Virus World

A new study finds that taking the antiviral Paxlovid doesn't treat Long COVID symptoms better than a placebo.  Taking the COVID-19 antiviral Paxlovid does not appear to improve Long COVID symptoms in a meaningful way, a new study finds. Those results are a blow to the millions of people living with the condition, which currently has no approved treatment or cure. Paxlovid has long been a source of hope for those with Long COVID. Scientists don’t know exactly what causes Long COVID, but many have hypothesized that viral material lingers in the body, potentially causing long-lasting symptoms including fatigue, the inability to exercise, brain fog, and more. Given that theory, a drug like Paxlovid, which stops the virus from multiplying and reduces the amount of it in the body, seemed to many like a promising treatment. But the new study, which was published June 7 in JAMA Internal Medicine, found that taking Paxlovid for 15 days was safe but did not improve key Long COVID symptoms better than a placebo. “I would have loved to bring forward a paper that said, ‘Great benefit,’” says senior author Dr. Upinder Singh, a professor of infectious diseases at Stanford University. Even though that wasn’t the result, Singh says, the study adds to scientists’ collective understanding of Paxlovid and Long COVID, and does not rule out the possibility of more positive results in the future. “Science is generative,” she says. “Data sometimes changes.”

Study published in JAMA  Internal Medicine (June 7, 2024):

https://doi.org/10.1001/jamainternmed.2024.2007 

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.

Background

Methods

Findings

Interpretation

Paxlovid, Pfizer’s pill to treat Covid-19, retained its 89% efficacy at preventing hospitalization and death in the full results of a study of 2,246 high-risk patients, the company said Tuesday.  In early November, Pfizer had released interim results from the first 1,219 patients in the study. But another oral antiviral targeting Covid, from Merck and Ridgeback Biotherapeutics, had seen estimates of its efficacy at preventing hospitalization drop from 50% to 30% between an interim result and a final one. A panel of experts advising the Food and Drug Administration on Nov. 30 recommended 13-11 that the Merck pill, molnupiravir, should be authorized for emergency use. The FDA has not announced a decision. The oral medicines are seen as important because they could be much easier to deliver to infected people than existing drugs like monoclonal antibodies, which must be infused intravenously or injected.  Experts contacted by STAT breathed a sigh of relief that the Pfizer results held up, though all emphasized the need to more fully examine the data, which were shared in a press release, not a scientific publication. “The protection from hospitalization is obviously fantastic,” said Andrew Pekosz, vice chair of microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health. “That number was a great number. The fact that it was conserved in that final analysis really points to this being a really important weapon in our arsenal to fight Covid-19 particularly as we see more variants that are going to be chipping at that efficacy number.”

Pfizer also reported results from a second study in adults with Covid at normal risk of developing severe disease, a group that included vaccinated people. That study failed to meet its main goal, of increasing the sustained alleviation of self-reported symptoms, at an interim analysis; the study is continuing. But Pfizer said that there was a decrease in hospitalization in that group, too, although numbers were small. In the study of high-risk patients, called EPIC-HR, 5 of 697 patients who received a five-day course of Paxlovid were hospitalized or died, compared to 44 of 682 who received a placebo. There were no deaths in the Paxlovid group and 9 in the placebo group. Adverse events occurred at similar rates between the placebo and Paxlovid groups, and patients on Paxlovid were less likely to have a severe problem or to stop taking the drug due to a perceived side effect. Patients in the study were considered high risk because they were not vaccinated and had at least one characteristic or underlying medical condition that increased their risk of Covid-19. These could include being over 65, being overweight, or having cardiovascular disease. The study of patients who were at lower risk, called EPIC-SR, showed that 2 of 333 patients who received a five-day course of Paxlovid were hospitalized compared to 8 of 329 who received placebo. The results were similar in a second analysis, Pfizer said, but barely missed statistical significance. Rates of adverse events were similar between the drug and placebo. Eric Topol, director and founder of the Scripps Research Translational Institute, said that despite this trial failing to succeed on its main goal of reducing symptoms, he was encouraged by the consistency between the results. “It all fits together,” he said. Céline Gounder, a clinical assistant professor of medicine and infectious diseases at the NYU Grossman School of Medicine and Bellevue Hospital, said that she was encouraged the efficacy was similar whether the treatment was given within three days of symptom onset or five. “It means you have a bigger window in order to get a diagnosis and get someone a drug,” Gounder said. “How impactful it will be will be determined by whether people are able to access it in time. The fact that you have a week of business days, that, to me, is really important.”

Paxlovid, if authorized, would be given as two pills of Paxlovid plus one of ritonavir, another antiviral, twice daily for five days. Ritonavir can interact with many other medicines, which could add logistical hurdles for its use. One big worry, Topol said, was supply of the drug. Pfizer says that it will have 200,000 courses of the medicine available this year and 80 million available next year. But he worried that may not be enough given the waves of Covid that could hit around the world. Annaliesa Anderson, a Pfizer senior vice president who played a leading role in the treatment’s development, said the company is working to ramp up production, just as it did with the Covid vaccine it developed with BioNTech, looking for ways it can work with partners to speed up production. “We’re doing what we can,” she said. Anderson said that Pfizer has “great confidence” that Paxlovid will remain potent against the Omicron variant based on in vitro data showing the pill inhibits a key protease enzyme in Omicron. However, she noted, antiviral assays for the new variant have not yet been developed. She also portrayed the development of the antiviral as, in some ways, bittersweet. Anderson said that a high point in its development had been when Covid vaccines proved effective, and some people asked if an antiviral was necessary. (It was, she said, because vaccines won’t work for everyone and not everyone will have access.) A low point was when other medicines against Covid failed, because she worried that no oral medicines would prove effective. “We all spent a lot of time developing this antiviral,” she said, “and we hoped we wouldn’t need it.” Information about how well the study represented people of different backgrounds and ethnicities was not immediately available. Those who were pregnant or breastfeeding were excluded from the trials.

Clinical trial results of Pfizer/BioNTech's Covid-19 vaccine show it is 100% efficacious and well tolerated in youths 12-15.  Pfizer/BioNTech plan to submit the data to the US Food and Drug Administration as soon as possible for expanded emergency use authorization of the two-dose vaccine. In a Phase 3 trial of 2,260 participants ages 12 to 15 in the US, the vaccine elicited strong antibody responses one month after the second dose -- exceeding those demonstrated in people ages 16 to 25 in previous trials, Pfizer reported. The vaccine is currently authorized in the US for emergency use in people 16 and older. Researchers observed 18 Covid-19 cases among the 1,129 participants who were given a placebo, and none among the 1,131 volunteers who got the vaccine. The data has yet to be peer reviewed.  Pfizer/BioNTech added that the side effects seen in the young teens were similar to those seen among 16 to 25-year-olds. Common side effects include pain at the injection site, fatigue and fever. The participants will be monitored for protection and safety for two years after their second dose. Those comparisons to the older population are important, because researchers are building off of the knowledge they gained in the adult trials.

Researchers can define a number of antibodies that are a correlate of the protection seen in adults, and then look for that level of antibodies in pediatric participants to know that the vaccine is providing protection. That's why the Covid-19 vaccine trials in children and adolescents have generally required fewer volunteers than the adult trials.  "We share the urgency to expand the authorization of our vaccine to use in younger populations and are encouraged by the clinical trial data from adolescents between the ages of 12 and 15," said Pfizer CEO Albert Bourla. "We plan to submit these data to FDA as a proposed amendment to our Emergency Use Authorization in the coming weeks and to other regulators around the world, with the hope of starting to vaccinate this age group before the start of the next school year." Dr. Peter Hotez, co-director of the Center for Vaccine Development at Texas Children's Hospital, said on CNN's New Day Wednesday, said schools can open without vaccinating students, but vaccines will help.  "I think it's likely a green light to move forward, to move down in terms of vaccinating adolescents 12 to 15," Hotez said, noting that the vaccine will still need to be evaluated for authorization in that age group. "The bottom line is that by the fall I think there's a good possibility we'll be vaccinating teenagers, 12 and up, and for middle schools, junior high schools, high schools, it's really good news in the United States for both teachers and staff. We'll have teachers and staff vaccinated, we'll have the students vaccinated in those middle schools and high schools." A return to the classroom isn't the only factor at play. Health experts have emphasized the importance of protecting as many people as possible through vaccination, as more infectious Covid-19 variants continue to spread throughout the nation.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.

Methods

In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.

Results

A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.

Conclusions

A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)

Published in NEJM (Dec. 10, 2020): 

https://doi.org/10.1056/NEJMoa2034577

Pfizer announced positive early results from its coronavirus vaccine trial, cementing the lead in a frenzied global race that has unfolded at record-breaking speed.  The drug maker Pfizer announced on Monday that an early analysis of its coronavirus vaccine trial suggested the vaccine was robustly effective in preventing Covid-19, a promising development as the world has waited anxiously for any positive news about a pandemic that has killed more than 1.2 million people. Pfizer, which developed the vaccine with the German drugmaker BioNTech, released only sparse details from its clinical trial, based on the first formal review of the data by an outside panel of experts. The company said that the analysis found that the vaccine was more than 90 percent effective in preventing the disease among trial volunteers who had no evidence of prior coronavirus infection. If the results hold up, that level of protection would put it on par with highly effective childhood vaccines for diseases such as measles. No serious safety concerns have been observed, the company said. Pfizer plans to ask the Food and Drug Administration for emergency authorization of the two-dose vaccine later this month, after it has collected the recommended two months of safety data. By the end of the year it will have manufactured enough doses to immunize 15 to 20 million people, company executives have said.

“This is a historical moment,” Kathrin Jansen, a senior vice president and the head of vaccine research and development at Pfizer, said in an interview. “This was a devastating situation, a pandemic, and we have embarked on a path and a goal that nobody ever has achieved — to come up with a vaccine within a year.” Independent scientists have cautioned against hyping early results before long-term safety and efficacy data has been collected. And no one knows how long the vaccine’s protection might last. Still, the development makes Pfizer the first company to announce positive results from a late-stage vaccine trial, vaulting it to the front of a frenzied global race that began in January and has unfolded at record-breaking speed. Eleven vaccines are in late-stage trials, including four in the United States. Pfizer’s progress could bode well for Moderna’s vaccine, which uses similar technology. Moderna has said it could have early results later this month. The news comes just days after Joseph R. Biden Jr. clinched a victory over President Trump in the presidential election. Mr. Trump had repeatedly hinted a vaccine would be ready before Election Day, Nov. 3. This fall, Pfizer’s chief executive, Dr. Albert Bourla, frequently claimed that the company could have a “readout” by October, something that did not come to pass.

Operation Warp Speed, the federal effort to rush a vaccine to market, has promised Pfizer $1.95 billion to deliver 100 million doses to the federal government, which will be given to Americans free of charge. But Dr. Jansen sought to distance the company from Operation Warp Speed and presidential politics, noting that the company — unlike the other vaccine front-runners — did not take any federal money to help pay for research and development. “We were never part of the Warp Speed,” she said. “We have never taken any money from the U.S. government, or from anyone.” She said she learned of the results from the outside panel of experts shortly after 1 p.m. on Sunday, and that the timing was not influenced by the election. “We have always said that science is driving how we conduct ourselves — no politics,” she said. The data released by Pfizer Monday was delivered in a news release, not a peer-reviewed medical journal. It is not conclusive evidence that the vaccine is safe and effective, and the initial finding of more than 90 percent efficacy could change as the trial goes on. “We need to see the actual data, and we’re going to need longer-term results,” said Jesse Goodman, a professor of medicine and infectious diseases at Georgetown University....

Pfizer Press releaase (Nov. 09, 2020): 

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against

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

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 

Background: Whether vaccine effectiveness against Coronavirus disease 2019 (Covid-19) lasts longer than 6 months is unclear.

Methods: A retrospective cohort study was conducted using Swedish nationwide registries. The cohort comprised 842,974 pairs (N=1,684,958), including individuals vaccinated with 2 doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals. Cases of symptomatic infection and severe Covid-19 (hospitalization or 30-day mortality after confirmed infection) were collected from 12 January to 4 October 2021. 

Findings: Vaccine effectiveness of BNT162b2 against infection waned progressively from 92% (95% CI, 92-93, P<0·001) at day 15-30 to 47% (95% CI, 39-55, P<0·001) at day 121-180, and from day 211 and onwards no effectiveness could be detected (23%; 95% CI, -2-41, P=0·07). The effectiveness waned slightly slower for mRNA-1273, being estimated to 59% (95% CI, 18-79) from day 181 and onwards. In contrast, effectiveness of ChAdOx1 nCoV-19 was generally lower and waned faster, with no effectiveness detected from day 121 and onwards (-19%, 95% CI, -97-28), whereas effectiveness from heterologous ChAdOx1 nCoV-19 / mRNA was maintained from 121 days and onwards (66%; 95% CI, 41-80). Overall, vaccine effectiveness was lower and waned faster among men and older individuals. For the outcome severe Covid-19, effectiveness waned from 89% (95% CI, 82-93, P<0·001) at day 15-30 to 42% (95% CI, -35-75, P=0·21) from day 181 and onwards, with sensitivity analyses showing notable waning among men, older frail individuals, and individuals with comorbidities.

Interpretation: Vaccine effectiveness against symptomatic Covid-19 infection wanes progressively over time across all subgroups, but at different rate according to type of vaccine, and faster for men and older frail individuals. The effectiveness against severe illness seems to remain high through 9 months, although not for men, older frail individuals, and individuals with comorbidities. This strengthens the evidence-based rationale for administration of a third booster dose.

Preprint available (Oct. 25, 2021) at:

https://dx.doi.org/10.2139/ssrn.3949410

The University of Oxford will lead the first trial exploring whether different Covid-19 vaccines can be used interchangeably, the University’s vaccine group said Thursday, an effort that could make vaccination programs more flexible and even provide better protection against the disease.  The study, run by the U.K. National Immunisation Schedule Evaluation Consortium, will recruit over 800 people over the age of 50 to evaluate the feasibility of using one vaccine for the first “prime” shot and different one for the second “booster” shot. At first, the trial will use the Oxford-AstraZeneca and Pfizer-BioNTech vaccines, both already cleared for emergency use in the U.K., with others potentially being added at a later date.  Britain’s Deputy Chief Medical Officer, Jonathan Van-Tam, said the trial would offer "greater insight" into the use of vaccines against Covid-19, and provide data that could support a “more flexible immunization programme" in light of global supply chain issues. 

Final results from Pfizer Inc's COVID-19 vaccine trial showed its shot had a 95% success rate and two months of safety data, paving the way for the drugmaker to apply for an emergency U.S. authorization within days, it said on Wednesday. The efficacy rate of the vaccine developed by Pfizer and its German partner BioNTech is the highest of any candidate in late-stage clinical trials so far, and experts said it was a significant achievement in the race to end the pandemic. Pfizer said 170 volunteers in its trial involving over 43,000 people contracted COVID-19 but 162 of them had only been given a placebo, meaning the vaccine was 95% effective. Of the 10 people who had severe COVID-19, one had received the vaccine. “A first in the history of mankind: less than a year from the sequence of the virus to the large-scale clinical trial of a vaccine, moreover based on a whole new technique,” said Enrico Bucci, biologist at Temple University in Philadelphia. “Today is a special day.”

Pfizer said it expected the U.S. Food and Drug Administration’s vaccine advisory committee to review and discuss the data in a public meeting that will likely be held in December. The final analysis comes a week after initial results from the trial showed the vaccine was more than 90% effective. Moderna Inc on Monday released preliminary data for its vaccine, showing 94.5% effectiveness. The better-than-expected results from the two vaccines, both developed with new messenger RNA (mRNA) technology, have raised hopes for an end to a pandemic that has killed more than 1.3 million people and wreaked havoc upon economies and daily life. “These are extraordinary results, and the safety data look good,” said David Spiegelhalter, a professor and expert in risk and evidence communication at the University of Cambridge. “It would be interesting to see what adverse reactions were reported by the group getting the placebo, since that gives an idea of how much of the adverse effects are due to the vaccination process, and how much is due to the vaccine itself.” Global shares edged higher on Wednesday as Pfizer’s trial results more than offset concerns around the stubbornly high global infection rate. Pfizer shares rose 2.9% when U.S. markets opened while BioNTech jumped 4%.

While some groups such as healthcare workers will be prioritized in the United States for vaccinations this year, it will be months before large-scale rollouts begin. Distribution of a Pfizer shot is complicated by the need to store it at ultra-cold temperatures of -70 degrees Celsius. It can, however, be kept in a normal fridge for up to five days, or up to 15 days in a thermal shipping box. Moderna’s vaccine can be stored for up to six months at -20C though it is expected to be stable for 30 days at normal fridge temperatures of 2 to 8 degrees Celsius (36°-46°F). 

Pfizer said the efficacy of the vaccine was consistent across different age and ethnic groups, a sign that the immunization could be employed broadly around the world. Efficacy in adults over 65 years was over 94%. “The 94% protection for older people is key. This is the evidence we needed to ensure that the most vulnerable people are protected,” said Andrew Hill, senior visiting research fellow at the University of Liverpool’s department of pharmacology.  Pfizer said its two-dose vaccine, BNT162b2, was well-tolerated and that side effects were mostly mild to moderate, and cleared up quickly. It said the only severe adverse events experienced by volunteers were fatigue and headaches. Out of 8,000 participants, 2% had headaches after the second dose while 3.8% experienced fatigue. Older adults tended to report fewer and milder adverse events. For its trial, Moderna named five severe side effects experienced by at least 2% of those who received its shot: fatigue at 9.7%, muscle pain at 8.9%, joint pain at 5.2%, headache at 4.5%, pain at 4.1% and redness around the injection site at 2%....

Pfizer Press Release (November 18, 2020):

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine