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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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Could your oral health be affecting fertility?

Chronic oral inflammation may impair female fertility by triggering a systemic immune response that affects the ovaries. A new study shows this leads to oxidative damage, reduced egg quality, disrupted follicle development and reduced live birth rate. These findings point to a potential biological link between oral health and unexplained infertility, opening new directions for future treatments.

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A new study led by Prof. Michael Klutstein at the Hebrew University of Jerusalem and Prof. Asaf Wilensky at the Hebrew University-Hadassah Medical center and spearheaded by the students Dr. Paz Kles and Stephen Ameho has uncovered a striking biological link between chronic oral inflammation and female fertility, suggesting that conditions in the mouth may have far-reaching effects on reproductive health.

Published in the Journal of Dental Research, the study shows that persistent inflammation in the oral cavity can impair ovarian function, reduce egg quality, and ultimately lower fertility rates.

Researchers examined in a mouse model inflammation associated with dental implants, a common clinical scenario, and tracked how immune signals spread throughout the body. Their findings reveal that inflammation does not remain confined to the oral cavity but triggers a systemic immune response that reaches the ovaries.

The consequences were significant. Chronic oral inflammation in the animals was linked to increased levels of inflammatory cytokines in the ovaries, along with shifts in immune cell populations. This was accompanied by oxidative damage to ovarian tissue, impaired development of follicles, and reduced quality of oocytes.

These biological changes translated into measurable reproductive outcomes, with markedly reduced birth rates observed under inflammatory conditions in the animals.

The study also identified deeper cellular effects. Oocytes exhibited DNA damage and epigenetic alterations resembling those seen in reproductive aging, pointing to a possible mechanism by which inflammation accelerates the decline in fertility.

“Inflammation is often thought of as a localized response, but our findings show that it can have systemic consequences that extend as far as the reproductive system,” said Prof. Michael Klutstein. “This work suggests that chronic oral inflammation may be an underrecognized factor in female infertility, potentially contributing to cases that currently have no clear explanation.”

The findings add to growing evidence that oral health is closely linked to overall health. Chronic oral inflammatory conditions such as periodontitis are widespread and have already been associated with a range of systemic diseases.

The researchers note that further investigation in clinical settings will be essential to determine how these findings translate to patient care. If confirmed, the work could open new avenues for diagnosis and treatment, including the use of anti-inflammatory or antioxidant approaches to improve fertility outcomes.

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Maintaining a healthy heart may require regular doses of positivity

The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization.

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Positive psychology interventions such as mindfulness, gratitude journaling and optimism training can consistently improve blood pressure, inflammation markers and other cardiovascular disease risk factors within a matter of weeks, a recent study found. However, since these benefits are associated with lifestyle changes such as eating healthier and greater physical activity, the researchers suggested that ongoing reinforcements may be needed to stay on course long term.

Rosalba (Rose) Hernandez, a professor of social work at the University of Illinois Urbana-Champaign, led a team that analyzed the findings of 18 randomized controlled trials that used positive psychological and mindfulness interventions to enhance mental or physical health.

The programs that the team reviewed included individual methods — such as structured telephone sessions, journaling with brief check-ins and digital platforms such as apps and text messaging — and interactive in-person group sessions, as well as hybrid formats that blended these with online tools and virtual meetings. Most of the programs consisted of weekly sessions and at-home activities that reinforced the skills taught, with the majority of programs lasting from six to 12 weeks, the team found.

In general, the programs included 50-200 adults with elevated cardiovascular risk factors such as uncontrolled hypertension, heart failure or other conditions. Typically, the participants were in their late 50s to mid-60s, and women comprised 35-55% of the samples across those studies that reported their participants’ gender, according to the researchers.

“In hypertension and postacute coronary syndrome cohorts, mindfulness-based programs delivered over an eight-week period reduced systolic blood pressure and lowered inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen,” said Hernandez, who is a Fellow of the American Heart Association. “A 12-week spirituality-based digital intervention achieved one of the largest reductions — reducing systolic blood pressure measured with a standard cuff by 7.6 points, and central systolic pressure — which is measured in the aorta as it leaves the heart — by 4.1 points.”

In prior research on positive psychology interventions, scientists seldom defined the dose that was needed to obtain the beneficial effects, Hernandez said. She and the team members sought to clarify the frequency and duration that was most likely to improve individuals’ cardiovascular health.

Programs that had more frequent contact with their participants yielded the most consistent physiological benefits, underscoring the opportunity to embed positive psychological strategies into long-term cardiovascular care, Hernandez said.

The team found that the strongest behavioral improvements were achieved by an eight-week program delivered over WhatsApp that combined weekly sessions with daily microtasks, motivating participants to engage in greater physical activity, eat a healthier diet and take their medication as prescribed. A program that included motivational interviewing succeeded in increasing cardiac patients’ levels of physical activity by 1,800 steps a day and their medication adherence, while the mindfulness programs improved participants’ activity levels and diets only, according to the study.

“The therapeutic dose that was most consistently linked with improvements in blood pressure, inflammation and endothelial function was daily practice reinforced by weekly sessions over eight to 12-week periods,” Hernandez said. “Therapeutic dosing typically involved high-frequency dosing over this time period to obtain short-term physiologic benefits, while ongoing less-intensive contact may be needed to sustain behavioral change.”

Published in the journal Cardiology Clinics, the study was co-written by University of South Florida social work professor Soonhyung Kwon; Alyssa M. Vela, a professor of surgery and of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine; and Katharine S. Edwards, a professor of cardiovascular medicine and of psychiatry and behavioral medicine at Stanford Medicine.

“The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization,” Vela said. “This speaks to the need for routine screening and integration of cardiac behavioral medicine to allow for access to important interventions.”

The current study adds to a growing body of research linking psychological well-being — including traits such as optimism, positive affect and gratitude — with cardioprotective benefits.

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Heart disease risk may start in the womb, study finds

Young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.

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A child’s future heart health may be partially shaped before they are born, reports a new Northwestern Medicine study that found pregnancy complications are linked to poorer cardiovascular health in offspring more than 20 years later.

The study found that young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.

The authors said the study adds to growing evidence that cardiovascular risk may be transmitted across generations through a combination of biological, environmental and behavioral factors.

“That means we must make sure people maintain good health from childhood into young adulthood, so that if or when someone becomes a parent, they pass on the best opportunity for good health to their children,” said study senior author Dr. Nilay Shah, assistant professor of medicine in the division of cardiology at Northwestern University Feinberg School of Medicine.

How the study was conducted

Shah and colleagues evaluated nearly 1,350 mother-child pairs from the Future of Families and Child Well-Being Study, which enrolled mothers and children at birth between 1998 and 2000 across 20 U.S. cities. The children were then followed into adulthood.

Using delivery hospitalization records, the Northwestern scientists first identified whether mothers experienced pregnancy complications, including high blood pressure during pregnancy, gestational diabetes (high blood sugar during pregnancy) or preterm birth (before 37 weeks of pregnancy).

The three pregnancy complications are on the rise, and affect almost one in four pregnancies in the U.S.

The research team then analyzed cardiovascular health of offspring at age 22, using blood pressure measurements, blood testing, body mass index assessments and carotid artery ultrasounds to look for signs of artery injury.

Finally, the scientists compared participants with and without exposure to each pregnancy complication and adjusted for factors like income, education, difference in birth weight and smoking during pregnancy.

Key findings

At around age 22, participants whose mothers had high blood pressure during pregnancy had:

  • Higher body mass index (+2.8 BMI points)
  • Higher diastolic blood pressure (+2.3 mm Hg)
  • Higher blood sugar levels (+0.2% HbA1c)
  • Thicker artery walls (~0.02 mm)

While the difference in artery wall thickness may seem small, the study authors said it corresponds to roughly three to five years of additional vascular aging. That means arteries looked older and less healthy than expected, which raises the risk of future heart disease.

Other pregnancy complications also showed some long-term effect:

  • Exposure to gestational diabetes was linked to worse blood pressure and some evidence of artery thickening
  • Being born preterm was associated with higher blood sugar levels

‘Most heart disease is preventable’

With pregnancy complications on the rise in the U.S., Shah said the study provides compelling evidence that improving health before and during pregnancy could help reduce heart disease risk in the next generation.

“There is evidence that both parents’ health at the time of conception and during pregnancy influences a child’s health,” he said. “So, promoting health from an early age, like exercising regularly, eating healthfully, never smoking and getting enough sleep, is not just meant for an individual, but doing so may help future generations be healthier, too.”

Shah also emphasizes that risk is not destiny.

“The good news is that most heart disease is preventable,” he said. “If you experienced high blood pressure or high blood sugar during pregnancy, or your child was born early, it does not absolutely mean that your child will have worse health as adults. But I would encourage you to pay attention now to your child’s health behaviors.

“What children learn in childhood sets the stage for their health across their lives. If you are wondering whether your children’s behaviors are healthy, or are considering making a change, please speak with your child’s pediatrician for advice and guidance.”

Other Northwestern co-authors include Emily Lam, Abigail Gauen, Dr. Sadiya Khan, Alexa Freedman and Norrina Allen.

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