Immune system dysfunction can alter the link between cannabis use and psychosis

Immune system dysfunction can alter the link between cannabis use and psychosis

  • June 17, 2021

The presence of pro-inflammatory cytokines in the blood can boost the effects of daily cannabis use and heighten the risk of developing psychosis in adulthood. Similar results have been observed, also in the presence of cytokines, when cannabis is used during adolescence. Psychotic disorders have symptoms such as delirium, loss of a sense of reality, hallucinations, hearing voices, and cognitive and social impairments.

A study by researchers at the University of São Paulo’s Ribeirão Preto Medical School (FMRP-USP) in Brazil, reported in an article in the journal Psychological Medicine, finds for the first time that individuals exposed to a combination of these two factors – the presence of pro-inflammatory cytokines in the blood and cannabis use (either daily or during adolescence) – are more likely to suffer from psychosis than those who are exposed to neither or to only one. According to the authors, the study provides “the first clinical evidence that immune dysregulation modifies the cannabis-psychosis association”.

The study was part of a project conducted by the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI), a consortium of research centers in 13 countries, including Brazil. An article published in The Lancet Psychiatry by the consortium in 2019 showed that daily cannabis use increased the likelihood of suffering from a psychotic disorder threefold.

In the more recent study, the researchers analyzed data for 409 people aged 16-64, including patients experiencing their first psychotic episode and community-based controls. The sample was drawn from the populations of Ribeirão Preto and 25 other cities in the region. The variables analyzed included cannabis use frequency (daily, not daily or never), duration (five years or less), and onset age (in adolescence or later).

In addition to the questionnaire on cannabis use, the researchers measured various cytokines in plasma donated by the volunteers and calculated scores representing their systemic inflammatory profiles. They also collected clinical and socio-demographic data, especially variables known as confounders, such as age, gender, schooling, ethnicity, body mass index, smoking, and use of psychoactive substances. The results obtained were independent of confounding factors.

Not everyone who uses cannabis develops psychosis. This suggests that the association may be modified by other factors, which may be biological, genetic or environmental. In a previous study conducted as part of my master’s research, we identified a correlation between plasma cytokines and the first psychotic episode. Following up on this discovery, and the consortium’s recent publication showing a higher incidence of psychosis among subjects who used cannabis on a daily basis, our next step was to see if the biological factor [inflammatory profile] affected the link between cannabis use and psychosis.”


Fabiana Corsi-Zuelli, First Author of the Article

The main conclusion was that such a link did indeed exist. “We found a statistically significant correlation between inflammatory profile and cannabis use on a daily basis or during adolescence. In sum, the results showed that immune system dysfunction can modify the association between cannabis use and psychosis and that a combination of these two factors increases the odds of suffering from a psychotic disorder,” she said.

Corsi-Zuelli is currently a PhD candidate in FMRP-USP’s graduate program in neurology and neurosciences, with support from São Paulo Research Foundation – FAPESP.

The principal investigator for the project is Cristina Marta Del-Ben, a professor at FMRP-USP’s Department of Neurosciences and Behavioral Sciences. According to Del-Ben, risk factors for psychosis may be biological, including genetic predisposition and problems during pregnancy, as well as environmental, including traumatic experiences during childhood and adolescence, and exposure to psychoactive substances, especially cannabis.

“The mechanisms of the disorder are poorly understood,” she said. “Our findings show that frequent current use of cannabis or use of the drug in adolescence is a risk factor for psychosis. We didn’t detect the same correlation with occasional or recreational use. In the multicenter study, which included European cities with varying levels and types of cannabis availability, we also found that the risk of psychosis is greater in users of stronger cannabis strains with a THC content or 10% of higher.” THC (delta-9-tetrahydrocannabinol) is the primary psychoactive constituent of cannabis or marijuana.

The medical explanation of psychosis is that it is a neuropsychiatric syndrome associated with anatomical and functional alterations in the brain, possibly linked to changes in the action of dopamine, a key neurotransmitter for communication among neurons. Excessive dopamine or direct damage to certain brain regions can lead to hallucinations, delusions, delirium and disorganized behavior.

Other neurotransmitters, such as glutamate, have also been implicated in the neurobiology of psychosis. Specialists are currently discussing what they call the neuroimmune link, and how immune system dysregulation may trigger neurochemical, morphological and behavioral alterations that heighten the risk of developing psychiatric disorders.

Psychotic symptoms may be present in several psychiatric disorders, which may or may not be affective. Recent research has taken note of cases of psychosis in patients infected by SARS-CoV-2. Treatment of psychosis involves a combination of medication, psychotherapy and family support.

Next steps

According to Corsi-Zuelli, the origin of the inflammatory alterations involved in psychosis is still obscure, but it may arise from a combination of genetic and environmental factors. “The inflammation seen in psychiatric disorders is considered low-level and isn’t as severe as in patients with autoimmune diseases or sepsis,” she said. “Nevertheless, experimental studies suggest it entails sufficient dysregulation to produce neurochemical and behavioral alterations.”

The researchers plan next to study genetic variants associated with the immune system and use neuroimaging data to explore the link with environmental risk factors. “Focusing in this way on the interactions between genetics and the environment will help us understand the neurobiology of psychosis, especially the role played by the immune system,” she said.

The association between inflammation and psychiatric disorders is highly relevant to clinical practice and has received growing attention. “It’s important to the search for alternative treatments for these disorders, and also to answering often neglected questions relating to the physical health of psychiatric patients,” Corsi-Zuelli said.

According to Del-Ben, in the pipeline for next steps is a partnership with Geraldo Busatto Filho, a professor at the Medical School (FM) in USP’s main campus, to investigate whether inflammatory markers in blood are linked to brain alterations in some of the patients studied.

The research has twice received international recognition. The Society of Biological Psychiatry selected the study for its Predoctoral Scholars Award, which was to have been formalized at SOBP’s 2020 annual meeting in New York, but the pandemic forced a postponement until April 2021, when the meeting was held online. And the study was selected by the Schizophrenia International Research Society (SIRS) for presentation at its 2020 Congress, also held online.urce:

Health expert explains how COVID-19 vaccines strengthen immune system to fight the virus

Health expert explains how COVID-19 vaccines strengthen immune system to fight the virus

  • June 15, 2021

BIRMINGHAM, Ala. (WBRC) – When getting vaccinated for the COVID-19 shot, it can make you feel crummy for a couple days but doctors say that doesn’t mean your immune system is slacking.

Even if you experience side effects, doctors say the vaccine does not weaken your immune system, instead, it strengthens it.

COVID-19 vaccines strengthen the immune system’s response to the virus, and the body having chills or fatigue is your immune system ramping up its power.

“We know that immune response can vary,” explained ADPH’s Dr. Karen Landers.

The data supports the conclusion that getting the vaccine will lessen the potential of a really bad case of COVID if you’re one of the people to contract it after getting the shot.

“Persons are less likely to have a severe illness, less likely to be hospitalized and they are less likely to die,” said Dr. Landers.

The vaccine arms the immune system with fighters, but they don’t always win; 800 Alabama residents who got the vaccine, got COVID after.

“We’ve had 54 people hospitalized which is an exceedingly small number,” said Dr. Landers.

She says the shot is the only surefire way to give your body the tools to effectively ward off worse case-scenarios.

Breakthrough cases are usually identified in people who go to the doctor with symptoms, so if you do have symptoms go get tested.

Copyright 2021 WBRC. All rights reserved.

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Macrophages can aid tumor growth by distracting cancer-killing CD8+ T cells

  • June 11, 2021

A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities-;which house the lungs and organs of the gastrointestinal tract, respectively-;were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

Start Your Mornings With Moringa To Boost Immunity

Start Your Mornings With Moringa To Boost Immunity

  • June 10, 2021

maintaining social distance

Image: Shutterstock

With COVID-19 possibly going to be around for a long time, exercising precautionary measures like staying home, wearing a mask, and maintaining social distance isn’t enough. Working on boosting immunity is equally important so our body has enough strength to fight back. Rishabh Chokhani, Founder, Naturevibe Botanical, says, “With lockdown implemented in most parts of the country and the ongoing shortage of most medicines, it is difficult to go out and buy regular multivitamins. In this case, it is recommended to explore the goodness of botanicals and indulge in rich vegetables and fruits to boost immunity.”

maintaining social distance

Image: Shutterstock

Speaking about one such plant, Chokhani says moringa is a miracle immunity booster that is widely used in India and can be easily grown at home. It is also versatile – it can be included in regular food and moringa capsules can be consumed as part of morning routine too. Chokhani shares some of the benefits of moringa.

maintaining social distance

Image: Shutterstock

• Rich In Antioxidants
Free radicals in the body are a threat to the immune system; antioxidants help clear free radicals and are even said to help prevent cancer. Chokhani says, “Moringa reduces oxidative stress and works as an excellent anti-ageing agent. Moreover, moringa is rich in iron and vitamin A – nutrients that enhance the functioning of the immune system.”

• Anti-Inflammatory
The corona virus is said to cause inflammation in the respiratory glands. Regular use of moringa may prevent inflammation, as the plant is rich in anti-inflammatory properties. It can also prevent arthritis.

maintaining social distance

Image: Shutterstock

• Packed With Vitamin C
The goodness of vitamin C has been overemphasised for building immunity and working to fight off viruses. Moringa is exceptionally rich in Vitamin C. One cup of fresh, sliced pods (100 grams) contains 157 percent of your daily requirement.

• Rich In Other Nutrients
Chokhani says, “Consuming any part of moringa – the leaves, fruit, or seeds – is beneficial in offering rapid recovery. The plant is rich in vitamin A, vitamin B6, vitamin C, iron, riboflavin, and magnesium, all of which help in getting back body strength and eliminate weakness and fatigue.”

Read more: 3 Tips To Protect Yourself From Carcinogens

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Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Common antidepressant drugs help the immune system to attack tumors in mice

  • June 10, 2021

A class of drug called monoamine oxidase inhibitors is commonly prescribed to treat depression; the medications work by boosting levels of serotonin, the brain’s “happiness hormone.”

A new study by UCLA researchers suggests that those drugs, commonly known as MAOIs, might have another health benefit: helping the immune system attack cancer. Their findings are reported in two papers, which are published in the journals Science Immunology and Nature Communications.

MAOIs had not been linked to the immune system’s response to cancer before. What’s especially exciting is that this is a very well-studied and safe class of drug, so repurposing it for cancer isn’t as challenging as developing a completely new drug would be.”


Lili Yang, Study Senior Author and Member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles Health Sciences

Recent advances in understanding how the human immune system naturally seeks out and destroys cancer cells, as well as how tumors try to evade that response, has led to new cancer immunotherapies — drugs that boost the immune system’s activity to try to fight cancer.

In an effort to develop new cancer immunotherapies, Yang and her colleagues compared immune cells from melanoma tumors in mice to immune cells from cancer-free animals. Immune cells that had infiltrated tumors had much higher activity of a gene called monoamine oxidase A, or MAOA. MAOA’s corresponding protein, called MAO-A, controls levels of serotonin and is targeted by MAOI drugs.

“For a long time, people have theorized about the cross-talk between the nervous system and the immune system and the similarities between the two,” said Yang, who is also a UCLA associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “So it was exciting to find that MAOA was so active in these tumor-infiltrating immune cells.”

Next, the researchers studied mice that didn’t produce MAO-A protein in immune cells. The scientists found that those mice were better at controlling the growth of melanoma and colon tumors. They also found that normal mice became more capable of fighting those cancers when treated with MAOIs.

Digging in to the effects of MAO-A on the immune system, the researchers discovered that T cells — the immune cells that target cancer cells for destruction — produce MAO-A when they recognize tumors, which diminishes their ability to fight cancer.

That discovery places MAO-A among a growing list of molecules known as immune checkpoints, which are molecules produced as part of a normal immune response to prevent T cells from overreacting or attacking healthy tissue in the body. Cancer has been known to exploit the activity of other previously identified immune checkpoints to evade attack by the immune system.

In the Science Immunology paper, the scientists report that MAOIs help block the function of MAO-A, which helps T cells overcome the immune checkpoint and more effectively fight the cancer.

But the drugs also have a second role in the immune system, Yang found. Rogue immune cells known as tumor-associated macrophages often help tumors evade the immune system by preventing anti-tumor cells including T cells from mounting an effective attack. High levels of those immunosuppressive tumor-associated macrophages in a tumor have been associated with poorer prognoses for people with some types of cancer.

But the researchers discovered that MAOIs block immunosuppressive tumor-associated macrophages, effectively breaking down one line of defense that tumors have against the human immune system. That finding is reported in the Nature Communications paper.

“It turns out that MAOIs seem to both directly help T cells do their job, and stop tumor-associated macrophages from putting the brakes on T cells,” Yang said.

Combining MAOIs with existing immunotherapies

Yang said she suspects that MAOIs may work well in concert with a type of cancer immunotherapies called immune checkpoint blockade therapies, most of which work by targeting immune checkpoint molecules on the surface of immune cells. That’s because MAOIs work on MAO-A proteins, which are inside cells and function differently from other known immune checkpoint molecules.

Studies in mice showed that any of three existing MAOIs — phenelzine, clorgyline or mocolobemide — either on their own or in combination with a form of immune checkpoint blockade therapy known as PD-1 blockers, could stop or slow the growth of colon cancer and melanoma.

Although they haven’t tested the drugs in humans, the researchers analyzed clinical data from people with melanoma, colon, lung, cervical and pancreatic cancer; they found that people with higher levels of MAOA gene expression in their tumors had, on average, shorter survival times. That suggests that targeting MAOA with MAOIs could potentially help treat a broad range of cancers.

Yang and her collaborators are already planning additional studies to test the effectiveness of MAOIs in boosting human immune cells’ response to various cancers.

Yang said MAOIs could potentially act on both the brain and immune cells in patients with cancer, who are up to four times as likely as the general population to experience depression.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” she said.

The experimental combination therapy in the study was used in preclinical tests only and has not been studied in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang, Xi Wang and Yu-Chen Wang as co-inventors.

Source:

Journal reference:

Wang, Y-C., et al. (2021) Targeting monoamine oxidase A-regulated tumor-associated macrophage polarization for cancer immunotherapy. Nature Communications. doi.org/10.1038/s41467-021-23164-2.

GoodBelly Launches Fast Melts Perfect for On-the-Go Immune System and Digestion Support | Colorado

GoodBelly Launches Fast Melts Perfect for On-the-Go Immune System and Digestion Support | Colorado

  • June 10, 2021

BOULDER, Colo., June 10, 2021 /PRNewswire/ — GoodBelly, maker of delicious, highly efficacious probiotic products, today announced the launch of a new line of quick-dissolving, fruity probiotic powder, called GoodBelly To Go™ Fast Melts. An innovative, convenient format for probiotic consumption, Fast Melts are shelf stable probiotic powders that deliver impactful, scientifically proven doses of probiotics in each serving. Available in two varieties – strawberry flavored with immunity support and lemon flavored with digestion support – Fast Melts are designed for easy, fun, on-the-go consumption. GoodBelly To Go™ Fast Melts can be enjoyed by simply pouring the powder directly into your mouth, and like magic, the probiotic powder will quickly dissolve. Alternatively, pour the GoodBelly To Go™ Fast Melts into a small amount of water or another beverage and enjoy, or simply add to a delicious smoothie.

GoodBelly To Go™ Fast Melts are a convenient and delicious new way to enjoy your daily dose of efficacious probiotics

The new GoodBelly To Go™ Digestion Fast Melts are made with a probiotic strain called Lactobacillus Plantarum 299v (LP299V®), evaluated in more than 16 research trials and used for 20 years to help balance the gut and promote healthy digestion.1 The GoodBelly To Go™ Immunity Fast Melts contain 1 billion live cultures, and are made from a blend of the scientifically backed strains Lactobacillus Plantarum HEAL9 and Lactobacillus Paracasei 8700:2, which together are clinically shown to support immune function.

All Fast Melts are low calorie, dairy free, contain zero added sugar, and dissolve immediately. The Strawberry flavor with immune support is also gluten free. Fast Melts are great for all ages, including children above 4 years of age, and can be easily enjoyed as part of a daily routine.

“GoodBelly To Go™ Fast Melts provide digestion and immunity support through an efficacious dose of probiotics, with a delicious fruit forward flavor and no added sugar,” said Juan Gluth, NextFoods Inc., makers of GoodBelly, CEO.  “At GoodBelly, probiotics is all we do. We are passionate about gut health and only use the most widely researched strains to promote healthy digestion.”

Maintaining a strong immune system is more important than ever. With 70% of the body’s immune system connected to the digestive tract, a properly functioning digestive system is essential to maintaining overall health. GoodBelly To Go™ Fast Melts offer a powerful daily dose of efficacious probiotics to help boost immunity and digestion. As the maker of the number one natural probiotic juice in the country2, GoodBelly is solely focused on delivering the highest quality probiotics in appealing and innovative formats, and this launch is a natural extension of the brand’s expertise.

“Our work is guided by the belief that better health starts in your belly, including immunity, and our team is proud to share a whole new, enjoyable way consumers can support their overall wellness,” continued Gluth.

GoodBelly To Go™ Fast Melts are available now on Amazon.comImmunity and Digestion – and retail for between $19.99$24.99/30 servings. For more information, visit GoodBelly.com or follow the brand on Instagram at @GoodBellyProbiotics.

About GoodBelly by NextFoods, Inc.

GoodBelly, by NextFoods, Inc., was founded in Boulder, Colo., in 2006 by two natural products industry veterans, Todd Beckman and Steve Demos, who shared a vision to empower consumers to achieve a better quality of life through functional solutions. Today, GoodBelly is recognized as a probiotic pioneer, intent on improving people’s lives by delivering impactful probiotics through convenient and efficacious foods, beverages and supplements. GoodBelly offerings are all made with the well-studied probiotic strains. All beverages contain Lactobacillus Plantarum 299v (LP299V®), which has been scientifically shown to help establish intestinal balance and can support overall digestive and immune health when consumed daily.* GoodBelly is available nationwide in natural, specialty, conventional, mass and convenience retailers. Shoppers can also purchase GoodBelly direct at https://www.Amazon.com or Shop.GoodBelly.com.

1 Some studies suggest that GoodBelly’s probiotics may help balance bacteria in your gut when consumed daily as part of a nutritious diet and healthy lifestyle. GoodBelly is a food product and not a treatment or cure for any medical disorder or disease. If you have any concerns about your digestive system, you should consult a healthcare professional.

2 IRI Database, L52wk ending 5/15/21

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SOURCE GoodBelly by NextFoods, Inc.

Study: Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Image Credit: Solarseven / Shutterstock

Mix and match COVID-19 vaccines safe and effective: German study

  • June 9, 2021

A new preprint study posted to the medRxiv* server shows an AstraZeneca’s ChAdOx1-nCov-19 and Pfizer/BioNTech BNT162b2 COVID-19 vaccine combination is immunologically superior to two AstraZeneca ChAdOx1-nCov-19 doses.

Led by German researchers, the study shows that having the first dose with AstraZeneca’s ChAdOx1 and the second with Pfizer/BioNTech BNT162b2 elicits significantly higher anti-spike titers and more neutralizing activity against B.1.1.7, P.1, and B.1.351 variants.

Both P.1 and B.1.351 variants have mutations that allow them to evade vaccine-induced immunity — increasing the risk of spreading SARS-CoV-2 and developing severe illness or death. In response, there have been discussions amongst vaccine developers for creating booster shots against variants.

The findings suggest mixing and matching vaccine doses could be enough to boost the immune system against different variants of concern.

Study: Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Image Credit: Solarseven / Shutterstock

Immune response from the first dose wanes over time

The researchers used the COVID-19 Contact Study cohort of Healthcare Professionals to evaluate immune responses from the first dose of the AstraZeneca vaccine before and 3 weeks after choosing a second dose with either the same vaccine or the Pfizer/BioNTech dose.

About 129 people who received the first AstraZeneca dose were never infected with COVID-19. Of this group, 32 chose the same booster, and 55 chose the Pfizer/BioNTech booster.

Both groups had comparable anti-S IgG and IgA antibody levels against the spike protein before receiving their second dose. However, the boosted antibody levels from the first dose declined by almost half 30 days after receiving the first dose but before getting the second.

Stronger humoral immune response against all SARS-CoV-2 variants following heterologous ChAdOx1 nCoV-19 (ChAd) / BNT162b2 (BNT) than homologous ChAd / ChAd vaccination.

Stronger humoral immune response against all SARS-CoV-2 variants following heterologous ChAdOx1 nCoV-19 (ChAd) / BNT162b2 (BNT) than homologous ChAd / ChAd vaccination.

Greater antibody response with AstraZeneca/Pfizer/BioNTech combo

Regardless of the vaccine, both groups who received a second dose showed a boost in anti-S IgG and IgA responses.

Having the Pfizer/BioNTech vaccine as the second dose significantly increased anti-S IgG antibody levels by 11.5-fold compared to a 2.9-fold increase observed in people who received both AstraZeneca vaccines. Similar increases in anti-S IgA antibody levels were also observed, suggesting a better humoral immune response with mixed-match doses.

Increased neutralizing activity against SARS-CoV-2 variants

The researchers next looked at neutralization effectiveness against SARS-CoV-2 and recent variants of concern, including B.1.1.7, P.1, and B.1.351 variants.

Of 81 out of 88 participants, neutralizing antibodies against the Wuhan strain were found. However, there were fewer neutralizing antibodies for B.1.1.7, 7 (17/88), P.1 (12/88), and B.1.351 (5/88).

Two to 3 weeks after the second vaccine dose, the researchers observed increases in titers of neutralizing antibodies against the Wuhan strain in both groups — with the mix-match group showing the highest neutralizing titers.

Against the variants of concern, getting two doses of AstraZeneca showed some immune response towards the B.1.17 variant. However, it was not effective against P.1 or B.1.351.

Getting a second Pfizer/BioNTech dose increased neutralizing antibodies against all variants of concern. The AstraZeneca- Pfizer/BioNTech group had the highest neutralizing response against the Wuhan strain, followed by the B.1.1.7 variant. While some neutralization was observed, the mixed-match doses were less efficient against the P.1 and B.1.351 variants.

“Altogether, these data indicate that the booster immunization led to an increase of neutralizing antibodies in both vaccination groups and that the heterologous ChAdOx/BNT booster booster vaccination efficiently induced neutralizing antibodies against all tested VoC.”

Higher number of B cells in Pfizer/BioNTech combo group

S-specific B cells strongly increased, and an increase in recent isotype switched B cells (IgDIgM) was observed in people who received Pfizer/BioNTech as a second dose.

The increase in B cells specific to the spike protein after receiving the Pfizer/BioNTech booster corresponded with neutralizing power against the variants of concern.

There were also greater increases in S-specific CD4 T cells and S-specific IFN-γ release in the mixed-matched group.

Future work

The results suggest mixing booster shots elicits a more significant immune response against SARS-CoV-2. However, more work is needed to characterize immune responses further. It would also help to understand how long vaccine immunity lasts and whether mixed-match doses provide a more robust immune response over time.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Study: Infectious disease mRNA vaccines and a review on epitope prediction for vaccine design. Image Credit: MattLphotography / Shutterstock

The potential of mRNA vaccines for a wide range of diseases

  • June 8, 2021

Vaccination is an important strategy to prevent the transmission of various infectious diseases such as rubella, smallpox, measles, mumps, and recently, coronavirus 2019 disease (COVID-19).

Vaccines typically contain either dead or weakened virus strains, or a small part of that virus, such as a protein or nucleic acid. When you get a vaccine, your immune system identifies it as foreign. In response, it creates memory cells and antibodies that guard against future infection.

Researchers have explained that messenger RNA (mRNA) vaccines can encode the preferred antigens from an mRNA sequence.  When the mRNA is inoculated, it offers specific information to the cells such that they can produce specific proteins in the cytoplasm. These proteins trigger immune responses associated with antigen-presenting cells (APCs) or antibodies/immunoglobulin. These immune cells protect the body against diseases.

A new review article published in the journal Briefings in Functional Genomics focuses on the general characteristic features and mechanisms of mRNA vaccines. Further, this review has summarized the current progress of mRNA vaccines that have been developed for wide-ranging diseases, including COVID-19 disease.

Study: Infectious disease mRNA vaccines and a review on epitope prediction for vaccine design. Image Credit: MattLphotography / Shutterstock

The main reasons the mRNA vaccine has been considered a strong vaccine candidate to prevent COVID-19 disease are its efficiency, cost-effectiveness, and rapid development speed.

Further, in comparison to other types of vaccines, mRNA vaccines have gained popularity owing to their characteristic features, which are most favorable for targeting infectious diseases with genetic instability.

Also, the main advantages of using mRNA as a source of antigen are its ability to induce MHC-I presentation and stimulating cytotoxic T-lymphocyte responses.

These characteristic features provide huge versatility in the types and number of antigenic determinants. Two of the main types of mRNA that are evaluated as vaccine candidates are (a) non-replicating mRNA and (b) virally derived self-amplifying mRNA.

One of the persisting issues in the development of mRNA vaccines is thermostability. Two recently developed mRNA-based COVID-19 vaccines require a steady temperature of -70°C during their storage and transportation. Such a feature limits their availability in rural areas and low-income countries. However, recently researchers have developed thermostable mRNA vaccines with a freeze-dry protocol. Scientists believe more research on the optimization of vaccine formulation may help improve the thermostability of mRNA vaccines.

Scientists have stated that epitopes are an important feature that is often ignored for enhancing the effectiveness of mRNA vaccines. These antigenic determinants are recognized by the immune system and determine the type of immune response to be triggered. Epitopes are divided into T-cell and B-cell epitopes. The T-cell epitopes are present on the surface of an APC and are attached to major histocompatibility. The B-cell epitopes are bound by immunoglobulin or antibodies. For peptide-based vaccines, the epitope-based vaccine design has been used. Two examples of epitope-based vaccines for SARS-CoV-2 are UB-612 and NVX-CoV2373.

Scientists have developed several epitope prediction models, which can be categorized into sequence-based and structure-based methods. Although the sequence-based methods have become obsolete, their concept is still being used in motif search. The neural network offers a suitable approach to study the relationships and describing non-linear data.

For epitope prediction, a support vector machine is widely used and has been demonstrated in models such as COBEPRO (linear B-cell epitope prediction model) and Pcleavage (cleavage sites prediction model). For structural models, standard computational models such as docking of peptides, knowledge-based threading algorithms, etc., are used. These epitope predictions help researchers to identify epitopes that can provide immunogenicity and cross-reactivity for a target pathogen. For many viruses, epitopes can be found in online databases, such as the Immune Epitope Database (IEDB).

Two of the mRNA-based COVID-19 vaccines have used similar immunogen design and delivery systems. They elicit immune responses which are comparable to natural viral infection. Even though both of these vaccines have shown promising efficacy in clinical trials, optimization related to epitopes may help develop more stable and effective vaccines. For example, prefusion conformation needs more factors to be maintained after inoculation, as the macromolecules could get modified by environmental parameters. Further, incorporating another immunogen (e.g., N protein) could provide an additional target for immune response. This could boost vaccine efficiency and lower the risk of mutation escape.

Even though the use of S protein in the vaccine could mimic a natural viral infection, the neutralizing antibodies and T-cells can only get attached to specific peptides. Therefore, encoding specific epitopes could enhance the stability of the mRNA vaccine. Also, in the case of extreme mutation in SARS-CoV-2’s S protein, the virus could escape immunity elicited by the currently available vaccines. It could be easier to adapt to new mutations by re-adjusting the epitopes instead of redesigning the vaccine. For vaccine designing, the use of computational models is highly advantageous because of their flexibility.

mRNA vaccines had been previously applied for preventing a range of infectious as well as non-infectious diseases such as influenza and cancer. Based on human epitope prediction models, this article illustrates how mRNA vaccine design can be improved by recent advances in bioinformatics.

Restoring gut microbes can improve antibiotic-induced dysbiosis and prevent colitis in mice

Restoring gut microbes can improve antibiotic-induced dysbiosis and prevent colitis in mice

  • June 8, 2021

A new study at the University of Chicago has determined that restoring a single microbial species — Bacteroides sp. CL1-UC (Bc) — to the gut microbiome at a key developmental timepoint can prevent antibiotic-induced colitis in a mouse model of the condition. The results, published on June 7 in Gastroenterology, have major implications for humans dealing with inflammatory bowel disease (IBD), and underscore the impact of early childhood exposures on health throughout the lifetime.

Prior studies in human patients have found that early life exposure to antibiotics can skew the gut microbiome, causing dysbiosis, or an imbalance of the microbial populations in the gut, which is correlated with increase risk for developing pediatric IBD.

We know that the kinds of microbes that you’re exposed to early in life actually determine how your immune system develops. Our immune system learns to recognize our own selves, and the trillions of microbes in our gut — they’re ‘us’ as well, so our immune system has to learn to tolerate these organisms, just as it tolerates our own cells. Early exposure to antibiotics can eradicate some of the organisms that are essential for educating the immune system to develop immune tolerance.”


Eugene Chang, MD, Senior Author, Martin Boyer Professor of Medicine, UChicago

Due to the challenges of conducting such studies in human patients, the researchers opted to use a common model for studying colitis: mice that lack a gene known as IL-10 (IL-10-/-). “This mouse model has been established as being genetically susceptible to IBD, and we know that the gut microbiome plays a crucial role in the development of colitis in this model,” said first author Jun Miyoshi, MD, PhD, a Senior Assistant Professor in the Department of Gastroenterology and Hepatology at Kyorin University School of Medicine, and a former postdoctoral scholar at UChicago.

While only very rarely do these mice develop spontaneous colitis without any intervention in a clean environment, if their mothers are exposed to antibiotics during pregnancy and nursing, the disrupted microbiome can be transmitted to the pups at an early age. Around 30% of pups with this vertically transmitted disrupted microbiome go on to develop colitis.

The investigators used a technique known as shotgun metagenomic sequencing to screen the fecal microbiomes of IL-10-/- mice that had antibiotic-induced dysbiosis, alongside an untreated control group, and identify specific microbial species that might distinguish the two groups. This led them to members of the bacterial phylum Bacteroides.

One clue of the phylum’s importance was that Bacteroides was very abundant in the microbiomes of untreated mice, but completely lacking in the mice that had been exposed to antibiotics. What’s more, the researchers never saw Bacteroides in the treated mice that did not go on to develop colitis — but they often found Bacteroides in the guts of mice that did end up with the condition.

“These bacteria were eradicated by early exposure to antibiotics and were essential for educating the immune system in developing immune tolerance,” said Chang. “When those mice later acquired the bacteria, their immune system had never seen it. It was viewed as foreign, not as self, and their immune systems reacted to it.”

In an effort to determine whether restoring important Bacteroides back to the microbiome could correct the dysbiosis, the researchers honed in on a particularly abundant species known as Bacteroides sp. CL1-UC (Bc). They tried adding Bc back to the microbiomes of the mice with dysbiosis at two timepoints: around infancy (three weeks of age) and adulthood (11 weeks of age).

Engrafting Bc into the younger mice, during the critical immune system developmental window, corrected their dysbiosis and prevented colitis, but adding Bc back to adult mice could not correct the dysbiosis, and even worsened their colitis.

“This shows that you can’t just restore the missing bacteria at any time point, it has to be at a specific time early in life to have a beneficial effect,” said Chang. “In young animals, we know that the immune system is developing, it’s naive, it has to be taught, and it’s taught by being exposed to certain kinds of microbes. In some ways, it’s similar to a peanut allergy — early exposure to the antigen can tolerize the immune system to help avoid a peanut allergy, but it has to happen within a very finite window.”

The researchers were surprised to learn that restoring a single microbe was enough to correct lifelong dysbiosis, and said it highlighted how relatively small changes can have a dramatic impact on a system. “It’s like the tall trees of the Amazon rainforest,” said Chang. “You need the tall trees, because if you don’t have them, the ecosystem below cannot develop properly. But if you have those trees in place, the rest of the ecosystem will flourish.”

The results also go against popular theories on the origin of IBD. “There’s a misconception that colitis is caused by a classical pathogen, like salmonella, and scientists have spent years looking for a culprit,” said Chang. “But what our data are pointing to is that these diseases are caused by our own commensal microbes. They are present in the normal, healthy microbiome, but given the right circumstance and opportunity, they can transform into disease-promoting microbes.”

While this early study was proof-of-concept, if the results translate to humans, the ripple effects are likely to be far-reaching. “This shows that we probably have to rethink our approach to these kinds of complex immune disorders,” said Chang. “We can see that risk is developing early in life — even in utero — and so this has implications for practices such as C-sections and formula feeding, which can impact the microbes an infant is exposed to. What this says to me is that, as physicians, we need to shift our thinking to not what immediately preceeds these diseases but what happens early in life. That’s where we need to intervene for these patients.”

Source:

Journal reference:

Miyoshi, J., et al. (2021) Early-life microbial restitution reduces colitis risk promoted by antibiotic-induced gut dysbiosis in IL-10-/- mice. Gastroenterology. doi.org/10.1053/j.gastro.2021.05.054.

Has Being So Careful During The COVID-19 Pandemic Altered Our Immune Systems?

Has Being So Careful During The COVID-19 Pandemic Altered Our Immune Systems?

  • June 7, 2021

Staying home during the COVID-19 pandemic was an invaluable public health measure that helped to greatly reduce transmission of the virus and save many lives (at least more than the incredible amount of people we lost).

But life in lockdown certainly isn’t typical for most of us. It has raised questions about what a year of relative isolation, masking and just general germ-avoidance may have done to our immune systems. Have they been wrecked? Are we basically just babies reborn? Do we need to behave differently now?

Of course, many people have been working and learning in-person for months now, while others are just starting to re-emerge. So here is what we know about what happened to people’s immune systems during the pandemic, as well as what to expect as even more people dive back into their old routines.

Most adults’ immune systems will NOT have been weakened by isolation

Perhaps you’ve heard about the hygiene hypothesis, which is the idea that exposure to certain viruses, bacteria or parasites in childhood helps the immune system develop. Based on that theory, some people are worried that people’s immune systems will be walloped when they go back out into the world, because they haven’t been exposed to many germs over the past year-plus. But experts aren’t concerned.

“There is no cause for concern that social distancing has weakened our immune systems,” Sindhura Bandi, an allergy and immunology specialist and associate professor of medicine and pediatrics with Rush University Medical Center, told HuffPost. “By adulthood, we have come into contact with many types of viruses and bacteria. Our immune system has created memory to these pathogens, so that when we come into contact with them we can make antibodies to fight off the disease.”

In other words, your body has already spent a lifetime developing antibodies to common illnesses through direct exposure or through vaccination, Bandi explained. One year of staying home and masking (which again, helped fight a deadly pandemic) is not going to drastically change that.

That said, you might come down with a cold when you head back into the office ― because you’re going to be around more germs again, and because, yes, your immune system is a bit out of practice.

“Our immune systems have not been exposed to common everyday pathogens,” explained Monaa Zafar, a doctor of internal medicine with Westmed Medical Group. She also noted that people’s immunity may have been hampered by other lifestyle changes over the past year — like the fact that many people have been drinking more, sleeping less, coping with chronic stress and not getting outdoors and getting sufficient vitamin D.

Experts also have questions about what the 2021-2022 flu season could be like after being virtually nonexistent this past year. There’s some speculation it could be particularly bad as experts struggle to predict which strains to target with next year’s vaccine, though no one really knows.

But concerns about a potentially tough flu season don’t have anything to do with people’s immune systems and being sheltered in 2020.

People who had COVID-19 might have long-term immune system changes that we don’t totally understand yet

While most adults’ immune systems haven’t been changed by the pandemic, some people who were infected with COVID-19 and recovered could, indeed, experience some long-term alterations to their immune system function.

“Some patients experienced a significant inflammatory response as the immune system worked to fight the disease,” Bandi said. “Recovery from the illness has led to long-term effects ― commonly referred to as ‘long-haul COVID’ ― which may be tied to the immune system.”

Experts are still unraveling what causes some people to come down with long-haul COVID ― or post-acute sequelae of SARS-CoV-2 infection (PASC) as it is now officially known ― as well as what causes it. One working theory is that lingering symptoms may stem from a persistent inflammatory or autoimmune response.

What all of that means in terms of people’s immune system function as they head back out into the world is still a question — and a pressing one. Estimates suggest up to 1 in 4 COVID-19 patients are long-haulers. And of course there have been more than 33 million reported cases of COVID-19 in the United States alone. So understanding the potential broader impact on the immune system in people who’ve had the virus will be important.

Kids might get more colds

There is a chance that young kids who’ve missed out on a year of day care or preschool could be prone to more colds and other infections when they begin spending more time together again.

“There are studies that demonstrate that toddlers who attend congregate child care settings, and presumably are exposed to more germs, are less likely to develop viral illnesses, allergies and autoimmune diseases in grade school,” Bandi said.

But context is really key here. Sure, young kids might have a harder time fighting off some common illnesses when they get back to their old routines, but it was essential to keep them isolated for much of the year because it lowered their risk of getting — and spreading — COVID-19.

Also, they still have ample opportunities to be exposed to germs down the road.

“As the general population becomes vaccinated and we are able to open up again, these young children will have plenty of opportunity for their immune systems to become exposed to and make antibodies to common childhood cold viruses,” Bandi said.

Sleep, socialization and staying home when sick will all be really important

Ultimately, there’s no clear scientific evidence that if you engage in certain habits or behaviors you can really directly “boost” your immune system, but taking care of your overall well-being certainly won’t hamper how it functions. Doing things like getting plenty of sleep and loading up on nutrients are always good ideas.

“Getting six to eight hours of sleep nightly, 150 minutes of exercise weekly, eating whole grains, lean protein, fruit and vegetables in a balanced diet all help strengthen our immune systems,” Zafar said.

“I believe the most powerful immune-booster is regular physical activity,” echoed Tuvana Bain, a doctor of internal medicine with Westmed Medical Group.

There’s been a lot of talk about how important social connection is for our mental health and well-being, but there may be an important immune-system element to reconnecting with friends and loved ones as the world slowly reopens as well.

“As people are able to connect again with family, friends and colleagues, this can have an indirect effect on boosting the immune system,” Bandi said. Indeed, research has linked loneliness to all kinds of poor physical outcomes, from heart disease to decreased levels of certain antiviral compounds in the body.

Lastly, it’s going to be really important over this next stretch to avoid the tendency to go into the office or send your kid off to school when sick. Staying home and resting not only gives your own immune system a chance to fight back, it also helps keep other people safe.

“In the past, we may try to stick it out for the workday or give our child some Tylenol before sending them off to school to suppress the fever,” Bandi said. “We have to remember there are vulnerable people around us.”

The good news is, most of us have become much more attune to how our own behaviors impact the health of others, and we’ve become pretty darn good at basic preventive measures.

“Nothing beats frequent hand-washing as the ultimate protection from infection,” Bain said.

Experts are still learning about COVID-19. The information in this story is what was known or available as of publication, but guidance can change as scientists discover more about the virus. Please check the Centers for Disease Control and Prevention for the most updated recommendations.

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