously had GBS should receive the vaccine. On December 17, the Food and Drug Administration reported cases of Bell's palsy in people who received the Pfizer and Moderna vaccines during clinical trials. Bell's palsy is a temporary facial paralysis, but in the CDC's updated guidance, it states that the FDA "does not consider these [cases] to be above the rate expected in the general population." "They have not concluded these cases were caused by vaccination. Therefore, persons who have previously had Bell's palsy may receive an mRNA COVID-19 vaccine," the CDC stated.

The CDC's updated guidance also states that even after receiving a COVID-19 vaccine, people should continue to follow the current guidance to combat the virus. The current guidelines include wearing a protective face mask while in public, following social distancing measures, washing hands, and following quarantine guidance after being exposed to the virus.  The updated guidance comes as the CDC and many other health authorities have said that those with preexisting medical conditions are at a heightened risk of developing serious cases of the novel virus. Newsweek reached out to the CDC for comment but did not receive a response in time for publication. The updated guidance comes as the CDC and many other health authorities have said that those with preexisting medical conditions are at a heightened risk of developing serious cases of the novel virus. Newsweek reached out to the CDC for comment but did not receive a response in time for publication.

Updated CDC guidelines (Dec. 29, 2020):

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/underlying-conditions.html

Introduction

The antiviral Molnupiravir (Lageviro) is widely used across the world to treat SARS-CoV-2 infection. Molnupiravir reduces viral replication by inducing mutations throughout the genome, yet in patients that do not clear the infection, the longer-term impact of the drug on virus evolution is unclear. Here, we used a case-control approach to monitor SARS-CoV-2 genomes through time in nine immunocompromised -patients with five treated with Molnupiravir. Within days of treatment, we detected a large number of low-frequency mutations in patients and that these new mutations could persist and, in some cases, were fixed in the virus population. All patients treated with the drug accrued new mutations in the spike protein of the virus, including non-synonymous mutations that altered the amino acid sequence. Our study demonstrates that this commonly used antiviral can supercharge viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic.

Preprint available in  medRxiv (Dec. 22, 2022):

 https://doi.org/10.1101/2022.12.21.22283811 

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.

Today, the U.S. Food and Drug Administration authorized a second booster dose of either the Pfizer-BioNTech or the Moderna COVID-19 vaccines for older people and certain immunocompromised individuals. The FDA previously authorized a single booster dose for certain immunocompromised individuals following completion of a three-dose primary vaccination series. This action will now make a second booster dose of these vaccines available to other populations at higher risk for severe disease, hospitalization and death. Emerging evidence suggests that a second booster dose of an mRNA COVID-19 vaccine improves protection against severe COVID-19 and is not associated with new safety concerns. The agency amended the emergency use authorizations as follows: 

• A second booster dose of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine may be administered to individuals 50 years of age and older at least 4 months after receipt of a first booster dose of any authorized or approved COVID-19 vaccine.
• A second booster dose of the Pfizer-BioNTech COVID-19 Vaccine may be administered to individuals 12 years of age and older with certain kinds of immunocompromise at least 4 months after receipt of a first booster dose of any authorized or approved COVID-19 vaccine. These are people who have undergone solid organ transplantation, or who are living with conditions that are considered to have an equivalent level of immunocompromise.
• A second booster dose of the Moderna COVID-19 Vaccine may be administered at least 4 months after the first booster dose of any authorized or approved COVID-19 vaccine to individuals 18 years of age and older with the same certain kinds of immunocompromise.

“Current evidence suggests some waning of protection over time against serious outcomes from COVID-19 in older and immunocompromised individuals. Based on an analysis of emerging data, a second booster dose of either the Pfizer-BioNTech or Moderna COVID-19 vaccine could help increase protection levels for these higher-risk individuals,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Additionally, the data show that an initial booster dose is critical in helping to protect all adults from the potentially severe outcomes of COVID-19. So, those who have not received their initial booster dose are strongly encouraged to do so.”

Today’s action applies only to the Pfizer-BioNTech and Moderna COVID-19 vaccines and the authorization of a single booster dose for other age groups with these vaccines remains unchanged. The agency will continue to evaluate data and information as it becomes available when considering the potential use of a second booster dose in other age groups.  The FDA-authorized Pfizer-BioNTech COVID-19 Vaccine and the FDA-approved Comirnaty can be used to provide the authorized booster dose(s). Similarly, the FDA-authorized Moderna COVID-19 Vaccine and the FDA-approved Spikevax are authorized to provide the authorized booster dose(s).

Information to Support Authorization of a Second COVID-19 Booster Dose

The FDA has determined that the known and potential benefits of a second COVID-19 vaccine booster dose with either of these vaccines outweigh their known and potential risks in these populations. The evidence considered for authorization of a second booster dose following primary vaccination and first booster dose included safety and immune response information provided to the agency as well as additional information on effectiveness submitted by the companies.  A summary of safety surveillance data provided to the FDA by the Ministry of Health of Israel on the administration of approximately 700,000 fourth (second booster) doses of the Pfizer-BioNTech COVID-19 Vaccine given at least 4 months after the third dose in adults 18 years of age and older (approximately 600,000 of whom were 60 years of age or older) revealed no new safety concerns.  The safety of Moderna COVID-19 Vaccine, when administered as a second booster dose, is informed by experience with the Pfizer-BioNTech COVID-19 Vaccine and safety information reported from an independently conducted study in which the Moderna COVID-19 Vaccine was administered as a second booster dose to 120 participants 18 years of age and older who had received a two-dose primary series and a first booster dose of Pfizer-BioNTech COVID-19 Vaccine at least 4 months prior.

No new safety concerns were reported during up to three weeks of follow up after the second booster dose. Immunogenicity data from an ongoing, open-label, non-randomized clinical study in healthcare workers at a single center in Israel were reported in a publication provided to the FDA. In this study, individuals 18 years of age and older who had received primary vaccination and a first booster dose with Pfizer-BioNTech COVID-19 Vaccine were administered a second booster dose of Pfizer-BioNTech COVID-19 Vaccine (154 individuals) or Moderna COVID-19 Vaccine (120 individuals) at least four months after the first booster dose. Among these individuals, increases in neutralizing antibody levels against SARS-CoV-2 virus, including delta and omicron variants were reported two weeks after the second booster as compared to 5 months after the first booster dose. The amendments to the EUAs to include a second booster dose for these populations were granted to Pfizer Inc. and ModernaTX Inc.

We identified the co-infection of the SARS-CoV-2 Omicron and Delta variants in two epidemiologically unrelated patients with chronic kidney disease requiring haemodialysis. Both SARS-CoV-2 variants were co-circulating locally at the time of detection. Amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified Omicron and Delta subpopulations in respiratory samples from the two patients. These findings highlight the importance of genomic surveillance in vulnerable populations.

Preprint available in medRxiv (Feb. 15, 2022):

https://doi.org/10.1101/2022.02.13.22270755

The authorization applies to people who received solid organ transplants and others with similarly compromised immune systems.  The Food and Drug Administration on Thursday authorized third doses of Pfizer-BioNTech’s and Moderna’s coronavirus vaccines for some people with weakened immune systems, giving physicians more leeway to protect those who did not respond enough to an initial series of shots. The authorization, in the form of updates to the existing emergency use authorizations for the two vaccines, applies to people who received solid organ transplants and others with similarly compromised immune systems, the F.D.A. said. The agency’s decision came a day before the Centers for Disease Control and Prevention’s independent advisory committee was set to consider and vote on whether to recommend the move. The committee is likely to give its approval, and the C.D.C. would follow with its own endorsement of the additional doses. “The F.D.A. is especially cognizant that immunocompromised people are particularly at risk for severe disease,” Dr. Janet Woodcock, the acting F.D.A. commissioner, said in a statement. “After a thorough review of the available data, the F.D.A. determined that this small, vulnerable group may benefit from a third dose of the Pfizer-BioNTech or Moderna Vaccines.”

The authorization of the third doses kicks off what promises to be a busy next stretch for federal vaccine regulators — and a new phase of the nation’s inoculation drive. By the start of next month, the agency is expected to grant full approval to Pfizer-BioNTech’s vaccine. That will most likely prompt a wave of vaccination mandates from companies and organizations that waited to require vaccination until the F.D.A. fully cleared a vaccine.  At the same time, government scientists and regulators are grappling with whether more Americans will need booster shots, a hotly debated move that many scientists argue is not yet supported by data. Other countries such as Israel and Germany have implemented booster policies. “Other individuals who are fully vaccinated are adequately protected and do not need an additional dose of Covid-19 vaccine at this time,” Dr. Woodcock said in her statement Thursday, adding that the agency was “actively engaged in a science-based, rigorous process with our federal partners to consider whether an additional dose may be needed in the future.” The United States is the latest country to begin offering third doses to those with weaker immune systems. France has offered additional vaccine doses to certain people with poor immune responses since April, and Germany and Hungary recently followed suit.

Long-term SARS-CoV-2 shedding was observed from the upper respiratory tract of a female immunocompromised patient with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and genomic and subgenomic RNA up to 105 days past initial diagnosis. The infection was not cleared after a first treatment with convalescent plasma, suggesting limited impact on SARS-CoV-2 in the upper respiratory tract within this patient. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2, with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised patients may shed infectious virus for longer durations than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2 positive individuals as a proxy for shedding of infectious virus.

Published in Cell (November 4, 2020):

https://doi.org/10.1016/j.cell.2020.10.049