'Moderna reveals new highly targeted COVID-19 vaccine mRNA-1283'

 Moderna has developed a new and improved version of its COVID-19 vaccine. The unique formulation (mRNA-1283) reduces the vaccine's content from the full-length SARS-CoV-2 spike protein to a narrowly focused encoding of just two segments—the N-terminal domain (NTD) and the receptor binding domain (RBD).

In a paper, "Domain-based mRNA vaccines encoding spike protein N-terminal and receptor binding domains confer protection against SARS-CoV-2," published in Science Translational Medicine, Moderna Inc. researchers share findings of the new vaccine.

Some of the highlights of the new formula include:

• Improved antigen expression: mRNA-1283 demonstrated improved antigen expression compared to the clinically available mRNA-1273, which encodes the full-length spike protein. This suggests that mRNA-1283 can produce higher levels of the target antigens.

• Enhanced antibody responses: When administered as a primary series, booster, or variant-specific booster, mRNA-1283 elicited similar or greater immune responses than the original mRNA-1273.

• Greater stability: mRNA-1283 showed greater stability at refrigerated temperatures (2° to 8°C). Specifically, mRNA-1283 reached 62% of its initial integrity at 12 months when stored at 2° to 8°C, while the original version reached 63% integrity after only six months under the same conditions, effectively doubling the shelf life.

• Dose-sparing: mRNA-1283 demonstrated the ability to elicit effective immunogenic responses even at lower doses, suggesting the possibility of dose-sparing, which could reduce potential reactogenicity.

• Protection against variants: mRNA-1283, including variant-specific versions, produced more significant neutralizing antibody (nAb) responses against variants such as B.1.351 and B.1.617.2 compared to mRNA-1273, indicating its effectiveness against emerging variants.

Protection in animal models

In animal studies, mice vaccinated with mRNA-1283 were protected from both the D614G mutation and BA.1 variants of SARS-CoV-2, further suggesting that mRNA-1283 can confer protection against different strains of the virus.

Overall, mRNA-1283 offers several advantages, including improved antigen expression, strong immune responses, stability, and dose-sparing, making it a promising candidate for further clinical evaluation as a COVID-19 vaccine.

Early research on the SARS-CoV-2 virus identified the spike protein as a critical component of viral entry into host cells. This knowledge laid the foundation for the original vaccine development by Moderna, which encoded the entire length of the spike protein in the original vaccine formulation.

Researchers have since recognized that not all parts of the spike protein are equally crucial for immune responses. Certain regions, particularly the receptor binding domain (RBD) and the N-terminal domain (NTD), were identified as critical sites for neutralization by antibodies.

Extensive research into the structure and function of the SARS-CoV-2 virus, including its spike protein, provided valuable insights into potential vaccine targets. Scientists used this research to design vaccines specifically focused on the RBD, NTD, or a combination of these domains.

A combination of a deep understanding of the virus, advances in vaccine technology, and rigorous scientific research contributed to the discovery that domain-based vaccines like mRNA-1283 can focus on just the critical antigenic domains of the spike protein.

An effective streamlined and targeted vaccine should also allow for a shorter response time to emerging strains as reformulation efforts only need to focus on the changes of two sites on the virus spike protein.

More information: Guillaume B. E. Stewart-Jones et al, Domain-based mRNA vaccines encoding spike protein N-terminal and receptor binding domains confer protection against SARS-CoV-2, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.adf4100

https://medicalxpress.com/news/2023-09-moderna-reveals-highly-covid-vaccine.html

Can a vitamin transform natural killer cells into a cancer therapy?

 Cancer patients appeared to benefit from natural killer cells obtained from donors in an experimental method of treating cancer that involved an aggressive army of immune system fighters endowed with the ability to home in on malignant cells and destroy them.

The natural killer cells were pre-treated with nicotinamide, a compound widely known to most people as niacin, or vitamin B3. It's a substance with a special affinity for natural killer cells, enhancing their capacity to annihilate cancers. Once primed in the laboratory, these natural killers are ready to be unleashed against formidable targets. The evolving methodology has shown promise in a preliminary study aimed at forcing hard-to-treat cancers of the blood into remission.

Prior to the new research, which is published in Science Translational Medicine, attempts by other teams to use natural killer cell infusions as a therapeutic for leukemias, lymphomas and other blood malignancies, weren't always effective. Doctors were confronted with a problem: some people simply didn't respond to the investigational treatment, which was offered after standard therapy failed.

Now, in a unique take on this emerging form of cancer treatment, medical scientists in the Division of Hematology, Oncology and Transplantation at the University of Minnesota, have devised a way to boost the effectiveness of natural killer cells, enhancing their role as a therapeutic. The innovative approach boosted the impact of natural killer cells and brought about remissions in patients with otherwise recalcitrant cancers.

"Allogeneic natural killer cell adoptive transfer has shown the potential to induce remissions in relapsed or refractory leukemias and lymphomas," writes Dr. Frank Cichocki and colleagues in the journal. "Strategies to enhance natural killer cell survival and function are needed to improve clinical efficacy. We demonstrated that natural killer cells cultured ex vivo with interleukin-15—IL-15—and nicotinamide exhibited stable induction of l-selectin, a lymphocyte adhesion molecule important for lymph node homing."

Nicotimamide helps the body turn food into energy and is chemically part of the coenzymes NAD+ and NADH, which are critical in oxidation-reduction reactions throughout the body. Among these activities is the production of adenosine triphosphate, ATP, which fuels cellular and metabolic processes.

In 1937, researchers discovered that the systemic disease known as pellegra is caused by a niacin deficiency. The disorder is typified by the three D's—dementia, diarrhea and dermatitis. Without treatment, which is simply providing niacin, pellegra can be fatal.

The team's choice of nicotinamide as an enhancer of natural killer cells shines a spotlight on the common water-soluble compound and demonstrates how it can boost the anti-cancer activity of natural killer cells. These cells are lymphocytes and members of the innate immune system, the body's first response to invasive disease. Natural killer cells' job is helping control cancer and invasive microbes.

Scientists, meanwhile, who are developing the experimental therapy have merely boosted these cells to help them attack cancers more efficiently. If further testing proves this method effective—and the Minneapolis-based scientists are convinced they're on the right track—then an innovative new approach to treating cancers of the blood will emerge.

"We conducted a first-in-human phase 1 clinical trial testing adoptive transfer of natural killer cells expanded ex vivo with IL-15 and nicotinamide combined with monoclonal antibodies in patients with relapsed or refractory non-Hodgkin lymphoma and multiple myeloma," Cichocki asserted in Science Translational Medicine.

In the small preliminary study, Cichocki and collaborators found that nicotinamide not only enhances the activity of natural killer cells but boosts their persistence in the blood and bolsters the capability of these cells not only to hunt down cancer cells, but to handily destroy them.

The combination of nicotinamide-enhanced natural killer cells and monoclonal antibody treatment was safe in 30 patients, including 20 with relapsed or difficult-to-treat non-Hodgkin lymphoma. Among 19 patients with non-Hodgkin lymphoma, 11 demonstrated a complete response and three had a partial response within 28 days of treatment. Nicotinamide appears to protect the natural killer cells from oxidative stress, while enhancing their ability to home in on lymph nodes, the team found.

"High frequencies of CD62L were associated with elevated transcription factor forkhead box O1, or FOXO1," Cichocki noted, referring to the homing molecule, CD62L, which shepherds natural killer cells to the lymph nodes. As a transcription factor, FOXO1 is responsible regulating a broad number of genes involved in metabolism, cell cycle progression and programmed cell death.

In cancers, FOXO1 acts as a suppressor of malignant cells mainly because of its roles promoting programmed cell death—apoptosis—and inhibiting cell cycle progression, angiogenesis and metastasis.

"Nicotinamide promoted the stability of FOXO1 by preventing proteasomal degradation," Cichocki lead author of the study added. "Natural killer cells cultured with nicotinamide exhibited metabolic changes associated with elevated glucose flux and protection against oxidative stress."

Natural killer cells treated with nicotinamide in the lab also demonstrated an increased ability to generate an inflammatory and toxic response against cancer cells. Cichocki and colleagues concluded that their findings suggest the new transfer strategy should be studied further in larger clinical trials.

More information: Frank Cichocki et al, Nicotinamide enhances natural killer cell function and yields remissions in patients with non-Hodgkin lymphoma, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.ade3341

https://medicalxpress.com/news/2023-09-vitamin-natural-killer-cells-cancer.html

Samsung Biologics expands agreement with Bristol to manufacture antibody cancer substance

 Samsung Biologics (KRX: 207940.KS) announced today a new agreement with Bristol Myers Squibb (NYSE: BMY) for large-scale manufacturing of a Bristol Myers Squibb commercial antibody cancer drug substance.

Bristol Myers Squibb and Samsung Biologics have an existing manufacturing agreement for a commercial antibody cancer drug and have expanded the strategic relationship over time. Under the terms of the new agreement, Samsung Biologics will provide drug substance manufacturing for an antibody cancer drug substance at the company's latest and largest biomanufacturing facility, Plant 4, in Songdo, South Korea. 

https://www.marketscreener.com/quote/stock/BRISTOL-MYERS-SQUIBB-COMP-11877/news/Samsung-Biologics-announces-expanded-strategic-agreement-with-Bristol-Myers-Squibb-to-manufacture-an-44859981/

Blair: PTC Could Overturn Regulatory Challenge

 Friday morning, the Committee for Medicinal Products for Human Use of the European Medicines Agency gave a negative opinion on the conversion of the conditional marketing authorization to full marketing authorization of PTC Therapeutics Inc's PTCT Translarna (ataluren) for nonsense mutation Duchenne muscular dystrophy. 

The negative opinion also applies to the renewal of the existing conditional authorization. 

PTC plans to submit a request for re-examination. Translarna will remain on the market and available until the re-examination process is completed. 

Following the re-examination process, the opinion would be expected to occur in January 2024, with the European Commission ratifying the opinion within the following 67 days.

Translarna received conditional marketing authorization in Europe in 2014 based on the results of Study 007, and the conditional authorization was renewed in 2017. 

PTC agreed to conduct a third placebo-controlled trial, Study 041, to renew the conditional marketing authorization. 

PTC shared the results of Study 041, which included nominally statistically significant results on several key endpoints in the overall enrolled Intent-to-Treat population of 359 boys, even though it did not meet statistical significance in the primary analysis subgroup.

William Blair considers the update to be unexpected and unfortunate; it's essential to note that PTC has previous experience in overturning the CHMP's stance on Translarna. 

In 2014, the CHMP initially issued a negative opinion regarding Translarna's conditional marketing authorization, and PTC successfully reversed that decision.

Moreover, in 2017, PTC effectively negotiated the renewal of Translarna's conditional marketing authorization, which included the commitment to conduct a long-term post-authorization trial.

Additionally, the analyst finds the change in rapporteur for the re-examination process and the positive data from all three studies, particularly when analyzing the 300-400m 6MWT baseline population as the primary group, to be supportive of the potential to overturn the CHMP's decision.

https://www.benzinga.com/analyst-ratings/analyst-color/23/09/34624156/european-authority-gives-thumbs-down-to-ptc-therapeutics-duchenne-therapy-analyst-s

New COVID Vaccines Force Bivalents Out­

 COVID vaccines will have a new formulation this year, according to a decision announced today by the US Food and Drug Administration that will focus efforts on circulating variants. The move pushes last year's bivalent vaccines out of circulation because they will no longer be authorized for use in the United States.

The updated mRNA vaccines for 2023-2024 are being revised to include a single component that corresponds to the Omicron variant XBB.1.5. Like the bivalents offered before, the new monovalents are being manufactured by Moderna and Pfizer.

The new vaccines are authorized for use in individuals age 6 months and older. And the new options are being developed using a similar process as previous formulations, according to the FDA.

Targeting Circulating Variants

In recent studies, regulators point out the extent of neutralization observed by the updated vaccines against currently circulating viral variants causing COVID-19, including EG.5, BA.2.86, appears to be of a similar magnitude to the extent of neutralization observed with previous versions of the vaccines against corresponding prior variants.

"This suggests that the vaccines are a good match for protecting against the currently circulating COVID-19 variants," according to the report.

Hundreds of millions of people in the United States have already received previously approved mRNA COVID vaccines, according to regulators who say the benefit to risk profile is well understood as they move forward with new formulations.

"Vaccination remains critical to public health and continued protection against serious consequences of COVID-19, including hospitalization and death," Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research, said in a statement. "The public can be assured that these updated vaccines have met the agency's rigorous scientific standards for safety, effectiveness, and manufacturing quality. We very much encourage those who are eligible to consider getting vaccinated."

Timing the Effort

The US Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices will meet tomorrow to discuss clinical recommendations on who should receive an updated vaccine, as well as further considerations for specific populations such as immunocompromised and older people.

Manufacturers have publicly announced that updated vaccines will be ready this fall and the FDA says it anticipates the updated vaccines will be available soon.

https://www.medscape.com/s/viewarticle/996300

Former Border Patrol Chief: Agents Can't Vet Illegal Immigrants From "Vast Majority Of The Globe"

 by Savannah Hulsey Pointer via The Epoch Times (emphasis ours),

Former Chief of Border Patrol Rodney Scott explained to members of the House that the vetting process used to keep criminals out of the United States is only accurate in cases where agents have access to correct information.

According to the former border chief, agents have no information about migrants from "the vast majority of the globe," including illegal immigrants from countries like the African nation of Mauritania.

Mr. Scott told the House Judiciary Subcommittee on Immigration Integrity, Security, and Enforcement during a Sept. 14 hearing that the process used by border protection agents is only as good as the information that the federal government has access to, which, globally speaking, is quite limited.

The witness, who is currently a Distinguished Senior Fellow for Border Security at the Texas Public Policy Foundation, formerly served for 29 years in the U.S. Border Patrol before retiring as Chief of the Border Patrol in August of 2021.

Questions about illegal immigrants from Mauritania surfaced after data about increased apprehensions by border patrol agents of individuals on the terror watch list was brought to light.

According to the lawmakers, from 2017 to 2020, Border Patrol encountered 14 illegal immigrants on the terror watch list.

But from 2021 to 2023, that number jumped to 263, and 149 of those encounters were in 2023 up to this point alone.

While several lawmakers voiced concern about potential known and unknown "gotaways" which could also have been problematic, Rep. Andy Biggs (R-Ariz.) questioned Mr. Scott about the potential that those not on any list the United States has access to could have terror connections.

Mr. Biggs asked if there were nations that illegal immigrations were traveling from that federal officials "can't get any background on?"

Mr. Scott responded, "That would be the vast majority of the globe. We have very little information. We act on what we have, but when you think about the total population of the world, we have very, very minuscule data."

Rodney Scott, retired Chief of the U.S. Border Patrol, testifies before the House Subcommittee on Immigration Integrity, Security, and Enforcement on Capitol Hill in Washington on May 23, 2023. (Win McNamee/Getty Images)

Mr. Biggs asked specifically about individuals from the nation of Mauritania, saying border patrol in his home state of Arizona has seen a sharp increase in illegal migrants from that area.

The lawmaker cited a call from a Customs and Border Patrol (CBP) agent asserting that in his Arizona sector, they apprehended a group of 250 Mauritanians.

According to Mr. Scott, Mauritania is a country that CBP has no access to background information about, and individuals from that area would have been largely unvetted.

'Fear-Mongering'

Committee ranking member Pramila Jayapal (D-Wash.) asked that the committee consider the "facts" pointing out during her opening statement that there has never been an American citizen killed due to terrorist attacks from an individual that has entered the United States illegally through the southern border.

"That's right," the Washington Democrat went on. "Not a single American has been injured or killed by a terrorist who crossed our southern border without authorization. So don't fall for Republican fear-mongering.

"This hearing is purely intended to scare the public to demonize immigrants and to score cheap political points as we head towards that next election," Ms. Jayapal said, going on to point out that those on the terror watch list who were apprehended were given vetting by the Department of Homeland Security.

Rep. Pramila Jayapal (D-Wash.) in Washington on April 28, 2022. (Kevin Dietsch/Getty Images)

She also asserted that bipartisan immigration reform could deter illegal immigration by creating "real legal pathways for people to enter the United States to be with their families to escape terrible situations in their countries and to contribute to our economy, our communities, and our country."

During his opening remarks, Committee Chairman Tom McClintock (R-Calif.) asserted that the Biden administration's executive orders have "opened our borders to the world by holding construction of the border wall, rescinding the remain in Mexico policy, and forbidding ICE from enforcing court-ordered deportations."

5.7 Million Illegals

Mr. McClintock cited information indicating that 5.7 million illegal aliens from over 160 countries have illegally crossed our border since the Biden administration's change in policy, and over 2.6 million of those individuals have been released into the United States. That number is higher than the population of New Mexico.

"Another 1.7 million known 'gotaways' have entered as well. That's an additional illegal population the size of West Virginia, and since we have no access to most foreign criminal databases," Mr. McClintock said. "We know little of the foreign criminal records of these 2.6 million illegal immigrants as they've been released into our communities."

https://www.zerohedge.com/political/former-border-patrol-chief-says-agents-cant-vet-illegal-immigrants-vast-majority-globe

Tax Rebate Loans Can Better Aid the Unemployed

 The Covid-19 pandemic drew attention to America’s ramshackle system of Unemployment Insurance.  As the number of claimants surged from 2 million in February to 21 million in May 2020, a third of benefits were not paid, as antiquated computer systems left many states unable to process applications. And today, the federal Government Accountability Office found that “fraudsters may have stolen $1 of every $7 in covid jobless aid,” that is, over $135 billion.

Even if it functioned as intended, America’s 87-year-old UI system is poorly suited to the modern economy.  It provides meager support to workers who most need help, entirely excludes those at greatest risk of being laid off, and mostly distributes aid to households who have little need for assistance. 

Congress would do well to set up a more robust and better targeted UI system before the next crisis hits: unemployed workers should be allowed to claim back up to $500 per week of taxes from the two previous tax years as an income-contingent loan, which they would repay with an additional 2% income tax after their return to work. The current 6% unemployment insurance tax on the first $7,000, then, could be done away with.

When workers suddenly lose their jobs, bills keep coming: housing costs, utilities, food, car loans, home repairs, and parenting expenses.  The median unemployment spell lasts for 8 weeks; but in 2022, only 37% of households had emergency savings sufficient to cover a month of lost income. 

The current Unemployment Insurance system is supposed to tide people over.  Federal law imposes a 6% payroll tax on the first $7,000 of earnings (effectively a $420 head tax on workers), which states can mostly capture by setting up their own compliant UI systems.  Benefits nationwide average $416 per week, but terms vary greatly between states.

States design benefits with an eye to mitigating disincentives to work: payments are proportioned according to prior wages (typically 50% of weekly earnings up to a cap), limited in duration (most often 26 weeks), and eligibility is restricted to workers fired without cause.  In 2022, the unemployed in Massachusetts could claim up to $37,986, while the maximum in Alabama was only $3,850.  Whereas 43% of the unemployed in Massachusetts received benefits, only 7% in Alabama did.

As a result, the system provides much larger benefits to those with higher prior earnings, even though such workers are generally able to self-insure against income risks with private savings and borrowing.  By contrast, those in the most insecure employment circumstances (the self-employed, gig workers, or those holding multiple jobs) are typically entirely ineligible for benefits.  In 2019, 64% of unemployment compensation went to families with incomes above the median.

UI benefits provide an implicit subsidy for firms to hire and fire workers in line with seasonal fluctuations in demand.  Indeed, most laid off workers are subsequently rehired by the same employer.  States attempt to deter this by adjusting employers’ UI payroll taxes in line with their past claims; but doing so concentrates the burden on businesses in declining industries.

Income-contingent loans would be better suited to assisting those temporarily pinched.  By maintaining personal responsibility over time, these could allow unemployment assistance to be made more broadly available to those in the greatest need, without deterring employment, imposing taxes on businesses, or encouraging claims by those who can provide for themselves. 

A new Manhattan Institute report recommends that the current patchwork of state UI benefits and their associated taxes should be replaced by a new national system.  This should allow unemployed workers to claim weekly benefits worth 50% of their average weekly income for the previous two tax years, up to $500, for up to six months – an amount similar to their Social Security payroll tax contributions over the previous two years.  Households claiming such benefits should subsequently be subject to an additional 2% income tax, until they have paid back whatever assistance they have claimed.

Such a system would greatly expand the availability of funds to workers in the most insecure employment circumstances.  But it would also cut out the bulk of payments to workers with the means to privately absorb income shocks – allowing the ramshackle present structure of UI taxes and bureaucracy to be eliminated.

Chris Pope is a senior fellow at the Manhattan Institute.

https://www.realclearpolicy.com/articles/2023/09/14/tax_rebate_loans_can_better_aid_the_unemployed_979675.html