Taser-maker halts project to arm drones with stun guns as ethics panel quits

 Taser-maker Axon Enterprise Inc said it was halting a project to equip drones with stun guns to combat mass shootings, a reversal that did not stop most of its ethics advisory board members from announcing their resignation on Monday in protest over the original plans.

The May 24 school shooting in Uvalde, Texas, which killed 19 children and two teachers, prompted Axon to announce last week it was working on a drone that first responders could operate remotely to fire a Taser at a target about 40 feet (12 m) away.

Nine of 12 members of the company's AI Ethics Board quit over concerns the drones would harm over-policed communities and that Axon publicized its ambitions without consulting the group. The resignations and Axon's scuttled plans were first reported by Reuters.

"In light of feedback, we are pausing work on this project and refocusing to further engage with key constituencies to fully explore the best path forward," Chief Executive Rick Smith said in a statement https://www.axon.com/news/technology/axon-committed-to-listening-and-learning.

The action by ethics board members marked a rare public rebuke for one of the watchdog groups some companies have set up to gather feedback on emerging technologies, such as drones and artificial intelligence (AI) software.

Smith said it was unfortunate that members withdrew before Axon could address their technical questions, but the company "will continue to seek diverse perspectives to challenge our thinking."

Axon, which also sells body-worn cameras and policing software, has said its clients include about 17,000 out of the roughly 18,000 law enforcement agencies in the United States.

It explored the idea https://www.wsj.com/articles/taser-explores-concept-of-drone-armed-with-stun-gun-for-police-use-1476994514 of a Taser-equipped drone for police since at least 2016, and Smith depicted how one could stop an active shooter in a graphic novel he wrote https://www.flipsnack.com/endofkillingcomic/the-end-of-killing/full-view.html. The novel shows a daycare center with what looks like an enlarged smoke alarm, which first recognizes the sound of gunfire and then ejects a drone, identifying and tasing the shooter in two seconds.

Axon first approached its ethics board more than a year ago about Taser-equipped drones, and the panel last month voted eight to four against running a limited police pilot of the technology.

The company announced the drone idea anyway, as it said it wanted to get past "fruitless debates" on guns after the Uvalde shooting, sending shares up nearly 6%. They were down 0.5% on Monday.

Ethics board members worried the drones could exacerbate racial injustice, undermine privacy through surveillance and become more lethal if other weapons were added, member Wael Abd-Almageed said in an interview.

"What we have right now is just dangerous and irresponsible," said Abd-Almageed, an engineering research associate professor at University of Southern California.

The board likewise had not evaluated use of the drones by first responders outside police, it said. And members questioned how a drone could navigate closed doors to stop a shooting.

The drone is "distracting society from real solutions to a tragic problem," resigning board members said in a Monday statement.

CEO Smith has said drones could be stationed in hallways and move into rooms through special vents. A drone system would cost a school about $1,000 annually, he said.

Formed in 2018, the ethics panel has guided Axon productively on sensitive technologies such as facial recognition in the past.

Giles Herdale, one of the remaining ethics board members, told Reuters he chose not to resign because he could have more influence "if I am in the tent than outside it."

For others, the company's drone announcement prior to a formal report by the board broke with practice, said member Ryan Calo, a University of Washington law professor.

"I’m not going to stay on an advisory board for a company that departs so far from expectation and protocol or, frankly, who believes ubiquitous surveillance coupled with remote non-lethal weapons is a viable response to school shootings," he said.

Barry Friedman, the board chairman, resigned as well.

https://www.marketscreener.com/quote/stock/AXON-ENTERPRISE-INC-34532659/news/Taser-maker-halts-project-to-arm-drones-with-stun-guns-as-ethics-panel-quits-40646976/

U.S. has wasted over 82 million Covid vaccine doses

 Pharmacies, states, U.S. territories and federal agencies discarded 82.1 million Covid vaccine doses from December 2020 through mid-May — just over 11 percent of the doses the federal government distributed, according to data the Centers for Disease Control and Prevention shared with NBC News. That’s an increase from the 65 million doses the CDC told the Associated Press had been wasted as of late February.

Two retail pharmacy chains, CVS and Walmart, were responsible for over a quarter of the doses thrown away in the United States in that time period, in part due to the sheer volume of vaccine they handled.

Five other pharmacies or dialysis centers — Health Mart, DaVita, Rite Aid, Publix and Costco — wasted fewer overall doses, but a higher share: more than a quarter of the vaccine doses they received, well above the national average. Two states also discarded more than a quarter of their doses: Oklahoma, which tossed 28 percent of the nearly 4 million doses it received, and Alaska, which threw away almost 27 percent of its 1 million doses, according to the CDC data.

The overall amount of waste is in line with World Health Organization estimates for large vaccination campaigns. But public health experts said the waste is still alarming at a time when less than half of fully vaccinated Americans have a booster shot — which is critical to fight newer, more contagious virus strains — and when many poorer countries continue to struggle with vaccine supply.

“It’s a tremendous loss to pandemic control — especially in the context of millions of people around the world who haven’t even been able to get a first dose,” said Dr. Sheela Shenoi, an infectious disease expert at the Yale School of Medicine.

The millions of wasted vaccine doses include some that expired on pharmacy shelves before they could be used, others that were spoiled by the thousands when power went out or freezers broke, and still others that were tossed at the end of the day when no one wanted the last few doses in an opened vial.

Unlike most other immunizations in the U.S., the coronavirus vaccines come in multidose vials, which means all the doses must be used within hours once the vials are opened — or discarded.

State health officials and pharmacies said that’s been a major contributor to vaccine waste. Some also said the vaccines come in such large minimum orders that they are left with more than they need.

Some pharmacies, including CVS and Rite Aid, said their priority has been offering the vaccine on demand. If getting a shot into an arm means opening a new vial and wasting the unused doses, that’s a tradeoff they’re willing to make.

CVS wasted nearly 11.8 million doses, or about 13 percent of the 89.9 million it received. The share of doses discarded is just above the national average, but in total still amounts to more wasted doses than any other pharmacy or state.

“​​We often have to open a multidose vial at the end of the day for a single walk-in,” the company said in a statement. “Those vials have a very limited shelf life, which unfortunately means unused vaccine will be disposed of. The same challenge is faced by others administering vaccinations.”

Walgreens, one of the nation’s largest pharmacy chains, wasted 8.3 million doses, or about 10.5 percent of the nearly 79.6 million doses it received.

In a statement, the company pointed to no-show appointments, cancellations and open vials expiring as reasons for the waste.

"The latest CDC guidance advises that providing COVID-19 vaccinations should be prioritized, even if it leads to vaccine waste," the company said.

The challenge of getting shots into arms and avoiding waste has become especially difficult as demand wanes for the vaccines, experts and officials say.

“The demand has plateaued or is coming down, and that leads to open-vial wastage — especially with multidose vials,” said Ravi Anupindi, a professor of operations research and management at the University of Michigan who has studied vaccination campaigns.

“It’s a demand problem,” he added.

https://www.nbcnews.com/news/us-news/covid-vaccine-doses-wasted-rcna31399

COVID mRNA vaccines can be quickly updated for new variants. So, where's my Omicron booster?

 Since Omicron was declared a variant of concern at the end of November, it quickly swept the globe, becoming the dominant COVID variant in many countries including Australia.

It's the latest in a growing line of variants, and probably not going to be the last.

Yet every one of the hundreds of millions of approved mRNA vaccines administered around the globe were made to their original recipe, which was based on the COVID virus that first emerged in Wuhan.

One of the most promising aspects of the new mRNA COVID vaccines is their ability to be rapidly adjusted for maximum protection in the face of new variants.

So where's my Omicron booster?

Vaccines based upon mRNA contain a blueprint in the form of genetic material — called messenger RNA — that, when injected into our muscle, is "read" by our cells.

Using that RNA message as a guide, our cells construct replicas of the spike protein that the SARS-CoV-2 virus uses to infect us.

The freshly built spike proteins are pushed outside the cells, a bit like a flag, alerting the immune system.

In response, a type of white blood cell called B cells pump out antibodies — Y-shaped molecules that form an immune "memory" of the spike.

But as the SARS-CoV-2 virus mutated its genetic code and slightly remoulded its spike protein, it was better able to fly under our immune system's radar.

The process of tailoring mRNA vaccines for new variants is "very straightforward", says Archa Fox, an RNA biologist at the University of Western Australia.

"The beauty of the RNA [vaccine] platform is that you can very easily change the DNA template that you use to make the RNA.

"It's the bread and butter of biochemists and molecular biologists, so very routine for [vaccine] companies."

Large companies such as Pfizer and Moderna can feasibly make an Omicron-specific vaccine for testing within a week or so, says Colin Pouton, a pharmaceutical biologist at Monash University.

"And if an Omicron vaccine is going to be any good to you and I, it has to produce new antibodies against Omicron."

So first, they test if the Omicron vaccine does that in mice.

"But if you do animal experiments [with an Omicron-specific booster shot], and look for protection against Omicron, an Omicron version of their vaccine actually doesn't do any better than the original Wuhan vaccine," Professor Pouton says.

So, what's going on?

Giving a person (or mouse) multiple vaccines with ever-so-slight differences in their makeup can cause a phenomenon called "immunological imprinting".

"When you give a vaccine, you prime the immune response to produce antibodies … then you boost it by giving a second dose or a third dose," Professor Pouton says.

But if you're then vaccinated against a slightly different variant, you might make fewer antibodies that specifically work on that new viral variant.

That's because, when confronted with a similar vaccine, your immune system prefers to recruit existing antibody-producing B cells back into action, rather than develop new ones.

(This also happens with the seasonal flu vaccine, and is partly why it's only partially effective. But you should still get it.)

And not all antibodies are created equal.

Our immune system, when presented with a spike protein, gets to work making antibodies that recognise and attach to many different parts of the spike.

Antibodies that help stop a virus from infecting cells are called neutralising antibodies.

We want these, and they work by blocking the very end of a virus's spike protein, called the "receptor-binding domain".

This is the bit that latches onto ACE2 receptors on our cells (hence "receptor binding"), and allows the virus to slip inside.

Another way to think of it is to imagine the spike protein is an arm, and the very end section is a hand that can grab hold of and twist open the ACE2 door handle.

If you get a really big, oversized clothes peg — this is a neutralising antibody — and clamp it onto the palm of the "hand" or between its fingers, you have a physical barrier between the hand and the door handle, and it won't be able to open the door and infect the cell.

Pegs that prefer to dangle off the elbow or up near the shoulder won't do much to stop the hand from working. These pegs are our non-neutralising antibodies.

And non-neutralising antibodies make up the lion's share of COVID-vaccine-generated antibodies, says Dale Godfrey, an immunologist at the Peter Doherty Institute for Infection and Immunity.

"Only about 10-20 per cent of antibodies bind the receptor-binding domain compared to the rest of the spike protein when people are immunised with whole-spike vaccine."

Scientists are looking for ways to beef up neutralising antibodies while avoiding immunological imprinting.

One way to do this is to make "slimmed down" versions of variant-specific vaccines.

Professors Pouton and Godfrey are involved in a trial of two such vaccines.

One is an mRNA vaccine, which contains instructions for our cells to make only the receptor-binding domain and not the rest of the spike, and the other comprises lab-made receptor-binding domain proteins.

"We're trying to say [to the immune system], 'here's a new target which you haven't seen before,'" Professor Pouton says.

The vaccines in the trial are based on the Beta variant, as that was the variant of concern when the project began.

The Beta variant shares some of Omicron's mutations, Professor Godfrey says.

"As to whether this means the vaccine will provide superior protection against Omicron, we think and hope so, but don't know yet."

Pfizer and Moderna are continuing with clinical trials to see how their Omicron-specific whole-spike vaccines fare in people.

Moderna is also trialling a "bivalent" version that combines the original vaccine, as well as the new Omicron-specific spike mRNA.

We might not have to wait too long to find out how well they work.

A Pfizer spokesperson said they would share next-generation vaccine data "in the coming weeks".

A Moderna spokesperson said the company expected to have first data on the bivalent vaccine this month "to inform selection of its candidate for the northern hemisphere [autumn] 2022 booster".

Moderna is also in phase one trials of a receptor-binding-domain-specific Omicron booster, Professor Pouton says, but it's very early days.

Eventually, he adds, the hope is COVID vaccines could become routine seasonal vaccines, like the yearly flu shot, and won't need to run the clinical trial gauntlet each time.

https://www.abc.net.au/news/science/2022-06-06/mrna-vaccines-covid-omicron-variant-booster-clinical-trials/101114566

Omicron BA.4 and BA.5: Starting From Scratch Yet Again

 Coronaviruses are single-stranded RNA viruses with large genomes and, until recently, consisted of the mild 229E, OC43, L69, and H53U1 strains, and the "novel" SARS and MERS strains. Sometime in late 2019, a third "novel" coronavirus called the "Wuhan" strain emerged. This began what we now know as the COVID-19 pandemic. With subsequent mutation, "variants of concern" soon emerged, starting with Alpha, and the most significant subsequently being Delta and then Omicron.

Mutations evolved and new strains replaced older variants. Now we are in the Omicron subvariant replacement phase. BA.1 was replaced by BA.2 and then BA.2 was replaced by BA.2.12.1. Starting in early 2022, the latest of these subvariants of concern became the BA.4 and BA.5 subvariants, originally described in South Africa. The earliest samples of BA.4 and BA.5 in the U.S. were collected on March 30 and March 29, respectively.

Each time a new variant comes along, it feels like we're starting from scratch all over again. How fast is the new variant spreading? What does the symptomatology and severity look like? While many questions remain about these new subvariants, below I review current insights into their transmissibility, disease severity, and survivability.

What We Know

Transmissibility

For any new variant to succeed, a number of things have to go right. We start with transmissibility with a high R₀ (the number of people that can be infected for every case), but transmissibility alone is not necessarily enough. There is a minimum quantity of virus (viral load) needed to stay around to infect. What about replicating more quickly by binding more tightly to the lung's ACE2 receptor? There is variable environmental survivability in different climates and hosts.

BA.4 and BA.5 have high transmission rates in South Africa and elsewhere. Why South Africa? It may have to do with the local population's immunity, but there are countless potential factors at play. These variants might have arisen because of the percentage of people there that have either been infected or vaccinated; the new strains may have been hidden in parts of Africa in safe harbors of land poorly tracked that we have paid little attention to; there may have arisen a new animal reservoir; or a genetic mutation might have occurred in a single immunosuppressed individual.

Disease Severity

Severity of disease is another key factor impacting spread: does the variant cause just the right amount of clinical disease? If, for example, it causes too mild illness, it will keep people who can transmit the disease in wide circulation and burn out quickly; if it causes too much clinical disease there will not be enough virus left to continue transmission. Generally, BA.4 and BA.5 variants cause mild disease but spread in large numbers potentially because, unlike the Wuhan strain, which settles in the lungs, these newer strains seem to attach to the more benign upper nasal passages. As with other Omicron variants, BA.4 and BA.5 symptoms are generally mild, and may include fever, malaise, and loss of smell, although the prevalence of long-term symptoms (long COVID) is still being evaluated. Serious illness is rare but possible, especially in the unvaccinated.

Variant Survivability

Variant survivability also involves testing evasion, vaccine evasion, and response to therapeutics. Duration and degree of viral shedding is important, as is surviving longer in the air or moving more readily through it. Possibly even more important is the percentage of infected people who become asymptomatic silent shedders, and the length of the incubation period, as this provides more time to infect more people without detection. All of these are key ingredients of COVID-19 variant transmissibility. The incubation of the newer variants seems to be slightly shorter (2 to 3 days).

The bottom line is that BA.4 and BA.5 are very highly transmissible, cause little severe disease, and are responsive to boosters (although protection wanes), monoclonal antibodies, and antivirals.

Unfortunately, both BA.4 and BA.5 are capable of escaping immune protection induced by infection with earlier Omicron and other prior variants, earning them the term "stealth" viruses. The unvaccinated are even less likely to be protected against symptomatic infection with BA.4 or BA.5. Sera from vaccinated individuals performed better in in vitro studies done thus far, but protection derived from currently available vaccines wanes over time. Fortunately, the third COVID vaccine booster dose slows down infection, spread, and serious disease from older variants. The effect of a third and fourth dose on BA.4 and BA.5 is still being evaluated. A universal Omicron vaccine is in development, but the efficacy is thus far unknown.

Rapid Mutation

Why are all these mutations happening so fast? BA.4 and BA.5 seem to undergo occasional mutational "sprints," mutating as much as four times faster than the normal Omicron mutation rate. More mutations can lead to more transmission, more severe disease, or evasion of the immune response -- much like flu's mutations. This may explain not only the rapid spread but also the non-linear spread, as in superspreader events where many get infected but some don't. There's also been genome swap between BA.1 and BA.2, and between Delta and Omicron in a single patient, as in the XE and "Deltacron" strains, respectively. BA.2.12.1 also seems to share properties with Delta. This exchange is also likely to be identified with BA.4 and BA.5.

Further Research Is Needed

Many questions remain: Will one or both of these two new subvariants take over? How much long COVID do they cause? Will they start to compete or augment each other? Will they dissolve into a fifth or sixth benign human coronavirus strain as it happened in the 1800's with a strain affecting cows and humans, or cause another large wave with increasing serious disease and case numbers -- or something in between? Why the escalation in new subvariants now? Novel flu strains only emerged three times in the last century. It took only two mutations this time. In other words, are mutations -- which have always been around -- increasing in frequency?

What are the implications for re-infection and needing yet another vaccine dose? Does a fourth dose help, and if so, for how long? Will waste water surveillance with sequencing help us recognize an evolving process early? Will the proposed vaccine for all Omicron variants work? How effective are masks and mandates in a world of COVID fatigue and very high transmissibility? And finally, what's the best course of action to fight BA.4 and BA.5 now and keep us safe?

The answer is likely testing, appropriate masking, ventilating properly, and vaccinating, as well as continued excellent biological and public health research to answer the many remaining questions.

Peter Katona, MD, is a clinical professor of Medicine in Infectious Diseases at the David Geffen School of Medicine and adjunct professor of Public Health at the Fielding School of Public Health at UCLA.

https://www.medpagetoday.com/opinion/second-opinions/99082

T1D Patient Achieves Full Insulin Independence After Stem Cell Transplant

 A stem-cell treatment restored insulin production and glucose control in two patients with type 1 diabetes (T1D), a researcher reported.

Following a 40-year history of T1D riddled with complications, a 64-year-old man received a single infusion with the investigational treatment VX-880 at a half target dose, said James F. Markmann, MD, PhD, of Massachusetts General Hospital in Boston, during the American Diabetes Association (ADA) annual meeting.

Developed by Vertex Pharmaceuticals, the treatment works as an allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy.

By day 90 of the phase I/II clinical trial, the patient experienced a slew of improvements in measures of pancreatic islet function and glycemic control:

• Fasting C-peptide level: undetectable at baseline vs 280 pmol/L at day 90
• Peak stimulated C-peptide level with mixed meal tolerance test: undetectable at baseline vs 560 pmol/L at day 90
• HbA1c: 8.6% at baseline vs 7.2% at day 90

The patient's daily insulin dose also dropped from 34 units/day down to only 2.9 units/day, representing a 91% decrease in daily exogenous insulin use. Moreover, glycemic variability dropped from 41.8% to 27.5% as measured by a continuous glucose monitor. Time spent in target range -- 70 to 180 mg/dL -- increased from 40.1% to 63.2%.

These measures continued to improve by day 150, Markmann said. At this time point, fasting C-peptide levels increased to 404 pmol/L and HbA1c dropped down to 6.7%. Time spent in target range also increased to 81.4%.

By day 270 after the initial half dose infusion, this patient achieved complete insulin independence, an HbA1c of 5.2%, and spent 99.9% of time in target range.

"This is the first-in-the-world administration of stem cell-derived islets in this manner where they're infused into the liver," Markmann said during an ADA press conference. "In the experience with cadaveric islets, the only site that was effective at really gaining full glycemic control was the liver. And so this was the first attempt to really have an important impact on the patient's glycemic control."

"This does bring hope that's closer than it was before," he added. "This is, I think, groundbreaking work and a real leap forward for the field."

The second patient in the study, who is 150 days out of the initial infusion, saw similarly promising results. This patient increased time spent in range (35.9% at baseline to 51.9% at day 150), lowered HbA1c (7.5% to 7.1%), and decreased daily insulin need (25.9 units to 18.2 units).

The stem cell treatment was administered as a single infusion at half the target dose. The infusion was delivered into the hepatic portal vein and required chronic immunosuppressive therapy in order to protect the islet cells from immune rejection.

"The patient had received an immunosuppression regimen that had been developed for the phase III clinical islet transplant consortium trials that had finished a couple years ago," Markmann elaborated. "It consisted of completion of lymphocytes at induction and then a maintenance regimen with two standard agents that we use in kidney transplant patients and others all the time -- that's a regimen that we found to be generally well-tolerated."

He pointed out that immunosuppression isn't for all patients, and therefore they're only targeting patients for whom the risk/benefit considerations make sense.

"This is part one of a two-part problem," he noted. "Part one is to have a reliable, consistent, effective cell therapy. The second part is to have an approach that doesn't require immunosuppression."

Right now the patients being targeted are patients with an absence of endogenous insulin production, impaired awareness of hypoglycemia and severe hypoglycemic events. Providing an update on patient 1, Markmann said he is "doing great" and "probably the most appreciative patient I've ever met."

"His life was being destroyed by diabetes. He couldn't work, he crashed his motorcycle from lows, and really was tremendously appreciative that he could participate," he added. "These people really suffer and this, I think, brings hope to them."

"If we had a way to transplant the cells without the need for immunosuppression, then it could be really widely available," Markmann continued. "That's one of the great opportunities hopefully in the future, since these cells can be made in unlimited quantities."

He explained that this is only the first step in a three-part clinical trial -- acting as the proof-of-concept "Part A" of the phase I/II study. So far, a third patient in Part B of the study has received a full target dose of VX-880, which was well-tolerated. Following these positive results at the half target dose, there are plans in place for a dose-escalation study, followed by a full-dose study. Five patients are planned to receive the full target dose in Part B.

However, last month the FDA placed a clinical hold on the study, stating that there was insufficient information to support the dose-escalation phase.

"The team at Vertex is working with the FDA to address the issues that were brought up regarding having enough justification to do the dose escalation," Markmann said, adding that his team is hoping for a quick resolution.

Disclosures

The study was funded by Vertex Pharmaceuticals.

Markmann and co-authors reported several relationships with pharmaceutical companies, including with Vertex Pharmaceuticals.

Primary Source

American Diabetes Association

Source Reference: Markmann JF, et al "Stem cell-derived, fully differentiated islet cells for type 1 diabetes" ADA 2022; Abstract 259-OR.

https://www.medpagetoday.com/meetingcoverage/ada/99083

VBI Updated Phase 2a Tumor Response and Overall Survival Data in Glioblastoma

  Median overall survival and 18-month overall survival data continue to show improvements over historical controls1

- One patient remains on protocol progression-free beyond two years, with a sustained 93% tumor reduction relative to baseline
- Next steps :

• Recurrent GBM: randomized, controlled evaluation with potential to support accelerated approval application expected to initiate in Q3 2022

• Primary GBM: randomized, controlled evaluation in the frontline setting expected to initiate in Q4 2022 as part of INSIGhT adaptive platform trial

https://finance.yahoo.com/news/vbi-vaccines-presents-updated-phase-120000913.html

Emergent says J&J breached vaccine contract

 Contract manufacturer Emergent BioSolutions Inc said on Monday U.S. drugmaker Johnson & Johnson had breached an agreement by failing to buy the minimum quantity of COVID-19 vaccines made by the company.

Emergent said J&J had failed to provide required forecasts for the amount of vaccines it needed and had wound down the agreement instead of fulfilling minimum requirements.

If the agreement is terminated, Emergent said J&J would owe it roughly $125 million to $420 million.

J&J did not immediately respond to Reuters' request for comment.

The use of J&J's COVID-9 vaccine has been stalled in the United States as the Food and Drug Administration in May had significantly restricted its use due to safety concerns.

J&J has also pulled its COVID-19 vaccine sales forecast for the year due to a supply glut led by low demand globally.

Manufacturing at Emergent's Baltimore plant was briefly halted last year after a discovery that ingredients from AstraZeneca's COVID-19 vaccine, also being produced there at that time, contaminated a batch of J&J's vaccines.

https://finance.yahoo.com/news/contract-manufacturer-emergent-says-j-125716810.html