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Tag: Infectious Diseases

  • Discovery of novel enzyme family holds potential for antibiotic development

    Discovery of novel enzyme family holds potential for antibiotic development

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    Researchers at Umeå University in Sweden, led by Professor Felipe Cava, have identified a new family of enzymes that creates a unique type of cross-linking between the building blocks of bacterial cell walls. This discovery could help develop new antibiotics against infectious diseases.

    Bacterial cell walls form mesh-like structures, shielding cells from rupturing under high internal pressure and safeguarding against external threats. The cell wall is comprised of sugar and amino acid molecules interconnected by various types of cross-links. These cross-links play a crucial role in providing strength and stability to the cell wall, while also enabling bacteria to adapt to diverse environments and stressors.

    In a groundbreaking study recently published in the esteemed journal Nature Communications, researchers from Umeå University and international institutions have unveiled a novel family of enzymes responsible for generating a unique cross-linkage between L-alanine and meso-diaminopimelic acid. These amino acids are integral components of the peptide chains constituting the cell wall of numerous bacterial species. Termed LD1,3-transpeptidase, this enzyme has been identified across various groups of alpha and beta proteobacteria, including opportunistic pathogens such as Burkholderia and Achromobacter.

    The researchers utilized Gluconobacter oxydans, a model organism employed in vinegar production, to identify the novel LD1,3-transpeptidase enzyme and elucidate its three-dimensional structure. They have demonstrated that this enzyme possesses unique characteristics distinguishing it from other known enzymes involved in cell wall cross-linkage. These distinctive properties enable the enzyme to utilize various substrates and execute diverse reactions, critical for maintaining the cell wall’s integrity. Specifically, their findings indicate that cells lacking these cross-links exhibit heightened sensitivity to β-lactam antibiotics, underscoring the potential of LD1,3-transpeptidases as promising targets for therapeutic interventions, particularly those aimed at enhancing antibiotic effectiveness.

    The principal investigator of the study is Felipe Cava, Professor of Infection Biology at Umeå University and Director of the Umeå Hypoxic Research Facility. With extensive expertise in bacterial cell wall research and its implications in bacterial survival and disease progression, Professor Cava has spearheaded investigations into this field for a significant duration.

    The bacterial cell wall stands as one of the most remarkable structures, yet much remains to be uncovered about its diversity and dynamics. Through the identification and characterization of novel enzyme families like LD1,3-transpeptidase, we not only expand our understanding of bacterial biology but also discover fresh targets for developing antibiotics to combat infectious diseases.”


    Felipe Cava

    The study was funded by, among others, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Kempe Foundations.

    Source:

    Journal reference:

    Espaillat, A., et al. (2024). A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria. Nature Communications. doi.org/10.1038/s41467-024-45620-5.

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  • Study reveals seasonal MERS-CoV peaks in Kenyan camels and potential human transmission

    Study reveals seasonal MERS-CoV peaks in Kenyan camels and potential human transmission

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    In a recent study published in the CDC’s journal Emerging Infectious Diseases, researchers estimated the incidence and potential human transmission of the Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedaries (nomadic camels) in northern Kenya. They found that the incidence of MERS-CoV among these animals was biphasic, peaking in October 2022 and February 2023. Further, slaughterhouse workers in contact with the dromedaries were found to show serologic signs of exposure to MERS-CoV.

    Dispatch: Biphasic MERS-CoV Incidence in Nomadic Dromedaries with Putative Transmission to Humans, Kenya, 2022–2023. Image Credit: Hamady / ShutterstockDispatch: Biphasic MERS-CoV Incidence in Nomadic Dromedaries with Putative Transmission to Humans, Kenya, 2022–2023. Image Credit: Hamady / Shutterstock

    Background

    MERS-CoV is prevalent in dromedary camels in the Arabian Peninsula and Africa, with >75% seroprevalence. Zoonotic transmission to humans, mainly in the Arabian Peninsula, has resulted in >2,400 cases and >800 deaths so far. Although camel breeding is a major activity in Kenya, only three cases of MERS-CoV were identified in camel-exposed humans in 2019, suggesting regional epidemiologic differences.

    MERS-CoV outbreaks in farmed dromedary camels are linked with annual camel parturition, with calves testing positive for MERS-CoV ribonucleic acid (RNA) after losing maternal antibodies. Nomadic camels in Africa, with fluctuating population densities due to seasonality and food availability, have shown correlations between high population density and MERS-CoV seropositivity in Kenya, indicating gaps in our understanding of MERS-CoV circulation.

    Limited infrastructure hinders field studies on nomadic camels, but the regular transportation of these animals to slaughterhouses allows for continuous testing. Leveraging this setup, researchers in the present study conducted a year-long study at a northern Kenyan slaughterhouse hub to estimate the MERS-CoV incidence in dromedaries and their potential transmission to individuals working there.

    About the study

    The study was conducted at a slaughterhouse hub in Isiolo, northern Kenya. Sampling was conducted from September 2022 to September 2023. Samples were collected from 10-15 dromedary camels at a frequency of 4-5 days per week. The camels (n = 2,711) originated from various administrative wards (n=12), primarily from Laisamis and Burat.

    MERS-CoV RNA detection was performed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Confirmation was done by open reading frame (ORF) 1ab qRT-PCR or sequencing. Phylogenetic analysis was additionally performed. Randomized camel serum samples (n = 369) were tested to assess MERS-CoV immunoglobulin G (IgG) levels using ELISA (short for enzyme-linked immunosorbent assay). Optical density ratio (ODR) values were obtained. Statistical analyses were conducted to explore the associations between MERS-CoV IgG levels, RNA-positivity, seasonality, camel sex, and age.

    Sero-epidemiologic investigation was conducted among slaughterhouse workers in contact with dromedaries. MERS-CoV S1 IgG reactivity was assessed using ELISA. Potential cross-reactivity with SARS-CoV-2 antibodies was excluded by comparing ELISA ODRs between MERS-CoV S1 and SARS-CoV-2 S1 assays. Neutralization tests (NT) were conducted using green fluorescent protein (GFP)–encoding vesicular stomatitis virus pseudoparticles (VSVpp) carrying MERS-CoV S protein from two clades. Testing was performed on seven serum samples at a 1:20 dilution. A plaque-reduction neutralization test (PRNT) based on MERS-CoV EMC/2012 was conducted.

    Results and discussion

    MERS-CoV RNA was detected in 1.3% of camels. The cumulative RNA positivity rate was found to be higher in September-October 2022 (5.0%) compared to January-March 2023 (2.3%). Incidence showed biphasic peaks in October 2022 and February 2023. Phylogenetic analysis revealed high similarity (>99.93% nucleotide identity) with MERS-CoV strains from Akaki, Ethiopia, in 2019. The sequences clustered within clade C2.2, which includes strains initially identified in Kenya in 2018, indicating three putative MERS-CoV outbreaks in Kenyan camels.

    MERS-CoV IgG levels had a median ODR of 2.14, with a seroprevalence of 80.76%. IgG levels were lowest in June and highest in March. A negative association was found between MERS-CoV IgG levels and RNA positivity. RNA-positivity was found to be negatively linked to the season. Compared to female camels, male camels showed a greater probability of being RNA-positive and a lower probability of being seropositive. Older animals (>3 years) had a higher (but statistically insignificant) seropositivity rate (86%) compared to animals ≤3 years (72%).

    MERS-CoV S1 IgG reactivity was detected in 14.6% of Isiolo abattoir workers. The absence of MERS-CoV S1 IgG reactivity was noted in a control cohort (n = 12) without camel exposure despite high SARS-CoV-2 S1 IgG levels (92%). Notably, one serum sample showed a VSVpp-NT 50–90% reduction of foci-forming units. Additionally, results from PRNT confirmed MERS-CoV seroconversion for the sample. None of the MERS-CoV ELISA-negative samples demonstrated neutralizing capacity in VSVpp-NT and PRNT assays.

    Conclusion

    In conclusion, the present study revealed a biphasic incidence of MERS-CoV in dromedary camels, potentially influenced by increased animal interactions during transport and seasonal factors. The evidence of human transmission in the study highlights the need for enhanced surveillance and preventive measures to mitigate zoonotic transmission risk. Further research is warranted to investigate the dynamics of MERS-CoV circulation and formulate strategies for potential disease control and prevention.

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  • Rabies in urban opossums signals health alert in São Paulo

    Rabies in urban opossums signals health alert in São Paulo

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    A female White-eared opossum (Didelphis albiventris) found dead in 2021 in Bosque dos Jequitibás Park in the center of Campinas, one of the largest cities in São Paulo state, Brazil, died from rabies meningoencephalitis, according to a group of researchers at the University of São Paulo (USP) and Adolfo Lutz Institute (IAL), the regional reference laboratory, working with health professionals affiliated with public institutions in São Paulo city and Campinas. 

    Reported in an article published in the journal Emerging Infectious Diseases, the finding serves as an alert to the presence of the virus, which is deadly to humans, in the urban environment. 

    Dog rabies is no longer present in São Paulo state, thanks to the success of vaccination campaigns for domestic animals. For this reason, it’s important to monitor other mammals that can act as vectors for the virus, especially animals neglected by this kind of surveillance, such as opossums.”


    Eduardo Ferreira Machado, first author of the article

    He conducted the study for his PhD research at the School of Veterinary Medicine and Animal Science (FMVZ-USP) with a scholarship from FAPESP. 

    Neurological signs of the disease detected in the animal pointed to the form of rabies that causes paralysis and is transmitted by bats. Viral particles identified in other organs also showed that the infection was in the systemic propagation phase. 

    The opossum was one of 22 tested for rabies and other diseases by the group in 2021 as part of an epidemiological surveillance project conducted in partnership with the São Paulo City Department of Health and the Campinas Center for Zoonosis Control. 

    In the same year, the team analyzed 930 bats, 30 of which tested positive for rabies. More than half of these (17 or 56.7%) belonged to frugivorous species of the genus Artibeus. The rest (13 or 43.4%) were insectivorous and belonged to three different genera. 

    Bridge to humans 

    Transmission among bats and opossums may occur via their interaction, as these animals compete for habitats in nature, such as tree crowns, and in man-made environments, such as roof gables or backyards, for example. 

    In 2014, a case of cat rabies was notified in Campinas. The infection was traced to a viral variant found in bats. Both cats and opossums may prey on bats, and this was the most likely transmission path. 

    The researchers also drew attention to the fact that 15 of the 22 opossums analyzed had been killed by dogs. “Dogs can be a bridge between opossums and us, bringing rabies and other diseases to humans. It’s therefore important to monitor wild animals that live in cities,” Machado said. 

    According to José Luiz Catão-Dias, a co-author of the article and Machado’s thesis advisor at FMVZ-USP, opossums are key to this type of surveillance because they adapt well to urban environments without necessarily ceasing to interact with areas of forest. 

    “Even so, they’re neglected. Hardly anything is known about the diseases they may have and might transmit to us,” said Catão-Dias, who is principal investigator and grantee for the project “Comparative pathology and investigation of diseases in Neotropical marsupials, order Didelphimorphia: a surveillance proposal for a group of mammals neglected in wild fauna health studies”, supported by FAPESP. 

    The authors note in the article that a study conducted in the 1960s led to initial suggestions of resistance to the rabies virus among opossums, an assumption reinforced by the scarcity of reports of rabies in these animals. 

    The low prevalence of rabies among opossums in North America, where wild carnivorous mammals are natural reservoirs for viruses, has been explained as due to their low body temperature (34.4 °C-36.1 °C) and the minimal possibility of surviving an attack by a rabid animal. However, the Brazilian study shows that transmission occurs and should be monitored. 

    The researchers continue to analyze dead animals brought to IAL’s Pathology Center, for the purposes of monitoring the presence of both rabies and other diseases. They plan to partner with institutions in other countries, such as Australia, so as to be able to conduct surveillance of opossums and other marsupials. 

    “The Australians have a great deal of experience in this area. We can make comparisons that will be useful to both countries,” Catão-Dias said. 

    Source:

    São Paulo Research Foundation (FAPESP)

    Journal reference:

    Ferreira-Machado, E., et al. (2023). Naturally Acquired Rabies in White-Eared Opossum, Brazil. Emerging Infectious Diseases. doi.org/10.3201/eid2912.230373.

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  • FDA approves omalizumab for food allergy reactions based on NIH research

    FDA approves omalizumab for food allergy reactions based on NIH research

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    Today’s Food and Drug Administration approval of a supplemental biologics license for the monoclonal antibody omalizumab (Xolair) highlights the vital role of the National Institutes of Health-supported research that underpins the FDA decision.

    FDA has approved omalizumab for the reduction of allergic reactions, including anaphylaxis, that may occur with an accidental exposure to one or more foods in adults and children aged 1 year and older with food allergy. People taking omalizumab still need to avoid exposure to foods to which they are allergic. Omalizumab previously received FDA approval for three other indications, including the treatment of moderate-to-severe persistent allergic asthma in certain patients.

    The new FDA approval is based on data from a planned interim analysis of a Phase 3 clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH. The trial is called Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Children and Adults, or OUtMATCH. Investigators in the NIAID-funded Consortium for Food Allergy Research conducted the trial.

    Detailed final results from the first stage of the trial will be presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting in Washington, D.C. during a late-breaking symposium titled, “Omalizumab for the Treatment of Food Allergy: The OUtMATCH Study” on Sunday, Feb. 25, 2024, at 1:45 pm ET. An online supplement of the Journal of Allergy and Clinical Immunology published an abstract outlining the final results on Feb. 5, 2024. 

    NIAID funds the trial with additional support from and collaboration with Genentech, a member of the Roche Group, and Novartis Pharmaceuticals Corporation. The two companies collaborate to develop and promote omalizumab and are supplying it for the trial. 

    Additional information about the ongoing OUtMATCH trial is available at ClinicalTrials.gov under study identifier NCT03881696.

    Source:

    NIH/National Institute of Allergy and Infectious Diseases

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  • City of Hope cures oldest person of blood cancer and achieves HIV remission

    City of Hope cures oldest person of blood cancer and achieves HIV remission

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    City of Hope®, one of the largest cancer research and treatment organizations in the United States, treated the oldest person to be cured of a blood cancer and then achieve remission for HIV after receiving a blood stem cell transplant from a donor with a rare genetic mutation. Research published in NEJM today demonstrates that older adults with blood cancers who receive reduced intensity chemotherapy before a stem cell transplant with donor cells that are resistant to HIV may be cured of HIV infection.

    Paul Edmonds, 68, of Desert Springs, California, is the fifth person in the world to achieve remission for acute myelogenous leukemia and HIV after receiving stem cells with a rare genetic mutation, homozygous CCR5 Delta 32. That mutation makes people who have it resistant to acquiring HIV. Edmonds is also the person who had HIV the longest -; for over 31 years -; among these five patients.

    Known as the “City of Hope patient” among these five patients, Edmonds received a transplant at City of Hope on Feb. 6, 2019, and is now considered to be cured of leukemia. Edmonds stopped taking antiretroviral therapies for HIV nearly three years ago and will be considered cured of HIV after he has stopped taking antiretrovirals for five years. 

    “City of Hope’s case demonstrates that it is possible to achieve remission from HIV even at an older age and after living with HIV for many years,” said Jana K. Dickter, M.D., a clinical professor in City of Hope’s Division of Infectious Diseases, who led the study. “Furthermore, remission can be achieved with a lower-intensity regimen than the therapy received by the four other patients who went into remission for HIV and cancer. As people with HIV continue to live longer, there will be more opportunities for personalized treatments for their blood cancers.”

    For Edmonds’ medical team, this meant they would need to tailor his treatment to address his age and the duration of his HIV. City of Hope’s decades-long expertise treating older adults with cancer and HIV -; efforts led by John A. Zaia, M.D., director of City of Hope’s Center for Gene Therapy and Aaron D. Miller and Edith Miller Chair for Gene Therapy, and other doctors -; proved to be invaluable in treating Edmonds and helping him go into remission for both leukemia and HIV.

    Under the care of City of Hope hematologist Ahmed Aribi, M.D., assistant professor in the Division of Leukemia and a study author, Edmonds received three different therapies to get him into remission before receiving a transplant. The therapy is needed to help the patient achieve remission, and the patient can then proceed with a transplant with the goal of curing the cancer.

    Edmonds received a chemotherapy-based, reduced-intensity transplant regimen prior to his transplant that was developed by City of Hope and other transplant programs for treatment of older patients with blood cancers. Reduced-intensity chemotherapy makes the transplant more tolerable for older patients and reduces the potential for transplant-related complications from the procedure.

    For the transplant, Aribi and his team worked with City of Hope’s Unrelated Donor Bone Marrow Transplant Program -; directed by Monzr M. Al Malki, M.D. -; to find a donor who was a perfect match for the patient and had the rare genetic mutation, which is found in just 1-2% of the general population.

    The mutation makes people who have it resistant to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and HIV uses that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating.

    Edmonds had mild to moderate side effects caused by graft-versus-host disease, which occurs when the donor’s T lymphocytes, a type of white blood cell that fights infections, attack the patient’s cells.

    Edmonds also achieved “full chimerism,” meaning that all of his bone marrow and blood stem cells originated from the donor.

    Stephen J. Forman, M.D., director of City of Hope’s Hematologic Malignancies Research Institute and a professor in the Department of Hematology & Hematopoietic Cell Transplantation, noted a confluence of several research initiatives by City of Hope over the years helped lead the institution to this moment.

    City of Hope and other institutions started performing successful stem cell transplants in older adults a decade ago, an intensive and high-risk procedure in this population that was unheard of prior to then. We have treated patients who are in their 80s with transplants and that is due to City of Hope’s emphasis on expanding therapies to more patients, as well as our compassionate, top-notch care of even the most vulnerable populations.”

    Stephen J. Forman, M.D., Director of City of Hope’s Hematologic Malignancies Research Institute 

    “City of Hope is not stopping there. Our researchers are working on creating stem cells that have the genetic mutation that makes them naturally resistant to HIV, among other research initiatives,” he added. 

    These milestones include:

    • City of Hope was one of the first institutions in the United States to perform a reduced intensity regimen for older patients with myelodysplasia, a blood disease that can evolve into leukemia and that Edmonds had prior to acute myelogenous leukemia.
    • Ryotaro Nakamura, M.D., director of City of Hope’s Center for Stem Cell Transplantation and Jan & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation, led the national trial that demonstrated a transplant could become standard of care for older people with myelodysplastic syndromes, which led to Medicare approving the therapy in older populations.
    • City of Hope was one of the first centers in the United States to perform effective, curative autologous transplants, which use a person’s own stem cells, for patients with HIV-related lymphoma. When many centers still treated patients with low-intensity, noncurative treatment approaches, City of Hope -; led by Forman and Amrita Krishnan, M.D., executive medical director of hematology, City of Hope Orange County – challenged that paradigm by demonstrating that autologous transplants could be used to cure patients with HIV-related lymphomas who would otherwise die.
    • City of Hope was also a primary national co-leader in two National Cancer Institute-sponsored trials for autologous as well as allogeneic stem cell transplantation, which use a donor’s stem cells, for patients with HIV and blood cancers. Led by Joseph Alvarnas, M.D., City of Hope’s vice president of government affairs and a hematology professor, these trials led to a change in the national standards of care on how best to manage this vulnerable patient population.

    City of Hope’s blood stem cell and bone marrow transplant (BMT) program has performed nearly 19,000 transplants, making it one of the largest programs in the nation. City of Hope has exceptional transplant outcomes year after year, according to the Center for International Blood & Marrow Transplant Research.

    Building on its BMT expertise, City of Hope is also a pioneer in the development of chimeric antigen receptor (CAR) T cells to treat blood cancers and solid tumors. More than 1,200 patients have been treated with CAR T cell therapy at City of Hope.

    Leveraging their expertise in cellular immunotherapy, City of Hope scientists have also developed chimeric antigen receptor CAR T cells that can target and kill HIV-infected cells and control HIV in preclinical research. A City of Hope clinical trial using CAR T cell therapy, which has the potential to provide HIV patients with a lifelong viral suppression without antiretroviral therapies, is expected to open later this year.

    Angelo Cardoso, M.D., Ph.D., City of Hope director of the Laboratory of Cellular Medicine, is also a study author and performed many of the experiments that confirmed Edmonds’ HIV remission.

    Source:

    Journal reference:

    Dickter, J. K., et al. (2024). HIV-1 Remission after Allogeneic Hematopoietic-Cell Transplantation. The New England Journal of Medicine. doi.org/10.1056/nejmc2312556.

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  • Maternal mRNA COVID-19 vaccination shields infants for six months

    Maternal mRNA COVID-19 vaccination shields infants for six months

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    Women who receive an mRNA-based COVID-19 vaccination or booster during pregnancy can provide their infants with strong protection against symptomatic COVID-19 infection for at least six months after birth, according to a study from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. These findings, published in Pediatrics, reinforce the importance of receiving both a COVID-19 vaccine and booster during pregnancy to ensure that infants are born with robust protection that lasts until they are old enough to be vaccinated.

    COVID-19 is especially dangerous for newborns and young infants, and even healthy infants are vulnerable to COVID-19 and are at risk for severe disease. No COVID-19 vaccines currently are available for infants under six months old. Earlier results from the Multisite Observational Maternal and Infant COVID-19 Vaccine (MOMI-Vax) study revealed that when pregnant volunteers received both doses of an mRNA COVID-19 vaccine, antibodies induced by the vaccine could be found in their newborns’ cord blood. This suggested that the infants likely had some protection against COVID-19 when they were still too young to receive a vaccine. However, researchers at the NIAID-funded Infectious Diseases Clinical Research Consortium (IDCRC), which conducted the study, did not know how long these antibody levels would last or how well the infants would actually be protected. The research team hoped to gather this information by following the infants through their first six months of life.

    In this portion of the study, researchers analyzed data from 475 infants born while their pregnant mothers were enrolled in the MOMI-Vax study. The study took place at nine sites across the United States. It included 271 infants whose mothers had received two doses of an mRNA COVID-19 vaccine during pregnancy. The remaining 204 infants in the study were born to mothers who had received both doses of an mRNA COVID-19 vaccine as well as a COVID-19 booster. To supplement data gathered during pregnancy and at birth, the infants were evaluated during at least one follow-up visit during their first six months after birth. Parents also reported whether their infants had become infected or had demonstrated COVID-19 symptoms.

    Based on blood samples from the infants, the researchers found that newborns with high antibody levels at birth also had greater protection from COVID-19 infection during their first six months. While infants of mothers who received two COVID-19 vaccine doses had a robust antibody response at birth, infants whose mothers had received an additional booster dose during pregnancy had both higher levels of antibodies at birth and greater protection from COVID-19 infection at their follow-up visits.

    While older children and adults should continue to follow guidance from the Centers for Disease Control and Prevention (CDC) to stay up-to-date on their COVID-19 vaccines and boosters, this study highlights how much maternal vaccination can benefit newborns too young to take advantage of the vaccine: During the course of this study, none of the infants examined required hospitalization for COVID-19. Researchers will continue to evaluate the data from the MOMI-Vax study for further insights concerning COVID-19 protection in infants.

    Source:

    NIH/National Institute of Allergy and Infectious Diseases

    Journal reference:

    Cardemil, C. V., et al. (2024). Maternal COVID-19 Vaccination and Prevention of Symptomatic Infection in Infants. Pediatrics. doi.org/10.1542/peds.2023-064252.

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  • U of M research offers new avenue of hope in the fight against chronic HIV

    U of M research offers new avenue of hope in the fight against chronic HIV

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    Published in the Journal of Infectious Diseases Oxford Academic, research led by the University of Minnesota Medical School offers a new avenue of hope in the fight against chronic human immunodeficiency virus (HIV) infection. 

    The researchers explored the use of Natural Killer (NK) cells aiming to restore their function for better infection control -; an approach that could be used in a broader HIV cure strategy as multiple companies are working on mass production of healthy NK cells.

    HIV has really excellent therapies thanks to the unprecedented progress in developing antiretroviral therapy, but even with that, the disease still causes early mortality and significant medical problems, and a cure is desperately needed.”


    Tim Schacker, MD, principal investigator and program director in HIV Medicine at the U of M Medical School

    NK cells are a frontline defense against viral infections. HIV can disable these cells, making it difficult to clear the infection. The research involved providing HIV-positive individuals with an infusion of healthy NK cells obtained from a close relative along with the drug N-803 from ImmunityBio, which enhances NK activity. All participants in this early-stage study experienced a marked decrease in the burden of infection, and the procedures were found to be safe and well-tolerated.

    While acknowledging the high cost and limited scalability of this approach for the over 35 million infected people worldwide, the study offers important insight into possible cure strategies by demonstrating that enhancing NK cell function can substantially reduce HIV burden. 

    Pending NIH funding, the research team plans a larger study combining NK cells with N-803 plus an HIV-specific broadly neutralizing antibody -; similar to what was successfully used to treat COVID-19 -; to determine if the combination can lead to even further reductions in the burden of infection and get us another step closer to curing HIV. 

    Funding was provided by The American Federation for AIDS Research (AMFAR).

    Source:

    University of Minnesota Medical School

    Journal reference:

    Miller, J. S., et al. (2024). Safety and virologic impact of haploidentical NK cells plus IL-2 or N-803 in HIV infection. The Journal of Infectious Diseases. doi.org/10.1093/infdis/jiad578.

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  • New guideline aims to improve diagnosis and treatment of cryptococcosis

    New guideline aims to improve diagnosis and treatment of cryptococcosis

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    A group of international mycology experts led by Professor Dr Oliver A. Cornely at the University of Cologne has jointly drafted a guideline for the diagnosis and treatment of cryptococcosis, which aims at improving infection management and thus the survival rate of patients. Cryptococcosis is a fungal infection of mainly the lungs that might lead to meningitis. The article ‘Global guideline for the diagnosis and management of cryptococcosis’ was published in the journal The Lancet Infectious Diseases.

    Cryptococcosis, especially cryptococcal meningitis (CM) as the most fatal form, is responsible for a high fatality rate among patients. It is one of the most widespread invasive fungal infections in the world and is a major threat particularly to people suffering from immunodeficiencies. For example, around one million cases of cryptococcal meningoencephalitis are diagnosed worldwide every year in people with HIV alone, and more than 600,000 people die from the disease each year. Patients who have undergone a bone marrow transplant or organ transplant are also at high risk of infection. It is transmitted through the inhalation of spores from soil. Other organs are then also infected via the bloodstream. The lungs, brain, skin and bones are most frequently affected.

    Invasive fungal infections are often difficult to recognize in everyday work in clinics because they occur so rarely. However, it is particularly important for patients at risk to be treated quickly and appropriately. At the same time, we must not forget that the conditions for recognizing the infection at an early stage are not equally good everywhere in the world and that resources are sometimes very limited. There are many countries with a high number of cases that are poorly equipped in this respect. As part of our Global Guideline Programme, we would like to contribute to improving this situation.”


    Dr Oliver A. Cornely from Department I of Internal Medicine at University Hospital Cologne and Director of the Institute of Translational Research at the University of Cologne’s CECAD Cluster of Excellence for Aging Research

    The cryptococcosis guideline is designed to support medical staff in handling invasive fungal infections. It is intended to provide practical guidance and support in decision-making and thus improve clinical approaches, diagnosis, management, and aftercare for the benefit of patients.

    The project was carried out by the mycological societies ECMM (European Confederation of Medical Mycology) and ISHAM (International Society for Human and Animal Mycology) in collaboration with the ASM (American Society for Microbiology). “More than 70 other international specialist institutions were involved in developing this new guideline. This is a great help for our scientific work and shows how great the interest, but also the need for such recommendations is,” explained Cornely. Authors from 22 countries contributed to this guideline. Dr Christina Chang from Monash University in Melbourne, Australia, and Professor Dr John Robert Perfect from Duke University in Durham, USA, were in charge of the project.

    Invasive fungal infections are emergencies. However, as a single pathogen often only occurs very rarely, it is often only discovered late. But patients’ lives depend on rapid detection and well-practiced procedures. Since 2017, University Hospital Cologne has been home to one of the European Centres of Excellence recognized by the ECMM. At the center, patients have access to modern testing procedures and treatment options. In addition, the experts under the direction of Professor Cornely serve as advisory contacts for colleagues in Germany and abroad.

    Source:

    Journal reference:

    Chang, C. C., et al. (2024). Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. The Lancet Infectious Diseases. doi.org/10.1016/s1473-3099(23)00731-4.

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  • Vaccines safe for pregnant women with HIV but show reduced immune response

    Vaccines safe for pregnant women with HIV but show reduced immune response

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    In a recent study published in the journal eClinicalMedicine, researchers performed a meta-analysis on the immunogenicity and safety of vaccines for pregnant women living with human immunodeficiency virus (HIV) infections (PWLWH), comparing their immunogenicity effect to those without HIV infections (PWWH).

    Increased access to lifelong combined antiretroviral therapy (cART) has significantly aided the global reduction in mother-to-child HIV transmission. HIV-exposed uninfected (HEU) infants have a higher burden of infectious diseases than HIV-unexposed and uninfected (HUU). Immunization of PWLWH individuals could potentially reduce the severity of infectious diseases in early infancy. However, previous reports indicate that maternal vaccines given to PWLWH may be less immunogenic than those administered to PWWH. Most HEU children live in low- and middle-income countries, particularly SSA, where the HIV burden is highest. The World Health Organization (WHO) recommends tetanus vaccines for pregnancy, and evidence from clinical trials supports the safety and immunogenicity of other maternal vaccines. However, data on safety and immunogenicity in pregnant women is scarce.

    Study: The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis. Image Credit: Hit Stop Media / ShutterstockStudy: The safety and immunogenicity of vaccines administered to pregnant women living with HIV: a systematic review and meta-analysis. Image Credit: Hit Stop Media / Shutterstock

    About the study

    In the present meta-analysis, researchers examined the immunogenicity and safety of vaccines for HIV-exposed pregnant women.

    The team searched the Embase, MEDLINE, Web of Science, Cochrane, and Virtual Health Library databases from study inception through January 31, 2022, and re-ran the search without language restrictions between February 1, 2022, and September 6, 2023. In addition, they searched the references to the relevant studies to identify additional records.

    The study included observational studies and randomized clinical trials administering vaccines to expecting women living with HIV infections and groups of HIV-uninfected women for comparison. They excluded animal studies, reviews, conference abstracts, and case series. Two researchers independently screened titles and abstracts, and a third researcher resolved disagreements.

    The researchers followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for analysis. They used the Newcastle-Ottawa Scale (NOS) to assess the methodological quality of non-randomized controlled trials. Three researchers evaluated bias risks related to generating random sequences, allocation concealing, personnel and participant blinding, outcome assessment blinding, selective reporting, and inadequate outcome data. They assessed publication bias based on funnel plot asymmetries.

    The team performed random effects modeling for the meta-analyses, assessing geometric mean titers (GMT) to compute effect sizes using the inverse variance-weighted method and report it as the mean difference. They used the I2 statistic to assess study heterogeneity. They performed group-stratified analyses, including HIV status and vaccine subtypes.

    Results

    The initial data search yielded 96,160 records, of which 75 underwent full-text screening, and 12 were eligible for the meta-analysis, including 3,744 expecting females, of which 1,714 were PWLWH. They identified three vaccines in the study, i.e., those for group B streptococci (GBS), influenza virus, and pneumococci. They rated the overall bias risk as low, but outcome assessment blinding-related bias as unclear.

    Five studies, including 3,456 PWLWH women, reported safety outcomes, with no increase in adverse events reported in PWLWH compared to PWWH. The GMT increase from baseline to weeks 28-35 post-vaccination in HA units ranged between 12 and 239. The pooled geometric mean difference in hemagglutination inhibition (HAI) titers following influenza vaccination was 56. The increase was less in PWLWH compared to PWWH: −142. The team observed the most significant difference in women receiving B strains (−166) and the most negligible difference among those receiving A/ H3N1 vaccinations (−112).

    One study documented one or more severe local reactions in four percent of PWLWH, whereas 19% had one or more severe systemic reactions a week post-vaccination. Compared to PWWH, five percent reported one or more severe local reactions, and 15% reported one or more severe systemic reactions. One study documented an increased frequency of injection-area adverse reactions with double-dosage influenza vaccinations among expecting women living with HIV infections. The most frequent serious adverse event was preterm birth, with higher rates among HIV-infected expecting women compared to their HIV-uninfected counterparts.

    Five studies evaluated immunogenicity for pneumococcal, influenza, and GBS vaccines, all reporting elevated antibody titers after four weeks of vaccination among PWLWH compared to baseline; however, antibody titers were lower compared to PWWH. Three studies on influenza vaccinations had adequate comparison information for meta-analytic research stratified by vaccine subtypes (A/H1N1 virus, A/H3N2 virus, B/Victoria virus, and B/Yamagata virus). The mean differences in antibody titers 28 to 35 days after influenza vaccinations were significantly higher in PWLWH than in PWWH.

    Overall, the study findings showed that there is limited data on the immunogenicity and safety of vaccines administered to HIV-infected expecting women. There was no difference in vaccine safety between PWLWH and PWWH concerning influenza, pneumococcal, and investigational GBS vaccines, but there was a significant elevation in antibody titers four weeks post-vaccination; however, the increase was lower in PWLWH compared to PWWH. The findings underscore the potential challenges for vaccine policy in countries with high HIV burdens and the need for PWLWH inclusion in maternal vaccine trials to promote vaccine confidence.

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  • Media stories on parental vaccine hesitancy drive a false narrative, distort reality

    Media stories on parental vaccine hesitancy drive a false narrative, distort reality

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    Media stories focusing on vaccine hesitancy can distort reality and drive a false narrative that a large percentage of parents are refusing to get their children vaccinated, according to an editorial in the New England Journal of Medicine by two pediatricians from the University of Colorado Anschutz Medical Campus.

    The article, published online Saturday in the Perspective section of the prestigious medical journal, said stories indicating widespread vaccine hesitancy among parents are at odds with the facts and can have long-term consequences.

    The algorithms that shape our media diets have been promoting the idea that parental hesitancy about routine childhood vaccines has become commonplace in the United States. The data, however, are undeniable: apart from important challenges with influenza and Covid­19 vaccina­tion, the vast majority of parents in the United States continue to choose to have their children vac­cinated according to the vaccina­tion schedule recommended by the Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics.”


    Sean O’Leary, MD, MPH, and David Higgins, MD, MPH, of the University of Colorado School of Medicine and Children’s Hospital Colorado

    According to the authors, a recent poll from the Pew Research Center found 88% of adults have robust confidence in the value of childhood vaccines such as those for measles, mumps, and rubella. The poll also showed little change in the numbers of adults who say the value of vaccines outweigh any associated risk.

    At the same time, a recent study from the CDC showed 93% of kindergarten students received state-required vaccines. Another study revealed that vaccination coverage for children at age 2 remained high and stable throughout the pandemic,

    “The headlines say vaccine resistance is through the roof, the sky is falling,” said O’Leary, professor of pediatrics and infectious diseases at the CU School of Medicine and Children’s Hospital Colorado. “There is a real risk of the community buying into this and treating it as the norm.”

    Higgins, a fellow and instructor in pediatrics at the CU School of Medicine and the Adult & Child Center for Outcomes Research & Delivery Science (ACCORDS) at the CU School of Medicine, said constant focus on vaccine hesitancy could become a “dangerous, self-fulfilling prophecy.”

    He said perceived social norms, or what people consider typical behavior, can powerfully influence their health care decisions.

    “The most important thing we can do is normalize vaccinations. That’s what the majority of parents do, vaccinate their children,” Higgins said. “We in the scientific community need to better communicate the value of vaccinations.”

    Studies show that vaccine recommendations from physicians are more effective when framed in a way that presumes parents want their kids vaccinated. If clinicians expect resistance, the recommendations may be less effective.

     “Legitimate inquiries about vaccines don’t necessarily indicate major parental vaccine hesitancy. In our experience, most parents with such inquiries aren’t `antivaccine;’ they believe vaccines are essential to their child’s health. One of the best parts of being a pediatrician is partnering with parents to address these good­faith questions,” the authors wrote.

    O’Leary, chair of the Committee on Infectious Diseases for the American Academy of Pediatrics, said not only do most adults support vaccinating their children, but since the onset of the pandemic and contrary to many media stories, pediatricians have told him that parents who had previously refused to vaccinate their kids are coming in to get the inoculations.

    Neither doctor is suggesting that vaccine hesitancy isn’t a significant health threat in the U.S.

    “We believe it will be essential to double down on efforts to increase confidence and trust in vaccines, including in populations that have experienced mistreatment by the medical community,” O’Leary and Higgins wrote. “Because of the complexity of this issue, addressing parental vaccine hesitancy requires partnerships among academic experts in vari­ous disciplines, community lead­ers, policymakers, public health professionals and parents.”

    Source:

    University of Colorado Anschutz Medical Campus

    Journal reference:

    Higgins, D. M., & O’Leary, S. T. (2024). The Risks of Normalizing Parental Vaccine Hesitancy. The New England Journal of Medicine. doi.org/10.1056/nejmp2313742.

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