Tag Archives: vaccine

Microbiology

Novel subset of memory B cells predicts long-lived antibody responses to influenza vaccination

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Reviewed by Emily Henderson, B.Sc.Mar 22 2023

Memory B cells play a critical role to provide long-term immunity after a vaccination or infection. In a study published in the journal Immunity, researchers describe a distinct and novel subset of memory B cells that predict long-lived antibody responses to influenza vaccination in humans.

These effector memory B cells appear to be poised for a rapid serum antibody response upon secondary challenge one year later, Anoma Nellore, M.D., Fran Lund, Ph.D., and colleagues at the University of Alabama at Birmingham and Emory University report. Evidence from transcriptional and epigenetic profiling shows that the cells in this subset differ from all previously described memory B cell subsets.

The UAB researchers identified the novel subset by the presence of FcRL5 receptor protein on the cell surface. In immunology, a profusion of different cell-surface markers is used to identify and separate immune-cell types. In the novel memory B cell subset, FcRL5 acts as a surrogate marker for positive expression of the T-bet transcription factor inside the cells. Various transcription factors act as master regulators to orchestrate the expression of many different gene sets as various cell types grow and differentiate.

Nellore, Lund and colleagues found that the FcRL5+ T-bet+ memory B cells can be detected seven days after immunization, and the presence of these cells correlates with vaccine antibody responses months later. Thus, these cells may represent an early, easily monitored cellular compartment that can predict the development of a long-lived antibody response to vaccines.

This could be a boon to the development of a more effective yearly influenza vaccine. “New annual influenza vaccines must be tested, and then manufactured, months in advance of the winter flu season,” Lund said. “This means we must make an educated guess as to which flu strain will be circulating the next winter.”

Why are vaccine candidates made so far in advance? Pharmaceutical companies, Lund says, need to wait many weeks after vaccinating volunteers to learn whether the new vaccine elicits a durable immune response that will last for months. “One potential outcome of the current study is we may have identified a new way to predict influenza vaccine durability that would give us an answer in days, rather than weeks or months,” Lund said. “If so, this type of early ‘biomarker’ could be used to test flu vaccines closer to flu season -; and moving that timeline might give us a better shot at predicting the right flu strain for the new annual vaccine.”

Seasonal flu kills 290,000 to 650,000 people each year, according to World Health Organization estimates. The global flu vaccine market was more than $5 billion in 2020.

To understand the Immunity study, it is useful to remember what happens when a vaccinated person subsequently encounters a flu virus.

Following exposure to previously encountered antigens, such as the hemagglutinin on inactivated influenza in flu vaccines, the immune system launches a recall response dominated by pre-existing memory B cells that can either produce new daughter cells or cells that can rapidly proliferate and differentiate into short-lived plasmablasts that produce antibodies to decrease morbidity and mortality. These latter B cells are called “effector” memory B cells.

“The best vaccines induce the formation of long-lived plasma cells and memory B cells,” said Lund, the Charles H. McCauley Professor in the UAB Department of Microbiology and director of the Immunology Institute. “Plasma cells live in your bone marrow and make protective antibodies that can be found in your blood, while memory B cells live for many years in your lymph nodes and in tissues like your lungs.

“Although plasma cells can survive for decades after vaccines like the measles vaccine, other plasma cells wane much more quickly after vaccination, as is seen with COVID-19,” Lund said. “If that happens, memory B cells become very important because these long-lived cells can rapidly respond to infection and can quickly begin making antibody.”

In the study, the UAB researchers looked at B cells isolated from blood of human volunteers who received flu vaccines over a span of three years, as well as B cells from tonsil tissue obtained after tonsillectomies.

They compared naïve B cells, FcRL5+ T-bet+ hemagglutinin-specific memory B cells, FcRL5neg T-betneg hemagglutinin-specific memory B cells and antibody secreting B cells, using standard phenotype profiling and single-cell RNA sequencing. They found that the FcRL5+ T-bet+ hemagglutinin-specific memory B cells were transcriptionally similar to effector-like memory cells, while the FcRL5neg T-betneg hemagglutinin-specific memory B cells exhibited stem-like central memory properties.

Antibody-secreting B cells need to produce a lot of energy to churn out antibody production, and they also must turn on processes that protect the cells from some of the detrimental side effects of that intense metabolism, including controlling the dangerous reactive oxygen species and boosting the unfolded protein response.

The FcRL5+ T-bet+ hemagglutinin-specific memory B cells did not express the plasma cell commitment factor, but did express transcriptional, epigenetic and metabolic functional programs that poised these cells for antibody production. These included upregulated genes for energy-intensive metabolic processes and cellular stress responses.

Accordingly, FcRL5+ T-bet+ hemagglutinin-specific memory B cells at Day 7 post-vaccination expressed intracellular immunoglobulin, a sign of early transition to antibody-secreting cells. Furthermore, human tonsil-derived FcRL5+ T-bet+ memory B differentiated more rapidly into antibody-secreting cells in vitro than did FcRL5neg T-betneg hemagglutinin-specific memory B cells.

Lund and Nellore, an associate professor in the UAB Department of Medicine Division of Infectious Diseases, are co-corresponding authors of the study, “A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.”

Co-authors with Lund and Nellore are Esther Zumaquero, R. Glenn King, Betty Mousseau, Fen Zhou and Alexander F. Rosenberg, UAB Department of Microbiology; Christopher D. Scharer, Tian Mi, Jeremy M. Boss, Christopher M. Tipton and Ignacio Sanz, Emory University School of Medicine, Atlanta, Georgia; Christopher F. Fucile, UAB Informatics Institute; John E. Bradley and Troy D. Randall, UAB Department of Medicine, Division of Clinical Immunology and Rheumatology; and Stuti Mutneja and Paul A. Goepfert, UAB Department of Medicine Division of Infectious Diseases.

Funding for the work came from National Institutes of Health grants AI125180, AI109962 and AI142737 and from the UAB Center for Clinical and Translational Science.

Source:

University of Alabama at Birmingham

Journal reference:

Nellore, A., et al. (2023). A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans. Immunity. doi.org/10.1016/j.immuni.2023.03.001.

Microbiology

Nasal Vaccines: Stopping the COVID-19 Virus Before It Reaches the Lungs

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The Pfizer-BioNTech and Moderna mRNA vaccines have played a large role in preventing deaths and severe infections from COVID-19. But researchers are still in the process of developing alternative approaches to vaccines to improve their effectiveness, including how they’re administered. Immunologist and microbiologist Michael W. Russell of the University at Buffalo explains how nasal vaccines work, and where they are in the development pipeline.

The immune system has two distinct components: mucosal and circulatory.

The mucosal immune system provides protection at the mucosal surfaces of the body. These include the mouth, eyes, middle ear, the mammary and other glands, and the gastrointestinal, respiratory, and urogenital tracts. Antibodies and a variety of other anti-microbial proteins in the sticky secretions that cover these surfaces, as well as immune cells located in the lining of these surfaces, directly attack invading pathogens.

The circulatory part of the immune system generates antibodies and immune cells that are delivered through the bloodstream to the internal tissues and organs. These circulating antibodies do not usually reach the mucosal surfaces in large enough amounts to be effective. Thus mucosal and circulatory compartments of the immune system are largely separate and independent.

The immune components people may be most familiar with are proteins known as antibodies, or immunoglobulins. The immune system generates antibodies in response to invading agents that the body identifies as “non-self,” such as viruses and bacteria.

Antibodies bind to specific antigens: the part or product of a pathogen that induces an immune response. Binding to antigens allows antibodies to either inactivate them, as they do with toxins and viruses, or kill bacteria with the help of additional immune proteins or cells.

The mucosal immune system generates a specialized form of antibody called secretory IgA, or SIgA. Because SIgA is located in mucosal secretions, such as saliva, tears, nasal and intestinal secretions, and breast milk, it is resistant to digestive enzymes that readily destroy other forms of antibodies. It is also superior to most other immunoglobulins at neutralizing viruses and toxins, and at preventing bacteria from attaching to and invading the cells lining the surfaces of organs.

There are also many other key players in the mucosal immune system, including different types of anti-microbial proteins that kill pathogens, as well as immune cells that generate antibody responses.

Mucus is one of the central secretions of the mucosal immune system.

Almost all infectious diseases in people and other animals are acquired through mucosal surfaces, such as by eating or drinking, breathing or sexual contact. Major exceptions include infections from wounds, or pathogens delivered by insect or tick bites.

The virus that causes COVID-19, SARS-CoV-2, enters the body via droplets or aerosols that get into your nose, mouth, or eyes. It can cause severe disease if it descends deep into the lungs and causes an overactive, inflammatory immune response.

This means that the virus’s first contact with the immune system is probably through the surfaces of the nose, mouth, and throat. This is supported by the presence of SIgA antibodies against SARS-CoV-2 in the secretions of infected people, including their saliva, nasal fluid, and tears. These locations, especially the tonsils, have specialized areas that specifically trigger mucosal immune responses.

Some research suggests that if these SIgA antibody responses form as a result of vaccination or prior infection, or occur quickly enough in response to a new infection, they could prevent serious disease by confining the virus to the upper respiratory tract until it is eliminated.

Vaccines can be given through mucosal routes via the mouth or nose. This induces an immune response through areas that stimulate the mucosal immune system, leading mucosal secretions to produce SIgA antibodies.

There are several existing mucosal vaccines, most of them taken by mouth. Currently, only one, the flu vaccine, is delivered nasally.

In the case of nasal vaccines, the viral antigens intended to stimulate the immune system would be taken up by immune cells within the lining of the nose or tonsils. While the exact mechanisms by which nasal vaccines work in people have not been thoroughly studied, researchers believe they work analogously to oral mucosal vaccines. Antigens in the vaccine induce B cells in mucosal sites to mature into plasma cells that secrete a form of IgA. That IgA is then transported into mucosal secretions throughout the body, where it becomes SIgA.

If the SIgA antibodies in the nose, mouth or throat target SARS-CoV-2, they could neutralize the virus before it can drop down into the lungs and establish an infection.

Nasal vaccines could provide a more approachable alternative to injections for patients leery of needles.

I believe that arguably the best way to protect an individual against COVID-19 is to block the virus at its point of entry, or at least to confine it to the upper respiratory tract, where it might inflict relatively little damage.

Breaking chains of viral transmission is crucial to controlling epidemics. Researchers know that COVID-19 spreads during normal breathing and speech, and is exacerbated by sneezing, coughing, shouting, singing and other forms of exertion. Because these emissions mostly originate from saliva and nasal secretions, where the predominant form of antibody present is SIgA, it stands to reason that secretions with a sufficiently high level of SIgA antibodies against the virus could neutralize and thereby diminish its transmissibility.

Existing vaccines, however, do not induce SIgA antibody responses. Injected vaccines primarily induce circulating IgG antibodies, which are effective in preventing serious disease in the lungs. Nasal vaccines specifically induce SIgA antibodies in nasal and salivary secretions, where the virus is initially acquired, and can more effectively prevent transmission.

Nasal vaccines may be a useful supplement to injected vaccines in hot spots of infection. Since they don’t require needles, they might also help overcome vaccine hesitancy due to fear of injections.

There have been over 100 oral or nasal COVID-19 vaccines in development around the world.

Most of these have been or are currently being tested in animal models. Many have reported successfully inducing protective antibodies in the blood and secretions, and have prevented infection in these animals. However, few have been successfully tested in people. Many have been abandoned without fully reporting study details.

According to the World Health Organization, 14 nasal COVID-19 vaccines are in clinical trials as of late 2022. Reports from China and India indicate that nasal or inhaled vaccines have been approved in these countries. But little information is publicly available about the results of the studies supporting approval of these vaccines.

Written by Michael W. Russell, Professor Emeritus of Microbiology and Immunology, University at Buffalo.

This article was first published in The Conversation.The Conversation

Michael W. Russell, University at Buffalo

Microbiology

Low-cost, universal oral COVID-19 vaccine prevents severe respiratory illness in hamsters

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Reviewed by Emily Henderson, B.Sc.Mar 22 2023

A UCLA-led team has developed an inexpensive, universal oral COVID-19 vaccine that prevented severe respiratory illness and weight loss when tested in hamsters, which are naturally susceptible to SARS-CoV-2. It proved as effective as vaccines administered by injection or intranasally in the research.

If ultimately approved for human use, it could be a weapon against all COVID-19 variants and boost uptake, particularly in low- and middle-income countries, and among those with an aversion to needles.

The study is published in the peer-reviewed journal Microbiology Spectrum.

The oral vaccine is based primarily on the nucleocapsid protein, which is the most abundantly expressed of the virus’s four major structural proteins and evolves at a much slower rate than the frequently mutating spike protein. The vaccine utilizes a highly weakened bacterium to produce the nucleocapsid protein in infected cells as well as the membrane protein, which is another highly abundant viral structural protein.

Being a universal vaccine based primarily upon the nucleocapsid protein, the vaccine is resistant to the incessant mutations of the SARS-CoV-2 spike protein upon which virtually all current vaccines are based. As a result, current vaccines rapidly become obsolete, requiring that they repeatedly be re-engineered. Hence, our vaccine should protect against new and emerging variants of SARS-CoV-2.”

Dr. Marcus Horwitz, senior author, distinguished professor of medicine in the Division of Infectious Diseases and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA

Oral delivery also makes it easier to distribute the vaccine in resource poor areas of the world by eliminating the need for needles, syringes, and trained personnel to deliver injectable vaccines, he added. “An oral vaccine may also be attractive to many people with vaccine hesitancy on account of fear of needles.”

The researchers noted that while it worked exceptionally well in preventing severe respiratory illness, it did not provide full protection against high viral loads in the hamsters. Also, they did not test it against the Omicron strain, which contains a nearly identical nucleocapsid protein, because of this strain’s low virulence in the golden Syrian hamsters they used.

But the vaccine, they write, “is efficacious when administered via the oral route against COVID-19-like disease in a highly demanding animal model. This conveniently administered, easily manufactured, inexpensive, and readily stored and transported vaccine could play a major role in ending the COVID-19 pandemic by protecting immunized individuals from serious disease from current and future strains of SARS-CoV-2.”

The next step in the process will be to manufacture the vaccine for oral administration via an acid-resistant enteric capsule that will allow the vaccine to be safely released in the small intestine, Horwitz said. It will then be tested for safety, immunogenicity, and efficacy in humans.

“We also plan to expand the vaccine to protect against infections caused by other types of potentially pandemic coronaviruses such as the virus that causes Middle Eastern Respiratory Syndrome (MERS),” he added.

Additional authors are Qingmei Jia and Saša Masleša-Galić of UCLA; Helle Bielefeldt-Ohmann of the University of Queensland, Australia; and Rachel Maison, Airn Hartwig, and Richard Bowen of Colorado State University.

This study was supported by a Corona Virus Seed grant from the UCLA AIDS Institute and Charity Treks and by the National Institutes of Health (AI141390).

Source:

UCLA Health

Journal reference:

Jia, Q., et al. (2023). Oral Administration of Universal Bacterium-Vectored Nucleocapsid-Expressing COVID-19 Vaccine is Efficacious in Hamsters. Microbiology Spectrum. doi.org/10.1128/spectrum.05035-22.

Microbiology

SARS-CoV-2 infection damages the CD8+ T cell response to vaccination

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Reviewed by Emily Henderson, B.Sc.Mar 20 2023

The magnitude and quality of a key immune cell’s response to vaccination with two doses of the Pfizer-BioNTech COVID-19 vaccine were considerably lower in people with prior SARS-CoV-2 infection compared to people without prior infection, a study has found. In addition, the level of this key immune cell that targets the SARS-CoV-2 spike protein was substantially lower in unvaccinated people with COVID-19 than in vaccinated people who had never been infected. Importantly, people who recover from SARS-CoV-2 infection and then get vaccinated are more protected than people who are unvaccinated. These findings, which suggest that the virus damages an important immune-cell response, were published today in the journal Immunity.

The study was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and led by Mark M. Davis, Ph.D. Dr. Davis is the director of the Stanford Institute for Immunity, Transplantation and Infection and a professor of microbiology and immunology at Stanford University School of Medicine in Palo Alto, California. He is also a Howard Hughes Medical Institute Investigator.

Dr. Davis and colleagues designed a very sensitive tool to analyze how immune cells called CD4+ T cells and CD8+ T cells respond to SARS-CoV-2 infection and vaccination. These cells coordinate the immune system’s response to the virus and kill other cells that have been infected, helping prevent COVID-19. The tool was designed to identify T cells that target any of dozens of specific regions on the virus’s spike protein as well as some other viral regions. The Pfizer-BioNTech vaccine uses parts of the SARS-CoV-2 spike protein to elicit an immune response without causing infection.

The investigators studied CD4+ and CD8+ T-cell responses in blood samples from three groups of volunteers. One group had never been infected with SARS-CoV-2 and received two doses of the Pfizer-BioNTech COVID-19 vaccine. The second group had previously been infected with SARS-CoV-2 and received two doses of the vaccine. The third group had COVID-19 and was unvaccinated.

The researchers found that vaccination of people who had never been infected with SARS-CoV-2 induced robust CD4+ and CD8+ T-cell responses to the virus’ spike protein. In addition, these T cells produced multiple types of cell-signaling molecules called cytokines, which recruit other immune cells—including antibody-producing B cells—to fight pathogens. However, people who had been infected with SARS-CoV-2 prior to vaccination produced spike-specific CD8+ T cells at considerably lower levels—and with less functionality—than vaccinated people who had never been infected. Moreover, the researchers observed substantially lower levels of spike-specific CD8+ T cells in unvaccinated people with COVID-19 than in vaccinated people who had never been infected.

Taken together, the investigators write, these findings suggest that SARS-CoV-2 infection damages the CD8+ T cell response, an effect akin to that observed in earlier studies showing long-term damage to the immune system after infection with viruses such as hepatitis C or HIV. The new findings highlight the need to develop vaccination strategies to specifically boost antiviral CD8+ T cell responses in people previously infected with SARS-CoV-2, the researchers conclude.  

Source:

National Institutes of Health

Journal reference:

Gao, F., et al. (2023). Robust T cell responses to Pfizer/BioNTech vaccine compared to infection and evidence of attenuated peripheral CD8+ T cell responses due to COVID-19. Immunity. doi.org/10.1016/j.immuni.2023.03.005.

Microbiology

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds

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Mar 20 2023Reviewed by Danielle Ellis, B.Sc.

COVID-19 has caused significant global panic after its rapid emergence more than 3 years ago. Although we now have highly effective vaccines against the SARS-CoV-2 virus, which causes COVID-19, scientists continue to study emerging SARS-CoV-2 variants in order to safeguard public health and devise global preventive strategies against emerging variants. A team led by Japanese researchers has recently discovered that the SARS-CoV-2 Omicron XBB.1.5 variant, prevalent in the Western hemisphere, has high transmissibility and infectivity.

New SARS-CoV-2 Omicron XBB.1.5 variant has high transmissibility and infectivity, study finds
New SARS-CoV-2 variant may jeopardize public health across the globe. The SARS-CoV-2 Omicron XBB.1.5 variant spreads rapidly and is more infectious than its historic precursor. Image Credit: The University of Tokyo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for millions of deaths worldwide. Although scientists have designed novel vaccines to counter COVID-19, they are constantly on the lookout for emerging variants that can bypass vaccine resistance and potentially jeopardize global public health. A team led by Japanese researchers has recently been successful in characterizing the new SARS-CoV-2 Omicron XBB.1.5 variant, which was first detected in October 2022. Their findings were published on January 31, 2023 in volume 23 of The Lancet Infectious Diseases.​​​

Says senior author Prof. Kei Sato from the Division of Systems Virology, The Institute of Medical Science, The University of Tokyo, Japan, “Because the Omicron XBB.1.5 variant can spread more rapidly than previous variants and has a potential to cause the next epidemic surge, we should carefully monitor it to safeguard public health.”

While studying emerging variants of the SARs-CoV-2 Omicron lineage, the research team made a startling discovery: the SARS-CoV-2 Omicron XBB.1.5 variant has a novel mutation in the spike (S) protein—the protein that anchors the virus firmly to the human angiotensin converting enzyme-2 (ACE2) receptor, thus facilitating the invasion of human cells. The serine-to-proline amino acid mutation noted at residue no. 486 in the S protein is virologically concerning because of a variety of reasons.

Sharing his concerns, first author Keiya Uriu from the Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan, says, “In late 2022, the SARS-CoV-2 Omicron BQ.1 and XBB lineages, characterized by amino acid substitutions in the S protein and increased viral fitness, had become predominant in the Western and Eastern Hemisphere, respectively. In 2022, we elucidated the characteristics of a variety of newly emerging SARS-CoV-2 Omicron subvariants. At the end of 2022, the XBB.1.5 variant, a descendant of XBB.1 that acquired the S:S486P substitution, emerged and was rapidly spreading in the USA.”

To gain mechanistic insights into the infectivity, transmissibility, and immune response associated with XBB.1.5, the team conducted a series of experiments. For instance, upon conducting epidemic dynamics analysis—statistical modeling that facilitates the analysis of the general characteristics of any epidemic—the team realized that the relative effective reproduction number (Re) of XBB.1.5 was 1.2-fold greater than that of the parental XBB.1. This indicated that an individual with the XBB.1.5 variant could infect 1.2 times more people in the population than someone with the parental XBB.1 variant. Moreover, the team also realized that, as of December 2022, XBB.1.5 was rapidly outcompeting BQ.1.1, the predominant lineage in the United States.

Co-first-author Jumpei Ito from the Division of Systems Virology, remarks, “Our data suggest that XBB.1.5 will rapidly spread worldwide in the near future.”

The team also studied the virological features of XBB.1.5 to determine how tightly the S protein of the new variant interacts with the human ACE2 receptor. To this end, the researchers conducted a yeast surface display assay. The results showed that the dissociation constant (KD) corresponding to the physical interaction between the XBB.1.5 S receptor-binding domain (RBD) and the human ACE2 receptor is significantly (4.3-fold) lower than that for XBB.1 S RBD. “In other words, the XBB.1.5 variant binds to human ACE2 receptor with very high affinity,” explains Shigeru Fujita from the Division of Systems Virology.

Further experiments using lentivirus-based pseudoviruses also showed that XBB.1.5 had approximately 3-fold higher infectivity than XBB.1. These results suggest that XBB.1.5 exhibits a remarkably strong affinity to the human ACE2 receptor, which can be attributed to the S486P substitution.

The study by Prof. Sato and his team led to another important discovery from an immunization perspective. The XBB.1.5 S protein was found to be highly resistant to neutralization antibodies elicited by breakthrough infection with the BA.2/BA.5 subvariants. In other words, patients with prior infection from the BA.2/BA.5 subvariants may not show robust immunity against XBB.1.5, increasing their chances of infection and disease.

The results of our virological experiments explain why the Omicron XBB.1.5 variant has a higher transmissibility than past variants: This variant acquired strong binding ability to human ACE2 while maintaining a higher ability to escape from neutralizing antibodies.”

​​​​​​​Yusuke Kosugi, Division of Systems Virology, Department of Microbiology and Immunology, The University of Tokyo, Japan

Contributing members of The Genotype to Phenotype Japan (G2P-Japan) Consortium conclude, “The SARS-CoV-2 Omicron XBB.1.5 variant does show enhanced transmissibility. Although few cases have been detected in the Eastern hemisphere, it could become a looming threat. Imminent prevention measures are needed.”

​​​​​​​Thanks to the research team for the early warning! Meanwhile, we must continue adopting safe practices to defend ourselves from XBB.1.5. 

Source:

The University of Tokyo

Journal reference:

Uriu, K., et al. (2023) Enhanced transmissibility, infectivity, and immune resistance of the SARS-CoV-2 omicron XBB.1.5 variant. The Lancet Infectious Diseases. doi.org/10.1016/S1473-3099(23)00051-8.

Microbiology

How Parents Decide if They Should Vaccinate Their Kids Against COVID-19

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Researchers conducted a qualitative study with in-depth interviews of 20 parents to understand their views about SARS-CoV-2 vaccination, with a goal to support future vaccination initiatives.

“Given the observed discrepancy between parental intention and decision to vaccinate their children against SARS-CoV-2, it is important to understand how and why parents make their decisions,” said Dr. Jonathon Maguire, a pediatrician at St. Michael’s Hospital, a site of Unity Health Toronto, and the University of Toronto. “Understanding the factors that influence parents’ decisions about SARS-CoV-2 vaccination for their children would help improve public health policies and interventions as well as inform health care professionals about parents’ perspectives and concerns.”

Few previous studies have explored how parents make decisions to vaccinate, or not vaccinate, their children once eligible for vaccination.

The decision was challenging for most parents in the study. Parents’ considerations related to the following:

These findings have implications for communicating information on SARS-CoV-2 vaccination.

“Future guidance should highlight both individual and collective benefits of SARS-CoV-2 vaccination for children; however, health care providers should prioritize individualized discussions with parents to help interpret evidence, consider their understanding of risks and benefits, and provide tailored recommendations,” said Dr. Janet Parsons, a research scientist at St. Michael’s Hospital, a site of Unity Health Toronto, and an associate professor at the University of Toronto.

Healthcare providers have a key role to play in supporting parents in decision-making.

“It is important for health care providers to understand that parents who seem hesitant to vaccinate their children may have a variety of reasons for feeling this way and may be reticent to ask questions to health care providers for fear of stigma,” said Dr. Parsons. The authors recommend that these conversations be approached with empathy and openness.

Reference: “Parents’ perspectives on SARS-CoV-2 vaccinations for children: a qualitative analysis” by Jannah Wigle, Kathryn Hodwitz, Clara Juando-Prats, Kate Allan, Xuedi Li, Lisa Howard, Barbara Fallon, Catherine S. Birken, Jonathon L. Maguire and Janet A. Parsons, 21 February 2023, Canadian Medical Association Journal.
DOI: 10.1503/cmaj.221401

Funding: Canadian Institutes of Health Research

Canadian Medical Association Journal

Microbiology

Poor Sleep May Weaken Vaccine Response, Increasing Risk of Infection

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In reviewing data from previous studies, a team lead by researchers at the University of Chicago and the French National Institute of Health and Medical Research (Inserm) found that individuals who had fewer than six hours of sleep per night in the days surrounding vaccination had a blunted antibody response. That indicates efforts to promote healthy sleep duration ahead of an immunization could be an easy way to improve vaccine effectiveness. The study was published on March 13 in the journal Current Biology.

The latest work builds off a 2002 study by members of the team showing that restricting sleep in participants diminished their antibody response to influenza vaccination, leading to about half of the antibody levels seen in controls at 10 days after an inoculation. Their interest in the work was revived during the COVID-19 pandemic lockdowns in 2020, when they began to connect with others who had studied this question and started to pull together the meta-analysis.

Across seven studies, which examined the impact of sleep duration on vaccination against viral illnesses such as influenza and hepatitis, the researchers found that insufficient sleep (defined as under six hours of sleep per night) in the days surrounding vaccination resulted in a decreased antibody response.

“Insufficient sleep is a behavioral factor that can be corrected before vaccination and may not only strengthen, but also extend, the vaccine response,” said Eve Van Cauter, PhD, Professor Emeritus of Medicine at UChicago and senior author on the meta-analysis. “We know that people respond differently to vaccination according to their age, sex, existing medical conditions and other factors that cannot be readily changed. Having an easily modifiable behavior that you can adjust around the time of your appointment gives you something you can control that is likely to improve your body’s response.”

Importantly, the association was seen only in studies that objectively assessed sleep duration using wearable activity trackers or sleep studies in the laboratory. Self-reported sleep duration was not a predictor of vaccine response. The researchers noted that while the association was strong for men, it was weaker and not statistically significant for women. They argue this was likely due to the fact that none of the studies in women accounted for variations in sex hormone levels by menstrual cycle, use of contraceptives and menopausal status.

“The link between sleep and vaccine effectiveness could be a major concern for people with irregular work schedules, especially for shift workers who typically have reduced sleep duration,” said Van Cauter. “This is something people should consider planning around, to ensure that they are getting enough sleep in the week before and after their vaccines.”

Using the results of the meta-analysis and comparing them to known data on the antibody response to the Pfizer-BioNTech COVID-19 vaccine, the researchers estimated that the effects of insufficient sleep on the vaccine response would be equivalent to two months of waning antibodies after vaccination.

“Interestingly, we saw the same outcomes in both influenza, which is a respiratory virus, and hepatitis, which affects the liver, suggesting that this effect could extend to all kinds of viruses, including coronaviruses like SARS-CoV-2,” said Karine Spiegel, PhD, first author on the study and a research scientist at Inserm. “Overall, we see these results as a call to action.”

The researchers hope that the study will inspire more research into the phenomenon to clarify the effects on men and women, as well as to better understand how different vaccines may be impacted by sleep duration and how sleep might be optimized to promote a better vaccine response.

“We need much larger studies that control for the sex hormone environment in women in particular,” said Spiegel. “We also need a better definition of how many days of short sleep duration affect the antibody response, and whether it is just before the vaccine, or also during and after. Large-scale studies that consider behavioral, demographic and hormonal characteristics should provide new insights that will translate to measurable impacts on vaccine efficacy.”

“The immune system is not the only one modulated by sleep,” said Van Cauter. “Insufficient sleep is linked to other health issues such as an increased risk of developing obesity, diabetes or hypertension. Vaccines are an important tool for preventing and reducing the impacts of infectious diseases, and we think that you may be able to implement a simple behavioral change — getting enough sleep — to derive an immediate benefit. It’s cheap, and there is no adverse effect.”

For more on this research, see Sleep and Vaccination: The Critical Connection You Should Know About.

Reference: “A meta-analysis of the associations between insufficient sleep duration and antibody response to vaccination” by Karine Spiegel, Amandine E. Rey, Anne Cheylus, Kieran Ayling, Christian Benedict, Tanja Lange, Aric A. Prather, Daniel J. Taylor, Michael R. Irwin and Eve Van Cauter, 13 March 2023, Current Biology.
DOI: 10.1016/j.cub.2023.02.017

The study included the additional authors Amandine E. Rey and Anne Cheylus of Inserm; Kieran Ayling of the University of Nottingham; Christian Benedict of Uppsala University; Tanja Lange of University of Lübeck; Aric A. Prather of the University of California San Francisco; Daniel J. Taylor of the University of Arizona; and Michael R. Irwin of the University of California Los Angeles.

University of Chicago Medical Center

Microbiology

New study focuses on genetic diversity of E. coli bacteria in hospitalized patients

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Reviewed by Emily Henderson, B.Sc.Mar 13 2023

The human intestine is an environment inhabited by many bacteria and other microorganisms collectively known as the gut microbiome, gut microbiota or intestinal flora. In most people, it contributes to wellness. A healthy gut indicates a stronger immune system, improved metabolism, and a healthy brain and heart, among other functions.

Escherichia coli is one of the bacteria found in practically everyone’s gut microbiota, where it performs important functions, such as producing certain vitamins.

But there’s a vast amount of genetic diversity in the species. Some of its members are pathogenic and can cause diseases such as urinary tract infections. E. coli is the main agent of this type of infection among both healthy people and hospitalized patients or users of healthcare services.”

Tânia Gomes do Amaral, Head of the Experimental Enterobacterial Pathogenicity Laboratory (LEPE), Federal University of São Paulo’s Medical School (EPM-UNIFESP), Brazil

Amaral is first author of an article published in the journal Pathogens on the virulence of these bacteria and their resistance to antibiotics in hospitalized patients.

“Our study focused on hospitalized patients because patients who stay in hospital for a long period are more likely to undergo various procedures, such as urine catheter insertion or venous access. Although these procedures are performed to assure life support, they may facilitate the entry of bacteria into the organism and cause an infection,” Amaral explained.

She earned a PhD in microbiology from EPM-UNIFESP in 1988, conducting part of her research at New York University Medical School and the Center for Vaccine Development at the University of Maryland, Baltimore (UMB) in the United States.

The article reports the findings of a broader study led by Amaral, with 12 co-authors who are researchers and graduate students, on the virulence and drug resistance of E. coli strains associated with urinary tract infections. The study was supported by FAPESP via three projects (18/17353-7, 19/21685-8 and 17/14821-7).

The main aim of this part of the study, described in the master’s dissertation of José Francisco Santos Neto, was to evaluate the diversity and drug resistance of pathogenic E. coli strains isolated from the gut microbiota of inpatients, and to analyze the frequency of endogenous infection (caused by bacteria from the patient’s own microbiota).

The UNIFESP group first investigated the genetic diversity and drug resistance of E. coli strains isolated from the gut microbiota of hospitalized patients, sequencing these strains as well as others isolated from their urine and comparing the results in order to evaluate dissemination of the bacteria in the hospital environment.

“We also compared the genomes of these strains with those of E. coli strains isolated in different parts of the world in order to see if any globally disseminated pathogenic bacteria were present in the study sample,” said Ana Carolina de Mello Santos, a postdoctoral researcher working on the LEPE team.

Urinary tract infections proved to be endogenous for the vast majority of the patients in the study (more than 70%). The results also showed that the patients’ gut microbiota contained at least two genetically different populations of E. coli and that about 30% were colonized by non-lactose-fermenting E. coli strains, which are less common, with some of the patients studied having only such strains in their gut microbiota.

“This finding is most interesting because previous research conducted in other countries to analyze the composition of human gut microbiota didn’t investigate non-lactose-fermenting E. coli,” Santos said.

The authors also note the presence of bacteria with all the genetic markers required for classification as pathogenic and the detection of pathogenic bacteria in the gut microbiota of all patients that had not yet developed an infection. “Hospitalized patients are more susceptible to infection because by definition they are already unwell. Colonization by pathogens is the first step in the spread of hospital-acquired infections now so frequent worldwide,” Santos said.

With regard to antibiotics and other antimicrobials, the authors stress that drug resistance is also a growing global problem, and enterobacterial resistance to third-generation cephalosporins as well as colistin is critical. In all patients whose gut microbiota was colonized by drug-resistant bacteria, the same bacteria also caused endogenous urinary tract infections. In other words, the multidrug-resistant bacteria colonized the gut and traveled to the urinary tract, where they caused an infection.

“In light of these findings, early assessment of gut microbiota in hospitalized patients, at least in cases of E. coli infection, can facilitate and guide their treatment, while also identifying patients who risk progressing to extra-intestinal diseases such as urinary tract infections, which were part of the focus for our study,” Amaral said. “We don’t yet know whether the findings also apply to other bacteria found in gut microbiota, such as the genera Klebsiella, Enterobacter, Pseudomonas and others that can cause infections when they travel to extra-intestinal sites.”

These bacterial genera tend to be even more drug-resistant than E. coli, representing a major public health problem in the hospital environment. As the researchers noted, the World Health Organization (WHO) considers E. coli strains resistant to cephalosporin and colistin to be a critical global health threat. “The presence in human gut microbiota of drug-resistant bacteria associated with severe infectious disease is a matter of great concern, not least because they could spread to people outside the hospital environment,” Amaral said.

Another point raised by the study is the importance of finding out when colonization of the patient’s gut by drug-resistant virulent bacteria occurred. The authors of the article were unable to determine whether the bacteria resistant to cephalosporins and colistin colonized the patients before or after they were hospitalized.

By analyzing the genomes of the strains, however, the researchers were able to identify global risk clones that can cause severe disease and are associated with antimicrobial resistance. “One such clone found in the gut microbiota of two patients was identical to others isolated from urinary tract infections in Londrina, Paraná [a state in South Brazil], and in the United States, as well as European and Asian countries. This shows that some strains found in the study are clones generally associated with infections in all regions of the world,” Amaral said.

This type of information is important when patients are hospitalized. Knowledge of bacterial virulence and drug resistance can be used to prevent infection in parts of the organism outside the intestine and stop the bacteria from spreading to other patients in the same hospital.

Source:

São Paulo Research Foundation (FAPESP)

Journal reference:

Santos-Neto, J.F., et al. (2023) Virulence Profile, Antibiotic Resistance, and Phylogenetic Relationships among Escherichia coli Strains Isolated from the Feces and Urine of Hospitalized Patients. Pathogens. doi.org/10.3390/pathogens11121528.

Microbiology

Clinical trial shows safety and immunogenicity of temperature-stable experimental TB vaccine

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Reviewed by Emily Henderson, B.Sc.Mar 6 2023

A clinical trial testing a freeze-dried, temperature-stable experimental tuberculosis (TB) vaccine in healthy adults found that it was safe and stimulated both antibodies and responses from the cellular arm of the immune system. The Phase 1 trial was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. A non-temperature stable form of the candidate previously had been tested in several clinical trials. However, this was the first clinical trial of any subunit TB vaccine candidate in a temperature-stable (thermostable) form. Results are published in Nature Communications.

The experimental vaccine, ID93+GLA-SE, was developed by Christopher B. Fox, Ph.D., and scientists at the Access to Advanced Health Institute (formerly the Infectious Disease Research Institute) in Seattle. It is a recombinant subunit vaccine made from four proteins of Mycobacterium tuberculosis bacteria combined with GLA-SE, an immune-stimulating adjuvant. The freeze-dried formulation does not require refrigeration and is mixed with sterile water just prior to injection. Thermostable vaccines are desirable in settings where maintaining cold or frozen vaccines for long periods can be costly and difficult.

The current trial investigated whether administering temperature-stable vaccine containing both ID93 and GLA-SE in a single vial would be as effective at inducing an immune response as a regimen in which non-thermostable ID93 and liquid GLA-SE are held in two vials and combined prior to injection. A single-vial presentation of a thermostable vaccine would have clear advantages in ease of storage, transport and administration, the investigators note.

Daniel F. Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, led the single-site trial at the university’s School of Medicine. Twenty-three participants received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well-tolerated. Recipients of the single-vialled thermostable vaccine had robust T-cell responses and produced higher levels of antibodies in the blood than those receiving the non-thermostable two-vial presentation.

The investigators note some limitations in this small trial. For example, no established correlates of protection define what immune responses are required for vaccine-induced protection from TB disease. Therefore, it is not possible to say whether the enhanced immune responses seen in the thermostable vaccine formulation would translate to improved protective vaccine efficacy. Nevertheless, they conclude, results of this trial demonstrate “a proof-of-concept that adjuvant-containing vaccines can be formulated in a freeze-dried single-vial presentation without detrimentally impacting clinical immunogenicity or safety characteristics.”

Source:

National Institutes of Health

Journal reference:

Sagawa, Z.K., et al. (2023) Safety and immunogenicity of a thermostable formulation of the ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults. Nature Communications. doi.org/10.1038/s41467-023-36789-2.

Microbiology

Study Finds Temperature-Stable Tuberculosis (TB) Vaccine Safe and Effective

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A clinical trial testing a freeze-dried, temperature-stable experimental tuberculosis (TB) vaccine in healthy adults found that it was safe and stimulated both antibodies and responses from the cellular arm of the immune system. The Phase 1 trial was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. A non-temperature stable form of the candidate previously had been tested in several clinical trials. However, this was the first clinical trial of any subunit TB vaccine candidate in a temperature-stable (thermostable) form. Results will be published today (March 6, 2023) in the journal Nature Communications.

The experimental vaccine, ID93+GLA-SE, was developed by Christopher B. Fox, Ph.D., and scientists at the Access to Advanced Health Institute (formerly the Infectious Disease Research Institute) in Seattle. It is a recombinant subunit vaccine made from four proteins of Mycobacterium tuberculosis bacteria combined with GLA-SE, an immune-stimulating adjuvant. The freeze-dried formulation does not require refrigeration and is mixed with sterile water just prior to injection. Thermostable vaccines are desirable in settings where maintaining cold or frozen vaccines for long periods can be costly and difficult. 

The current trial investigated whether administering temperature-stable vaccine containing both ID93 and GLA-SE in a single vial would be as effective at inducing an immune response as a regimen in which non-thermostable ID93 and liquid GLA-SE are held in two vials and combined prior to injection. A single-vial presentation of a thermostable vaccine would have clear advantages in ease of storage, transport and administration, the investigators note.

Daniel F. Hoft, M.D., Ph.D., director of the Saint Louis University Center for Vaccine Development, led the single-site trial at the university’s School of Medicine. Twenty-three participants received the thermostable single-vial regimen, while 22 participants received the two-vial, non-thermostable regimen. Both vaccine presentations were safe and well-tolerated. Recipients of the single-vialled thermostable vaccine had robust T-cell responses and produced higher levels of antibodies in the blood than those receiving the non-thermostable two-vial presentation. 

The investigators note some limitations in this small trial. For example, no established correlates of protection define what immune responses are required for vaccine-induced protection from TB disease. Therefore, it is not possible to say whether the enhanced immune responses seen in the thermostable vaccine formulation would translate to improved protective vaccine efficacy. Nevertheless, they conclude, results of this trial demonstrate “a proof-of-concept that adjuvant-containing vaccines can be formulated in a freeze-dried single-vial presentation without detrimentally impacting clinical immunogenicity or safety characteristics.” 

Reference: “Safety and immunogenicity of a thermostable formulation of the ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults” by ZK Sagawa et al., 6 March 2023, Nature Communications.
DOI: 10.1038/s41467-023-36789-2

National Institute of Allergy and Infectious Diseases