Virus World

The BEQVEZ gene therapy inserts a working copy of the Factor IX (FIX) gene that codes for a high-activity FIX variant.  Patients with moderate to severe hemophilia B can now take Pfizer’s BEQVEZ (fidanacogene elaparvovec-dzkt) with the approval of the FDA. Hemophilia B is an inherited bleeding disorder that affects more than 38,000 people globally and is caused by impaired blood clotting due to a factor IX (FIX) deficiency. The current gold standard for FIX replacement therapy prevention is infusions given once weekly or monthly. These infusions supplement or temporarily replace low blood clotting factor levels. Despite receiving prophylaxis and regular intravenous infusions, people with moderate to severe hemophilia B may still experience spontaneous bleeding episodes. Additionally, the current standard of care places a burden on healthcare systems’ budgets and resource allocation...

In vitro-transcribed (IVT) mRNAs are modalities that can combat human disease, exemplified by their use as vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). IVT mRNAs are transfected into target cells, where they are translated into recombinant protein, and the biological activity or immunogenicity of the encoded protein exerts an intended therapeutic effect1,2. Modified ribonucleotides are commonly incorporated into therapeutic IVT mRNAs to decrease their innate immunogenicity3–5, but their effects on mRNA translation fidelity have not been fully explored. Here we demonstrate that incorporation of N1-methylpseudouridine into mRNA results in +1 ribosomal frameshifting in vitro and that cellular immunity in mice and humans to +1 frameshifted products from BNT162b2 vaccine mRNA translation occurs after vaccination.

The +1 ribosome frameshifting observed is probably a consequence of N1-methylpseudouridine-induced ribosome stalling during IVT mRNA translation, with frameshifting occurring at ribosome slippery sequences. However, we demonstrate that synonymous targeting of such slippery sequences provides an effective strategy to reduce the production of frameshifted products. Overall, these data increase our understanding of how modified ribonucleotides affect the fidelity of mRNA translation, and although there are no adverse outcomes reported from mistranslation of mRNA-based SARS-CoV-2 vaccines in humans, these data highlight potential off-target effects for future mRNA-based therapeutics and demonstrate the requirement for sequence optimization. A study demonstrates that nucleotide modifications in mRNA-based therapeutics can lead to +1 ribosomal frameshifting during translation, yielding products that can trigger immune responses.

Published in Nature (Dec. 6, 2023):

https://doi.org/10.1038/s41586-023-06800-3 

On May 25, the FDA approvedopens in a new tab or window nirmatrelvir-ritonavir (Paxlovid) for treating adult outpatients with mild to moderate COVID-19 who are at risk for severe disease. Until then, nirmatrelvir-ritonavir had only received emergency use authorizationopens in a new tab or window. Upon approval, the Center for Drug Evaluation and Research director Patrizia Cavazzoni, MD, proclaimedopens in a new tab or window, "Today's approval demonstrates that Paxlovid has met the agency's rigorous standards for safety and effectiveness." But, just how rigorous were the standards? This question matters in terms of the risk-benefit analysis for prescribing nirmatrelvir-ritonavir to patients, as well as for the standard it sets for approval of other drugs. 

The approval was based on two studies. Published in February 2022, the EPIC-HR (HR is for High Risk) randomized trial reportedopens in a new tab or window that nirmatrelvir-ritonavir reduces the risk of hospitalization and death at 28 days by 86% compared to placebo. The 86% relative risk was calculated from hospitalizations and deaths among those taking nirmatrelvir-ritonavir in relation to the rate for those randomly assigned to placebo. Eight of 1,039 (0.77%) patients who started nirmatrelvir-ritonavir within the first 5 days of COVID symptom onset were hospitalized within 28 days. None died. In contrast, 66 out of 1,046 (6.3%) people who took the placebo were hospitalized and 7 died.

Notably, this study was completed during the dangerous Delta waveopens in a new tab or window -- and it was against this backdrop that the 6.3% hospitalization rate in the control group resulted. Times have now changed, with cases at a significantly lower level than pandemic peaks. During the EPIC-HR study in fall 2021, hospitalizations peaked at 25.4/100,000. For the week ending June 3, 2023, CDC reportedopens in a new tab or window 2.17/100,000 hospitalizations -- a rate approximately 12 times lower than during the EPIC-HR study. Furthermore, EPIC-HR exclusion criterionopens in a new tab or window turned away people who had been vaccinated or previously infected. According to CDC estimates, 96% of the U.S. populationopens in a new tab or window now meet these exclusion criteria. In 2023, it is difficult to find people like the participants in the EPIC-HR study....

The clinical trials are designed to evaluate multiple treatments simultaneously to identify more swiftly those that are effective....

The Food and Drug Administration (FDA) on Thursday granted full approval to Pfizer’s COVID-19 oral antiviral pill Paxlovid for use in adults who are at high risk for progression to severe disease. The agency’s approval comes nearly a year and a half after the drug received an emergency use authorization, and as hospitalization and deaths from the virus continue to decline. The agency’s approval comes nearly a year and a half after the drug received an emergency use authorization, and as hospitalization and deaths from the virus continue to decline. Paxlovid is given as a 5-day treatment course, and FDA said it should be initiated as soon as possible after a diagnosis of COVID-19 has been made, but no more than five days after symptom onset.  The drug is specifically advised for use in people aged 50 and older as well as those who suffer from certain medical conditions that put them at high risk of developing complications, including hospitalization and severe disease from COVID-19. In March, an FDA independent advisory committee recommended the agency fully approved Paxlovid, finding the medicine was safe and effective for treating COVID-19 in high-risk adults based on three of Pfizer’s clinical trials.  The agency further said Paxlovid does not cause “rebound” COVID-19 infection. 

Paxlovid has been shown to be most effective among patients who have not received a COVID-19 vaccine and those who have not been previously infected. One of Pfizer’s clinical trials showed Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death by 86 percent compared to placebo among patients treated within five days of symptom onset, and 89 percent in those treated within three days, “Today’s approval demonstrates that Paxlovid has met the agency’s rigorous standards for safety and effectiveness, and that it remains an important treatment option for people at high risk for progression to severe COVID-19, including those with prior immunity,” said Patrizia Cavazzoni, director for the FDA’s Center for Drug Evaluation and Research. “The FDA remains committed to working with sponsors to facilitate the development of new prevention and treatment options for COVID-19,” she said. The federal government owns 1.1 million doses of Paxlovid that it already purchased, that are available at pharmacies nationwide. Once that stockpile is used up, distribution will shift to the private sector, and Pfizer will sell directly to health providers. The company sells to the government for about $530 for a 5-day course of treatment, but has not said what it will charge commercially.

FDA Press Release (May 25, 2023):

https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-antiviral-treatment-covid-19-adults 

On September 1, 2022, the Moderna and Pfizer–BioNTech bivalent vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) containing equal amounts of spike messenger RNA from the ancestral and omicron BA.4–BA.5 subvariants replaced their monovalent counterparts as booster doses for persons who are 12 years of age or older in the United States. We previously reported surveillance data from North Carolina on the effectiveness of these two bivalent boosters against coronavirus disease 2019 (Covid-19) during the first 3 months after deployment (September 1 to December 8, 2022); the BA.4–BA.5 subvariants were predominant during the first 2.5 months of this period.1 Here, we present two additional months of data that were obtained during a period when the omicron BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants had become predominant to show the durability of protection conferred by these two bivalent boosters against a wider range of clinical outcomes than were included in our previous report. The data sources and study design have been described previously,1-3 and updated information is provided in the Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org. The current study used data regarding booster doses and clinical outcomes from September 1, 2022, to February 10, 2023, for all North Carolina residents who were 12 years of age or older. During this period, a total of 6,306,311 residents were eligible to receive bivalent boosters; of these residents, 1,279,802 received the injections. A total of 19,462 of the 154,581 SARS-CoV-2 infections, 253 of the 2208 Covid-19–related hospitalizations, and 79 of the 867 Covid-19–related deaths occurred after receipt of the bivalent booster (Table S1 in the Supplementary Appendix).

We considered four outcome measures: infection, severe infection resulting in hospitalization, severe infection resulting in hospitalization or death, and severe infection resulting in death. We fit the Cox regression model with a time-varying hazard ratio for severe infection and fit the proportional-rates model with a time-varying rate ratio for recurrent infection for each additional booster dose that was received (i.e., first booster vs. primary vaccination, second booster vs. first booster, or third booster vs. second booster); all measures were adjusted for the baseline characteristics shown in Table S1. We estimated the booster effectiveness on a particular day as 1 minus the hazard ratio or rate ratio on that day multiplied by 100%. 

Effectiveness against severe infection resulting in hospitalization was slightly lower, and effectiveness against infection was much lower. The effectiveness against severe infection resulting in death was the highest despite uncertainty because of the small number of events. We also analyzed the data separately for participants who received bivalent boosters before November 1, 2022 (when the BA.4–BA.5 subvariants were predominant) and after November 1, 2022 (when the BQ.1–BQ.1.1 subvariants were more prevalent and then were gradually replaced by the XBB–XBB.1.5 subvariants). The results are shown in the right column of Figure 1 and in Tables S3 and S4. The effectiveness was broadly similar between the two booster cohorts. Finally, we performed subgroup analyses according to the participant’s age and previous infection status and according to the manufacturers of the bivalent vaccine and the previous vaccine. Effectiveness against infection was higher for the Moderna bivalent vaccine than for the Pfizer–BioNTech bivalent vaccine and higher among previously infected participants than among those with no previous infection (Fig. S1).

The two types of bivalent boosters were associated with an additional reduction in the incidence of omicron infection among participants who had previously been vaccinated or boosted. Although the two bivalent vaccines were designed to target the BA.4–BA.5 subvariants, they were also associated with a lower risk of infection or severe infection with the BQ.1–BQ.1.1 and XBB–XBB.1.5 subvariants. The effectiveness was higher against hospitalization and death than against infection and waned gradually from its peak over time.

Published in NEJM (April 12, 2023):

https://doi.org/10.1056/NEJMc2302462 

Advisers to the US Food and Drug Administration voted 16-1 on Thursday in support of approval of Paxlovid, stating that the benefits outweigh the risks of the drug for treatment of mild-to-moderate Covid-19 in adult high risk for progression to severe disease, including hospitalization and death. Before the antiviral medication is fully approved, the FDA – which typically follows the recommendations of the independent advisory committee – must conduct its own review. That’s expected to wrap up in May. Over 8 million people in the US have received Paxlovid, a combination of the drugsnirmatrelvir and ritonavir, since it became available under emergency use authorization in December 2021. “I’d say besides oxygen, Paxlovid has probably been the single most important tool in this epidemic, and it continues to be,” said Dr. Richard Murphy, chief of infectious diseases with the Veterans Affairs White River Junction Medical Center and a member of the FDA’s Antimicrobial Drugs Advisory Committee who voted in support of approval at the meeting. “We still have many groups that stand to benefit from the use of Paxlovid, including unvaccinated persons, undervaccinated persons, elderly, immunocompromised, and the other treatment options that we have have significant disadvantages,” he said. Data from phase 2 and 3 clinical trials supports the efficacy of Paxlovid regardless of Covid vaccination status or prior infection, the FDA said in documents released ahead of Thursday’s meeting. The agency also said it is reasonable to conclude, despite limited data, that Paxlovid is “likely to retain clinical efficacy” in high-risk adults with Covid infection caused by the Omicron variant of the coronavirus, as with earlier variants. “I thought that the efficacy data were clear and convincing,” said Dr. Shankar Swaminathan, chief of infectious diseases at the University of Utah School of Medicine, who voted in support of approval Thursday. “I think that the fact that the drug has retained activity against various evolutionary strains of the virus is also reassuring and gives hope that this will continue to be the case going forward.”

Not linked to Covid rebound

The FDA also concluded that Paxlovid is not associated with Covid-19 rebound, in which people test positive or see their symptoms return after they finish the five-day course of the drug. The agency said it has reviewed data regarding rebound cases, which some users have reported since Paxlovid was authorized in 2021. Last year, both President Biden and his former chief medical adviser, Dr. Anthony Fauci, reported rebound symptoms after taking Paxlovid. However, based on clinical trial data, the FDA “did not identify a clear association between Paxlovid treatment and Covid-19 rebound.” Covid rebound rates ranged from 10% to 16%, with no difference between people who took Paxlovid and those who got a placebo. This was also regardless of a person’s risk of severe disease with the Omicron variant compared with the Delta variant, according to clinical trial data reviewed by the FDA. Overall, the agency said, the findings indicate that Covid-19 rebound may occur in a subset of infections as part of the natural progression and resolution of the disease.

Monitoring drug-drug interactions

No major safety concerns were identified in the clinical trial data, the FDA said. However, the agency has flagged 137 medications with Paxlovid drug-drug interactions (DDIs) that may lead to serious adverse reactions. Paxlovid may keep the body from metabolizing certain drugs, leading to higher drug concentrations that can lead to serious or life-threatening reactions, according to an FDA Emergency Use Authorization Fact Sheet. Drugs that should not be taken with Paxlovid include some medications to treat conditions such as high cholesterol, gout, migraine, irregular heartbeat and benign prostatic hyperplasia. According to the agency, over 50% of Paxlovid-eligible patients may be on medication with a DDI at the time of Covid diagnosis. “I would just emphasize that we underscore the importance of risk-mitigation to the prescriber, primary care physicians and other prescribers in terms of drug-drug interactions,” said FDA committee member Dr. David Hardy, an adjunct clinical professor at the Keck School of Medicine at the University of Southern California, who voted in support of approval. “That’s where I think we may get into trouble – or I can say where they can get into trouble – prescribing this medication without a good knowledge of what ritonavir does to other medications.” The committee said the benefits of Paxlovid may not outweigh the risk of adverse drug reactions in all patients. For those at high risk of severe Covid-19, DDIs can be managed by holding the drug, adjusting the dose or increasing monitoring. Clinical trials on the safety and efficacy of Paxlovid in children, people who are pregnant and those with weakened immune systems are ongoing.

Over the course of a two-day meeting, vaccine advisers to the US Food and Drug Administration voted in favor of approval for RSV vaccines for adults over the age of 60. The vaccine candidates, made by Pfizer and GlaxoSmithKline, could become the world's first approved vaccines against the common virus. On Wednesday, committee members voted 10-2 in support of the safety and unanimously in support of the effectiveness of GSK’s vaccine for the prevention of lower respiratory tract disease caused by RSV among older adults. For Pfizer’s shot, committee members voted on Tuesday with 7-4 with one abstention that there is adequate data to support the vaccine’s safety and effectiveness. The FDA, which typically follows the committee’s recommendations, is expected to decide on approval of the vaccines in May, ahead of RSV’s typical winter surge. Respiratory syncytial virus is a highly contagious virus that causes flu-like illness in people of all ages that increases in severity with age. According to the US Centers for Disease Control and Prevention, RSV is responsible for an estimated 177,000 hospitalizations and 14,000 deaths per year among adults 65 or older. GSK’s RSV vaccine candidate for older adults was 82.6% effective in preventing lower respiratory tract disease defined by either two or more symptoms or and one or more signs or three or more symptoms. The shot was 94.1% effective at preventing severe disease. The Pfizer vaccine was 66.7% effective at preventing moderated lower respiratory tract illness with two or more symptoms and 85.7% effective at preventing illness with three or more symptoms, according to Pfizer.

Focus on safety

Though a majority of the committee voted in support of the vaccines, some committee members expressed concerns over both vaccines’ risk of Guillain-Barre syndrome, a rare neurological disorder in which the immune system attacks its own nerves, causing muscle weakness and sometimes paralysis. The incidence of Guillain-Barre is about 1.5 to 3 cases for 100,000 adults over age 60 in the US annually, according to the FDA. Two adults among 20,000 vaccine recipients in Pfizer’s Phase 3 clinical trial developed symptoms consistent with the rare neurological disorder within nine days of receiving the shot. Of roughly 15,000 vaccine recipients of GSK’s Phase 3 clinical trial, one man developed Guillain-Barre syndrome within nine days of vaccination. “It seems to me that one case is a red flag. Two cases is very concerning,” said Dr. Marie Griffin, professor of health policy at Vanderbilt University Medical Center, who voted that the data demonstrated that both vaccines are effective but not safe

The FDA has called Guillain-Barre syndrome an “important potential risk” of Pfizer and recommended the company conduct a safety study for further evaluation of Guillain-Barre syndrome and other immune-mediated demyelinating conditions after potential vaccine approval, which the company has agreed to.

GSK has said they will closely monitor cases after approval. While Pfizer did not provide data on co-administration with other vaccines, GSK’s data showed potential safety risks when the RSV and flu shots were administered together. Two adults in their 70s who received both the flu and RSV vaccine developed acute disseminated encephalitis, a rare neurological disorder that involves swelling of the brain and spinal cord, and one of the individuals died. The FDA considers these cases as possibly related to either RSV or flu vaccination, but review is ongoing. “This is a disease with incidence 0.1 in 100,000 usually, the majority being in children and then a scatter in young adults. So two cases in elders within three to four weeks post-vaccine is highly anomalous from a statistical standpoint,” said Dr. Hana El Sahly, the FDA advisory committee chair, who voted against the GSK shot based on its safety profile but in favor based on efficacy. Dr. Adam Berger, who voted in favor of GSK’s vaccine based on safety and efficacy, says it seems to be an issue with co-administration and that concerns with acute disseminated encephalitis and Guillain-Barre syndrome won’t be answered until larger studies are conducted. “I suggest a heavy reliance on the postmarketing surveillance and not only just reliance but making sure there is an enforcement around the requirements about this,” Berger said. “At the moment, I think the profile seems to be within the acceptable range.”

Search for an effective RSV vaccine

Some vaccine advisers wanted to see more data on the Pfizer vaccine’s effectiveness at preventing hospitalization or death, especially among high-risk individuals including adults over 80, those with comorbidities, or those who are immunocompromised. “I think the data does support the effectiveness of this vaccine, it’s just the population was underrepresented by people who could most benefit from the vaccine,” Griffin said of Pfizer’s clinical trial. The available safety and efficacy data is from the first season of Pfizer’s clinical trial scheduled over two RSV seasons and the first of three seasons for GSK’s trial. Some experts want to wait for more data. “I’m desperately eager to have a vaccine that works for RSV. This has been a terrible disease my whole career. I would love to see it. No doubt about it,” said Dr. Jay Portnoy, professor of pediatrics at Children’s Mercy Hospital, who voted in support of GSK’s vaccine but against Pfizer based on efficacy. Portnoy said waiting for a second season of data would provide more robust numbers and complete analysis. “It’s not an emergency use authorization. We can take the time to finish the studies and get the information we need before licensing this product going forward. So I remain a little bit skeptical given the data that we have,” he said. Others think the benefits of the candidate vaccines outweigh the potential risks of deadly RSV infection. “Despite the challenges, despite the additional hurdles, our obligation is to do what’s right for the public,” said Dr. Daniel Kim who voted in favor of both shots. “And in this case, we have a bad disease, we have a good vaccine – so far, anyway, given the clinical trials – it’s a safe vaccine, and the vaccine can be used to prevent disease.”

Background

Methods

Findings

Interpretation

Millions of Americans got both shots at the same time this winter following a major White House public health push, which said: God gave us two arms - one for the flu shot and the other for the Covid shot.' Getting Pfizer's Covid bivalent booster and a flu shot on the same day may raise the risk of a stroke, a small official analysis suggests. The Food and Drug Administration (FDA) found the preliminary link while scouring vaccine injury databases after a separate safety concern was raised about Pfizer's jab. FDA officials who have been investigating the link said most of the patients had also received their flu shot on the same day, which might be a factor. Millions of Americans got both shots at the same time this winter following a major public health push by the White House. In September, Dr Ashish Jha, White House Covid Response Coordinator, said: 'I believe this is why God gave us two arms — one for the flu shot and the other for the Covid shot.' The FDA is launching a bigger study to examine potential safety problems arising from vaccinating against Covid and flu simultaneously. The findings will help the agency decide whether to continue with its recommendation to get both vaccines at the same time next winter.

For now health officials are still recommending people get both shots at once because getting infected with flu or Covid also raises the risk of strokes.  Dr Walid Gellad, professor of medicine at the University of Pittsburgh who was not involved in the analysis, said the issue required further investigation. 'Sometimes signals are not clear. It makes sense to look into it more, and it doesn't make sense to change practice given the known benefits (of getting the booster) in this age group.' The possible link between the shots and strokes was found as part of an independent FDA review into Pfizer's Covid vaccine.  The findings were presented today at a meeting of outside experts that advise the FDA on vaccine policy. In November, a small real-time government surveillance system that monitors vaccine injuries known as the Vaccine Safety Datalink (VSD) detected a possible link between the Covid shot and strokes among over-65s. Investigators found that 130 seniors suffered strokes in the 21 days after receiving Pfizer's booster among about 550,000 recipients in the VSD database.  One man in his 70s died a month after the stroke, which was determined his likely cause of death. But officials said the overall increase in strokes seems to wane with time, weakening the link to the Covid shot. Richard Forshee, deputy director of the FDA's biostatistics office, told the agency's independent vaccine committee: 'So far the data that we have seen suggests the absence of a safety risk for the bivalent boosters in age 65 years and older.'

The FDA reviewed data from 4.25 million seniors who received Pfizer's omicron booster and did not identify any increased stroke risk.  The agency's review of VAERS database also did not find an increased risk. The FDA also reached out to international health agencies and Pfizer to find out what they observed in their data, and the stroke link was not corroborated. However, the FDA reviewers ran a small analysis that indicated seniors who received both the Pfizer omicron booster and a high-dose or adjuvanted flu vaccine on the same day may have a higher risk of stroke. Its comes as a key panel of advisors to the FDA recommended switching the entire vaccine series to bivalent booster doses. Currently, a person receiving the original two-dose vaccine regimen will receive the original vaccine doses tailored to the Wuhan strain, but the bivalent shot as a booster. The Vaccines and Related Biological Products Advisory Committee, which is made up of outside experts that advise regulators, voted 21-0 to make the original regimen the bivalent shots too. The FDA will now need to approve of this change, which it is likely to do in the coming days. While it will only impact people who are still unvaccinated against the virus, the change could be a key step towards making the Covid vaccine an annual shot - like it is for the flu.

Nearly 6 million Americans have taken Paxlovid for free, courtesy of the federal government. But the government plans to stop footing the bill within months, and millions of people who are at the highest risk of severe illness and are least able to afford the drug may have to pay the full price. And that means fewer people will get the potentially lifesaving treatments, experts said. “I think the numbers will go way down,” said Jill Rosenthal, director of public health policy at the Center for American Progress, a left-leaning think tank. A bill for several hundred dollars or more would lead many people to decide the medication isn’t worth the price, she said. In response to the unprecedented public health crisis caused by COVID, the federal government spent billions of dollars on developing new vaccines and treatments, to swift success: Less than a year after the pandemic was declared, medical workers got their first vaccines. But as many people have refused the shots and stopped wearing masks, the virus still rages and mutates. In 2022 alone, 250,000 Americans have died from COVID, more than from strokes or diabetes. But soon the Department of Health and Human Services will stop supplying COVID treatments, and pharmacies will purchase and bill for them the same way they do for antibiotic pills or asthma inhalers. Paxlovid is expected to hit the private market in mid-2023, according to HHS plans shared in an October meeting with state health officials and clinicians. Merck’s Lagevrio, a less-effective COVID treatment pill, and AstraZeneca’s Evusheld, a preventive therapy for the immunocompromised, are on track to be commercialized sooner, sometime in the winter.

The U.S. government has so far purchased 20 million courses of Paxlovid, priced at about $530 each, a discount for buying in bulk that Pfizer CEO Albert Bourla called “really very attractive” to the federal government in a July earnings call. The drug will cost far more on the private market, although in a statement to KHN, Pfizer declined to share the planned price. The government will also stop paying for the company’s COVID vaccine next year — those shots will quadruple in price, from the discount rate the government pays of $30 to about $120. Bourla told investors in November that he expects the move will make Paxlovid and its COVID vaccine “a multibillion-dollars franchise.” Nearly 9 in 10 people dying from the virus now are 65 or older. Yet federal law restricts Medicare Part D — the prescription drug program that covers nearly 50 million seniors — from covering the COVID treatment pills. The medications are meant for those most at risk of serious illness, including seniors. Paxlovid and the other treatments are currently available under an emergency use authorization from the FDA, a fast-track review used in extraordinary situations. Although Pfizer applied for full approval in June, the process can take anywhere from several months to years. And Medicare Part D can’t cover any medications without that full stamp of approval. Paying out-of-pocket would be “a substantial barrier” for seniors on Medicare — the very people who would benefit most from the drug, wrote federal health experts. “From a public health perspective, and even from a health care capacity and cost perspective, it would just defy reason to not continue to make these drugs readily available,” said Dr. Larry Madoff, medical director of Massachusetts’ Bureau of Infectious Disease and Laboratory Sciences. He’s hopeful that the federal health agency will find a way to set aside unused doses for seniors and people without insurance.

In mid-November, the White House requested that Congress approve an additional $2.5 billion for COVID therapeutics and vaccines to make sure people can afford the medications when they’re no longer free. But there’s little hope it will be approved — the Senate voted that same day to end the public health emergency and denied similar requests in recent months. Many Americans have already faced hurdles just getting a prescription for COVID treatment. Although the federal government doesn’t track who’s gotten the drug, a Centers for Disease Control and Prevention study using data from 30 medical centers found that Black and Hispanic patients with COVID were much less likely to receive Paxlovid than white patients. (Hispanic people can be of any race or combination of races.) And when the government is no longer picking up the tab, experts predict that these gaps by race, income, and geography will widen. People in Northeastern states used the drug far more often than those in the rest of the country, according to a KHN analysis of Paxlovid use in September and October. But it wasn’t because people in the region were getting sick from COVID at much higher rates — instead, many of those states offered better access to health care to begin with and created special programs to get Paxlovid to their residents. About 10 mostly Democratic states and several large counties in the Northeast and elsewhere created free “test-to-treat” programs that allow their residents to get an immediate doctor visit and prescription for treatment after testing positive for COVID. In Massachusetts, more than 20,000 residents have used the state’s video and phone hotline, which is available seven days a week in 13 languages. Massachusetts, which has the highest insurance rate in the country and relatively low travel times to pharmacies, had the second-highest Paxlovid usage rate among states this fall.

States with higher COVID death rates, like Florida and Kentucky, where residents must travel farther for health care and are more likely to be uninsured, used the drug less often. Without no-cost test-to-treat options, residents have struggled to get prescriptions even though the drug itself is still free. “If you look at access to medications for people who are uninsured, I think that there’s no question that will widen those disparities,” Rosenthal said. People who get insurance through their jobs could face high copays at the register, too, just as they do for insulin and other expensive or brand-name drugs. Most private insurance companies will end up covering COVID therapeutics to some extent, said Sabrina Corlette, a research professor at Georgetown University’s Center on Health Insurance Reforms. After all, the pills are cheaper than a hospital stay. But for most people who get insurance through their jobs, there are “really no rules at all,” she said. Some insurers could take months to add the drugs to their plans or decide not to pay for them. And the additional cost means many people will go without the medication. “We know from lots of research that when people face cost sharing for these drugs that they need to take, they will often forgo or cut back,” Corlette said. One group doesn’t need to worry about sticker shock. Medicaid, the public insurance program for low-income adults and children, will cover the treatments in full until at least early 2024. HHS officials could set aside any leftover taxpayer-funded medication for people who can’t afford to pay the full cost, but they haven’t shared any concrete plans to do so. The government purchased 20 million courses of Paxlovid and 3 million of Lagevrio. Fewer than a third have been used, and usage has fallen in recent months, according to KHN’s analysis of the data from HHS. Sixty percent of the government’s supply of Evusheld is also still available, although the COVID prevention therapy is less effective against new strains of the virus. The health department in one state, New Mexico, has recommended against using it. HHS did not make officials available for an interview or answer written questions about the commercialization plans. The government created a potential workaround when they moved bebtelovimab, another COVID treatment, to the private market this summer. It now retails for $2,100 per patient. The agency set aside the remaining 60,000 government-purchased doses that hospitals could use to treat uninsured patients in a convoluted dose-replacement process. But it’s hard to tell how well that setup would work for Paxlovid: Bebtelovimab was already much less popular, and the FDA halted its use on Nov. 30 because it’s less effective against current strains of the virus. Federal officials and insurance companies would have good reason to make sure patients can continue to afford COVID drugs: They’re far cheaper than if patients land in the emergency room. “The medications are so worthwhile,” said Madoff, the Massachusetts health official. “They’re not expensive in the grand scheme of health care costs.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Paxlovid, the antiviral pill that reduces the risk of hospitalization and death from Covid-19, also reduces the risk of long Covid, according to a new study by researchers at the US Department of Veterans Affairs. The study, posted online as a preprint on Saturday, analyzed electronic records for more than 56,000 veterans with Covid-19, including more than 9,000 who were treated with Paxlovid within the first five days of their infection. The analysis showed people treated with Paxlovid had a 26% reduced risk of developing several long Covid conditions, including heart disease, blood disorders, fatigue, liver disease, kidney disease, muscle pain, neurocognitive impairment and shortness of breath. That corresponded to 2.3 fewer cases of long Covid conditions per 100 people three months after their diagnosis. Paxlovid also reduced the risk of hospitalization or death following acute Covid-19.  In the analysis, there wasn’t a statistically significant link between taking Paxlovid and risk of two long Covid conditions: cough and new diabetes diagnosis. The study was posted to the preprint server medRxiv and hasn’t been peer-reviewed or published in a medical journal. Patients included in the study had an average age of 65 and were diagnosed with Covid-19 between March 1 and June 30, 2022. They all had at least one risk factor for progression to severe Covid-19, such as older age, diabetes or being a current smoker. Paxlovid reduced the risk of long Covid in people who were unvaccinated, vaccinated and boosted, and in people experiencing their first Covid-19 infection or a reinfection, the study said.

“Paxlovid reduces the risk of severe COVID-19 in the acute phase, and now, we have evidence that it can help reduce the risk of long COVID,” Dr. Ziyad Al-Aly, chief of research and development at the VA St. Louis Health Care System and leader of the study, said in a news release. “This treatment could be an important asset to address the serious issue of long COVID.” The study has several limitations, including that the majority of people included were White and male, which might limit its relevance more generally. The analysis captured Paxlovid use only through the VA system and considered only 12 long Covid conditions, although many people with long Covid describe a wide variety of symptoms.

Millions of people who had Covid-19 face a range of lasting symptoms since their initial illness, but there is no specific treatment for long Covid. Paxlovid is an antiviral treatment for Covid-19 that combines a newer antiviral, nirmatrelvir, with an older drug, ritonavir. It’s available for people as young as 12 and has been shown to sharply reduce risk of hospitalization and death in people at risk of severe Covid-19.   The drug is made by Pfizer and comes as pills taken over five days. It works best if started within five days of symptom onset; researchers noted it’s not clear whether longer duration or higher dose or both might reduce risk of long Covid conditions even more, or whether starting Paxlovid after acute illness from Covid-19 would reduce risk of long Covid. The National Institutes of Health said last month it would launch a study of Paxlovid as a treatment for patients already experiencing long Covid. “The totality of evidence suggests the need to improve uptake and utilization of nirmatrelvir in the acute phase as a means of not only preventing progression to severe acute disease, but to also reduce the risk of post-acute adverse health outcomes,” authors of the VA study wrote.

Study cited in medRxiv (Nov. 5, 2022):

https://doi.org/10.1101/2022.11.03.22281783 

With the study only meeting one of its two primary endpoints, the result leaves scope to question how Pfizer will fare against AstraZeneca and Sanofi.  Pfizer has halted a pivotal trial of its respiratory syncytial virus (RSV) vaccine candidate early for efficacy, positioning the Big Pharma to file for approval by the end of the year. But with the study only meeting one of its two primary endpoints, the top-line result leaves scope to question how Pfizer will fare against AstraZeneca and Sanofi’s rival antibody. At the preplanned interim efficacy analysis, Pfizer linked the administration of its bivalent RSV prefusion vaccine candidate RSVpreF, also known as PF-06928316, during pregnancy to a significant reduction in the rate of severe medically attended lower respiratory tract illness (MA-LRTI) in newborns. The efficacy against severe MA-LRTI was 81.8% through the first 90 days of life, falling to 69.4% over the six-month follow-up period. The result was enough for the study to meet one of its co-primary endpoints. However, the study came up short against the second co-primary endpoint, which looked at the effect of RSVpreF on the rate of all severities of MA-LRTI. Pfizer called the 57.1% efficacy for MA-LRTI over the first 90 days of life clinically meaningful. But the figure, which slipped to 51.3% over the six-month follow-up period, wasn’t statistically significant and may suggest AstraZeneca and Sanofi’s antibody nirsevimab has an advantage over RSVpreF. The company plans to release secondary endpoint data later that includes impact on hospitalized patients, Pfizer CEO Albert Borla said during a Nov. 1 earnings call. “When you look at this dramatic effect on the severe infections, it seems very reasonable to project that we will have a dramatic impact in lowering hospitalizations,” Borla said, referring to the study.

It's estimated that more than 177,000 older adults are hospitalized from RSV in the U.S. each year, and 14,000 of them die, the CEO said.    While Pfizer is working to protect newborns from RSV using a maternal vaccine, AstraZeneca and Sanofi are developing a long-acting antibody that is administered to infants. In a phase 3 clinical trial, the Big Pharma partners linked nirsevimab to 74.5% efficacy against medically attended RSV-associated lower respiratory tract infection.  When asked about how RSVpreF could stack up to AstraZeneca and Sanofi’s RSV antibody for infants, Angela Hwang, Pfizer’s chief commercial officer and president of global biopharmaceuticals business, said Pfizer is the only company that has both an adult vaccine as well as the maternal vaccine in development. She said most infant RSV deaths are in those younger than six months old, citing 102,000 infant deaths reported worldwide each year. “So you really need that protection from day one,” Hwang said, which is where the company believes it can stand out. “Literally, from the moment of birth you have protection, and duration of protection throughout the six months, which is what we've shown in our clinical trials,” Hwang said. “While obviously, it's great to have many different options, I think that the option that we have with our vaccine is truly a unique one.”  Pfizer is hot on the heels of AstraZeneca and Sanofi, which have secured a recommendation for approval of nirsevimab in the EU but are yet to get the nod in the U.S. A filing for FDA approval of the breakthrough-designated RSVpreF is planned for this year.  With GSK halting enrollment in studies of its maternal RSV vaccine candidate, Pfizer, which said RSVpreF was well tolerated with no safety concerns for both the vaccinated individuals and their newborns, has a clear run at the vaccine market. But AstraZeneca and Sanofi are addressing the same unmet need from a different angle, suggesting RSVpreF will face competition from deep-pocketed rivals.

Pfizer Press Release (Nov. 1, 2022):

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-top-line-data-phase-3-global 

Paxlovid does not reduce the risk of long COVID for vaccinated people who’ve tested positive for the first time, according to a new study by UCSF researchers. The COVID-19 treatment Paxlovid does not reduce the risk of long COVID for vaccinated people who’ve tested positive for the virus for the first time, according to a new study by UCSF researchers. The study, published Thursday in the Journal of Medical Virology, also found that a higher share than previously reported experienced rebound symptoms and tested positive for COVID after taking the antiviral medication.  The new study suggests that other COVID-19 prevention strategies, like vaccination, masking and social distancing, “are still relevant,” said one study author, Dr. Matthew Durstenfeld, a cardiologist and UCSF assistant professor of medicine.

TUESDAY, Nov. 14, 2023 (HealthDay News) — For patients receiving nirmatrelvir-ritonavir (N-R) for acute COVID-19, virologic rebound (VR) occurs in about one in five, according to a study published online Nov. 14 in the Annals of Internal Medicine. Gregory E. Edelstein, from Brigham and Women’s Hospital in Boston, and colleagues conducted an observational study to compare the frequency of VR in 72 patients receiving and 55 not receiving N-R treatment for acute COVID-19. The intervention was five days of N-R treatment versus no COVID-19 treatment. The researchers found that VR occurred in 20.8 and 1.8 percent of those taking N-R versus untreated persons. All participants with VR had a positive viral culture result after a previous negative result. Only N-R use was associated with VR in multivariable models (adjusted odds ratio, 10.02).

Compared with those who started therapy two or more days after symptom onset, those who started therapy within two days of symptom onset more often had VR (26.3 versus 0 percent). Among participants receiving N-R, shedding of replication-competent virus was prolonged in those who had versus did not have VR (median, 14 versus three days). Symptom rebound occurred in eight of the 16 patients with VR; two patients were completely asymptomatic. There were no post-VR resistance mutations noted. “These data support the possibility of an N-R-specific VR phenomenon, which substantially increases the duration of shedding of replication-competent virus and has implications for post-N-R monitoring and isolation recommendations,” the authors write.

Study published in Annals of Int. Medicine:

https://doi.org/10.7326/M23-1756 

Pfizer Inc said on Thursday its updated COVID-19 shot, which is being tested against emerging variants, showed neutralizing activity against the "Eris" subvariant in a study conducted on mice. 

Despite the major decline in COVID-19 vaccine sales since the 2022 peak, the infectious disease market is still expected to grow by 5.7% through 2029 with Pfizer, Gilead and GSK all set to be the dominant forces in this market. That’s according to a new report out by analysts at GlobalData, which found the infectious disease market is forecast to grow at a compound annual growth rate of 5.7% between 2023 and 2029 to reach $150 billion in annual sales by the decade’s end. Three Big Pharmas will also emerge as the dominant players: Pfizer, Gilead and GSK, which will, according to GlobalData’s estimates, collectively generate 62% of total infectious disease drug sales in that six-year period. And that comes despite a 63.8% decline in forecast sales for COVID-19 vaccines this year alone, with that partly offset by an “increasing demand for HIV drugs and continued high sales of COVID-19 therapeutics,” the firm said.

Pfizer will be boosted by its COVID med Paxlovid as well as its Prevnar pneumococcal disease vaccine franchise. Meanwhile, Gilead will rely on its major HIV products, and GSK, known for its strong presence in infectious disease, boasts a blockbuster shingles vaccine along with recent developments such as a new respiratory syncytial virus vaccine and an HIV pill. “Pfizer annual sales are forecast to decline by 9.2% from 2023 to 2029 due to easing pandemic pressures and the relaxation of government COVID-19 vaccination programs,” explained Kevin Marcaida, pharma analyst at GlobalData, in a release. Nevertheless, Pfizer is anticipated to retain its leading stance in the infectious disease market, primarily due to the sustained robust performance of its COVID-19 product lineup, spearheaded by the sales of Comirnaty, its COVID vaccine, and Paxlovid, according to the report. “This is due to strategic price hikes in 2023 for the U.S. market and persisting COVID-19 incidences in emerging economies. As a result, Comirnaty and Paxlovid are projected to achieve an astounding $122 billion in sales between 2023 to 2029,” Marcaida added. 

Gilead, meanwhile, is set to experience “steady infectious disease sales growth” of 12.4% from 2023 to 2029, the report finds, with HIV drug Biktarvy at the core of that, with GlobalData forecasting $92 billion in sales between 2023 and 2029. GSK, meanwhile, will grow out two blockbuster drugs: shingles vaccine Shingrix and HIV drug Dovato. Total sales for Shingrix are set to hit $41 billion between 2023 to 2029 while Dovato will do around half that, $20 billion, over the same period. “Pfizer, Gilead Sciences, and GSK are the three major companies driving growth in the infectious disease market” added Marcaida. “With their innovative products, these three industry leaders are well-positioned to capitalize on the expanding opportunities in the infectious diseases market.”

At least 58,000 children younger than 5 years old are hospitalized each year with RSV infections. A Pfizer vaccine given to pregnant people could help protect their infants from severe RSV illness. Advisers to the Food and Drug Administration recommended that the agency should approve the first vaccine to protect infants from RSV, or respiratory syncytial virus. But some of the experts expressed reservations about the adequacy of data in support of the vaccine's safety. In a two-part vote, the experts voted unanimously, 14-0, that the available data support the effectiveness of the Pfizer vaccine in preventing severe RSV-related respiratory illness. They then voted 10-4 that the data supports the vaccine's safety. RSV is a leading cause of infant hospitalization in the U.S. From 58,000 to 80,000 children younger than 5 years old are hospitalized each year with RSV infections, according to the Centers for Disease Control and Prevention. Infants 6 months old and younger are at elevated risk for severe RSV illness. The votes came after a day of testimony and discussion during a public meeting of the agency's expert panel on vaccines. The FDA isn't bound to follow the advice of its expert panels, but it usually does. A decision on the vaccine for infants is expected by late August.

The vaccine isn't given to babies. Instead, pregnant people are immunized during the late second to third trimester of pregnancy. The antibodies they develop against RSV pass to the fetus in the womb and later protect the newborn. A clinical study involving 7,400 people found the vaccine had 81.8% efficacy in preventing severe respiratory illness caused by RSV within three months after birth and 69.4% in the first six months. There was some evidence that those who got vaccinated might have been more likely to give birth prematurely. And committee members worried about pregnant people getting the vaccine at the same time as some other vaccines, such as TDAP (tetanus-diphtheria-pertussis), because it could interfere with their effectiveness. "I worry that if preterm births are in any way a consequence of this vaccine, that would be tragic," said Dr. Paul Offit, professor of pediatrics at The Children's Hospital of Philadelphia. He voted no on the adequacy of safety data. The same Pfizer vaccine is under FDA review to protect people 60 and older people from RSV. Advisers voted to support approval of the vaccine at February meeting. Separately, in a first, the agency approved an RSV vaccine from drugmaker GSK in early May for people 60 and older.

BACKGROUND

Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)–associated lower respiratory tract illness in newborns and infants is uncertain.

METHODS

In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks’ gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein–based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points.

RESULTS

At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively).

CONCLUSIONS

RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316. opens in new tab.)

Published in NEJM (April 5, 2023): https://doi.org/10.1056/NEJMoa2216480 

Could taking Paxlovid reduce the risk of getting long COVID? Preliminary data suggests it might, but experts say there’s much more to learn. Long COVID, a wide-ranging set of sometimes debilitating symptomsfollowing a COVID infection, is a pressing and worrisome challenge for both patients and medical researchers, who are racing to figure out how to both prevent and treat the disease. Some evidence has emerged that Paxlovid, an oral antiviral medication used to treat COVID-19, can help reduce the risk of ending up with long COVID, experts said — and it’s one more reason to seek the treatment. Dr. Bob Wachter, UCSF’s chair of medicine, said in an email that the evidence, which comes from a study out of the Department of Veterans Affairs, isn’t huge, but shows Paxlovid can make “a meaningful difference” in warding off long COVID. It’s one of the reasons he’d take Paxlovid if he had COVID, he said. The November 2022 study of 56,000 people with COVID found that the more than 9,000 who took Paxlovid in the first five days of their infection had a 25% lower risk of long COVID symptoms, including heart disease, blood disorders, fatigue, liver disease, kidney disease, muscle pain, neurocognitive impairment and shortness of breath. In an interview with Wachter live streamed Thursday for the UCSF medical school’s grand rounds series, Dr. Eric Topol, director of the Scripps Research Translational Institute and a leading voice on COVID, agreed with Wachter, saying even the chance that Paxlovid helps prevent long COVID or reduce its severity is one of the main reasons to take the drug early.

Two people who received Pfizer's respiratory syncytial virus (RSV) vaccine during a clinical trial were later diagnosed with Guillain-Barre syndrome, and the US Food and Drug Administration has asked Pfizer to conduct a safety study if the shot is approved, according to agency documents released Friday. The cases were confirmed in two adults in their 60s who were among 20,000 vaccine recipients in Pfizer’s Phase 3 clinical trial. One person’s illness had completely resolved after three months, and another was improving after six months. There were no Guillain-Barre cases among people who didn’t receive the shot. “Given the temporal association and biological plausibility, FDA agrees with the assessments of the investigators that these events were possibly related to study vaccine. … Therefore, [Guillain-Barre] is being considered an important potential risk,” the FDA says in the documents, which were released ahead of a meeting of its independent vaccine advisers, the Vaccines and Related Biological Products Advisory Committee, on Tuesday and Wednesday.

The committee is scheduled to discuss and make recommendations on RSV vaccines for adults 60 and older from Pfizer and GSK. Guillain-Barre syndrome is a rare neurological disorder in which the immune system attacks its own nerves, causing muscle weakness and sometimes paralysis. Although most people recover completely, some cases can be fatal or have lasting effects. The incidence of Guillain-Barre is about 1.5 to 3 cases for 100,000 adults over age 60 in the US annually, according to the FDA.

“Given the higher than background rate of GBS observed in the Phase 3 study, FDA will recommend a postmarketing study and enhanced surveillance for further evaluation of GBS and other immune-mediated demyelinating conditions with postmarketing use,” the FDA says. In a briefing document submitted for next week’s meetings, Pfizer says that the cases have other possible explanations and that its shot is a “well-tolerated and safe vaccine, with a benefit-to-risk ratio that is favorable.” The company says it will conduct a safety study on Guillain-Barre syndrome if its RSV shot is approved. RSV is a highly contagious virus that causes flu-like illness in people of all ages that increases in severity with age. According to the US Centers for Disease Control and Prevention, RSV is responsible for an estimated 177,000 hospitalizations and 14,000 deaths per year among adults 65 or older. There are no vaccines approved for immunization against RSV in either children or with adults. The Pfizer vaccine was 66.7% effective at preventing moderated lower respiratory tract illness with two or more symptoms and 85.7% effective at preventing severe illness, the FDA documents say. GSK’s RSV vaccine candidate for older adults was 83.5% effective at preventing severe lower respiratory tract disease. The company similarly reported a potential case of Guillain-Barre syndrome among vaccine recipients but said there was insufficient evidence to confirm a diagnosis. The FDA considers the case to be related to the vaccine and said it will review GSK’s safety plan. Data from both vaccines was discussed Thursday during a meeting of the CDC’s Advisory Committee on Immunization Practices. The working group concluded that the vaccines “demonstrated significant efficacy against lower respiratory tract illness caused by RSV among older adults” but that “post licensure surveillance for both safety and vaccine effectiveness will be critical” if the vaccines are approved by the FDA.

Under new rules just issued by the Food and Drug Administration (FDA), you no longer need a positive COVID-19 test to get a prescription for Paxlovid, an antiviral drug that treats the virus.   The FDA revised the emergency use authorization (EUA) for both Paxlovid and Lagevrio on Wednesday. Fact sheets regarding the updated EUA note a “removal of the requirement for SARS-CoV-2 viral testing.” The reason why a test is no longer necessary is unclear. While removing this barrier to prescription may help to make antivirals more accessible to those who need them, experts say giving COVID medication to someone who may not really need it isn’t a great idea. When Verywell asked for clarification, an FDA spokesperson said “the agency continues to recommend that providers use…viral testing to help diagnose COVID-19.” Recommend, of course, is different than require. Some physicians have voiced concern about the change because COVID symptoms can be similar to other viruses, like RSV. Certain viruses may need very different treatment approaches than Paxlovid or Lagevrio in order to prevent them from progressing to something more severe. “It is impossible to distinguish COVID-19 clinically (without a test) from influenza, RSV, and a myriad of other respiratory viruses,” Amesh Adalja, MD, senior scholar at the Center for Health Security at the Johns Hopkins Bloomberg School of Public Health, told Verywell.

“Regardless of the EUA, best medical practice is to actually confirm COVID-19 before prescribing an antiviral. I don’t think the FDA should be dictating to physicians how to practice medicine, so I would advise my colleagues to ignore the change the FDA made and continue to practice sound, evidence-based medicine.” Others believe the change eliminates an unnecessary barrier to getting people treatment when it’s clear they’re sick. “Although it will still be at the provider’s discretion, we believe these EUA changes will make providers comfortable with prescribing Paxlovid in cases where a participant self-attests to a positive result but is not able to show proof of that result,” Home Test to Treat program director Andrew Weitz, PhD, told Verywell. Home Test to Treat is a new project from the National Institutes of Health (NIH) aimed at providing exclusively virtual COVID care for free, including rapid tests, telehealth sessions, treatments. “This is helpful because some participants may have tested positive but no longer have their test available; perhaps because it was thrown away.”  The change may also be hedging against a future lack of tests. Easy access to free COVID tests will end in May when the COVID-19 public health emergency declaration is lifted, taking federal funding along with it.  

“If the delinking of tests and prescriptions had not happened, the uninsured could face cost barriers if and when they can’t find a free rapid home test or a center offering a PCR test when the public health emergency ends or when the federal supply of tests is depleted,” Jen Kates, PhD, senior vice president at nonprofit health policy group the Kaiser Family Foundation, told Verywell.

The agencies said the surveillance signal “is very unlikely” to represent a “true clinical risk” and said they continued to recommend the vaccine. The CDC and FDA announced on Friday that their surveillance system flagged a possible link between the new Pfizer-BioNTech bivalent Covid-19 vaccine and strokes in people aged 65 and over, but said they were continuing to recommend the shots. The surveillance “raised a question of whether” stroke risk was elevated in the 21-day period post-vaccination versus 22 to 44 days post-vaccination, according to a statement on the CDC website. The agencies said other data from the Centers for Medicare and Medicaid Services, Department of Veterans Affairs and other sources haven’t shown an elevated risk of stroke. “Although the totality of the data currently suggests that it is very unlikely that the signal … represents a true clinical risk, we believe it is important to share this information with the public, as we have in the past, when one of our safety monitoring systems detects a signal,” the statement said. The real-time surveillance system, CDC’s Vaccine Safety Datalink, met criteria warranting further investigation into whether the bivalent Pfizer vaccine led to a higher risk of ischemic stroke, which occurs when arteries pumping blood to the brain are blocked by a blood clot. Pfizer and BioNTech said in a statement that there is “there is no evidence to conclude that ischemic stroke is associated with the use of the companies’ COVID-19 vaccines.”

The announcement prompted a response from House Energy and Commerce Chair Cathy McMorris Rodgers (R-Wash.), who said CDC and FDA will testify before her committee. “These agencies must rapidly investigate, in an open and transparent manner, whether or not the vaccine may have contributed to the reported strokes,” McMorris Rodgers said in a statement. “If there’s one lesson that the CDC and FDA should have taken away from the pandemic, it’s the importance of providing honest, clear, precise, and timely information to the American people about the potential risks and benefits of COVID-19 interventions, including vaccination.” The announcement comes as the Biden administration has aggressively promoted the updated vaccine to older Americans. Individuals over 65 are most at risk for serious illness from Covid, including hospitalization and death, and CDC data shows that 70 percent of average new daily hospital admissions of patients with confirmed Covid-19 over the last week were 60 and older. Less than 40 percent of people over 65 have gotten the booster shot that became available in the fall, according to the CDC, despite the administration’s six-week push to increase vaccination in that age group ahead of the holidays. Ninety-four percent of seniors have gotten the two primary series messenger-RNA shots. Millions of doses of the messenger-RNA Covid vaccines made by Pfizer-BioNTech and Moderna — the agencies said the Moderna shot was not flagged by its surveillance — have been administered in the U.S., and federal health officials have repeatedly deemed them safe and effective for use in anyone 6 months of age and older.

Still, rare but serious side effects — which can occur with any pharmaceutical product — have arisen since the vaccines’ debut. Data has shown an elevated risk of myocarditis and pericarditis — inflammation of the heart muscle and membrane, respectively — after the second mRNA vaccine dose among males ages 12 to 39, with those in their late teens and 20s most affected. The condition can also occur after infection with Covid and other ailments and tends to be more severe in those cases, and the FDA and the CDC say the benefits of vaccination outweigh the risks. Federal officials paused use of the Johnson & Johnson single-dose Covid vaccine for 10 days in April 2021, just weeks after its debut, after vaccine adverse event surveillance systems detected a possible link between a serious blood-clotting condition and the shots. The FDA later found that about 15 percent of the cases of thrombosis with thrombocytopenia syndrome, known as TTS, were fatal, with the highest reporting rate among women ages 30 to 49. That vaccine, made with a different technology, has largely fallen out of favor in the U.S. in favor of the mRNA shots, with the FDA limiting the J&J vaccine’s use in May 2022 to adults who are unable or unwilling to get the Pfizer or Moderna products.

In the light of emerging SARS-CoV-2 variants of concern (VOC), bivalent COVID-19 vaccines combining the wild-type spike mRNA with an Omicron VOC BA.1 or BA.4-5 spike mRNA became available. This non-randomized controlled study examined adverse reactions, PRN (pro re nata) medication intake and inability to work after a fourth COVID-19 vaccination among 76 healthcare workers. As fourth dose either the original, monovalent BNT162b2mRNA (48.7%) or the bivalent BNT162b2mRNA original/Omicron BA.4-5 vaccine (51.3%) was administered. The rate of adverse reactions for the second booster dose was significantly higher among participants receiving the bivalent 84.6% (95% CI 70.3%-92.8%; 33/39) compared to the monovalent 51.4% (95% CI 35.9-66.6%; 19/37) vaccine (p=0.0028). Also, there was a trend towards an increased rate of inability to work and intake of PRN medication following bivalent vaccination. In view of preprints reporting inconclusive results in neutralizing antibody levels between the compared vaccines, our results and further studies on safety and reactogenicity of bivalent COVID-19 booster vaccines are highly important to aid clinical decision making in the choice between bivalent and monovalent vaccinations.

Preprint available in medRxiv (Nov.8, 2022):

https://doi.org/10.1101/2022.11.07.22281982 

The emergence of the highly divergent SARS-CoV-2 Omicron variant has jeopardized the efficacy of vaccines based on the ancestral spike. The bivalent COVID-19 mRNA booster vaccine within the United States is comprised of the ancestral and the Omicron BA.5 spike. Since its approval and distribution, additional Omicron subvariants have been identified with key mutations within the spike protein receptor binding domain that are predicted to escape vaccine sera. Of particular concern is the R346T mutation which has arisen in multiple subvariants, including BA.2.75.2 and BQ.1.1.

Using a live virus neutralization assay, we evaluated serum samples from individuals who had received either one or two monovalent boosters or the bivalent booster to determine neutralizing activity against wild-type (WA1/2020) virus and Omicron subvariants BA.1, BA.5, BA.2.75.2, and BQ.1.1. In the one monovalent booster cohort, relative to WA1/2020, we observed a reduction in neutralization titers of 9-15-fold against BA.1 and BA.5 and 28-39-fold against BA.2.75.2 and BQ.1.1. In the BA.5-containing bivalent booster cohort, the neutralizing activity improved against all the Omicron subvariants. Relative to WA1/2020, we observed a reduction in neutralization titers of 3.7- and 4-fold against BA.1 and BA.5, respectively, and 11.5- and 21-fold against BA.2.75.2 and BQ.1.1, respectively. These data suggest that the bivalent mRNA booster vaccine broadens humoral immunity against the Omicron subvariants.

Preprint in bioRxiv (Nov. 1, 2022):

 https://doi.org/10.1101/2022.10.31.514636