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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

New, Better Models Show How Infectious Diseases Like COVID-19 Spread

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The COVID-19 pandemic has emphasized the significance of modeling in comprehending the spread of diseases and in providing crucial insights into disease prevention and control. A new model has utilized COVID-19 data and combined two classic methodologies to enhance predictions about disease spread.

A widely used modeling technique involves dividing the population into compartments, such as susceptible (S), infected (I), and recovered (R), in what is known as the SIR model. This approach models the rates of change that describe the movement of individuals from one compartment to another.

KAUST researchers, led by Paula Moraga, integrated SIR compartment modeling in time and a point process modeling approach in space–time, while also taking into account age-specific contact patterns. To do this, they used a two-step framework that allowed them to model data on infectious locations over time for different age groups.

“The model gives more accurate predictions than previous approaches when making short/mid-range predictions in space and time,” says lead researcher André Amaral.

“It also accounts for different age classes so we can treat these groups separately, resulting in finer control over the number of infectious cases.”

Their approach paid off. In a simulation study to assess the model’s performance, and in a case study of COVID-19 cases in Cali, Colombia, the model performed better when making predictions and provided similar results for past time points, compared with models commonly used in predictive modeling.

“The model’s features can help decision-makers to identify high-risk locations and vulnerable populations to develop better strategies for disease control,” says Amaral.

It also can be used with any infectious disease that fits the compartment model assumptions, such as influenza. Furthermore, the model can account for different age groups and their associated contact patterns, meaning it allows more detailed conclusions about where, when, and to which population group decision-makers should focus their resources if they want to control disease spread.

“In future work, we might extend such an approach and use different temporal models to replace the SIR model. This would allow us to account for different epidemic dynamics and expand the number of scenarios that the model can be used for,” says Amaral.

“Finally, to improve the model’s predictive capabilities, we might work on developing ensemble approaches that combine a number of predictions from a number of different models and also account for potential time delays in collecting data,” he adds.

Moraga says the model’s performance demonstrates the importance of quality and detailed data by location, time, and population group to understand infectious disease dynamics while highlighting the need to strengthen national surveillance systems to improve public health decision-making.

Reference: “Spatio-temporal modeling of infectious diseases by integrating compartment and point process models” by André Victor Ribeiro Amaral, Jonatan A. González and Paula Moraga, 13 December 2022, Stochastic Environmental Research and Risk Assessment.
DOI: 10.1007/s00477-022-02354-4

King Abdullah University of Science & Technology (KAUST)

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

Usefulness of dried blood spot samples for monitoring HCV infection in people who inject drugs

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Reviewed by Emily Henderson, B.Sc.Mar 17 2023

A study with people who inject drugs evaluated a minimally invasive test based on dried blood spots (DBS) for the monitoring of hepatitis C virus (HCV) infection. The use of DBS samples for HCV RNA detection and genotyping was shown to effectively assess cure after treatment and to differentiate between reinfection and treatment failure. The results support the viability of decentralizing treatment and post-treatment monitoring for people who inject drugs, who frequently face challenges accessing the healthcare system. The study, which has been published in the Journal of Medical Virology, was carried out as part of a project with support from the “Conquering Hepatitis Via Microelimination” (CHIME) programme and a PFIS grant. Investigators from various research institutions collaborated in the project, including the Clinical Virology and New Diagnostic Tools research group, led by Dr Elisa Martró, at Germans Trias i Pujol Research Institute (IGTP) and Dr Sabela Lens from Hospital Clínic’s Viral Hepatitis Group.

Towards elimination of hepatitis

In line with the strategy proposed by the World Health Organization for the elimination of viral hepatitis as a public health threat by 2030, and the Plan for Prevention and Control of Hepatitis in Catalonia, which Dr Martró actively participates in, her group has been focused for years on simplifying the diagnosis of hepatitis C by developing and validating an assay which can detect the virus RNA using DBS samples. These minimally invasive samples can be collected at harm reduction centres or drug dependence care and follow-up centers (known as CAS in Catalan), improving access to hepatitis C diagnosis for vulnerable populations, such as people who inject drugs. While this new test has demonstrated good clinical performance as a diagnostic tool for detecting HCV RNA before treatment in previous studies by the Clinical Virology and New Diagnostic Tools research group, the use of DBS samples had not been evaluated as a test for cure or for detecting reinfection after treatment.

A multidisciplinary research group has been able to pursue a project with a new model of care for hepatitis C, based on point-of-care diagnosis, treatment, and reinfection follow-up at the REDAN La Mina harm reduction centre. Since 2019, approximately 750 individuals who inject drugs have been tested though this initiative, which was designed by Dr Sabela Lens from Hospital Clínic’s Viral Hepatitis Unit, in collaboration with the Clinical Virology and New Diagnostic Tools Research Group at Germans Trias i Pujol Research Institute (IGTP), led by Dr Martró from the Microbiology Service (LCMN) of the Germans Trias i Pujol Hospital (HUGTiP), as well as CEEISCAT and the Public Health Agency of Catalonia. The project had the support of the “Conquering Hepatitis Via Microelimination” (CHIME) programme from Gilead Sciences awarded to Dr Lens, as well as a PFIS grant of the Instituto de Salud Carlos III and the Fondo Social Europeo awarded to Anna Not, who is a member of Dr Martró’s group, and aligns with the World Health Organization’s global health strategy, which aims to eliminate hepatitis C as a public health problem by 2030.

A model of decentralized care

In this project, Dr Martró’s group aimed to evaluate the clinical performance of a previously developed HCV-RNA assay based on DBS, for the assessment of cure and the detection of recurrent viremia after on-site treatment at the harm reduction center, compared to the commercially available HCV-RNA point-of-care test. Furthermore, they sought to assess the possibility of distinguishing between reinfection and treatment failure through HCV genotyping from baseline and follow-up DBS samples. Typically, these assessments (cure and reinfection) are performed using venipuncture blood samples collected at healthcare centres, which can be difficult for people who inject drugs and have often limited access to the healthcare system. The recently published results demonstrate how the collection of DBS samples before and after treatment can simplify these assessments in decentralized test-and-treat programmes.

“The success of the CHIME project lies in the decentralized diagnosis and treatment provided at REDAN La Mina. A nurse trained in hepatology assessments was included in the study to enrol and visit participants. The hepatologists at Hospital Clínic also reviewed each case and prescribed decentralized treatment. Additionally, Dr Martró’s group carried out HCV detection and sequencing from DBS samples collected before and after treatment. This pilot program involves HCV diagnosis on-site in less than an hour, treatment at the same center, and follow-up to assess reinfection”, states Dr Lens.

Detection made easier

Reinfection is common in people who inject drugs and must be treated to prevent further transmission of the virus. During early reinfection, low levels of the virus may be present, making its detection in DBS samples challenging, as they only contain a small amount of blood. Of the 193 DBS samples tested after treatment, the DBS-based assay showed 100% specificity and sensitivity ranging from 84% to 96% based on different relevant viral load cut-offs, and similar rates as a test of cure (three months after treatment). It must be born in mind that among the patients with recurrent viremia after treatment, one tenth had low viral loads. Moreover, HCV genotyping allowed researchers to classify 73% of viremic cases as either reinfection or treatment failure.

Collection of DBS samples was done before antiviral treatment and after treatment if recurrent viremia was detected by the commercially available point-of-care assay. Anna Not, the first author of the article (which will be part of her PhD), explains that it “the use of DBS allowed us to sequence the virus before and after treatment and compare the sequences to determine if the virus was the same (indicating a treatment failure) or if it was different (indicating reinfection). This information enabled the hepatologist to decide on the most appropriate antiviral combination for the second treatment”.

The research shows the potential of using DBS samples for determining cure and differentiating between reinfection and relapse after antiviral treatment for hepatitis C in people who inject drugs. The use of DBS samples makes it possible to decentralize treatment and follow-up, improving access to care for these people. Even so, Dr Martró points out that “a small number of patients had low viral loads, which can hinder the detection of viremia and genotyping in DBS. As a result, repeat testing (e.g. every six months) is advised for individuals who are at risk of HCV reinfection”.

Source:

Germans Trias i Pujol Research Institute

Journal reference:

Not, A., et al. (2023) Usefulness of dried blood spot samples for monitoring hepatitis C treatment outcome and reinfection among people who inject drugs in a test-and-treat program. Journal of Medical Virology. doi.org/10.1002/jmv.28544.

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

“COVID Rebound” Is Common – Even in Patients Not Treated With Paxlovid

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Preliminary results from a Scripps Research and eMed digital medicine study show an unexpectedly high proportion of COVID-19 rebound cases in untreated people, as well as those treated with Paxlovid.

“COVID rebound,” in which evidence of the illness disappears and then returns days or weeks later, is surprisingly common—whether or not patients are given the antiviral Paxlovid.

The results, reported recently in the journal Clinical Infectious Diseases by scientists at Scripps Research and the digital health company eMed, are a preliminary readout from an ongoing observational study of people who order SARS-CoV-2 antigen test kits online. The researchers found that in an initial group of 170 eMed Test-to-Treat™ kit users, the disappearance and then return of evidence of the virus on antigen tests and in self-reported COVID-19 symptoms occurred in 9.3% and 7.0% of patients who opted not to take antiviral treatment, and in 14.2% and 18.9% of those who opted for Paxlovid.

Although a higher proportion of the Paxlovid-treated group reported COVID-19 rebound, the difference was not statistically significant in this early snapshot of the ongoing study, which is designed ultimately to enroll a total of 800 patients.

“These preliminary results suggest that rebound after clearance of SARS-CoV-2 test positivity or COVID-19 symptom resolution is more common than previously reported in both treated and untreated patients,” says study lead author Jay Pandit, MD, an assistant professor and director of Digital Medicine at the Scripps Research Translational Institute. “We’re going to need a larger set of participants and more extended follow-up to better understand this rebound phenomenon.”

The study, conducted from August to November of last year, was a collaboration with eMed, including epidemiologist and Chief Science Officer Michael Mina, MD, PhD, previously professor at Harvard T.H. Chan School of Public Health, and others at the Test-to-Treat company, which is also implementing the NIH Home Test to Treat COVID-19 program.

Reports of COVID-19 rebound started appearing in the medical literature in 2022. The cause of rebound has been unclear, although the suggestion in most of these reports has been that rebound occurs more often in patients treated with Paxlovid. The latter, a mix of two antiviral compounds (nirmatrelvir and ritonavir), received emergency use approval in late 2021 from the U.S. Food and Drug Administration (FDA) for treating patients who have mild-to-moderate COVID-19 and are at high risk of developing severe COVID-19.

To help illuminate the rebound phenomenon and any connection to Paxlovid, Pandit and his colleagues teamed up with eMed to drive a “real-world” study of outcomes among people using the company’s COVID-19 Test-to-Treat antigen test kits with telehealth proctoring and telemedicine.

“As the COVID-19 landscape continues to evolve, the importance of making timely and effective treatments accessible and thereby helping reduce severe disease outcomes cannot be overstated,” Mina says. “Collaborations such as this with the Scripps Research Translation Institute are a key part of efforts to gather evidence-based data and answer critical questions associated with treatment outcomes. We are also proud that this study not only offers new data surrounding COVID-19 recovery and treatment outcomes, but also highlights the benefits of industry and academic partnerships to accelerate high-quality public health and translational research.”

The researchers offered Test-to-Treat telehealth kit users participation in the study if they had a verified positive test. If users consented to participate, the researchers sent them more test kits, and asked each participant to take a test and fill out a symptom questionnaire every other day for 16 days. The team then compared the rates of rebound for those who did and didn’t opt to take Paxlovid. Rebound was measured in two ways: a positive test result after a negative test, or a reported recurrence of symptoms after symptom resolution. For this preliminary analysis, there were 127 people in the Paxlovid-treated group, and 43 in the non-Paxlovid group.

Either way rebounds were measured, the Paxlovid group experienced them at a higher rate: 14.2% vs. 9.3% for antigen test rebounds, and 18.9% vs. 7.0% for symptom rebounds. With the small participant numbers included in this preliminary analysis, these differences were not statistically significant. Moreover, on other measures (such as the time from first positive antigen test to first negative antigen test, and time from symptom onset to first symptom resolution), the two groups had essentially identical outcomes. Age, gender and pre-existing conditions also did not appear to influence rebound.

Pandit emphasizes that the study is not currently powered to detect statistically significant results, and a final analysis should include up to 800 participants and thus should have much more power to generate conclusive findings. However, he adds, the preliminary findings already make clear that the rebound rates for both treated and untreated groups are higher than the rates reported in prior studies. For example, an analysis of their clinical trial results by Pfizer, the maker of Paxlovid, found rebound rates of only about 2% in both Paxlovid and placebo groups over a two-week period.

In addition to increasing the number of participants in their ongoing study, Pandit and colleagues plan to start sequencing the virus found in participants and testing participants’ blood samples for antibody levels and other immune markers.

“We’re hoping to answer key questions about the rebound phenomenon, such as whether it’s enhanced by Paxlovid, how much it depends on the viral variant and what is the role of the patient’s immune system,” Pandit says.

He and his team also plan to improve the balance of ethnic and racial representation between the treatment and control groups: In the initial group of 170, Whites were much more likely than Blacks and Latinos to opt for Paxlovid treatment.

Reference: “The COVID-19 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated with Nirmatrelvir Plus Ritonavir Versus Untreated Controls” by Jay A Pandit, Jennifer M Radin, Danielle Chiang, Emily G Spencer, Jeff B Pawelek, Mira Diwan, Leila Roumani and Michael J Mina, 22 February 2023, Clinical Infectious Diseases.
DOI: 10.1093/cid/ciad102

Support for the study was provided by eMed, the National Institute of Allergy and Infectious Diseases (3U01AI151812-03S2), and the National Center for Advancing Translational Sciences (NCATS UL1 TR002550).

Scripps Research Institute

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

Streptococcus pyogenes, which is often called group A Streptococcus, infects people around the world. While estimates vary, these …

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Streptococcus pyogenes, which is often called group A Streptococcus, infects people around the world. While estimates vary, these infections could be responsible for the deaths of over half a million individuals every year. The pathogen can also cause an illness known as scarlet fever, which usually occurs in kids between the ages of 5 and 15. Scarlet fever was once a major health threat for children, and there were infection rates as high as 20 percent in the early 20th century. The disease became less of a public health concern until its recent reemergence in the UK, Hong Kong, and mainland China.

Colorized scanning electron micrograph of Group A Streptococcus (Streptococcus pyogenes) bacteria (blue) and a human neutrophil (purple). Credit: NIAID

Isolates taken from patients have shown that S. pyogenes can carry resistance genes that shield it from the effects of antibiotics including tetracycline, erythromycin and clindamycin. These bacteria can also generate powerful toxins, like molecules called SSA and SpeC, known as superantigens, and an enzyme called Spd1.

While S. pyogenes infections are still rare, they can kill as many as 20 percent of people who are infected.

In 2019, a variant isolated in the UK, the so-called M1UK strep A variant, was shown to produce five times more strep A toxins compared to previous strains. The SpeA superantigen generated by this variant can short-circuit host immunity and was once known as the scarlet fever toxin. The M1UK variant also carried a few genetic mutations compared to previous strains, and one of those mutations was located close to the toxin gene. The findings have been reported in Nature Communications.

More research will be needed to know whether this variant has gotten better at moving from one person to another to cause infection.

Strep A is very rare, and the study authors noted that people should not be concerned about this novel variant at this time. Basic hygiene practices, like hand washing, can still protect us from dangerous germs like S. pyogenes. Strep A infections are spread through close contact with infected people, who may be coughing and sneezing. Other symptoms include a rash and fever.

The study authors also noted that these findings have highlighted the importance of developing a vaccine for Strep A infections.

An unrelated study reported in mBio has also revealed a different mutation that occurs in a Strep A variant that increases the production of a toxin called streptolysin O (SLO). SLO can help Strep A survive in the host, evade host immunity, and is destructive to host tissues. Variants that did not express SLO were not as virulent, noted the study authors.

Right now, scientists are working on a Strep A vaccine, as described in the video above.

Sources: Nature Communications, Griffith University, mBio


Carmen Leitch

Microbiology

COVID-19 Pandemic Increased Rates and Severity of Depression – Even for People Not Infected

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The COVID-19 pandemic impacted just about every part of people’s lives. Quarantining, social distancing, societal disruptions, and an ever-shifting, uncertain landscape of rules and restrictions and variants created stress and isolation that impacted the mental health of millions of Americans.

Now, in a new study of nearly 136,000 patients from Intermountain Health in Salt Lake City, researchers found that depressive symptoms and severity of depression was significant among all patients in the study, regardless of whether they were infected with COVID-19 or not.

In the study, results of which were presented at the American College of Cardiology’s 2023 scientific session in New Orleans on March 4, Intermountain researchers found that depression symptoms rose significantly during the pandemic, with more than half of all patients reporting some degree of clinically-relevant depressive symptoms.

“It didn’t matter if a patient was positive or negative for the virus. We found increased rates of depression and depression severity across the board,” said Heidi T. May, PhD, cardiovascular epidemiologist at Intermountain Health and principal investigator of the study. “As poor mental health can impact chronic diseases, including cardiovascular disease, screening for and treating mental health is a critical part of any overall patient care process right now. Doing so will both help patients in this moment, and protect their future health.”

In the Intermountain study, researchers examined 135,864 patients who completed their first Patient Healthcare Questionnare-9 (PHQ-9), which is used to screen for depression, in a primary care setting from January 1, 2016, to April 20, 2022.

They then looked at how those scores, which categorize patients’ depression into none (<10), mild (10-14), moderate (15-19) and severe (>20), over time.

The researchers found a significant increase in PHQ-9 scores, with the mean PHQ-9 score rising by 1.5 points.

They also found that before the pandemic, about 45% of patients reported some degree of depression. Starting in 2021, that changed to 55% of patients showing at least some degree of depression. There was no significant difference in scores among COVID positive and negative patients.

Depression, anxiety, stress, and PTSD are linked to higher rates of high blood pressure and higher levels of cortisol, which can lead to calcium buildup in the arteries, metabolic disease, and heart disease, according to the CDC.

“We know depression is a risk factor for chronic disease, so given these findings, it’s really important to mitigate some of the effects of depression so these patients can lead healthier and happier lives right now, and in the future,” said Dr. May.

Meeting: American College of Cardiology’s 72nd Annual Scientific Session Together With World Heart Federation’s World Congress of Cardiology

Intermountain Healthcare

Microbiology

Study Finds Omega-3 May Be Protective Against COVID-19 Infection

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Omega-3 fatty acids, especially EPA and DHA, might be protective against contracting and/or suffering adverse outcomes of COVID-19 infection.

A study just published in the American Journal of Clinical Nutrition (AJCN) explored the role of omega-3 fatty acids, especially EPA and DHA, and whether they might be protective against contracting and/or suffering adverse outcomes of COVID-19 infection.

The study compared the risk for three COVID-19 outcomes: 1-testing positive, 2-hospitalization, and 3-death as a function of baseline plasma DHA levels.

DHA levels (% of total fatty acids) were measured by Nuclear Magnetic Resonance (NMR) spectroscopy but were converted to Omega-3 Index (red blood cell EPA+DHA%) for this analysis. The three outcomes and relevant covariates were available for 110,584 subjects (hospitalization and death) and for 26,595 ever-tested subjects (positive COVID-19 PCR test result) via the UK Biobank prospective cohort study. These COVID-19 outcomes were assessed between January 2020 and March 2021.

In the fully adjusted models, subjects in quintile 5 (with the highest Omega-3 Index levels) were 21% less likely to test positive than those in quintile 1, and the risk for a positive test was 8% lower for each 1-SD (standard deviation) increase in plasma DHA%. Quintile 5 subjects were also 26% less likely to be hospitalized than those in quintile 1, and risk for hospitalization was 11% lower per 1-SD increase in DHA%.

For death with COVID-19, risk was monotonically lower through quintile 4, but in quintile 5, the risk reduction was partially attenuated and became non-significant. Estimated Omega-3 Index values across the five DHA quintiles ranged from 3.5% (quintile 1) to 8% (quintile 5).

“These values comport well with the Omega-3 Index risk cut points [originally proposed in 2004 for death from cardiovascular disease] of <4% (high risk) and >8% (low risk) and imply that these target levels apply to COVID-19 outcomes as well,” researchers noted in their paper.

The investigators also point out that South Korea and Japan have reported an extremely low severity of COVID-19 disease and that although masking practices, social distancing policies and other population-wide interventions no doubt contributed to this, it is interesting to note that the Omega-3 Index values of healthy South Korean and Japanese individuals are about 8-12% and 7–11% respectively, which is much higher compared to an Omega-3 Index of 4-5% in Western populations such as the United States.

“A worldwide pattern linking higher omega-3 fatty acid intakes with lower rates of death with COVID-19 was documented by Vivar-Sierra et al. Although only suggestive, this observation adds further support for a potential role of omega-3s EPA and DHA in the prevention of fatal COVID-19 disease,” the researchers said.

“This study confirms previous findings that low omega-3 status is associated with increased risk for hospitalization with COVID-19. We extended these findings by also showing reduced risk for testing positive with the infection and by providing evidence that the risk for death may also be reduced,” said Dr. William S. Harris, PhD, FASN, President, Fatty Acid Research Institute (FARI). “Furthermore, we identified the Omega-3 Index levels associated with the least (<4%) and greatest (>8%) protection from COVID-19. Altogether these results support the practice of increasing consumption of oily fish like salmon or omega-3 fish oil supplements as a potential risk reduction strategy when it comes to COVID-19.”

Dr. Philip Calder, who wrote an editorial accompanying this publication, said these findings suggest that consuming more long-chain omega-3 fatty acids (EPA and DHA) should be encouraged as a strategy to reduce the impact of the ongoing SARS-CoV-2 pandemic and of future respiratory virus infection outbreaks. Dr. Calder, BSc(Hons), PhD, DPhil, RNutr, FSB, FAfN, is Professor of Nutritional Immunology within Medicine at the University of Southampton, UK.

References:

“Association between blood N-3 fatty acid levels and the risk of coronavirus disease 2019 in the UK Biobank” by William S. Harris, Nathan L. Tintle, Swaminathan Perinkulam Sathyanarayanan and Jason Westra, 28 February 2023, American Journal of Clinical Nutrition.
DOI: 10.1016/j.ajcnut.2022.11.011

“Bioactive omega-3 fatty acids are associated with reduced risk and severity of SARS-CoV-2 infection” by Philip C. Calder, 28 February 2023, American Journal of Clinical Nutrition.
DOI: 10.1016/j.ajcnut.2022.12.007

Fatty Acid Research Institute (FARI)