Trial of hundreds of thousands in Bangladesh finds masking 'modestly' decreased COVID infections

 A mask promotion campaign in villages in Bangladesh modestly reduced COVID-19 infections, according to a massive new study that is the first of its kind.

Conducted by researchers from Yale University, Stanford University, the University of California, Berkeley, and nonprofit organization Innovations for Poverty Action, the study employed a randomized controlled trial considered the gold standard in medical research.

"Community-wide masking can be an extremely effective tool to combat COVID," tweeted Jason Abaluck, a Yale professor of economics who co-authored the study.

The researchers randomly assigned 600 villages in Bangladesh to two groups, with households in half of the villages receiving free masks, as well as education and training on proper mask use. The other half of the villages, the control group, did not receive any mask education. Researchers monitored the villages for mask use in the following weeks.

The study found that the rate of mask-wearing was about 42% in the treatment villages, but only 13% in the control villages.

Over 335,000 participants in the villages filled out surveys asking if they experienced any COVID-19-like symptoms, and over 27,000 said they had. About 40% of those who said they had symptoms consented to blood tests.

The blood tests revealed that 0.76% of villagers in the control group tested positive for COVID-19 versus 0.69% in the treatment villages, a reduction of 9%.

The “intervention demonstrates a scalable and effective method to promote mask adoption and reduce symptomatic SARS-CoV-2 infections,” the researchers concluded.

The study also examined surgical masks versus cloth ones. There was no difference in infections among villages that used cloth masks versus control villages, but there was an 11% drop in infections among villages that used surgical masks.

The study has several limitations. Because researchers did not take blood samples from those who did not report symptoms, the study was unable to determine if mild or asymptomatic infections were higher among villages with lower rates of mask use. Nor could the study rule out the possibility that those who consented to blood tests were in some important way different between the treatment and control groups, thereby biasing the results.

https://news.yahoo.com/randomized-trial-hundreds-thousands-bangladesh-162300590.html

Moderna Submits Initial Data to FDA for Its COVID-19 Vaccine Booster

 Moderna, Inc. (Nasdaq:MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, today announced it has initiated its submission to the U.S. Food and Drug Administration (FDA) for the evaluation of a booster dose of the Moderna COVID-19 vaccine (mRNA-1273) at the 50 µg dose level. The Company expects to submit data to the European Medicines Agency (EMA) and other regulatory authorities around the world in the coming days.

“We are pleased to initiate the submission process for our booster candidate at the 50 µg dose with the FDA. Our submission is supported by data generated with the 50 µg dose of our COVID-19 vaccine, which shows robust antibody responses against the Delta variant,” said Stéphane Bancel, Chief Executive Officer of Moderna. “We remain committed to staying ahead of the virus and following the evolving epidemiology of SARS-CoV-2. We will continue to generate data and transparently share to support governments and regulators as they make evidence-based decisions regarding future vaccination strategies.”

The Phase 2 study of mRNA-1273 was amended to offer a booster dose of mRNA-1273 at the 50 µg dose level to interested participants 6 months following their second dose (n=344). Neutralizing antibody titers had waned significantly prior to boosting at approximately 6 months. A booster dose of mRNA-1273 at the 50 µg dose level boosted neutralizing titers significantly above the Phase 3 benchmark. After a third dose, a similar level of neutralizing titers was achieved across age groups, notably in older adults (ages 65 and above). The safety profile following dose 3 was similar to that observed previously for dose 2 of mRNA-1273. These data will be submitted to a peer-reviewed publication.

An additional analysis showed that a booster dose of mRNA-1273 at the 50 µg dose level induced robust antibody responses and significantly increased geometric mean titers (GMT) for all variants of concern including Beta (B.1.351) by 32- fold, Gamma (P.1) by 43.6-fold and Delta (B.1.617.2) by 42.3-fold.

https://www.businesswire.com/news/home/20210901006016/en/Moderna-Announces-Submission-of-Initial-Data-to-U.S.-FDA-for-Its-COVID-19-Vaccine-Booster

Japan Begins Recall of Tainted Moderna COVID-19 Vaccine

 After suspending the use of 1.63 million doses of the Moderna COVID-19 vaccine over contamination concerns last week, Japan is now recalling those doses, Moderna Inc. and its Japanese partner, Takeda Pharmaceutical Co. Ltd. said Wednesday.

Last week, some vials of the vaccine were found to be contaminated with stainless steel.

Japanese officials said Wednesday that they did not think the stainless steel particles posed a health risk, while Moderna said the contamination was probably caused by pieces of metal rubbing together in the machinery that puts stops on the vials.

"Stainless steel is routinely used in heart valves, joint replacements and metal sutures and staples. As such, it is not expected that injection of the particles identified in these lots in Japan would result in increased medical risk," Takeda and Moderna said in a joint statement.

According to Taro Kono, the Japanese minister overseeing vaccinations, around 500,000 people received shots from the suspended Moderna batches.

The focus on the contaminated doses was heightened after two men died within days of receiving second doses from the contaminated batches.

While their deaths are still being investigated, Moderna and Takeda said there was no evidence the vaccine played a role in their deaths.

"The relationship is currently considered to be coincidental," the companies said in the statement.

https://www.voanews.com/covid-19-pandemic/japan-begins-recall-tainted-moderna-covid-19-vaccine

Assembly Bio to Discontinue Clinical Development of Hep B Med

 --Decision follows observation of elevated alanine transaminase (ALT) levels in Phase 2 study

--Company will focus on advancing ongoing triple combination studies and earlier pipeline candidates

Assembly Biosciences, Inc. (Nasdaq: ASMB), a clinical-stage biotechnology company developing innovative therapeutics targeting hepatitis B virus (HBV), today announced its decision to discontinue development of ABI-H2158 (2158) following the observation of elevated ALT levels consistent with drug-induced hepatotoxicity in an ongoing Phase 2 trial.

“Patient safety is always our priority, which is why we have elected to discontinue the development of 2158,” said John McHutchison, AO, MD, chief executive officer and president of Assembly Bio. “We remain committed to our pursuit of developing finite and curative therapies for individuals with chronic hepatitis B, and our strategy remains unchanged. We will continue to evaluate our core inhibitor portfolio, to ultimately choose the best and safest candidate to take forward into later stage clinical trials as we believe this mechanism will be an important and key component of future curative regimens. We remain focused on expeditiously advancing our additional clinical programs, including the two ongoing Phase 2 triple combination studies, accelerating the clinical development for 3733 and 4334, and progressing additional research programs in our HBV portfolio with complementary mechanisms. And, as always, we will continue evaluating strategic opportunities to build additional value in the company’s pipeline.”

The Phase 2 clinical study for 2158 is a multi-center, randomized, placebo-controlled trial in treatment-naïve patients with HBeAg positive or HBeAg negative chronic hepatitis B infection without cirrhosis. A total of 88 patients were enrolled and randomized three-to-one to receive either 300 mg 2158 plus entecavir or placebo plus entecavir once daily for up to 72 weeks. In the study, two patients receiving 2158 experienced Grade 4 elevations in ALT leading to drug discontinuation. Two additional patients also receiving 2158 developed Grade 3 ALT elevations. No alternate causes for the ALT elevations have been identified, and these four patients continue to be closely monitored. The company has communicated the findings with the U.S. Food & Drug Administration (FDA) and has voluntarily chosen to discontinue development of 2158 and the Phase 2 study. After communicating the company’s decision to the FDA, the FDA noted that 2158 would also be placed on clinical hold.

Assembly Bio maintains a deep pipeline of investigational core inhibitor candidates. The most advanced core inhibitor candidate, vebicorvir (VBR), has demonstrated favorable safety and a potent antiviral profile in patients treated for up to 1.5 years in the Phase 2 program. VBR is being evaluated in two ongoing triple combination studies for which initial on-treatment data are anticipated during 2022. ABI-H3733 (3733) has completed its Phase 1a study and initial data is planned to be announced at an upcoming medical meeting. Additionally, the company expects to advance its recently-selected core inhibitor candidate ABI-4334 (4334) into clinical development in 2022. 4334 has a best-in-class preclinical profile with single-digit nanomolar potency against the production of new virus, as well as the formation of covalently closed circular DNA (cccDNA). Importantly, 3733 and 4334 are structurally distinct from 2158.

Assembly Bio will also continue to advance a research pipeline of programs focusing on HBV antiviral mechanisms beyond core inhibition. In a collaboration with Door Pharma, Assembly Bio is developing a novel class of HBV core protein modulators that have the potential to interfere with viral nucleic acid including cccDNA transcription. Additionally, the company has proprietary internal research programs underway for two novel targets.

https://www.globenewswire.com/news-release/2021/09/01/2290389/0/en/Assembly-Bio-Announces-Decision-to-Discontinue-Clinical-Development-of-ABI-H2158.html

High virus count in the lungs drives COVID-19 deaths

 A buildup of coronavirus in the lungs is likely behind the steep mortality rates seen in the pandemic, a new study finds. The results contrast with previous suspicions that simultaneous infections, such as bacterial pneumonia or overreaction of the body's immune defense system, played major roles in heightened risk of death, the investigators say.

Led by researchers at NYU Grossman School of Medicine, the new study showed that people who died of COVID-19 had on average 10 times the amount of virus, or viral load, in their lower airways as did severely ill patients who survived their illness. Meanwhile, the investigators found no evidence implicating a secondary bacterial infection as the cause of the deaths, although they cautioned that this may be due to the frequent course of antibiotics given to critically ill patients.

"Our findings suggest that the body's failure to cope with the large numbers of virus infecting the lungs is largely responsible for COVID-19 deaths in the pandemic," says study lead author Imran Sulaiman, MD, Ph.D., an adjunct professor in the Department of Medicine at NYU Langone Health.

Current guidelines from the Centers for Disease Control and Prevention, he notes, do not encourage use of antivirals such as remdesivir for severely ill patients on mechanical ventilation. But Sulaiman says the NYU Langone study results suggest that these medications may still remain a valuable tool in treating these patients.

Despite previous concerns that the virus may prompt the immune system to attack the body's own lung tissue and lead to dangerous levels of inflammation, the investigators found no evidence that this was a major contributor to COVID-19 deaths in the group studied. In fact, Sulaiman notes that the strength of the immune response appeared proportionate to the amount of virus in the lungs.

The coronavirus has so far killed over 4 million people worldwide, researchers say. Those placed on mechanical ventilators in order to breathe fare particularly poorly, with 70 percent nationwide succumbing to the illness. Notably, experts attribute the high mortality seen in other viral pandemics such as the Spanish flu in 1918 and swine flu in 2009 to a secondary bacterial infection. However, it remained unclear whether a similar issue afflicted people with COVID-19.

The new study, publishing online Aug. 31 in the journal Nature Microbiology, was designed to clarify the role of secondary infections, viral load, and immune cell populations in COVID-19 mortality, according to Sulaiman. He says the investigation provides the most detailed survey of the lower airway environment in coronavirus patients.

For the investigation, the researchers collected bacterial and fungal samples from the lungs of 589 men and women who were hospitalized in NYU Langone facilities in Manhattan and on Long Island. All required mechanical ventilation. For a subset of 142 patients who also received a bronchoscopy procedure to clear their air passages, the investigators analyzed the amount of virus within their lower airways and identified the microbes present by studying small pieces of the germs' genetic code. The study authors also surveyed the type of immune cells and compounds located in the lower airways.

Among the findings, the study revealed that those who died had on average 50 percent lower production of a type of immune chemical that targets the coronavirus compared with the COVID-19 patients who survived the illness. These customized proteins are part of the body's adaptive immune system, a subset of cells and chemicals that "remember" invading newly encountered microbes, leaving the body better prepared for future exposure.

"These results suggest that a problem with the adaptive immune system is preventing it from effectively combating the coronavirus," says study senior author Leopoldo Segal, MD. "If we can identify the source of this issue, we may be able to find an effective treatment that works by bolstering the body's own defenses," says Segal, an associate professor in the Department of Medicine at NYU Langone.

He cautions that the investigators only studied coronavirus patients who survived their first two weeks of hospitalization. It is possible, he says, that bacterial infections or autoimmune reactions may play a greater role in COVID-19 mortality that occurs earlier.

Segal says the research team next plans to observe how the microbe community and immune response in the lungs of coronavirus patients change over time.

https://medicalxpress.com/news/2021-08-high-virus-lungs-covid-deaths.html

Take Another Look at Spacing Between COVID Vaccine Doses

 When most Americans showed up to get their first dose of an mRNA vaccine, they were sternly warned that they must schedule a second dose within a month. In my case, I politely explained that I would come back for my second dose at 3 months. The scheduler got flustered and treated me like I was a fugitive of the law. But a growing body of evidence over the last several months has shown that a longer interval provides better immunity in the long-term. It may even eliminate the need for a booster shot that's now being recommended.

In May, researchers at the University of Birmingham found that delaying the second Pfizer dose to 12 weeks after the first resulted in a 3.5 times greater antibody response in older people. The increase is likely even greater in a younger cohort. Hematologist Paul Moss, MBBS, PhD, a co-author of the study, concluded that it's a good idea to extend the time between the first and second doses of the vaccine. "An extended interval may help to sustain immunity against COVID-19 over the longer term and further improve the clinical efficacy of this powerful vaccine platform," he wrote.

Similarly, data showed delaying the second Oxford/AstraZeneca vaccine by 12 weeks resulted in a stronger antibody response. That became the U.K.'s recommendation, which not only conferred better immune protection but also enabled the U.K. to ration its limited vaccine supply in a way that saved more lives. It was a winning strategy.

The U.S. basis for designing the 2-dose regimen with a short interval was that the pandemic was raging and there was an urgency to getting the trial done quickly. It was also believed that a short interval could more rapidly address a spike in cases. Based on the thinking at the time, the short interval may have made sense. But some vaccinologists have pointed out that the two doses were so close together that they functioned as a single primer dose.

Given the current data, it appears that if we had spaced the two doses farther apart, we would have had two benefits: 1) We would have had more first doses on hand to protect Americans from January through March when we were supply constrained and 2) We might not be calling for boosters for the general population so quickly.

While we can't go back in time, we should consider where this growing body of data leaves us today.

Some may be concerned with studies showing that one dose is less effective than two doses against the Delta variant, even with the U.K.'s 12-week spacing approach. However, efficacy against simply infection is not the best endpoint. Instead, we need to look at death and hospitalizations.

Beyond only better immunity in the long-term, other considerations contribute to the present-day case for spacing the two doses. There are numerous anecdotal experiences suggesting that the typical vaccine side effects such as fatigue and malaise may be less common when the second dose is spaced at 3 months. The current short interval between vaccine doses may contribute to the rash of myocarditis cases we have seen in children. The heart complications are clustered after the second vaccine dose. (Incidentally, a Tel Aviv study found that a single dose of the Pfizer vaccine alone was 100% effective in children 12-15 years of age.) Such preliminary observations merit further study.

If the rigidity of the 3- and 4-week interval between doses represents one extreme, the other extreme is the lax guidance behind current booster recommendations. Time frames for booster shots are being suggested without any data to show when the vaccine protection against hospitalizations is waning. Anthony Fauci, MD, told CNN on Sunday that they are "aiming at around 8 months" after the second dose for a booster shot, "but there's flexibility on that and that's what we'll keep looking at." We need to show that same flexibility on the timing of the first two doses of the mRNA vaccine.

As the data are emerging, they are telling us to extend the original 3- and 4-week dosing interval. For me personally, I felt good about evidence to support waiting for my second dose until 3 months after my first. For people who have not yet received their second vaccine dose, let's use a data-driven approach to delay the second dose to 3 months. Doing so could yield more durable immune protection and may reduce the need for boosters.

Marty Makary MD, MPH, is editor-in-chief of MedPage Today as well as professor at the Johns Hopkins University School of Medicine and author of The Price We Pay: What Broke American Health Care -- and How to Fix It.

https://www.medpagetoday.com/opinion/marty-makary/94315

FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks

 The FDA has finished its review of a large postmarketing safety study of tofacitinib (Xeljanz, Xeljanz XR), and its conclusions do not bode well for the popular drug and the larger class of JAK inhibitors.

Data from the trial revealed increased risks for serious heart-related events -- including myocardial infarction (MI) and stroke -- as well as a higher risk for cancer, blood clots, and death. Even the lower 5-mg dose of tofacitinib turned up an increased risk of blood clots and death in the final analysis, the agency noted.

FDA is requiring new and updated warnings for tofacitinib, as well as two other arthritis medicines in the JAK inhibitor class -- baricitinib (Olumiant) and upadacitinib (Rinvoq). All three JAK inhibitors are approved for rheumatoid arthritis (alone or in combination), while tofacitinib is also approved in psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.

"Since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks," the agency said.

In the safety trial, tofacitinib was compared to tumor necrosis factor (TNF) blockers in rheumatoid arthritis patients also on methotrexate. Treatment with the JAK inhibitor was associated with an increased risk for major adverse cardiac events (MACE), including MI, cardiovascular death, and stroke (HR 1.33, 95% CI 0.91-1.94), which missed criteria for non-inferiority, as well as a higher risk for cancer (HR 1.48, 95% CI 1.04-2.09).

"To ensure the benefits of these three medicines outweigh the risks in patients who receive them, we are limiting all approved uses to certain patients who have not responded or cannot tolerate one or more TNF blockers," FDA said. "This is particularly the case in patients who are current or past smokers, those with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy other than a successfully treated nonmelanoma skin cancer."

Notably, the restrictions will not apply to two JAK inhibitors used for certain blood disorders -- ruxolitinib (Jakafi) and fedratinib (Inrebic) -- as these are not indicated for arthritis and other inflammatory conditions.

https://www.medpagetoday.com/rheumatology/arthritis/94314