Sunday, September 22, 2024

A two-dose schedule could make HIV vaccines more effective

MIT researchers find that the first dose primes the immune system, helping it to generate a strong response to the second dose, a week later

Massachusetts Institute of Technology

One major reason why it has been difficult to develop an effective HIV vaccine is that the virus mutates very rapidly, allowing it to evade the antibody response generated by vaccines.

Several years ago, MIT researchers showed that administering a series of escalating doses of an HIV vaccine over a two-week period could help overcome a part of that challenge by generating larger quantities of neutralizing antibodies. However, a multidose vaccine regimen administered over a short time is not practical for mass vaccination campaigns.

In a new study, the researchers have now found that they can achieve a similar immune response with just two doses, given one week apart. The first dose, which is much smaller, prepares the immune system to respond more powerfully to the second, larger dose.

This study, which was performed by bringing together computational modeling and experiments in mice, used an HIV envelope protein as the vaccine. A single-dose version of this vaccine is now in clinical trials, and the researchers hope to establish another study group that will receive the vaccine on a two-dose schedule.

“By bringing together the physical and life sciences, we shed light on some basic immunological questions that helped develop this two-dose schedule to mimic the multiple-dose regimen,” says Arup Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT’s Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.

This approach may also generalize to vaccines for other diseases, Chakraborty notes.

Chakraborty and Darrell Irvine, a former MIT professor of biological engineering and materials science and engineering and member of the Koch Institute for Integrative Cancer Research, who is now a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the study, which appears in Science Immunology. The lead authors of the paper are Sachin Bhagchandani PhD ’23 and Leerang Yang PhD ’24.

Neutralizing antibodies

Each year, HIV infects more than 1 million people around the world, and some of those people do not have access to antiviral drugs. An effective vaccine could prevent many of those infections. One promising vaccine now in clinical trials consists of an HIV protein called an envelope trimer, along with a nanoparticle called SMNP. The nanoparticle, developed by Irvine’s lab, acts as an adjuvant that helps recruit a stronger B cell response to the vaccine.

In clinical trials, this vaccine and other experimental vaccines have been given as just one dose. However, there is growing evidence that a series of doses is more effective at generating broadly neutralizing antibodies. The seven-dose regimen, the researchers believe, works well because it mimics what happens when the body is exposed to a virus: The immune system builds up a strong response as more viral proteins, or antigens, accumulate in the body.

In the new study, the MIT team investigated how this response develops and explored whether they could achieve the same effect using a smaller number of vaccine doses.

“Giving seven doses just isn’t feasible for mass vaccination,” Bhagchandani says. “We wanted to identify some of the critical elements necessary for the success of this escalating dose, and to explore whether that knowledge could allow us to reduce the number of doses.”

The researchers began by comparing the effects of one, two, three, four, five, six, or seven doses, all given over a 12-day period. They initially found that while three or more doses generated strong antibody responses, two doses did not. However, by tweaking the dose intervals and ratios, the researchers discovered that giving 20 percent of the vaccine in the first dose and 80 percent in a second dose, seven days later, achieved just as good a response as the seven-dose schedule.

“It was clear that understanding the mechanisms behind this phenomenon would be crucial for future clinical translation,” Yang says. “Even if the ideal dosing ratio and timing may differ for humans, the underlying mechanistic principles will likely remain the same.”

Using a computational model, the researchers explored what was happening in each of these dosing scenarios. This work showed that when all of the vaccine is given as one dose, most of the antigen gets chopped into fragments before it reaches the lymph nodes. Lymph nodes are where B cells become activated to target a particular antigen, within structures known as germinal centers.

When only a tiny amount of the intact antigen reaches these germinal centers, B cells can’t come up with a strong response against that antigen.

However, a very small number of B cells do arise that produce antibodies targeting the intact antigen. So, giving a small amount in the first dose does not “waste” much antigen but allows some B cells and antibodies to develop. If a second, larger dose is given a week later, those antibodies bind to the antigen before it can be broken down and escort it into the lymph node. This allows more B cells to be exposed to that antigen and eventually leads to a large population of B cells that can target it.

“The early doses generate some small amounts of antibody, and that’s enough to then bind to the vaccine of the later doses, protect it, and target it to the lymph node. That's how we realized that we don't need to give seven doses,” Bhagchandani says. “A small initial dose will generate this antibody and then when you give the larger dose, it can again be protected because that antibody will bind to it and traffic it to the lymph node.”

T-cell boost

Those antigens may stay in the germinal centers for weeks or even longer, allowing more B cells to come in and be exposed to them, making it more likely that diverse types of antibodies will develop.

The researchers also found that the two-dose schedule induces a stronger T-cell response. The first dose activates dendritic cells, which promote inflammation and T-cell activation. Then, when the second dose arrives, even more dendritic cells are stimulated, further boosting the T-cell response.

Overall, the two-dose regimen resulted in a fivefold improvement in the T-cell response and a 60-fold improvement in the antibody response, compared to a single vaccine dose.

“Reducing the ‘escalating dose’ strategy down to two shots makes it much more practical for clinical implementation. Further, a number of technologies are in development that could mimic the two-dose exposure in a single shot, which could become ideal for mass vaccination campaigns,” Irvine says.

The researchers are now studying this vaccine strategy in a nonhuman primate model. They are also working on specialized materials that can deliver the second dose over an extended period of time, which could further enhance the immune response.

The research was funded by the Koch Institute Support (core) Grant from the National Cancer Institute, the National Institutes of Health, and the Ragon Institute of MIT, MGH, and Harvard.

###

Written by Anne Trafton, MIT News

Journal

Science Immunology

DOI

10.1126/sciimmunol.adl3755

Article Title

Two-dose priming immunization amplifies humoral immunity by synchronizing vaccine delivery with the germinal center response

Article Publication Date

20-Sep-2024

COSMOLOGY

FAA proposes $630,000 fine against SpaceX for 2023 regulatory violations

SPARE CHANGE

A SpaceX Falcon Heavy rocket launches the Jupiter 3/Echostar 24 communications satellite for the Hughes Network System at the Kennedy Space Center on July 28, 2023. The FAA fined SpaceX for that launch and another on Tuesday. File Photo by Joe Marino/UPI | License Photo

Sept. 18 (UPI) -- The Federal Aviation Administration on Tuesday said it plans to fine SpaceX for regulatory violations.

The FAA proposed to fine the company more than $630,000, saying it failed to comply with regulations during two launches in 2023.

SpaceX on June 18, 2023, used an unapproved launch control room for the PSN Satria mission and did not conduct the required hour poll, the FAA said. On July 28, 2023, the agency used an unapproved rocket propellant farm for the EchoStar XXIV/Jupiter mission.

"Safety drives everything we do at the FAA, including a legal responsibility for the safety oversight of companies with commercial space transportation licenses," FAA Chief Counsel Marc Nichol said. "Failure of a company to comply with the safety requirements will result in consequences."

The proposed fine drew the ire of SpaceX's founder Elon Musk, who threatened legal action against the agency.

"SpaceX will be filing suit against the FAA for regulatory overreach," Musk said on X.

SpaceX remains in a holding pattern with the FAA over the fifth test of its Starship, which is expected to deliver humans and goods back to the Moon and eventually Mars. The FAA has been slow to approve the flight even though SpaceX it's been ready since August.

SpaceX railed against the FAA on Sept. 10 for its latest delay.

"We recently received a launch license date estimate of late November from the FAA," SpaceX said in a statement. "This is a more than two-month delay to the previously communicated date of mid-September.

"This delay was not based on a new safety concern but instead driven by superfluous environmental analysis. The four open environmental issues are illustrative of the difficulties launch companies face in the current regulatory environment for launch and reentry licensing."

SkAI launched to further explore universe

NCSA and partner institutions received a $20 million grant to create new artificial intelligence tools for space exploration

National Center for Supercomputing Applications

Funded by a five-year, $20 million grant from the U.S. National Science Foundation (NSF) and the Simons Foundation, the National Center for Supercomputing Applications is partnering with other academic institutions and federal laboratories in the Midwest to develop new artificial intelligence (AI) tools to advance astrophysics research and exploration of the universe.

Led by Northwestern University, the collaboration will establish the NSF-Simons AI Institute for the Sky or SkAI (pronounced “sky”), one of two AI research centers that will help astronomers better understand the cosmos.

Located close to NCSA’s home in Illinois, SkAI will bring together researchers to create and deploy innovative AI mechanisms that will analyze large datasets from astronomical surveys and transform physics-based simulations in pursuit of furthering deep space exploration. SkAI will unite 83 team members from 25 partner organizations, including NCSA, Northwestern University, the University of Illinois Urbana-Champaign, the University of Chicago, Argonne National Laboratory, Fermi National Accelerator Laboratory, the University of Illinois Chicago, the Adler Planetarium and University of Wisconsin-Madison.

“Our mission at the Center for AstroPhysical Surveys (CAPS) in NCSA has been to bring together innovative software and cutting-edge hardware to tackle the most pressing questions in the universe” said SkAI co-principal investigator and CAPS Deputy Director Gautham Narayan. “We’re very excited to have our students, postdocs, faculty and staff deepen our involvement with our colleagues at Northwestern and U of Chicago, provide the entire SkAI community access to NSF’s Delta and DeltaAI supercomputers here at NCSA and build tools and services that lead to AI methods becoming more interpretable and reliable. Our goal is to democratize AI and make it more trustworthy – not just for astrophysics and cosmology, or our campus, but for everyone. This is a big leap forward, and Illinois will lead the way.”

“I am thrilled to receive this opportunity to work with our amazing cross-disciplinary, multi-institutional team, so we can accelerate the data-driven revolution that wide and deep sky surveys will bring to the field of astronomy,” said Northwestern’s Vicky Kalogera, SkAI director and principal investigator of the grant. “We will transform our astrophysical understanding across an enormous range of scales – from stars and the transients they produce to the evolving galaxies they live in, the black holes they form, and to the dark sector of the universe and its cosmological origins.”

Astronomical surveys like the Vera C. Rubin Observatory and CMB-Stage 4 experiment promise transformational advances in astrophysics and cosmology. Realizing these breakthroughs will require overcoming enormous challenges in data analysis, modeling and experiment design. Researchers will need assistance provided by these SkAI resources to sufficiently interpret increasingly large and complex datasets.

The massive amount of data that will be gathered in the coming years by the NSF-DOE Vera C. Rubin Observatory and other large-scale astronomical projects is simply too vast and rich to be fully explored with existing methods. With reliable and trustworthy AI in their toolbox, everyone from students to senior researchers will have exciting new ways to gain valuable insights leading to amazing discoveries that might otherwise remain hidden in the data.
Sethuraman Panchanathan, NSF Director

SkAI will also be a bastion for open science and emphasize diversity of disciplines and researchers in its work. Building on existing partnerships with urban and rural community colleges, minority serving institutions, youth organizations, the Adler Planetarium, artists and art organizations, and industry professionals, the new institute will develop Astro-AI educational and workforce-development resources for high school students through postdocs. SkAI will engage the public around Astro-AI concepts and enhance local, regional and national research capacity and knowledge transfer to the community, higher-learning institutions and in industry. Activities will be designed to lower barriers to access and grow a more diverse STEM workforce.

“Our research will be guided by AI ethics principles and all SkAI members will be trained in key AI ethics practices,” Narayan said. “Our commitment to open collaboration ensures that SkAI research products are adopted widely. We will develop new, trustworthy AI tools in an open-source ecosystem and train a diverse generation of scientists and engineers to ethically apply and extend AI within academia and beyond.

“University of Illinois leadership and their vision in creating the Center for AstroPhysical Surveys has enabled us to get a head start in these areas, and was crucial to the success of SkAI, and their continuing support gives us the freedom and ability to innovate. By pushing the frontier of computing, we’re reaching ever more distant horizons in the universe.”

For more details on SkAI, check out the announcements from NSF and Northwestern University.

ABOUT ASPO/CAPS

NCSA’s Center for AstroPhysical Surveys (CAPS) brings cohesion and advancement to astrophysical survey science efforts across the University of Illinois Urbana-Champaign. CAPS offers annual postdoctoral and graduate fellowship programs, publishes vast amounts of astronomical data from a broad portfolio of astrophysical surveys and collaborates across disciplines to enable trailblazing research.

Wastewater monitoring can detect foodborne illness, researchers find

Results of a new study suggest sewage monitoring could provide early warning of foodborne disease outbreaks to public health authorities

Penn State

sewage treatment plant in central Pennsylvania — image:
The researchers tested raw sewage samples collected twice a week from two treatment plants in central Pennsylvania for non-typhoidal Salmonella and characterized isolates using whole genome sequencing. They recovered 43 Salmonella isolates from wastewater samples.
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Credit: Provided by Ed Dudley/Penn State

UNIVERSITY PARK, Pa. — First used in the 1940s to monitor for polio, wastewater surveillance proved such a powerful disease monitoring tool that the U.S. Centers for Disease Control and Prevention (CDC) established the National Wastewater Surveillance System to support SARS-CoV-2 monitoring in September of 2020. Now, a team of scientists from Penn State and the Pennsylvania Department of Health have shown that domestic sewage monitoring is useful for a foodborne pathogen as well.

In findings published today (Sept. 19) in the Journal of Clinical Microbiology, the researchers report that the bacteria Salmonella enterica was detected in samples from two wastewater treatment plants in central Pennsylvania during June 2022.

“Non-typhoidal Salmonella is a common cause of gastroenteritis worldwide, but current surveillance for the disease is suboptimal, so in this research we evaluated the utility of wastewater monitoring to enhance surveillance for this foodborne pathogen,” said Nkuchia M’ikanatha, lead epidemiologist, Pennsylvania Department of Health and an affiliated researcher in Penn State’s Department of Food Science, in the College of Agricultural Sciences. "In this study, we explored wastewater monitoring as a tool to enhance surveillance for this foodborne pathogen. Wastewater testing can detect traces of infectious diseases circulating in a community, even in asymptomatic individuals, offering an early warning system for potential outbreaks."

While health care providers are required to report salmonellosis cases, many go undetected. Salmonella bacteria, inhabiting the intestines of animals and humans, are shed in feces. The CDC estimates Salmonella causes roughly 1.35 million infections, 26,500 hospitalizations and 420 deaths annually in the U.S., primarily through contaminated food.

In June 2022, the researchers tested raw sewage samples collected twice a week from two treatment plants in central Pennsylvania for non-typhoidal Salmonella and characterized isolates using whole genome sequencing. They recovered 43 Salmonella isolates from wastewater samples, differentiated by genomic analysis into seven serovars, which are groupings of microorganisms based on similarities. Eight of the isolates, or nearly 20%, were from a rare type of Salmonella called Baildon.

The researchers assessed genetic relatedness and epidemiologic links between non-typhoidal Salmonella isolates from wastewater and similar bacteria from patients with salmonellosis. The Salmonella Baildon serovars isolated from wastewater were genetically indistinguishable from a similar bacteria found in a patient associated with a salmonellosis outbreak in the same period in the area. Salmonella Baildon from wastewater and 42 outbreak-related isolates in the national outbreak detection database had the same genetic makeup. One of the 42 outbreak-related isolates was obtained from a patient residing in the wastewater study sample collection catchment area, which serves approximately 17,000 people.

Salmonella Baildon is a rare serovar — reported in less than 1% of cases nationally over five years, noted M’ikanatha, the study’s first author. He pointed out that this research demonstrates the value of monitoring sewage from a defined population to supplement traditional surveillance methods for evidence of Salmonella infections and to determine the extent of outbreaks.

“Using whole genome sequencing, we showed that isolates of variant Salmonella Baildon clustered with those from an outbreak that occurred in a similar time frame,” he said. “Case reports were primarily from Pennsylvania, and one individual lived within the treatment plant catchment area. This study provides support for using domestic sewage surveillance in assisting public health agencies to identify communities impacted by infectious diseases.”

Ed Dudley, a professor of food science and the senior author on the study, said these findings highlight the potential of wastewater monitoring as an early warning system for foodborne disease outbreaks, potentially even before physicians and laboratories report cases. This proactive approach could enable health officials to swiftly trace the source of contaminated food, ultimately reducing the number of people affected, suggested Dudley, who also directs Penn State’s E. coli Reference Center.

“While it may not happen overnight, I foresee a future where many, if not most, domestic wastewater treatment plants contribute untreated sewage samples for monitoring evidence of various illnesses,” he said. “This would likely involve collaboration among public health agencies, academia and federal entities, much like our pilot study. I see this as yet another crucial lesson from the pandemic.”

Contributing to the research at Penn State were Jasna Kovac, associate professor of food science and Lester Earl and Veronica Casida Career Development Professor of Food Safety; Erin Nawrocki and Yezhi Fu, postdoctoral scholars in the Dudley Lab; Zoe Goldblum, undergraduate researcher in the Department of Food Science; and Nicholas Cesari, Division of Infectious Disease Epidemiology, Pennsylvania Department of Health.

The CDC, the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s National Institute of Food and Agriculture provided funding for this research.