Published in Science, Science Immunology, and Science Translation Medicine on May 16, 2024, the findings are outlined in four individual papers and build on a 2022 phase I clinical trial conducted by the nonprofit scientific research organization IAVI. The findings represent a key step forward in an immunization strategy that could protect against the virus.

“All in all, these studies show that we have a good chance at creating an effective HIV vaccine — we just need to keep iterating and build on these findings in future clinical trials,” says co-senior author of all four studies, William Schief, PhD, who is also a Scripps Research professor; vice president for antigen design and selection, Infectious Disease Research, at Moderna, Inc.; and executive director of vaccine design at IAVI’s Neutralizing Antibody Center.

The HIV vaccine strategy involves stimulating the body to produce mature broadly neutralizing antibodies (bnAbs). bnAbs are among the immune system’s key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare. The IAVI trial, spearheaded in part by Schief, focused on inducing the immune cells that could eventually evolve into the right bnAbs — ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen — a customized molecule to “prime” the immune system and elicit responses from the correct precursor cells.

But the primer also requires additional “booster” immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs — a rare and specific class of antibodies known to neutralize more than 90 percent of diverse HIV strains. Boosters are also needed for the production of BG18 — another important bnAb class that binds to sugars on the HIV spike protein. That’s where the new studies come in: Researchers developed immunization regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path toward becoming bnAbs.

“The results contained in these papers are deeply exciting and further support the germline-targeting strategy to HIV vaccine development that IAVI and our partners are pursuing,” says Mark Feinberg, MD, PhD, president and CEO of IAVI. “We look forward to continuing our collaboration with Scripps Research and partners to advance further research building on these promising findings.”

This groundbreaking science is enabled by collaboration between scientific institutions and funding partners. Without the ongoing, critical support of the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), the Collaboration for AIDS Vaccine Discovery (CAVD), the Bill & Melinda Gates Foundation, and Moderna (the manufacturer of the mRNA used in these studies), this research would not have been possible.

Priming rare antibodies

In the first study, which focused on BG18, Scripps Research scientists collaborated with co-senior authors Shane Crotty, PhD, chief scientific officer at La Jolla Institute for Immunology, and Devin Sok, PhD, former vice president, discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.

To confirm they were able to prime the correct precursors, the researchers then teamed up with Andrew Ward, PhD, Scripps Research integrative structural and computational biology professor and co-senior author of the study. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.

“The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans,” says co-first author, Jon Steichen, PhD, an institute investigator in the Department of Immunology and Microbiology at Scripps Research.

Steichen was also co-first author on a second study, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with the team of co-senior author Facundo Batista, PhD, associate director and scientific director of the Ragon Institute of MGH, MIT, and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that this time, they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognize more native-like versions of HIV.

“This study showed that we can start to walk the B cells along toward bnAb development,” Steichen explains.

Supercharging the immune system into action

For the third study, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI clinical trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response toward becoming matured bnAbs — the next vital step in a sequential immunization series that could effectively fight HIV. The results: a “prime-boost” regimen that can drive VRC01-class B cells toward bnAb development.

“The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster, which administers a different version of the vaccine than was given previously,” says Christopher Cottrell, PhD, a senior staff scientist at Scripps Research who was the first co-author on this study.

Understanding the immunology

In the fourth and final study, on which Cottrell was also a co-first author, the team worked again with Batista’s team at the Ragon Institute and used the same immunogens — but in a different mouse model where his team could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to take a deeper dive into the immunology associated with HIV vaccination by examining the germinal centers — specialized microstructures in the body that protect against viral reinfection. Germinal centers provide B cells with a space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight off viral strains.

In addition, the researchers examined how germinal centers accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B-cell activity in germinal centers across different lineages, which could eventually lead to an increase in matured VRC01-class bnAbs.

What’s next

Overall, all four papers confirm that the priming step to turn on the right bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it’s also possible to guide antibody precursors toward becoming bnAbs that can fight HIV.

“Taken together, the findings give us more confidence that we’re able to prime precursors from multiple bnAb targets, and they also show that we’re starting to learn the rules for how to advance precursor maturation through heterologous boosting,” Schief added.

Following these results, the researchers are advancing phase 1, experimental medicine trials for both the VRC01 and BG18 projects. Vaccines aiming to prime and boost VRC01-class antibodies are being further evaluated in two clinical trials run by IAVI, IAVI G002 and IAVI G003, and a vaccine to prime BG18-class responses is being evaluated in HVTN144. These studies use both adjuvanted protein immunizations (IAVI G001 and HVTN144) and mRNA delivery (IAVI G002 and G003).

The results of these studies will guide the critical next steps on the discovery path to an HIV vaccine.

Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.

While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. The mothers also had obesity, but in addition had experienced postnatal depression.

To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).

Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.

Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”

TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons — nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.

Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.

Professor Sadaf Farooqi from the Institute of Metabolic Science at the University of Cambridge said: “There’s a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ — which enable humans and animals to survive — such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people — around three-quarters of whom were women — that carried variants of the gene and had a higher-than-average body mass index.

The researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”

There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. The team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.

Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

The study, published in the Journal of Ethnicity in Substance Abuse, reviewed 18 RCTs conducted over the last 15 years that tested treatments for post-traumatic stress and alcohol use disorder. The researchers found that despite women having double the rates of post-traumatic stress and alcohol use disorder than men, and people of color having worse chronicity than white people, most participants were white (59.5%) and male (about 78%).

“Because RCTs are the gold standard for treatment studies and drug trials, we rarely ask the important questions about their limitations and failings,” said Nicole Buchanan, co-author of the study and professor in MSU’s Department of Psychology. “For RCTs to meet their full potential, investigators need to fix barriers to inclusion. Increasing representation in RCTs is not simply an issue for equity, but it is also essential to enhancing the quality of our science and meeting the needs of the public that funds these studies through their hard-earned tax dollars.”

The researchers found that the design and implementation of the randomized controlled trials contributed to the lack of representation of people of color and women. This happened because trials were conducted in areas where white men were the majority demographic group and study samples almost always reflected the demographic makeup where studies occurred. Additionally, those designing the studies seldom acknowledged race or gender differences, meaning they did not intentionally recruit diverse samples.

Furthermore, the journals publishing these studies did not have regulations requiring sample diversity, equity or inclusion as appropriate to the conditions under investigation.

“Marginalized groups have unique experiences from privileged groups, and when marginalized groups are poorly included in research, we remain in the dark about their experiences, insights, needs and strengths,” said Mallet Reid, co-author of the study and doctoral candidate in MSU’s Department of Psychology. “This means that clinicians and researchers may unknowinglyremain ignorant to how to attend to the trauma and addiction challenges facing marginalized groups and may unwittingly perpetuate microaggressions against marginalized groups in clinical settings or fail to meet their needs.”

They published their results in Advanced Materials.

“People have been developing soft and stretchable conductors for almost a decade, but the conductivity is not usually very high,” said corresponding author Tao Zhou, Penn State assistant professor of engineering science and mechanics and of biomedical engineering in the College of Engineering and of materials science and engineering in the College of Earth and Mineral Sciences. “Researchers realized they could reach high conductivity with liquid metal-based conductors, but the significant limitation of that is that it requires a secondary method to activate the material before it can reach a high conductivity.”

Liquid metal-based stretchable conductors suffer from inherent complexity and challenges posed by the post-fabrication activation process, the researchers said. The secondary activation methods include stretching, compressing, shear friction, mechanical sintering and laser activation, all of which can lead to challenges in fabrication and can cause the liquid metal to leak, resulting in device failure.

“Our method does not require any secondary activation to make the material conductive,” said Zhou, who also has affiliations with the Huck Institutes of the Life Sciences and the Materials Research Institute. “The material can self-assemble to make its bottom surface be very conductive and its top surface self-insulated.”

In the new method, the researchers combine liquid metal, a conductive polymer mixture called PEDOT:PSS and hydrophilic polyurethane that enables the liquid metal to transform into particles. When the composite soft material is printed and heated, the liquid metal particles on its bottom surface self-assemble into a conductive pathway. The particles in the top layer are exposed to an oxygen-rich environment and oxidize, forming an insulated top layer. The conductive layer is critical for conveying information to the sensor — such as muscle activity recordings and strain sensing on the body — while the insulated layer helps prevent signal leakage that could lead to less accurate data collection.

“Our innovation here is a materials one,” Zhou said. “Normally, when liquid metal mixes with polymers, they are not conductive and require secondary activation to achieve conductivity. But these three components allow for the self-assembly that produces the high conductivity of soft and stretchable material without a secondary activation method.”

The material can also be 3D-printed, Zhou said, making it easier to fabricate wearable devices. The researchers are continuing to explore potential applications, with a focus on assistive technology for people with disabilities.

The papers other authors are Salahuddin Ahmed, Marzia Momin and Jiashu Ren, all doctoral students in the Penn State engineering science and mechanics department, and Hyunjin Lee, a doctoral student in the biomedical engineering department at Penn State. This work was supported by the National Taipei University of Technology-Penn State Collaborative Seed Grant Program and by the Department of Engineering Science and Mechanics, the Materials Research Institute and the Huck Institutes of the Life Sciences at Penn State.

The research team, led by scientists from the U.S. National Science Foundation National Center for Atmospheric Research (NSF NCAR), used an innovative model that allows for higher-resolution simulations of hurricane formation than ever before. This allowed researchers to study the effects of increased regional moisture over Africa, which is the birthplace of weather systems that later produce hurricanes over the Atlantic.

Past research has suggested that warmer ocean water and a moister atmosphere could cause hurricanes to become more intense with greater amounts of rainfall. But how atmospheric moisture, which is predicted to increase in a warming climate, may be impacting hurricane formation itself has not been studied in detail until now.

The researchers found that a moister environment produced weaker and slower-moving African easterly waves, or disturbances which are the primary precursor or “seed” for hurricanes in the Atlantic. The addition of moisture moved the location of thunderstorms within the wave, making it harder for the wave to grow. Increased moisture also slowed the movement of the wave resulting in weaker and delayed hurricane seed formation by the time it reached eastern Atlantic waters.

“Considerable work during the last two decades has emphasized the role of deep moist convection to explain the development of African easterly waves,” said NSF NCAR scientist and lead author Kelly Núñez Ocasio. “But, the precise role of moisture has proven somewhat elusive. With the development of new modeling capabilities, I was able to focus on the role of moisture in cyclogenesis stemming from the hurricane seed.”

The study is funded by NSF NCAR and published in the Journal of Advances in Modeling Earth Systems. Núñez Ocasio pursued the research through the NSF NCAR Advanced Study Program which allows graduate and postdoctoral students to focus on emerging areas of science.

Next-gen modeling

The birth of hurricanes and other tropical cyclones, known as cyclogenesis, is a complex process where small-scale weather events and large-scale atmospherics happen simultaneously. This complexity has made it difficult to study and model the formation of tropical cyclones. Most climate models provide only a grainy picture of what is happening with localized weather, which makes it difficult to learn anything about the role of individual ingredients, like moisture, that mix together to create cyclogenesis.

To address this, the research team turned to the Model for Prediction Across Scales (MPAS). MPAS has the ability to model weather both locally and globally. This capability allowed Núñez Ocasio and her colleagues to zoom out and simulate global moisture and then zoom in to see how that would interact with localized weather events that lead to the formation of tropical cyclones.

The researchers started the experiment by using MPAS to reproduce a moisture-driven African easterly wave that became hurricane Helene in 2006. The team used that base to add or take away moisture and study what happened with those changes.

“When I increased the moisture we saw more convection and thunderstorms, which is to be expected; however, we discovered that the waves struggled to pair with the more intense and deep convection,” said Núñez Ocasio. “With increased moisture, the energy source of tropical cyclone seeds moved north and further away, reducing the kinetic energy available to the African easterly wave, which led to weak, energy-starved tropical cyclone seeds.”

Studying the evolution of tropical cyclones after this initial phase was outside the scope of this study. More research is needed to discover whether these weaker seeds lead to weaker tropical cyclones and hurricanes or if it will just take them longer to form.

The conditions leading to tropical cyclone formation are complex, but researchers hope these newer modeling techniques will lead to better predictions. For instance, Núñez Ocasio is beginning to run simulations where she alters other atmospheric variables key to generating tropical cyclones.

“In addition to moisture, I’m altering other variables in the model to more realistically reproduce a future climate scenario in collaboration with Erin Dougherty, NSF NCAR project scientist,” she said. “So far, I’m seeing similarities to the results of this study even as I alter those other significant pieces.”

Carbonate fragments provide remarkable information

Professor Cees W. Passchier and Dr. Gül Sürmelihindi from Johannes Gutenberg University Mainz (JGU), in collaboration with colleagues from France and Austria, have now unraveled the history of the mill complex using calcium carbonate deposits that are now stored in the Archaeological Museum of Arles. These deposits had formed towards the end of the roughly 100-year operational life of the Barbegal water mills on the sides and base of the wooden supply system that conveyed the water to the wheels. “We show that it is possible to reconstruct to a large extent the history of a water mill on the basis of such carbonate deposits,” stated Passchier, head of the JGU team. First, the researchers had to fit some of the total of 140 stored pieces together like a jigsaw puzzle, then they analyzed the layers using various techniques, including mass spectrometry.

Wooden water wheels and gutters were replaced

The researchers have now published their results in Geoarchaeology. “We were able to show, for example, that wooden water wheels and water channels had to be replaced after three to eight years. In at least one case, an old water wheel was replaced by a larger one,” said Passchier. The researchers drew this conclusion from the unusual shape of the carbonate deposits that had formed in the water channel. While the lower and earlier layers indicate that water levels must have originally been relatively low, upper and later carbonate layers indicate a higher water level. The possibility that there was originally less water flowing through the water channel which was subsequently increased was rejected by the researchers. They established that — for a gently sloping water channel and low water level — the amount of water provided would not have been sufficient to drive a mill wheel. Therefore, the inclination of the water channel must have been altered, from what was at first a steeper angle with a low water level to a shallower slope transporting water at a correspondingly higher level. “The entire structure of this water mill must have been modified,” said Passchier. “If you uplift the water channel alone, the water tends to splatter, losing the power to drive the wheel efficiently. Thus, when you uplift the water channel, you also need a larger water wheel.” In fact, a section of carbonate deposit formed on the water wheel corroborates this conclusion as it does not contain all the carbonate layers but only those of the latter years of operation.

Results of isotope analysis provide evidence of the mill’s service life

Using isotope analysis of the carbonate layers, the researchers were even able to ascertain the operating periods before which parts of the mill required renewal. Carbonate contains oxygen and the relative ratios of oxygen isotopes differ depending on water temperature. Based on the isotope composition in the carbonate layers, the researchers were able to infer water temperatures and thus identify the seasons in which the layers were deposited. They concluded that the carbonate from the samples in the Archaeological Museum in Arles had been deposited in the water channels over a period of seven to eight years. “The uppermost and thus youngest carbonate layer contains mollusk shells and fragments of wood, showing that the mill must have been abandoned by then and was disintegrating. The water continued to flow for a while so that carbonate deposits also continued to form, but maintenance of the water channels ceased,” said Passchier.

The researchers were able to answer yet another question. It was not previously known whether the mills had been run in combination by a single operator or whether the 16 water wheels had been used independently of each other. Judging from the layers of three investigated water channels, which are clearly different from each other, the mills were in operation separately — at least towards the end of their lifetime. Moreover, the western side of the complex was abandoned earlier than the eastern side. Finally, long pieces of carbonate from the water channels were later used as partition screens in a water basin for other industrial purposes after the mills had already been abandoned.