The findings were published on September 29, 2022, in Immunity in two individual papers. The research describes the first steps in a vaccine approach that aims to prompt the creation of broadly neutralizing antibodies (bnAbs) — antibodies that are broad enough to fight and protect against many different variants of a virus. By identifying the most promising bnAbs and the human genes needed to make them — as well as designing protein and mRNA vaccine candidates to begin bnAb creation and verifying the vaccine candidates — the team is paving the way to create an effective HIV vaccine.

“Our two studies describe a collaborative effort to genetically and structurally understand bnAbs, and ultimately ‘reverse engineer’ vaccines to elicit these bnAbs,” says senior author William Schief, PhD, a Scripps Research professor and executive director of vaccine design at IAVI’s Neutralizing Antibody Center at Scripps Research. “HIV has remained one of the most difficult viruses to protect against because of its natural ability to quickly mutate and evade capture from the immune system. Working closely together across scientific disciplines and institutions, our team’s findings mark a crucial step forward in overcoming these historic hurdles and creating an effective HIV vaccine.”

Building Backwards

Researchers have long studied how a small percentage of infected individuals with HIV are able to make bnAbs. Even when bnAbs do develop during infection in these cases, they arise too late to help block the virus. However, researchers have demonstrated that bnAbs can protect against the virus if they are present before a person gets infected with HIV. This observation has led scientists to try to develop vaccines that induce bnAbs in healthy individuals, but designing such vaccines has proved difficult.

The new work at Scripps Research, IAVI and Ragon aims to break the logjam by carefully choosing the bnAbs to elicit, and then designing custom vaccines that coax the immune system to produce the target bnAbs in a stepwise manner. The team focused on bnAbs that bind to the apex of the HIV spike protein (analogous to the spike protein of SARS-CoV-2). These apex bnAbs employ extremely long loops (called HCDR3 loops) to pierce the spike protein like a spear. By binding to the apex of the HIV spike, the bnAbs prevent HIV from infecting human cells.

Engineering Immunity

The scientists first needed to determine if the general population had the precursor cells that would eventually lead to the creation of these potent bnAbs.

“Finding the bnAbs we need is like searching for a needle in a haystack,” says co-first author of both papers Zachary Berndsen, PhD, assistant professor of biochemistry at the University of Missouri. “To make an effective vaccine, we must first find the precursor antibodies that can eventually become bnAbs, while also seeing if those precursor antibodies are common enough throughout the general population to stimulate,” adds Berndsen, who was previously a research associate in the lab of Scripps Research professor Andrew Ward.

All bnAbs mature from a type of antibody-producing white blood cell, called a naive B cell. These B cells are often referred to as “germline” precursors. Through bioinformatic analyses of a massive database of 1.2 billion human antibody sequences, the researchers learned that two apex bnAbs had the most frequent precursor B cells. This discovery led the team to focus on developing a vaccine tailored to induce those two types of bnAb.

“The long HCDR3 loops in apex bnAbs are rare in human antibodies, thus one might expect that precursors to these apex bnAbs are also rare,” says co-first author Jordan Willis, PhD, senior principal scientist at the IAVI Neutralizing Antibody Center at Scripps Research. “However, we found that two classes of apex bnAbs had relatively common precursors, so we decided to focus our vaccine design strategy on those two bnAbs.”

The researchers then found that natural HIV spike proteins do not bind to the germline precursors of the two target bnAbs, meaning that using a natural HIV spike protein as a vaccine would not induce the desired bnAb responses. To solve that problem, the researchers engineered a modified HIV spike protein that can bind to the germline precursors for both target bnAbs. This engineered spike protein serves as the “priming immunogen,” the first shot of the vaccine that binds and activates the right precursor B cells to start the process of producing the desired apex bnAbs.

“The first step in designing a vaccine to induce these apex bnAbs was to engineer a priming immunogen with a high binding affinity to the right germline precursors,” says co-first author Krystal Ma, a PhD graduate student at Scripps Research. “The next steps will be to design a series of boosting immunogens that can mature the precursors into bnAbs.”

After many rounds of design and extensive in vitro testing — combined with cryo-electron microscopy ‘snapshots’ from the Ward lab, which provided insight into how the virus may eventually fight back against the bnAbs — the team created a successful priming immunogen.

The Final Steps

The Scripps Research and IAVI scientists collaborated with the lab of Facundo Batista, PhD, associate director of the Ragon Institute, to show the new immunogen was able to successfully bind to the germline precursor B cells and elicit the desired responses in mice expressing the bnAb germline genes at the same low frequency they appear in humans.

“This is a very important step, as it shows that vaccinating with our immunogen can actually elicit responses from the precursors we were targeting,” adds Willis. “We also showed that vaccinating with an unmodified HIV protein could not elicit those responses, which proves that our affinity engineering was required.”

The antibody responses have potential to develop into bnAbs that could fight HIV, which the scientists will attempt to achieve in future studies with different boost immunogens that are still in the design stage.

“We and our collaborators are building on this approach, developing and testing immunogens to drive the later stages of bnAb maturation,” says Batista.

As a successful vaccine needs to be viable from a manufacturing perspective as well, the team collaborated with scientists from Moderna to successfully formulate their germline-targeting immunogens into mRNA vaccines (similar to the COVID-19 vaccines). This approach gave even better antibody responses in the mice than the typical vaccine formulation, while also being much easier and faster to manufacture.

With this validation in hand, the researchers are continuing refine their vaccine approach and test it in additional models with the intent to ultimately enter the clinic for human trials.

Funding was provided by the IAVI Neutralizing Antibody Center; the Bill and Melinda Gates Foundation; the National Institute of Allergy and Infectious Diseases (NIAID); the Ragon Institute of MGH, MIT and Harvard; and by an EMBO fellowship.

They’ve done an amazing job with photovoltaic cells which convert sunlight directly into energy. And still, with all the research, history and science behind it, there are limits to how much solar power can be harvested and used — as its generation is restricted only to the daytime.

A University of Houston professor is continuing the historic quest, reporting on a new type of solar energy harvesting system that breaks the efficiency record of all existing technologies. And no less important, it clears the way to use solar power 24/7.

“With our architecture, the solar energy harvesting efficiency can be improved to the thermodynamic limit,” reports Bo Zhao, Kalsi Assistant Professor of mechanical engineering and his doctoral student Sina Jafari Ghalekohneh in the journal Physical Review Applied. The thermodynamic limit is the absolute maximum theoretically possible conversion efficiency of sunlight into electricity.

Finding more efficient ways to harness solar energy is critical to transitioning to a carbon-free electric grid. According to a recent study by the U.S. Department of Energy Solar Energy Technologies Office and the National Renewable Energy Laboratory, solar could account for as much as 40% of the nation’s electricity supply by 2035 and 45% by 2050, pending aggressive cost reductions, supportive policies and large-scale electrification.

How Does it Work?

Traditional solar thermophotovoltaics (STPV) rely on an intermediate layer to tailor sunlight for better efficiency. The front side of the intermediate layer (the side facing the sun) is designed to absorb all photons coming from the sun. In this way, solar energy is converted to thermal energy of the intermediate layer and elevates the temperature of the intermediate layer.

But the thermodynamic efficiency limit of STPVs, which has long been understood to be the blackbody limit (85.4%), is still far lower than the Landsberg limit (93.3%), the ultimate efficiency limit for solar energy harvesting.

“In this work, we show that the efficiency deficit is caused by the inevitable back emission of the intermediate layer towards the sun resulting from the reciprocity of the system. We propose nonreciprocal STPV systems that utilize an intermediate layer with nonreciprocal radiative properties,” said Zhao. “Such a nonreciprocal intermediate layer can substantially suppress its back emission to the sun and funnel more photon flux towards the cell.

We show that, with such improvement, the nonreciprocal STPV system can reach the Landsberg limit, and practical STPV systems with single-junction photovoltaic cells can also experience a significant efficiency boost.”

Besides improved efficiency, STPVs promise compactness and dispatchability (electricity that can be programmed on demand based on market needs).

In one important application scenario, STPVs can be coupled with an economical thermal energy storage unit to generate electricity 24/7.

“Our work highlights the great potential of nonreciprocal thermal photonic components in energy applications. The proposed system offers a new pathway to improve the performance of STPV systems significantly. It may pave the way for nonreciprocal systems to be implemented in practical STPV systems currently used in power plants,” said Zhao.

Story Source:

Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.

Although they need eight to 10 hours of sleep per night to maintain physical health, emotional well-being and school performance, according to the National Sleep Foundation and the American Academy of Sleep Medicine, most adolescents get less than eight, especially on school nights.

Newly published research from RUSH in the journal SLEEP sheds light on how adolescents can get more shut-eye.

“There are a lot of changes a teen goes through,” said Stephanie J. Crowley, PhD, associate professor of psychiatry and behavioral sciences and the director of the Pediatric Chronobiology and Sleep Research Program at RUSH. “One specifically is a change to sleep biology that happens during puberty.”

“The brain systems that control sleep change in such a way that it’s easier for an adolescent to stay awake later into the evening. One of these systems — the 24-hour circadian clock — shifts later in time,” Crowley said.

So there are two competing forces: one to go to bed earlier for the school schedule and the other a biological change that happens naturally to a teen’s body.

Because of this complex conflict, RUSH researchers set out to test a two-week intervention that targets the circadian system with different behavioral measures and tries to help the teens figure out a better nighttime routine.

To combat teen sleep deprivation, the researchers used bright light therapy on two weekend mornings for a total of 2.5 hours. The bright light cues the internal clock to wake up a little earlier. This shift should make it easier for the teen to fall asleep at an appropriate time.

Less tired, irritable

Crowley and her team then helped counteract sleep deprivation by providing time management tools and addressing barriers to an earlier bedtime, like limiting certain after-school activities.

Researchers were able to shift the teens’ bedtime by an hour and a half earlier, and their total sleep time increased by approximately an hour.

“The interesting thing is that teens with late circadian clocks shifted by up to two hours earlier,” Crowley said. “And the teens who had an earlier circadian clock didn’t need to be shifted any earlier. They just needed the behavioral support of trying to manage their time in the evening and increase their sleep duration.”

The researchers also found that the teens in the intervention group were less tired, less irritable and less worried, and they exhibited better concentration. The students’ morning alertness improved as well.

The RUSH researchers are following the participants in another study to determine whether the adolescents were able to maintain their improved sleep routine.

Story Source:

Materials provided by Rush University Medical Center. Original written by Nancy Di Fiore. Note: Content may be edited for style and length.