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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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Down on Vitamin D? It could be the cause of chronic inflammation

Lead researcher, UniSA’s Dr Ang Zhou, says the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

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Inflammation is an essential part of the body’s healing process. But when it persists, it can contribute to a wide range of complex diseases including type 2 diabetes, heart disease, and autoimmune diseases.

Now, world-first genetic research from the University of South Australia shows a direct link between low levels of vitamin D and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component.

The study examined the genetic data of 294 ,970 participants in the UK Biobank, using Mendelian randomization to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.

Lead researcher, UniSA’s Dr Ang Zhou, says the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

“Inflammation is your body’s way of protecting your tissues if you’ve been injured or have an infection,” Dr Zhou says. “High levels of C-reactive protein are generated by the liver in response to inflammation, so when your body is experiencing chronic inflammation, it also shows higher levels of C-reactive protein. This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation. Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”

Supported by the National Health and Medical Research Council and published in the International Journal of Epidemiology the study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.

Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, says these results are important and provide an explanation for some of the controversies in reported associations with vitamin D.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen says.  “These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”

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Fatigue, headache among top lingering symptoms months after COVID

Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from having COVID-19, investigators report.

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Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from having COVID-19, investigators report.

Muscle aches, cough, changes in smell and taste, fever, chills and nasal congestion were next in the long line of lingering symptoms.

“Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infections,” Medical College of Georgia investigators write in the journal ScienceDirect

“There are a lot of symptoms that we did not know early on in the pandemic what to make of them, but now it’s clear there is a long COVID syndrome and that a lot of people are affected,” says Dr. Elizabeth Rutkowski, MCG neurologist and the study’s corresponding author.

The published study reports on preliminary findings from the first visit of the first 200 patients enrolled in the COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia, or CONGA, who were recruited on average about 125 days after testing positive for the COVID-19 virus.

CONGA was established at MCG early in the pandemic in 2020 to examine the severity and longevity of neurological problems and began enrolling participants in March 2020 with the ultimate goal of recruiting 500 over five years.

Eighty percent of the first 200 participants reported neurological symptoms with fatigue, the most common symptom, reported by 68.5%, and headache close behind at 66.5%. Just over half reported changes in smell (54.5%) and taste (54%) and nearly half the participants (47%) met the criteria for mild cognitive impairment, with 30% demonstrating impaired vocabulary and 32% having impaired working memory.

Twenty-one percent reported confusion, and hypertension was the most common medical condition reported by participants in addition to their bout with COVID-19.

No participants reported having a stroke, weakness or inability to control muscles involved with speaking, and coordination problems were some of the less frequently reported symptoms.

Twenty-five percent met the criteria for depression, and diabetes, obesity, sleep apnea and a history of depression were associated with those who met the criteria. Anemia and a history of depression were associated with the 18% who met the objective criteria for anxiety.

While the findings to date are not surprising and are consistent with what other investigators are finding, Rutkowski says the fact that symptoms reported by participants often didn’t match what objective testing indicated, was surprising. And, it was bidirectional.

For example, the majority of participants reported taste and smell changes, but objective testing of both these senses did not always line up with what they reported. In fact, a higher percentage of those who did not report the changes actually had evidence of impaired function based on objective measures, the investigators write. While the reasons are not certain, part of the discrepancy may be a change in the quality of their taste and smell rather than pure impaired ability, Rutkowski says.

“They eat a chicken sandwich and it tastes like smoke or candles or some weird other thing but our taste strips are trying to depict specific tastes like salty and sweet,” Rutkowski says. Others, for example, may rely on these senses more, even when they are preparing the food, and may be apt to notice even a slight change, she says.

Either way, their data and others suggest a persistent loss of taste and smell following COVID-19, Rutkowski and her colleagues write.

Many earlier reports have been based on these kinds of self-reports, and the discrepancies they are finding indicate that approach may not reflect objective dysfunction, the investigators write.

On the other hand, cognitive testing may overestimate impairment in disadvantaged populations, they report.

The first enrollees were largely female, 35.5% were male. They were an average of 44.6 years old, nearly 40% were Black and 7% had been hospitalized because of COVID-19. Black participants were generally disproportionately affected, the investigators say.

Seventy-five percent of Black participants and 23.4% of white participants met criteria for mild cognitive impairment. The findings likely indicate that cognitive tests assess different ethnic groups differently. And, socioeconomic, psychosocial (issues like family problems, depression and sexual abuse) and physical health factors generally may disproportionately affect Black individuals, the investigators write. It also could mean that cognitive testing may overestimate clinical impairment in disadvantaged populations, they write.

Black and Hispanic individuals are considered twice as likely to be hospitalized by COVID-19 and ethnic and racial minorities are more likely to live in areas with higher rates of infection. Genetics also is a likely factor for their increased risk for increased impact from COVID, much like being at higher risk for hypertension and heart disease early and more severely in life.

A focus of CONGA is to try to better understand how increased risk and effects from COVID-19 impact Blacks, who comprise about 33% of the state’s population.

A reason fatigue appears to be such a major factor among those who had COVID-19 is potentially because of levels of inflammation, the body’s natural response to an infection, remain elevated in some individuals. For example, blood samples taken at the initial visit and again on follow up showed some inflammatory markers were up and stayed up in some individuals.

These findings and others indicate that even though the antibodies to the virus itself may wain, persistent inflammation is contributing to some of the symptoms like fatigue, she says. She notes patients with conditions like multiple sclerosis and rheumatoid arthritis, both considered autoimmune conditions that consequently also have high levels of inflammation, also include fatigue as a top symptom.

“They have body fatigue where they feel short of breath, they go to get the dishes done and they are feeling palpitations, they immediately have to sit down and they feel muscle soreness like they just ran a mile or more,” Rutkowski says.

“There is probably some degree of neurologic fatigue as well because patients also have brain fog, they say it hurts to think, to read even a single email and that their brain is just wiped out,” she says. Some studies have even shown shrinkage of brain volume as a result of even mild to moderate disease. 

These multisystem, ongoing concerns are why some health care facilities have established long COVID clinics where physicians with expertise in the myriad of problems they are experiencing gather to see each patient.

CONGA participants who reported more symptoms and problems tended to have depression and anxiety. Problems like these as well as mild cognitive impairment and even impaired vocabulary may also reflect the long-term isolation COVID-19 produced for many individuals, Rutkowski says.

“You are not doing what you would normally do, like hanging out with your friends, the things that bring most people joy,” Rutkowski says. “On top of that, you may be dealing with physical ailments, lost friends and family members and loss of your job.”

For CONGA, participants self-report symptoms and answer questions about their general state of health like whether they smoked, drank alcohol, exercised, and any known preexisting medical conditions. But they also receive an extensive neurological exam that looks at fundamentals like mental status, reflexes and motor function. They also take established tests to assess cognitive function with results being age adjusted. They also do at-home extensive testing where they are asked to identify odors and the ability to taste sweet, sour, bitter, salty, brothy or no taste. They also have blood analysis done to look for indicators of lingering infection like those inflammatory markers and oxidative stress.

Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how symptoms evolve over time, the investigators write.

And particularly for some individuals, symptoms definitely linger. Even some previously high-functioning individuals, who normally worked 80 hours a week and exercised daily, may find themselves only able to function about an hour a day and be in the bed the remainder, Rutkowski says.

The investigators are searching for answers to why and how, and while Rutkowski says she cannot yet answer all their questions, she can tell them with certainty that they are not alone or “crazy.”  

One of the best things everyone can do moving forward is to remain diligent about avoiding infection, including getting vaccinated or boosted to help protect your brain and body from long COVID symptoms and help protect others from infection, Rutkowski says. There is evidence that the more times you are infected, the higher the risk of ongoing problems.

Rutkowski notes that their study findings may be somewhat biased toward high percentages of ongoing symptoms because the study likely is attracting a high percentage of individuals with concerns about ongoing problems.

SARS-CoV-2 is thought to have first infected people in late 2019 and is a member of the larger group of coronaviruses, which have been a source of upper respiratory tract infections, like the common cold, in people for years.

At least part of the reason SARS-CoV-2 is believed to have such a wide-ranging impact is that the virus is known to attach to angiotensin-converting enzyme-2, or ACE2, which is pervasive in the body. ACE2 has a key role in functions like regulating blood pressure and inflammation. It’s found on neurons, cells lining the nose, mouth, lungs and blood vessels, as well as the heart, kidneys and gastrointestinal tract. The virus attaches directly to the ACE2 receptor on the surface of cells, which functions much like a door to let the virus inside.

Experience and study since COVID-19 started both indicate immediate neurological impact can include loss of taste and smell, brain infection, headaches and, less commonly, seizures, stroke and damage or death of nerves. As time has passed, there is increasing evidence that problems like loss of taste and smell, can become chronic, as well as problems like brain fog, extreme fatigue, depression, anxiety and insomnia, the investigators write. Persistent conditions including these and others are now referenced as “long Covid.”

The research was supported by funding from the National Institute of Neurological Disorders and Stroke and philanthropic support from the TR Reddy Family Fund.

Read the full study.

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Vitamin B6 supplements could reduce anxiety and depression

The study showed that Vitamin B12 had little effect compared to placebo over the trial period, but Vitamin B6 made a statistically reliable difference.

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Taking high-dose Vitamin B6 tablets has been shown to reduce feelings of anxiety and depression by new research.

Scientists at the University of Reading measured the impact of high doses of Vitamin B6 on young adults and found that they reported feeling less anxious and depressed after taking the supplements every day for a month.

The study, published in the journal Human Psychopharmacology: Clinical and Experimental, provides valuable evidence to support the use of supplements thought to modify levels of activity in the brain for preventing or treating mood disorders.

Dr David Field, lead author from the School of Psychology and Clinical Language Sciences at the University of Reading, said: “The functioning of the brain relies on a delicate balance between the excitatory neurons that carry information around and inhibitory ones, which prevent runaway activity.

“Recent theories have connected mood disorders and some other neuropsychiatric conditions with a disturbance of this balance, often in the direction of raised levels of brain activity.

“Vitamin B6 helps the body produce a specific chemical messenger that inhibits impulses in the brain, and our study links this calming effect with reduced anxiety among the participants.”

While previous studies have produced evidence that multivitamins or marmite can reduce stress levels, few studies have been carried out into which particular vitamins contained within them drive this effect.

The new study focused on the potential role of Vitamins B6, which is known to increase the body’s production of GABA (Gamma-Aminobutyric Acid), a chemical that blocks impulses between nerve cells in the brain.

In the current trial, more than 300 participants were randomly assigned either Vitamin B6 or B12 supplements far above the recommended daily intake (approximately 50 times the recommended daily allowance) or a placebo, and took one a day with food for a month.

The study showed that Vitamin B12 had little effect compared to placebo over the trial period, but Vitamin B6 made a statistically reliable difference.

Raised levels of GABA among participants who had taken Vitamin B6 supplements were confirmed by visual tests carried out at the end of the trial, supporting the hypothesis that B6 was responsible for the reduction in anxiety. Subtle but harmless changes in visual performance were detected, consistent with controlled levels of brain activity.

Dr Field said: “Many foods, including tuna, chickpeas and many fruits and vegetables, contain Vitamin B6. However, the high doses used in this trial suggest that supplements would be necessary to have a positive effect on mood.

“It is important to acknowledge that this research is at an early stage and the effect of Vitamin B6 on anxiety in our study was quite small compared to what you would expect from medication. However, nutrition-based interventions produce far fewer unpleasant side effects than drugs, and so in the future people might prefer them as an intervention.

“To make this a realistic choice, further research is needed to identify other nutrition-based interventions that benefit mental wellbeing, allowing different dietary interventions to be combined in future to provide greater results.

“One potential option would be to combine Vitamin B6 supplements with talking therapies such as Cognitive Behavioural Therapy to boost their effect.”

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