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Stealth Mission: Novel mRNA Vaccine Delivery System

In this final webinar of a four-part series on RNA, cohosted by GEN and The CRISPR Journal, we will delve into the delivery question surrounding mRNA…

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Broadcast Date:  October 21, 2022
Time: 8:00 am PT, 11:00 am ET, 17:00 CET

The recent success of mRNA vaccines during the COVID pandemic has vaulted this technology from its humble research beginnings to international recognition by the scientific and medical community as a groundbreaking measure in combating a host of diseases. The delivery of mRNA molecules has been dominated by the use of lipid nanoparticles (LNPs). However, while LNPs have proven effective, they provide investigators with several challenges—most importantly, the activation of unwanted cell-mediated immune responses. Alternative mRNA delivery systems offer the capability to stealthily deliver nucleic acids to their target and evade the immune system while generating a potent antigen-specific CD8+ T-cell response.

In this final webinar of a four-part series on RNA, cohosted by GEN and The CRISPR Journal, we will delve into the delivery question surrounding mRNA research and therapeutics. Dr. Helen McCarthy will review the key issues around RNA delivery and describe a novel peptide-based drug delivery system that her company has developed. This system is based on a sequence of 30 amino acids and condenses anionic cargo, like mRNA, irrespective of size, into nanoparticles for highly efficient entry into cells.

 

A live Q&A session followed the presentation, offering a chance to pose questions to our expert panelist.

Helen McCarthy, PhD
CEO, pHion Therapeutics
Professor, Queen’s University Belfast

TriLink Biotechnologies logo

The post Stealth Mission: Novel mRNA Vaccine Delivery System appeared first on GEN - Genetic Engineering and Biotechnology News.

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FDA’s drug shortages leader wants companies to start reporting increases in demand

It is no secret that drug shortages have been prevalent in 2022. Several major drug products, such as amoxicillin and Adderall, have been in short supply…

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It is no secret that drug shortages have been prevalent in 2022. Several major drug products, such as amoxicillin and Adderall, have been in short supply for several months and have led to members of Congress applying pressure on the FDA and HHS to resolve the situation.

Valerie Jensen

Speaking at a webinar hosted by the Alliance for a Stronger FDA, Valerie Jensen, the associate director of the FDA’s Drug Shortage Staff, noted both the rise in quality-related issues and increased demand for some products. She called on companies to report such demand increases, even though they are not currently required to do so.

During the Covid-19 pandemic, she said, the agency has seen new challenges mainly related to these increases in demand.

“During the pandemic as well, we had competition on manufacturing lines and that’s still occurring due to vaccine production and other Covid products,” Jensen said. “So, the same products are being made on those lines that are making the vaccines and Covid-related products, and then that creates a competition situation.”

Jensen added that an increase in demand for manufacturing commodities due to large-scale vaccine production is also leading to shortages. Items such as glass, filters and vial hoppers are in short supply. And now the increased demand is centered around the increase in drugs to counter respiratory illnesses.

She said the physical number of drug shortages currently sits at 123, which is “a little above normal,” but there have been around 100 shortages at any given time over the past seven years. Some of those can be chalked up to companies not producing the volumes required to meet market demand. She also added that there were 38 new shortages in 2021, but the FDA is still dealing with them this year.

For some temporary solutions, Jensen said that she has been coordinating with international regulatory authorities more often, to find out what is being marketed and to see if they can import a drug in short supply in the US. She is also coordinating experts to try to mitigate the situation, providing the public with widely available information as well as expediting the review of anything that manufacturers need to boost supplies.

However, Jensen said that the increase in the demand for drugs is not something that will be going away anytime soon.

“One thing that we really see going forward are these demand increases, this is something that is fairly new to us. It’s something that we’re looking at closely,” she said. “We would really want companies to inform us if they’re seeing spikes in demand because that’s currently not required.”

While producers do need to let the FDA know of supply disruption, companies do not need to let the FDA know of spikes in demand, and Jensen would like to see this changed. Also, she would like to apply different uses for supply chain data to look for signals or patterns and ultimately predict shortages.

Jensen added that in some cases it is impossible to prevent a shortage, but she stresses that better notification of when companies are seeing a spike in demand can be a key solution:

In those cases, when we can prevent (a shortage), we are using those same tools to prevent it. So, we’re expediting review, we’re looking at potential ways that we can use flexibility to allow a product to be on the market while the company fixes a problem. All of those tools are really the same for prevention and mitigation. But I think that really the key is early notification. The earlier companies let us know about an issue the earlier we can deal with it.

With the uptick in respiratory illnesses and shortages of drugs such as amoxicillin, Jensen noted that it’s a matter of reaching out and monitoring the market to see what manufacturers are contending with. Also, Jensen will look to work with pharmacy associations and other trade groups to see what is occurring at the pharmacy level and then “put all of those pieces together” to try and help end the shortage.

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nTIDE November 2022 Jobs Report: People with disabilities continue to outperform people without disabilities in labor market

East Hanover, NJ – December 2, 2022 – Job numbers rose again for people with disabilities, in contrast to people without disabilities, according to…

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East Hanover, NJ – December 2, 2022 – Job numbers rose again for people with disabilities, in contrast to people without disabilities, according to today’s National Trends in Disability Employment – Monthly Update (nTIDE), issued by Kessler Foundation and the University of New Hampshire’s Institute on Disability (UNH-IOD). People with disabilities continued to show strength in the labor market in November, as evidenced by the substantial rise in their employment-to-population ratio.

Credit: Kessler Foundation

East Hanover, NJ – December 2, 2022 – Job numbers rose again for people with disabilities, in contrast to people without disabilities, according to today’s National Trends in Disability Employment – Monthly Update (nTIDE), issued by Kessler Foundation and the University of New Hampshire’s Institute on Disability (UNH-IOD). People with disabilities continued to show strength in the labor market in November, as evidenced by the substantial rise in their employment-to-population ratio.

Month-to-Month nTIDE Numbers (comparing October 2022 to November 2022)

Based on data from the U.S. Bureau of Labor Statistics (BLS) Jobs Report released today, the employment-to-population ratio for people with disabilities (ages 16-64) increased from 35.5 percent in October to 36.5 percent in November (up 2.8 percent or 1 percentage point). For people without disabilities (ages 16-64), the employment-to-population ratio decreased from 74.6 percent in October to 74.4 percent in November (down 0.3 percent or 0.2 percentage point). The employment-to-population ratio, a key indicator, reflects the percentage of people who are working relative to the total population (the number of people working divided by the number of people in the total population multiplied by 100).

“Similar to last month, the employment-to-population ratio for people with disabilities increased and remains above historic highs. For those without disabilities, however, the ratio dropped,” said John O’Neill, PhD, director of the Center for Employment and Disability Research at Kessler Foundation. “This decline may be a sign of the Fed’s efforts to slow the labor market. This is interesting in light of this month’s strong gain for people with disabilities.”

Findings were similar for November’s labor force participation rate. For people with disabilities (ages 16-64), the labor force participation rate was increased slightly from 38.7 percent in October to 38.8 percent in November (up 0.3 percent or 0.1 percentage point). Conversely, the labor force participation rate decreased slightly for people without disabilities (ages 16-64), from 77.1 percent in October to 76.9 percent in November (down 0.3 percent or 0.2 percentage point). The labor force participation rate is the percentage of the population that is working, not working, and on temporary layoff, or not working and actively looking for work.

“While labor force participation for people with disabilities remains stable, increases in the employment to population ratio for people with disabilities suggest that more people with disabilities are succeeding in finding jobs,” remarked Debra Brucker, PhD, research associate professor at the UNH-IOD. “Keep in mind that gains in employment may in part reflect the need to boost income in the face of rising prices. Also, these data are not seasonally adjusted, so some of this increase may be due to seasonal employment.”

Why have people with disabilities been outperforming people without disabilities? Favorable changes in the workplace as employers adapted to COVID-19 restrictions may be a factor. Our new survey compares the workplaces of 2017 and 2022, revealing gains in recruiting, hiring, accommodating, and retaining employees with disabilities. Read more about the 2022 National Employment & Disability Survey: Effects of COVID-19 Pandemic Supervisor Perspectives.

Year-to-Year nTIDE Numbers (Comparing November 2021 to November 2022)

Reflecting the continued strength of the employment of people with disabilities over the course of the year, the employment-to-population ratio for working-age people with disabilities increased substantially from 34.6 percent in November 2021 to 36.5 percent in November 2022 (up 5.5 percent or 1.9 percentage points). However, the employment-to-population ratio increased slightly for working-age people without disabilities, from 73.8 percent in November 2021 to 74.4 percent in November 2022 (up 0.8 percent or 0.6 percentage points).

Similarly, for people with disabilities (16-64), the labor force participation rate increased substantially from 37.7 percent in November 2021 to 38.8 percent in November 2022 (up 2.9 percent or 1.1 percentage points). The labor force participation rate increased slightly for people without disabilities (ages 16-64), from 76.7 percent in November 2021 to 76.9 percent in November 2022 (up 0.3 percent or 0.2 percentage points).

In November, among workers ages 16-64, the 5,962,000 workers with disabilities represented 4 percent of the total 148,009,000 workers in the U.S.

Ask Questions about Disability and Employment

Each nTIDE release is followed by an nTIDE Lunch & Learn online webinar. This live broadcast, hosted via Zoom Webinar, offers attendees Q&A on the latest nTIDE findings, provides news and updates from the field, as well as invited panelists to discuss current disability-related findings and events. On December 2, 2022 at 12:00 pm Eastern, Chai Feldblum, JD, vice chair the of Ability One Commission, a federal agency devoted to the employment of people with significant disabilities, joins Drs. O’Neill and Brucker, and Denise Rozell, Policy Strategist at the Association of University Centers on Disabilities (AUCD). Join our Lunch & Learns live or visit the nTIDE archives at: ResearchonDisability.org/nTIDE.

NOTE: The statistics in the nTIDE are based on Bureau of Labor Statistics numbers but are not identical. They are customized by UNH to combine the statistics for men and women of working age (16 to 64). nTIDE is funded, in part, by grants from the National Institute on Disability, Independent Living and Rehabilitation Research (NIDILRR) (90RT5037) and Kessler Foundation.

About the Institute on Disability at the University of New Hampshire

The Institute on Disability (IOD) at the University of New Hampshire (UNH) was established in 1987 to provide a university-based focus for the improvement of knowledge, policies, and practices related to the lives of persons with disabilities and their families. For information on the NIDILRR-funded Research and Training Center on Disability Statistics, visit ResearchOnDisability.org.

About Kessler Foundation

Kessler Foundation, a major nonprofit organization in the field of disability, is a global leader in rehabilitation research that seeks to improve cognition, mobility, and long-term outcomes – including employment – for people with neurological disabilities caused by diseases and injuries of the brain and spinal cord. Kessler Foundation leads the nation in funding innovative programs that expand opportunities for employment for people with disabilities. For more information, visit KesslerFoundation.org.

Stay Connected with Kessler Foundation

Twitter | Facebook | YouTube | Instagram | iTunes & SoundCloud

To interview an expert, contact:

Deborah Hauss, DHauss@kesslerfoundation.org;

Carolann Murphy, CMurphy@KesslerFoundation.org.

 

 


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Scientists reveal encouraging findings in first-in-human clinical trial evaluating HIV vaccine approach

NEW YORK and LA JOLLA, CA—While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy being…

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NEW YORK and LA JOLLA, CA—While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy being pursued by researchers at Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) shows new promise, according to data from a first-in-human clinical trial.

Credit: CHRISTOPHER COTTRELL, CREATED WITH BIORENDER.COM

NEW YORK and LA JOLLA, CA—While scientists have struggled in the past to create an effective vaccine against HIV, a novel vaccine design strategy being pursued by researchers at Scripps Research, IAVI, Fred Hutchinson Cancer Center (Fred Hutch) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center (VRC) shows new promise, according to data from a first-in-human clinical trial.

In a paper published in Science on December 2, 2022, the scientists reveal critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants. 

“The data we are publishing in Science demonstrates for the first time that one can design a vaccine that elicits made-to-order antibodies in humans. We specified in advance certain molecular properties of the antibodies that we wanted to elicit, and the results of this trial show that our vaccine antigen consistently induced precisely those types of antibodies,” says co-senior author William Schief, PhD, a professor and immunologist at Scripps Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, whose laboratory developed the vaccine antigen. “We believe this vaccine design strategy will be essential to make an HIV vaccine and may help the field create vaccines for other difficult pathogens.”

The Phase 1 trial, known as IAVI G001, tested the first stage in a multi-stage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favorable safety profile and induced the targeted response in 97% of people who were vaccinated. Importantly, the Science study also provides a detailed immunological analysis of the vaccine responses.

“HIV represents an area of dire unmet need across the world, which is what makes the findings from our Phase 1 clinical trial so encouraging,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “Through the close-knit collaboration of many different scientists, disciplines and institutions, we are that much closer to designing an effective vaccine that could help end the HIV pandemic.”  

Priming the Immune System

Broadly neutralizing antibodies (bnAbs) are a rare type of antibody that can fight and protect against many different variants of a virus—including HIV. This is why scientists have tried to develop an HIV vaccine that induces bnAbs, but thus far without success.   

The researchers in the study are using a strategy known as ‘germline targeting’ to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells—known as bnAb-precursor B cells—that can eventually evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this first step, the researchers designed a customized molecule—known as an immunogen—that would “prime” the immune system and elicit responses from these rare bnAb-precursor cells.

The overarching goal of the IAVI G001 trial was to determine if the vaccine had an acceptable safety profile and could induce responses from these bnAb-precursor B cells.

“Through extensive safety and tolerability monitoring during the trial, we showed the vaccine had a favorable safety profile, while still inducing the necessary target cells,” says study author Dagna Laufer, MD, vice president and head of clinical development at IAVI. “This represents a large step forward in developing an HIV vaccine that is both safe and effective.”

To determine if the targeted bnAb-precursor B cells were induced, the researchers carried out a sophisticated analytical process.

“The workflow of multidimensional immunological analyses has taken clinical trial evaluation to the next level,” says co-senior author Adrian B. McDermott, PhD, former chief of the Vaccine Immunology Program at the NIAID VRC. “In evaluating these important immunological factors, we helped show why the vaccine antigen was able to induce the targeted response in 97% of vaccine recipients.” 

IAVI G001 was sponsored by IAVI and took place at two sites: George Washington University (GWU) in Washington, D.C., and Fred Hutch in Seattle, enrolling 48 healthy adult volunteers. Participants received either a placebo or two doses of the vaccine antigen, eOD-GT8 60mer, along with an adjuvant developed by the pharmaceutical company GSK. Julie McElrath, MD, PhD, co-senior author, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division, and David Diemert, MD, professor of medicine at GWU School of Medicine and Health Sciences, were lead investigators at the trial sites.

A Deeper Immunological Dive

The study also carefully examined the properties of the antibodies and B cells induced by the vaccine antigen, in what Schief likens to “looking under the car hood” to understand how the immune system operated in response to the vaccine. One analysis showed that the vaccine antigen first stimulated an average of 30 to 65 different bnAb precursors per person vaccinated, and then caused those cells to multiply. This helped explain why the vaccine induced the desired response in almost all participants.

Other analyses delved into the specific mutations the bnAb-precursor B cells acquired over time and how tightly they bound to the vaccine antigen. These investigations showed that that after each dose of the vaccine, the bnAb-precursor B cells gained affinity and continued along favorable maturation pathways.

One concern for this type of vaccine approach is the notion of “competitors”—in other words, the B cells induced by the vaccine antigen that are not bnAb precursors. The researchers extensively studied the “competitor” responses, and the results were very encouraging. Although the majority of the B cells triggered by vaccination were, in fact, “competitors”, these undesired B cells could not match the binding strength of the desired bnAb precursors and did not seem to impede maturation of the bnAb-precursor responses.

“These findings were very encouraging, as they indicated that immunogen design principles we used could be applied to many different epitopes, whether for HIV or even other pathogens,” adds Schief.

With these promising data in hand spanning both safety and immune responses, the researchers will continue to iterate and design boosting immunogens that could eventually induce the desired bnAbs and provide protection against the virus. These findings also come shortly after two additional studies in Immunity published in September 2022, which helped validate the germline-targeting approach for vaccinating against HIV.

“Working together with IAVI, Scripps Research, the VRC, GWU, additional investigators at Fred Hutch and many others, this trial and additional analyses will help inform design of the remaining stages of a candidate HIV vaccine regimen—while also enabling others in the field to develop vaccine strategies for additional viruses,” says McElrath of Fred Hutch.

IAVI, Scripps Research, NIAID, the Bill & Melinda Gates Foundation and the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID) are partnering with the biotechnology company Moderna to develop and test mRNA delivery of these HIV vaccine antigens. Two Phase I clinical trials are underway that build on IAVI G001, one (IAVI G002) at four sites in the U.S. and another (IAVI G003) at the Center for Family Health Research in Kigali, Rwanda, and The Aurum Institute in Tembisa, South Africa. Both are testing mRNA delivery of the eOD-GT8 60mer that was evaluated as recombinant protein in IAVI G001, and the U.S. trial includes a boost antigen designed by the Schief lab and delivered with Moderna mRNA technology. A third trial (HVTN302), at ten sites in the U.S., is testing mRNA delivery of three different stabilized HIV trimers designed in the Schief laboratory that are candidates for late-stage boosters in multi-stage vaccines aiming to induce bnAbs. Using mRNA technology could significantly accelerate the pace of HIV vaccine development as it allows for faster production of clinical trial material.

This work was supported by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; the IAVI Neutralizing Antibody Center; NIAID; Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and Scripps Consortium for HIV/AIDS Vaccine Development; and the Ragon Institute of MGH, MIT, and Harvard. Other collaborating organizations include Duke Human Vaccine Institute, Karolinska Institutet, and La Jolla Institute. 

Research at the IAVI Neutralizing Antibody Center that contributed to the development of the vaccine antigen eOD-GT8 60mer was also made possible by the government of the Netherlands through the Minister of Foreign Trade & Development Cooperation and through the generous support of the American people through PEPFAR through USAID. The contents are the responsibility of IAVI and Scripps Research and do not necessarily reflect the views of PEPFAR, USAID, or the United States government.

About IAVI

IAVI is a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges including HIV and tuberculosis. Its mission is to translate scientific discoveries into affordable, globally accessible public health solutions. Read more at iavi.org.

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.


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