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Study shows why second dose of COVID-19 vaccine shouldn’t be skipped

The second dose of a COVID-19 vaccine induces a powerful boost to a part of the immune system that provides broad antiviral protection, according to a study led by investigators at the Stanford University School of Medicine.

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The second dose of a COVID-19 vaccine induces a powerful boost to a part of the immune system that provides broad antiviral protection, according to a study led by investigators at the Stanford University School of Medicine.

The finding strongly supports the view that the second shot should not be skipped.

“Despite their outstanding efficacy, little is known about how exactly RNA vaccines work,” said Bali Pulendran, PhD, professor of pathology and of microbiology and immunology. “So we probed the immune response induced by one of them in exquisite detail.”

The study, published in Nature, was designed to find out exactly what effects the vaccine, marketed by Pfizer Inc., has on the numerous components of the immune response.

The researchers analyzed blood samples from individuals inoculated with the vaccine. They counted antibodies, measured levels of immune-signaling proteins and characterized the expression of every single gene in the genome of 242,479 separate immune cells’ type and status.

“The world’s attention has recently been fixed on COVID-19 vaccines, particularly on the new RNA vaccines,” said Pulendran, the Violetta L. Horton Professor II.

He shares senior authorship of the study with Kari Nadeau, MD, PhD, the Naddisy Foundation Professor of Pediatric Food, Allergy, Immunology, and Asthma and professor of pediatrics, and Purvesh Khatri, PhD, associate professor of biomedical informatics and of biomedical data science. The study’s lead authors are Prabhu Arunachalam, PhD, a senior research scientist in Pulendran’s lab; medical student Madeleine Scott, PhD, a former graduate student in Khatri’s lab; and Thomas Hagan, PhD, a former postdoctoral scholar in Pulendran’s Stanford lab and now an assistant professor at the Yerkes National Primate Research Center in Atlanta.

Uncharted territory

“This is the first time RNA vaccines have ever been given to humans, and we have no clue as to how they do what they do: offer 95% protection against COVID-19,” said Pulendran.

Traditionally, the chief immunological basis for approval of new vaccines has been their ability to induce neutralizing antibodies: individualized proteins, created by immune cells called B cells, that can tack themselves to a virus and block it from infecting cells.

“Antibodies are easy to measure,” Pulendran said. “But the immune system is much more complicated than that. Antibodies alone don’t come close to fully reflecting its complexity and potential range of protection.”

Pulendran and his colleagues assessed goings-on among all the immune cell types influenced by the vaccine: their numbers, their activation levels, the genes they express and the proteins and metabolites they manufacture and secrete upon inoculation.

One key immune-system component examined by Pulendran and his colleagues was T cells: search-and-destroy immune cells that don’t attach themselves to viral particles as antibodies do but rather probe the body’s tissues for cells bearing telltale signs of viral infections. On finding them, they tear those cells up.

In addition, the innate immune system, an assortment of first-responder cells, is now understood to be of immense importance. It’s the body’s sixth sense, Pulendran said, whose constituent cells are the first to become aware of a pathogen’s presence. Although they’re not good at distinguishing among separate pathogens, they secrete “starting gun” signaling proteins that launch the response of the adaptive immune system — the B and T cells that attack specific viral or bacterial species or strains. During the week or so it takes for the adaptive immune system to rev up, innate immune cells perform the mission-critical task of holding incipient infections at bay by gobbling up — or firing noxious substances, albeit somewhat indiscriminately, at — whatever looks like a pathogen to them.

A different type of vaccine

The Pfizer vaccine, like the one made by Moderna Inc., works quite differently from the classic vaccines composed of live or dead pathogens, individual proteins or carbohydrates that train the immune system to zero in on a particular microbe and wipe it out. The Pfizer and Moderna vaccines instead contain genetic recipes for manufacturing the spike protein that SARS-CoV-2, the virus that causes COVID-19, uses to latch on to cells it infects.

In December 2020, Stanford Medicine began inoculating people with the Pfizer vaccine. This spurred Pulendran’s desire to assemble a complete report card on the immune response to it.

The team selected 56 healthy volunteers and drew blood samples from them at multiple time points preceding and following the first and second shots. The researchers found that the first shot increases SARS-CoV-2-specific antibody levels, as expected, but not nearly as much as the second shot does. The second shot also does things the first shot doesn’t do, or barely does.

“The second shot has powerful beneficial effects that far exceed those of the first shot,” Pulendran said. “It stimulated a manifold increase in antibody levels, a terrific T-cell response that was absent after the first shot alone, and a strikingly enhanced innate immune response.”

Unexpectedly, Pulendran said, the vaccine — particularly the second dose — caused the massive mobilization of a newly discovered group of first-responder cells that are normally scarce and quiescent.

First identified in a recent vaccine study led by Pulendran, these cells — a small subset of generally abundant cells called monocytes that express high levels of antiviral genes — barely budge in response to an actual COVID-19 infection. But the Pfizer vaccine induced them.

This special group of monocytes, which are part of the innate museum, constituted only 0.01% of all circulating blood cells prior to vaccination. But after the second Pfizer-vaccine shot, their numbers expanded 100-fold to account for a full 1% of all blood cells. In addition, their disposition became less inflammatory but more intensely antiviral. They seem uniquely capable of providing broad protection against diverse viral infections, Pulendran said.

“The extraordinary increase in the frequency of these cells, just a day following booster immunization, is surprising,” Pulendran said. “It’s possible that these cells may be able to mount a holding action against not only SARS-CoV-2 but against other viruses as well.”

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The look and feel of your neighborhood may affect your sleep

Those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape.

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Your neighborhood’s “streetscape”—the physical environment of your street—is something that you have probably never consciously thought about, despite seeing it every day. But what if the streetscape was affecting you on a subconscious level and disrupting your sleep? 

This intriguing question is posed by the findings of a study led by Professor Daisuke Matsushita of the Graduate School of Human Life and Ecology at Osaka Metropolitan University. The research team used AI to analyze more than 200,000 Google Street View images to identify visual neighborhood characteristics. They then linked these characteristics to the self-reported sleep of 1,089 working adults living on the lower floors of apartments in Tokyo, who were most likely to be affected by the streetscape.  

They found that those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape. Generally, people slept longer in areas with lots of greenery, such as leafy trees, on the street. Similarly, high “enclosure”—meaning many tall vertical buildings and few wide-open spaces—was also associated with longer sleep and fewer insomnia symptoms. 

However, the study also made a surprising finding. The researchers found that highly walkable streetscapes, such as those with more sidewalks and traffic signs, were associated with a lowered sense of safety and shortened sleep duration.  

This suggests that walkability does not always represent a reassuring environment. Instead, a possible explanation is that streets with extensive pedestrian infrastructure are often busier, more crowded, and used by more strangers, which may be perceived as less safe or less relaxing than quieter residential streets.  

“This study demonstrates the potential for evaluating streetscape characteristics across large geographic areas in a cost-effective manner,” Dr. Matsushita said. “Based on the technique used in this study, cities could potentially measure perceived safety, beauty, liveliness, and enclosure as well as pollution and noise.”  

“We hope that opening up this new perspective creates further possibilities for designing healthier neighborhoods,” he concludes.  

The findings were published in Building and Environment.

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Workout or nap? Either can help your sleepless brain, study finds

People who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither.

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A short workout or a nap can help protect memory after a sleepless night, a McGill University-led study has found.

Researchers found people who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither. The findings, published in Proceedings of the National Academy of Sciences (PNAS), point to practical ways to counter the effects of sleep deprivation.

“Sleep loss affects nearly every aspect of how we think and function, but many people can’t simply stop what they’re doing and get more sleep,” said senior author Marc Roig, Professor in McGill’s School of Physical and Occupational Therapy. “Our findings show that even a brief bout of exercise may help preserve one of our most important cognitive abilities.”

The study involved 54 healthy young adults who stayed awake for 30 consecutive hours under lab supervision. Participants were then assigned to one of three groups: a 20-minute cycling session, a 90-minute nap or a control condition. Three days later, researchers tested their memory for images they had viewed immediately after the intervention. Those who exercised or napped remembered significantly more images than participants who did neither.

Same result, different pathways

While the memory benefits were nearly identical, brain recordings revealed that exercise and napping helped in different ways.

Napping appeared to help the brain recharge, making it easier to take in and remember new information. Exercise, by contrast, helped the brain use its remaining resources more efficiently, without making participants feel more tired.

The findings could eventually inform fatigue-management strategies in workplaces where sleep loss is common and mistakes can have serious consequences, such as health care, transportation and emergency response.

“A nap isn’t always possible in the middle of a shift,” said first author Madhura Lotlikar, a doctoral candidate in McGill’s Department of Neurology and Neurosurgery. “Exercise is accessible, inexpensive and easy to implement. That makes it a promising tool to help people stay cognitively sharp when sleep is limited.”

The researchers emphasize that exercise cannot replace sleep, but it may help people function better when getting enough rest isn’t possible.

About the study

“Protecting episodic memory after sleep loss: Similar benefits of exercise and naps via distinct neural contributions” by Madhura Lotlikar and Marc Roig et al., was published in Proceedings of the National Academy of Sciences of the United States of America.

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Study links coffee consumption to metabolic health and sex hormones

Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.

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Coffee is one of the world’s most widely consumed beverages, and previous research has linked its consumption to a lower risk of conditions such as type 2 diabetes and cardiovascular disease. However, the biological mechanisms behind these benefits remain unclear. A new Finnish study links habitual coffee consumption to healthier body composition and metabolic markers, while revealing distinct associations with sex hormones in men and women.

The study, conducted at the University of Oulu, analysed data from 2,264 participants aged 46 in the Northern Finland Birth Cohort 1966. Researchers examined how habitual coffee consumption was associated with circulating metabolites, cardiometabolic risk markers and sex hormones.

Despite having a similar body mass index (BMI), individuals with higher coffee consumption had lower total and visceral fat and greater skeletal muscle mass than those who consumed less coffee.

In both men and women, higher coffee consumption was correlated with lower circulating levels of branched-chain amino acids, biomarkers that have previously been linked to insulin resistance and an increased risk of type 2 diabetes when chronically elevated.

The strongest sex-specific associations were observed in men. Higher coffee consumption was linked to a more favourable glucose–insulin profile, higher concentrations of total and bioavailable testosterone, and increased levels of sex hormone-binding globulin (SHBG). At the same time, free testosterone and the free androgen index were modestly lower. In women, hormonal associations were more limited and were primarily characterised by higher SHBG and lower measures of free androgens.

“Coffee is consumed by millions of people every day, yet we still know surprisingly little about how it relates to our metabolism and hormones. What stood out in our findings was a distinct hormonal signature that didn’t disappear even after we took into account BMI and lifestyle factors, with several of these associations differing between men and women,” says Luca Verroest, lead author of the study and Doctoral Researcher at the University of Oulu.

The results suggest that hormonal pathways may partly explain the relationship between coffee consumption and metabolic health. However, as this was an observational study, the findings demonstrate associations rather than cause-and-effect relationships.

The study is particularly relevant in Finland, one of the world’s highest coffee-consuming countries, where annual consumption averages around 11.8 kilograms per person.

The researchers say the findings provide a foundation for future studies aimed at determining whether coffee itself drives these biological changes and identifying the compounds responsible. These questions are currently being investigated in animal models, with the long-term goal of progressing to human intervention studies. Further research will be needed before the findings could inform dietary recommendations.

The study, Associations of habitual coffee intake with testosterone and cardiometabolic markers: the Northern Finland Birth Cohort 1966 study, has been published in the European Journal of Nutrition.

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