Virus World

BACKGROUND

METHODS

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.

A quarter patients with high-risk, BCG-unresponsive disease were recurrence free at 3 years.

WASHINGTON -- The gene therapy nadofaragene firadenovec (Adstiladrin) continued to demonstrate clinical activity in patients with high-risk bladder cancer, researchers reported.

The long-term follow-up data came from a phase III study of patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. The data showed that of 55 patients who had achieved a complete response (CR) to the therapy at 3 months, 14 (25.5%) were still high-grade recurrence free at 3 years, according to Stephen A. Boorjian, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues, at the Society of Urologic Oncologyopens in a new tab or window (SUO) annual meeting. The findings emphasize the importance of obtaining long-term data from novel therapies in order to set treatment expectations, he said. Primary trialopens in a new tab or window results, reported at the 2019 SUOopens in a new tab or window meeting, demonstrated that the 55 patients who achieved a CR at 3 months represented 53.4% of 103 patients eligible for analysis. Here, Boorjian and colleagues reported that the long-term high-grade recurrence free results were:

• 40.8% (n=42 patients) at 6 months
• 35.0% (n=36) at 9 months
• 24.3% (n=25) at 1 year
• 19.4% (n=20) at 2 years
• 13.6% (n=14) at 3 years

In addition to the 3-year results, of those 55 patients who achieved a CR, the percentage who maintained that response was:

• 76.4% (n=42) at 6 months
• 65.5% (n=36) at 9 months
• 45.5% (n=25) at 12 months
• 36.4% (n=20) at 24 months

The median duration of CR was 9.7 months, and the probability of duration of CR for at least 36 months was 34.2%. The cystectomy-free survival rate at 36 months was 53.8% (95% CI 43.3-63.1), and the 3-year overall survival rate was 90.4% (95% CI 82.3-94.9).

Nadofaragene firadenovecopens in a new tab or window is an adenoviral vector-based product that the FDA approvedopens in a new tab or window in 2022 as the first gene therapy for the treatment of high-risk BCG-unresponsive NMIBC for adult patients with CIS, with or without papillary tumors. The single-arm, open-label, multicenter trialopens in a new tab or window enrolled 107 patients, 103 of whom met the protocol definition of BCG-unresponsive NMIBC and were included in an efficacy analysis. Patients received nadofaragene 75 mL intravesical instillation (3 x 1011 viral particles/mL) once every 3 months for up to 12 months (4 doses) or until unacceptable toxicity or recurrent high-grade NMIBC. Per protocol, a five-site biopsy of the bladder was performed at 12 months, and patients who were high-grade recurrence free were offered continued treatment. The trial is ongoing with a planned 5-year treatment and monitoring phase. The median age of the entire cohort of 107 patients was 72, 89% were male, and 99% had received at least two BCG courses before enrolling in the study. Boorjian and colleagues reported that 3.9% (n=4) of patients experienced progression to muscle-invasive disease as documented by transurethral resection of bladder tumor at the time of high-grade recurrence. Two patients discontinued treatment due to adverse events (AE), including a grade 3 bladder spasm and a grade 2 instillation site discharge. Neither event was considered a serious AE.

Michael Dahl walked into a UCSF clinic in San Francisco the other day, as he has done many times since the brain-sapping symptoms of long COVID changed his life nearly two years ago.

But this time, he and his doctors hoped it would be Dahl who will change long COVID. On Aug. 22, Dahl became the first person to receive an infusion of monoclonal antibodies aimed at treating the confounding condition that has impaired millions of people around the world. The clinical trial is one of only a small number testing a treatment or cure for the post-COVID condition, which is bafflingly complex, often robbing people of the ability to think clearly, wake up refreshed from sleep, exercise, or even breathe deeply. Yet, the repair that Dahl is testing is surprisingly simple. It rests on evidence that pieces of the coronavirus that causes COVID can linger in the body for years after infection. UCSF scientists want to see if annihilating those bits can improve or even erase the debilitating symptoms. “This is just hypothetical, but that is why we’re doing the study,” said Dr. Michael Peluso, principal investigator of the trial dubbed outSMART-LC. “We’re going to take the virus out of commission — we think — and see if people feel better.”

Part of NIH’s STRIVE consortium, the therapeutic may prevent overactive immune systems from causing severe symptoms. A clinical trial has launched to test whether early intensive immune modulation for hospitalized COVID-19 patients with relatively mild illness is beneficial. The placebo-controlled study, part of the global clinical trials consortium known as Strategies and Treatments for Respiratory Infections and Viral Emergencies (STRIVE), will enroll approximately 1,500 people at research sites around the world. It is supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) in partnership with NIH’s National Center for Advancing Translational Sciences (NCATS). Immune modulators—treatments for modifying the immune system to better respond to disease or illness—are lifesaving for certain hospitalized COVID-19 patients. However, the optimal timing for administering the medicines to achieve the best outcomes has not been defined. “The evidence is clear that immune modulation can be beneficial for severely ill COVID-19 patients,” said NIAID Acting Director Hugh Auchincloss, M.D. “Patients with milder cases of COVID-19 are often administered one immune modulator, and a second treatment is added only if the patient becomes severely ill. It is possible that adding a second therapeutic earlier in the patient’s treatment could prevent progression to severe illness and improve recovery. This clinical study aims to answer that question.”

The drug being used to test the strategy of early intensification of immune modulation, abatacept (or Orencia), is manufactured by Bristol Myers Squibb, Princeton, New Jersey. It was first approved by the U.S. Food and Drug Administration in 2005 as a treatment for rheumatoid arthritis in adults and subsequently has been approved to treat other forms of arthritis in adults and children. Researchers think it may also be useful as an immune modulator for COVID-19 by tamping down over-active immune responses. Abatacept works by binding to and blocking molecules that normally activate T cells, a key part of the immune system. Other immune cells may also be affected by the drug. For patients taking abatacept, the immune system may be less likely to “overreact” when fighting an infection such as COVID-19. Symptoms from an unregulated immune response to COVID-19 can include severe respiratory distress, which can be fatal. Participants may enroll in the current trial if they are receiving supplemental low-flow oxygen upon being hospitalized for COVID-19 infection at one of the participating study sites. In addition to the local standard of care (which varies by site but must include an immune modulator drug), participants will be randomized to immediately receive either a single intravenous infusion of abatacept with dosage dependent on the patient’s weight, or a placebo infusion. Neither the investigators nor the participants will know who is receiving early immunomodulator intensification and who is not.

Throughout the trial, patient safety will be monitored. Study investigators will closely track participants’ progress over the course of 60 days and will note when they are well enough to be discharged from the hospital and return home. These data, together with the patients’ status at 60 days, will help the study team to understand whether patients benefit from early immune modulator intensification. Through the STRIVE platform, multiple therapeutic interventions for respiratory infections may be tested at once across a global network of study sites. More than 270 international sites plan to participate in this program, which enables continuous enrollment as COVID-19 surges in different parts of the world. The platform is designed to rapidly test new interventions to combat outbreaks of any respiratory disease, including pathogen X. STRIVE began its first trial, a test of the antiviral S-217622, in February 2023. For more information about the trial, please visit ClinicalTrials.gov and search identifier NCT05822583.

STRIVE emerged from the NIH ACTIV public-private-partnership initiated in April 2020. The purpose of ACTIV was to develop a coordinated research strategy for prioritizing and speeding development of the most promising treatments and vaccines for COVID-19. STRIVE builds on the efforts of prior ACTIV master protocols that evaluated various therapeutics for people hospitalized with COVID-19. STRIVE is composed of global clinical trial experts from several medical specialties including infectious diseases, pulmonology, intensive care, and emergency medicine. Trial leadership includes Protocol co-chairs Christina Barkauskas, M.D., Duke University, Durham, N.C.; Jane O’Halloran, M.D., Ph.D., Washington University in St. Louis; Nnakelu Eriobu, M.D., Institute of Human Virology in Nigeria; and Tom Murray, Ph.D., from the University of Minnesota in Minneapolis.

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

BACKGROUND

Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.

METHODS

In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein–based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated.

RESULTS

A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.

CONCLUSIONS

A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596. opens in new tab.)

Published in NEJM (Feb. 16, 2023):

https://doi.org/10.1056/NEJMoa2209604 

In a recent study published in The New England Journal of Medicine, researchers used the TOGETHER platform trial protocol to perform a phase III randomized controlled trial (RCT) to evaluate the effectiveness of pegylated interferon (IFN) lambda (λ) therapy in outpatients with coronavirus disease 2019 (COVID-19) in Canada and Brazil. They implemented this trial between June 24, 2021, and February 7, 2022. The TOGETHER platform trial evaluated 12 different therapeutic interventions against COVID-19 since its commencement in June 2020.

Background

Type III IFNs represent the first line of defense in upper respiratory tract (URT) infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, SARS-CoV-2 elicits weak expression of type III IFNs. Thus, COVID-19 treatment with an exogenous source, such as pegylated IFN λ, could trigger broad-spectrum antiviral immunity to help treat SARS-CoV-2 infection at an early stage. Two phase II studies have characterized the influence of pegylated interferon lambda treatment on SARS-CoV-2 viral load. Likewise, over 20 clinical trials covering over 4,000 patients with multiple diseases, including hepatitis B, C, and D, and COVID-19, have shown the safety and side effects of pegylated interferon lambda.

About the study

In the present study, researchers screened patients attending the trial outpatient care clinics to identify adults ≥ 18 years who presented with COVID-19 within seven days of symptom onset or met the high-risk criterion for proceeding to COVID-19 (e.g., older age, type II diabetes, obesity). All patients who met the eligibility criteria provided written informed consent, and trial personnel performed a SARS-CoV-2 rapid antigen test. Prior to randomization, trial personnel gathered each patient's sociodemographic characteristics, pre-existing health conditions, and the World Health Organization (WHO) clinical progression scale for COVID-19. A pharmacist randomized all participants using a block randomization procedure at a trial facility, stratifying participants in age-based groups (less than or greater than 50 years) for the administration of pegylated interferon lambda (study group) or placebo. The treating physicians and other staff involved in the trial remained blinded to the randomized assignments. The primary study outcome was hospitalization due to the progression of COVID-19 or an emergency department (ED) visit within 28 days after randomization. Likewise, they assessed secondary outcomes within 28 days after randomization, which covered SARS-CoV-2 clearance, time lapse since randomization to COVID-19-related hospitalization or death, days spent in hospital or intensive care unit (ICU) with mechanical ventilation, and adverse reactions to treatment or placebo. They recorded adverse events as they occurred and other data on prespecified days. The team performed virological assessments virtually on days three and seven after randomization using mid-turbinate nasal swabs. The data and safety monitoring committee assessed the safety and efficacy of pegylated interferon lambda therapy vs. placebo based on set thresholds in the statistical plan. They ceased enrolling patients into the study group as soon as they met the prespecified threshold for efficacy. The researchers applied a Bayesian framework to all statistical analyses to present the supremacy of interferon over placebo concerning the primary and the safety outcomes.

Results

Of 2,617 patients recruited in the trial, 933 and 1,018 were randomized to receive interferon treatment and placebo, respectively. The average age of the trial patients was 43 years, and 57.1% were women. Concerning primary outcome, both intention-to-treat and modified intention-to-treat populations yielded similar results. A primary outcome event ensued in 25/931 patients in the interferon lambda group and 57/1018 of the placebo group, with a relative risk (RR) of 0.49 and 95% Bayesian credible interval (CI) in the former. For the latter, it occurred in 23/929 and 55/1018 patients in the interferon and placebo groups, respectively, with RR of 0.47; 95% Bayesian CI. The most frequent primary-outcome event was hospitalization, which occurred in a median of five days post-randomization and comprised 74% of all events in the intention-to-treat population. The effect of interferon treatment increased among patients who had received it within three days of symptom onset. Accordingly, only 11/567 and 28/590 patients in the interferon and placebo groups experienced a primary event, with RR of 0.42; 95% Bayesian CI.

Conclusions

This phase III trial demonstrated that a single subcutaneous dose of pegylated interferon lambda administered within a week of the onset of symptoms reduced the risk of a primary outcome event (hospitalization) by more than 50%. It also reduced the time to COVID-19-related hospitalization or death by 41%, hazard ratio (HR) equal to 0.59, 95% Bayesian CI. Among patients who received the treatment within three days after symptom onset, it further reduced to 65%, RR equals 0.42; 95% Bayesian CI. Intriguingly, among the patients with a baseline viral load >192 million copies per milliliter (high), interferon treatment showed its effect at day 7 only. The median log10 decline in viral loads was 8.29 in the interferon group and 5.16 in the placebo group; the same for hospitalized patients was 7.19 and 3.16 in the interferon and placebo groups, respectively. To summarize, this large-scale trial involving most COVID-19 vaccinated outpatients with symptomatic COVID-19 showed that a single dose of pegylated interferon lambda reduced the incidence of hospitalization or an ED visit due to COVID-19 regardless of infecting SARS-CoV-2 variant. Thus, this treatment regimen could play a vital role in response to COVID-19.

Published in NEJM (Feb. 9, 2023):

https://www.nejm.org/doi/full/10.1056/NEJMoa2209760   

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 

After a slow start, researchers are beginning to test ways to combat the lasting symptoms of the disease.  Bhasha Mewar has had it with doctors. Over the past two years, Mewar has spent nearly all of her life savings seeing heart and respiratory specialists, haematologists, urologists, dermatologists and more, in a desperate bid to tame her long-COVID symptoms. She has taken a slew of drugs: beta blockers to calm her racing heart, steroid inhalers to ease her laboured breathing and an antimalarial drug prescribed to her for reasons she never fully understood. And when Mewar — a curator at an art museum in Ahmedabad, India, who has been sick since what was probably a bout of COVID-19 in March 2020 — would visit her lung doctor twice a month, he always told her the same thing: you need to exercise. “I can’t even walk to the bathroom,” she would reply. It’s an unwelcome odyssey undertaken by millions of people living with long COVID, a complex and sometimes debilitating syndrome that can linger for months or years after an acute SARS-CoV-2 infection. There is no proven treatment, leaving physicians and people with the condition to play whack-a-mole with its many symptoms. And sometimes, people with the syndrome turn to untested, self-prescribed therapies. Although at least 26 randomized clinical trials of long-COVID therapies are under way (see ‘Trials take off’), many are too small or lack the necessary control groups to give clear results. “If you look at long COVID at this moment in time, I’d paint a slightly ‘Wild West’ and desperate picture really,” says immunologist Danny Altmann at Imperial College London. Even so, researchers are narrowing in on the pathology that underlies long COVID. In the next year, key trials could yield results for drugs that target the immune system, blood clots or lurking fragments of the coronavirus itself. “I’m still optimistic,” Altmann says. “The right stuff is going on, and there’s a fair amount of funding out there. Something is going to give.”

Complex condition

A key barrier to developing long-COVID treatments has been uncertainty about the condition’s root cause. Over the past two years, a number of hypotheses have emerged as frontrunners, and researchers hope that insight into which ones are correct could help them to develop therapies. Evidence is mounting that lingering SARS-CoV-2 — or fragments of it — continues to cause trouble by stimulating the immune system. There are also signs that the infection generates antibodies that mistakenly attack the body’s own proteins, causing damage long after the initial illness. Researchers have found hints that COVID-19 could cause microscopic blood clots that block oxygen flow to tissues. It is also possible that a SARS-CoV-2 infection can wreak long-term havoc on gut microorganisms. These hypotheses are not mutually exclusive: many researchers think that long COVID can have multiple causes. Each idea suggests a route to relief. Antiviral drugs might vanquish persistent reservoirs of SARS-CoV-2. Drugs that suppress the immune system could quench a misguided immune response. Powerful anti-coagulants could dissolve micro-clots. Although evidence is gradually accumulating in support of each of these possibilities, their links to long COVID are still tenuous enough to give some investigators pause before launching clinical trials. “The hypotheses are getting a bit stronger,” says Altmann. “But they’re not cast iron.” This uncertainty could dissuade researchers from launching trials, says epidemiologist Martin Landray, at the University of Oxford, UK. If long COVID has a number of causes, a promising treatment could be ruled ineffective in a clinical trial simply because it was given to the wrong group. Plus, there is no shortlist of key symptoms to help to enroll  participants or sort them into subgroups. More than 200 symptoms have been associated with the syndrome1, and many — such as fatigue and brain fog, two of the most common and debilitating — are hard to measure objectively, and can wax and wane. “I’ve had a whole list of symptoms; half of them I’ve forgotten,” says Mewar, who keeps a library of photographs of the medicines she has tried, to keep track of her treatments amid the brain fog that permeates her memory. “They would come and go, here a week, and then gone.” All of this complicates clinical-trial design, says Landray, an architect of RECOVERY, a large UK trial of treatments for acute COVID-19. That trial took just four months to find that low doses of the steroid dexamethasone reduced deaths from severe COVID-19 by one-third. Landray has received requests from people with long COVID and their families to engineer a similar effort to address long COVID. “I haven’t gotten involved in this space,” he says. “The science hasn’t seemed sufficiently mature.”

A trickle of trials

But some researchers have pushed ahead. Several trials try to tame errant immune responses. Some of these rely on familiar drugs, such as colchicine, an anti-inflammatory drug that treats gout and is often prescribed to people with long COVID. Other trials are using drugs that have shown some success in treating severe acute COVID-19, including steroids and other immunosuppressants, such as sirolimus, which is used to prevent organ rejection after a transplant. Small trials and anecdotal reports suggest that antihistamines show some promise, and they provide “a Band-Aid solution”, says Hannah Davis, who has long COVID and lives in New York City. Davis is a co-founder of the Patient-Led Research Collaborative, a research and advocacy group. “But it would be good to confirm that it’s helping.” Rheumatologist James Andrews at the University of Washington in Seattle is investigating a new approach to taming inflammation in people with long COVID: an experimental drug called RSLV-132. The drug, made by Resolve Therapeutics in St Petersburg, Florida, is designed to remove RNA circulating in the blood, where it is thought to promote inflammation, says Andrews. The company has tested its drug in small trials for other conditions and has found some success in reducing fatigue in people with Sjögren’s syndrome, an autoimmune disorder. Other approaches aim to manage symptoms, such as extreme fatigue, muscle weakness and memory and concentration difficulties. Roger McIntyre, who studies psychiatry and pharmacology at the University of Toronto, Canada, is enrolling participants in a trial of vortioxetine, an antidepressant that has been shown to boost cognition, to find out whether it alleviates the brain fog associated with long COVID. Another set of trials aims to tackle COVID-19’s lingering impact on the cardiovascular system. Some studies have found evidence of inflammation in the lining of blood vessels and suggest that, in some people, this could trigger the formation of microclots that then clog the lung’s tiniest vessels, the capillaries2. Cardiologist Rae Duncan, at Newcastle upon Tyne Hospitals NHS Foundation Trust, UK, and her colleagues are planning to launch a clinical trial to test a cocktail of drugs targeting this clotting process. Duncan says when she presented her clinical-trial plans to a panel of people with long COVID and their advocates, two of them became emotional: “They said, ‘This is the trial we’ve been waiting for.’”...

Published in Nature (August 9, 2022):

https://doi.org/10.1038/d41586-022-02140-w 

A team of researchers at Atara Biotherapeutics has conducted a small Phase I clinical trial of a therapeutic called ATA188 that targets Epstein-Barr infections (EBV) as a treatment for multiple sclerosis (MS). Representatives from Atara Biotherapeutics presented their findings at an EBV and MS Day event. A press release from late last year described the results of their clinical trial. MS is a disease of the central nervous system in which the immune system attacks the sheath that covers and protects nerve cells. And EBV is a virus also known as human herpesvirus 4; it is one of the most common viral infections in humans. Some scientists have estimated that approximately 95% of people alive today have been infected by the virus at some point. In addition to being the root cause of mononucleosis, it is believed to play a role in several autoimmune diseases such as chronic fatigue syndrome, encephalomyelitis and possibly MS. Prior research has shown that the virus enters a dormant state after attack by the immune system, only to reemerge later, causing difficult-to-isolate problems.

Prior work has shown that the immune system might become confused when attacking EBV attached to nerve cells, down the myelin sheath breakage. If that is the case, they reasoned, then killing the virus should stop efforts by the immune system. To that end, they developed ATA188, a therapy using donor white blood cells to hunt down and kill cells hosting the virus by targeting antigens on their surfaces. The trial involved 24 volunteers, each of whom had the progressive form of MS. Twenty of them saw improvements or stability of symptoms. The researchers also found that none of the volunteers experienced any adverse side effects. Brain scans of the volunteers indicated signs of damage reversal, where remyelination was occurring. The researchers acknowledge that their results are extremely preliminary—the volunteer group was small and there was no control group. But they contend that their results are significant nonetheless and plan to conduct a Phase II trial in the near future.

BACKGROUND

Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19–related medically attended visit or death from any cause by day 28.

RESULTS

A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.

CONCLUSIONS

Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952. opens in new tab;

Published in NEJM (Dec. 22, 2021):

https://doi.org/10.1056/NEJMoa2116846 

Final trial data for molnupiravir were less convincing than what Merck previously reported and could alter how the FDA views the drug, which will be evaluated at a meeting Tuesday.  New study results disclosed by Merck & Co. on Friday indicated its COVID-19 pill molnupiravir may not be as effective as the company previously stated, a finding that could change how the Food and Drug Administration and its advisers view the drug at an upcoming meeting. In October, Merck said the drug reduced hospitalizations and deaths by nearly 50% in a large trial among people who had mild or moderate COVID-19. That announcement was based on a preliminary results from 775 trial participants, and the data were so convincing that outside study monitors directed Merck to stop testing early.  The result positioned Merck to bring the first oral COVID-19 treatment to market, a potentially significant tool to control outbreaks and protect vulnerable people. The company quickly filed for an emergency clearance in the U.S., an application FDA advisers will scrutinize at a public hearing Tuesday. The Biden administration has already preordered more than 3 million treatment courses. The drug was cleared for use in the U.K. on Nov. 4, and a regulatory review is underway in Europe as well. But the final study results Merck announced Friday, from all 1,433 volunteers enrolled in the study, raise questions about the drug's benefit. Overall, treatment reduced the relative risk of hospitalization and death in the trial by 30% versus placebo. Roughly 10% of the 699 people who received a placebo were hospitalized or died, compared to about 7% of the 709 patients treated with molnupiravir, Merck said.

Nine people given a placebo died, according to Merck, versus only one who was treated with molnupiravir. The drug's side effect profile was consistent with what the company previously reported. Briefing documents posted by the FDA on Friday indicated the agency is ready to authorize molnupiravir based on the interim study results, but struggling to decide who should be eligible for treatment. Merck has sought clearance for people with mild or moderate COVID-19 who are at "high risk" of worse outcomes, a similar group to those who can receive infused or injectable antibody drugs from Regeneron, Eli Lilly and Vir Biotechnology. But staff scientists raised some concerns about molnupiravir, including around evidence from animal studies of impaired bone and cartilage growth as well as the potential for birth defects. And because molnupiravir works by introducing a series of errors into a virus' genetic code, FDA scientists questioned whether the drug might trigger unwanted long-term effects or create new coronavirus variants. Additionally, the available safety data is limited, meaning rare side effects that haven't been detected in testing could occur when the drug is cleared for use in the broader population, FDA reviewers said. The agency plans to ask its advisors who should be authorized to receive the drug. The FDA and Merck agree that children won't be eligible, and molnupiravir hasn't proven effective for patients who are already hospitalized. But the agency suggested treatment may not be authorized for pregnant women, too.

The drug also didn't help patients who were "seropositive," or had antibodies against the coronavirus because of a previous infection, though the FDA appears wary of excluding that group — or vaccinated people — as a whole. Each have some risk of hospitalization or death, particularly the subsets of people more likely to develop severe disease, the agency said. All of these conclusions were reached before Merck released its final efficacy results, which indicated lower effectiveness for the drug overall. Surprisingly, among the half of study participants who weren't included in the initial analysis, 4.7% given placebo were hospitalized or died, compared to 6.2% of those who received molnupiravir. Merck didn't offer any explanations for why the drug seems to have performed worse, though Jefferies analysts speculated there may have been more seropositive patients involved, driving efficacy downward. In an amendment to its briefing documents, the FDA indicated its assessment of molnupiravir may now differ from the original review. The agency will provide "additional key safety and efficacy results" at Tuesday's hearing. The limitations could disadvantage Merck's drug from a COVID-19 pill developed by Pfizer which is also being reviewed by the FDA. Though it can be difficult to compare medicines across trials, Pfizer's drug, known as Paxlovid, lowered the risk of hospitalization and death by about 90% in a large study. That number could also change once the final numbers are tallied, however. Paxlovid is administered with ritonavir, an HIV medicine that's meant to extend Paxlovid's effects but interacts with many other types of drugs and could therefore limit use. Pfizer shares climbed 6% on Friday, while Merck's sank by about 4%. Merck is developing molnupiravir in partnership with Ridgeback Biotherapeutics, which licensed the drug from Emory University. 

Merck Press Release (Nov. 26, 2021):

https://www.merck.com/news/merck-and-ridgeback-biotherapeutics-provide-update-on-results-from-move-out-study-of-molnupiravir-an-investigational-oral-antiviral-medicine-in-at-risk-adults-with-mild-to-moderate-covid-19/ 

Background

Methods

Findings

Interpretation

Background

Methods

Findings

Interpretation

After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response. Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia.

Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge. Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.

Published (Nov. 2, 2023) in Scientific Reports:

https://doi.org/10.1038/s41598-023-45072-9 

(Bloomberg) -- In a real-world study of people with Covid-19, Pfizer Inc.’s antiviral Paxlovid was less effective at preventing the infection’s most serious cases than it was in initial trials.  The pill was just 37% effective at preventing hospitalization or death in high-risk patients when compared to no Covid treatment at all, according to an observational study published Thursday in JAMA Network Open. In earlier studies, it cut the risk of hospitalization or death by as much as 89%.  Paxlovid is still an important drug for Covid’s worst outcome: The new study showed it was 84% effective against death alone. The study published Thursday measures how the drug is performing in the real world, rather than carefully designed and monitored clinical trials. Both the earlier trial and the newer study measured people at high risk of developing Covid complications. Pfizer’s initial Paxlovid studies were conducted in unvaccinated people, which could explain some of the differences in outcomes. The coronavirus has also evolved since the studies that provided more positive results.

Despite the lower efficacy against hospitalization and death in the new study, the antiviral is still “definitely recommended for high-risk patients,” says Danyu Lin, a biostatistics professor at the University of North Carolina at Chapel Hill and lead author of the study. The study also found that another therapy — Merck & Co.’s Lagevrio — had similar efficacy to Paxlovid. Merck’s drug works through a genetic mechanism and isn’t recommended for use in pregnant women. Sill, it should be considered when patients can’t take Pfizer’s, which sometimes interacts with other medications, Lin said. High-risk patients who took Lagevrio saw a 41% reduction in hospitalizations and deaths in the observational study compared to those who took no treatment, while earlier studies showed reductions of only about 30%. The Merck drug was also 77% effective against death in the JAMA study. The study looked at electronic health records of 68,867 patients at several hospitals in Cleveland and Florida.

Cited study published in JAMA Network Open (Sept. 21, 2023):

https://doi.org/10.1001/jamanetworkopen.2023.35077 

A new analysis published in The Lancet Microbe shows how the SARS-CoV-2 virus spreads from the nose to the air and surfaces in the immediate surroundings. The findings are the second batch of results to come from the COVID-19 Human Challenge Program, led by Imperial College London and partners, and provide granular insights into how people infected with SARS-CoV-2 spread the virus to their immediate surroundings. In February 2021, 36 healthy, young participants with no previous immunity to the virus were infected with SARS-CoV-2 under controlled clinical conditions in a residential facility at the Royal Free Hospital in London, where they could be carefully monitored. They remained at the facility until they were no longer infectious. The facility enabled researchers to track the course of infection in great detail, with the clinical team taking daily swabs from participants' noses and mouths, as well as environmental samples of the air and swabs of surfaces in their rooms.

Viral emissions

Out of 36 initial participants, a total of 18 became infected. Analysis showed that two individuals emitted substantially more virus into the air than the other infected participants, but displayed no significantly worse symptoms. The researchers suggest this may represent the small proportion of individuals who have potential to be highly infectious, sometimes described as "superspreading." Analysis found large amounts of viral RNA in air samples, in exhaled breath, as well as swabs of participants hands and on surrounding surfaces, including frequently touched surfaces such as door handles and TV remote controls, showing how an infected person contaminates their surrounding environment and can spread the virus. Viral emissions correlated strongly with the level of virus detected in people's noses, more than in their throat, highlighting the nose as a significant route for infected people shedding virus into the air and environment. According to the researchers, the latest analysis further highlights the routes by which the virus is transmitted from person to person—directly into the air, depositing onto nearby surfaces, and transferred from contaminated hands to frequently touched surfaces, such as door handles and remote controls.

Reliable indicators

They also show that positive lateral flow tests and visible symptoms were reliable indicators of when people were infectious and emitting virus into the air and environment. The vast majority of virus was emitted after people noticed their first symptoms, with very little virus released into the environment before that (pre-symptomatically). They found no significant link between the severity of participants' symptoms and the amount of virus they shed into the environment. According to the researchers, the findings highlight the need to reinforce public health messaging around proper face mask use, hand washing and surface cleaning, as well as how human challenge studies continue to add to our knowledge of COVID-19 infection and transmission. Dr. Anika Singanayagam, NIHR Academic Clinical Lecturer in the Department of Infectious Disease at Imperial College London, and joint first author of the study, said, "Our latest findings add to the existing body of knowledge on COVID-19 transmission. By studying infection in a controlled environment, we can collect unique, detailed measurements of virus emitted that allow us to understand how and when people with COVID-19 are contagious to others. These types of measurements are challenging to collect in real-world studies. "Our data indicate that much of the virus people shed comes from the nose, further highlighting the importance of face masks covering the nose as well as the mouth when they're used. But it also shows how virus can be transferred from hands to contaminate surfaces, like door handles or remote controls, which become a source of infection."

Dr. Jay, Jie Zhou, research associate in the Department of Infectious Disease at Imperial College London, and joint first author of the study, said, "Understanding when infected people are contagious and how to detect when they are contagious is important—it can help us to use interventions like face masks or social distancing more effectively. The data in our study highlights that being aware of, and acting on, the first minor symptoms that signal an infection, coupled with frequent self-testing with lateral flow tests, can effectively reduce onward spread." Professor Wendy Barclay, head of the Department of Infectious Disease at Imperial College London, said, "One of the most important things we need to know for controlling the spread of respiratory viruses, such as SARS-CoV-2, is when are people who are actively infected with the virus most likely to infect others? That information can help to tell us how the virus will spread, and how best to use interventions to stop the outbreak. "Human challenge studies enable us to gain granular insights into the infection which we might not otherwise be able to. They play an important role in our understanding of infectious diseases, and should be considered a part of future pandemic preparedness."

Previous findings

The latest findings add to several key clinical insights already gained from the COVID-19 Human Challenge Program, published in February 2022. These include that symptoms start to develop on average two days after contact with the virus, that infection first appears in the throat, infectious virus peaks about five days into infection and, at that stage, is significantly more abundant in the nose than the throat. The first analysis also found that lateral flow tests (LFTs) are a reassuringly reliable indicator of whether infectious virus is present in the nose and throat (i.e., whether they are a likely to be infectious to other people).

Original research published (June 9, 2023) at The Lancet Microbe:

https://doi.org/10.1016/S2666-5247(23)00101-5 

Background

Methods

Findings

Interpretation

US biotech company Moderna on Tuesday announced positive interim trial results for its vaccine against respiratory syncytial virus (RSV) in adults over the age of 60. There are no jabs currently available for the virus, which is a top cause of lower respiratory diseases, commonly leading to bronchiolitis in children and pneumonia in the elderly. However numerous vaccines and treatments are under development, most notably by Moderna's rival COVID-19 vaccine maker Pfizer. Moderna's vaccine was found to be nearly 84 percent effective against RSV-linked diseases in Phase III trials—the final stage of human testing—the firm said in a statement. The trial of the vaccine, which uses the new mRNA technology from Moderna's COVID jab, involves some 37,000 adults over 60 in 22 countries including the United States.

The company released the findings of an interim analysis, which has not been peer-reviewed. In the placebo group, there were 55 cases of RSV-linked lower respiratory tract disease with at least two symptoms, compared to nine in the group that received the vaccine, it said. The vaccine had no serious side effects, the company added. Moderna plans to apply for regulatory approval for the vaccine in the US, Europe and other regions in the coming months. This could make it available for the RSV season in the Northern Hemisphere's winter this year, Moderna's chief medical officer Paul Burton told AFP. The company is also testing the vaccine for use in children, but those trials are still at the first phase.

'Good news'

In high-income countries, RSV caused 5.2 million cases of severe disease among adults over 60 in 2019, Moderna said. Up to 30,000 elderly patients die every year in G7 countries due to the virus, Burton added. He said that the number of doses required for Moderna's vaccine was yet to determined. The positive results come after Pfizer announced in December that its own RSV vaccine for over-60s was granted priority review status by the US Food and Drug Administration. The previous month, Pfizer said another of its RSV vaccines, which is given to pregnant mothers, was effective at protecting newborns. Also in November, the European Union approved a preventative treatment which works similarly to a vaccine made by AstraZeneca and Sanofi which has been shown to prevent severe illness from RSV in infants. When asked about other RSV vaccines being developed by Moderna's rivals, Burton said "it's good news". "The public has gone seven decades with nothing" to fight the virus, and soon could have multiple options, he said. Moderna is also looking at whether the RSV jab can be combined with COVID and even influenza vaccines, after soaring cases of all three in recent months was dubbed a "tripledemic".

Moderna's Press Release:

https://investors.modernatx.com/news/news-details/2023/Moderna-Announces-mRNA-1345-an-Investigational-Respiratory-Syncytial-Virus-RSV-Vaccine-Has-Met-Primary-Efficacy-Endpoints-in-Phase-3-Trial-in-Older-Adults/default.aspx 

Gilead Sciences has new data showing COVID drug Veklury maintained efficacy despite changes in a coronavirus structure it targets, just as the company explores expedited ways to launch a pivotal tr | Gilead Sciences has new data showing COVID drug Veklury maintained efficacy despite changes in a coronavirus structure it targets, just as the company explores expedited ways to launch a pivotal trial for an investigational oral antiviral. Compared with the original SARS-CoV-2 virus, Veklury (remdesivir) showed no major shifts in its ability to tackle coronaviruses with substitutions in the RNA-dependent RNA polymerase (RdRp), according to data presented at IDWeek 2022. Also known as nsp12, RdRp is a protein key in the replication of RNA viruses like SARS-CoV-2.  Coronaviruses with RdRp mutations isolated from patients in the phase 3 ACTT-1 trial—which got Veklury its FDA approval—showed up to about a 3.4-fold decrease in their susceptibility to Veklury compared with the original virus, the data showed. The fold change was measured by increases in half-maximal effective concentration of the drug, or EC50, and investigators called the difference “low.” ACTT-1 was conducted in 2020, before the delta and omicron variants were identified. What’s more, the RdRp substitutions didn’t seem to affect clinical outcomes. Among Veklury takers who were eligible for this analysis, 67% of patients with the mutations recovered from COVID, compared with 58% of those without the mutations. Because Veklury targets RdRp, theoretically the drug might not work as well if the protein underwent major structural changes, Anu Osinusi, Gilead’s vice president of clinical research for hepatitis, respiratory and emerging viruses, explained in an interview with Fierce Pharma.

The new data were consistent with other analyses Gilead has done, Osinusi said, and they continue to “bolster the story that there is a high barrier to resistance developing against remdesivir in patients.” The results were better than findings from a recent Science Translational Medicine study. In that study, in which several Gilead scientists participated, researchers reported multiple pathways, including combinations of RdRp substitutions, that could give the coronavirus varying degrees of resistance to Veklury.  Introducing one specific combo of substitutions resulted in 38-fold Veklury resistance but also a viral replication defect, the study found. However, as the researchers noted, the substitutions selected from lab dishes merely described possible pathways to Veklury-resistant mutations, and that they were either rare or simply not detected in the more than 6 million publicly available RdRp sequences with or without Veklury treatment.  Watching for mutants has become a main theme in the fight against COVID. Antibody drugs like Regeneron’s REGEN-COV have lost their emergency use authorizations because of reduced activity against omicron. Most SARS-CoV-2 variants identified show mutations on the spike protein on the surface of the virus, making neutralizing antibody therapies that target the protein ineffective. “To date, we haven’t really seen any major genetic changes in any of the variants of concern, or even variants of interest, that have emerged that would significantly alter that viral RNA polymerase that is targeted by Veklury,” Osinusi said.

Still, as COVID cases drop, Veklury sales declined 46% year-over-year in the second quarter to $445 million despite an expanded FDA approval for non-hospitalized patients in January. Veklury’s recent decrease also has Pfizer’s more convenient oral antiviral Paxlovid to thank. But the Pfizer therapy has its own problem, including potentially dangerous drug-drug interactions and reported fast COVID rebound. That’s why Gilead is working on its own oral COVID drug. Gilead is moving a remdesivir prodrug coded GS-5245 “with full speed” potentially across the disease spectrum, Osinusi said. As the COVID treatment landscape is changing, the company is collaborating with global health authorities to launch a phase 3 global clinical trial that will “prioritize sites that can move quickly with clinical trial enrollment,” a Gilead spokesperson told Fierce Pharma. The California drugmaker previously disclosed a phase 1 trial for GS-5245 in January. The proposed phase 3 trial will be randomized and double-blinded, pitting GS-5245 against placebo in non-hospitalized COVID patients who are at high risk of progression to hospitalization. Investigators will measure the rate of COVID-related hospitalization and all-cause death by day 29 as the trial’s primary endpoint, according to Gilead. The trial hasn’t started enrolling, pending endorsement from regulatory authorities, the spokesperson said. Veklury remains a standard of care for COVID, “but we also recognize the limitations of it being an intravenous agent,” Osinusi said. “There is a need for having additional oral antiviral agents because that’s really when you’re going to be able to meet the needs of the broader population.”

BACKGROUND

Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown.

METHODS

Part 1 of this ongoing phase 2–3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported.

RESULTS

In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant.

CONCLUSIONS

Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896. opens in new tab.)

Published in NEJM (May 11, 2022):

https://doi.org/10.1056/NEJMoa2203315 

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.