How health system hesitancies contributed to COVID risks

Experts at Cincinnati Children’s explore issues that need resolving before next public health crisis strikes

Peer-Reviewed Publication

CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER

More than 1.2 million people have died in the United States during the COVID-19 pandemic to date, more documented deaths than any other nation on Earth.

While many have attributed the high death toll on widespread personal hesitancy to wear masks, avoid crowded places or receive vaccines once they were developed, there were several “system hesitancies” that contributed to the tragic outcomes that need addressing, according to an analysis published Dec. 6, 2023, in Health Affairs Forefront.

The analysis was written by first author David Hartley, PhD, MPH, and corresponding author Andrew Beck, MD, MPH, at Cincinnati Children’s and several co-authors based in Cincinnati and Boston.

“Such hesitancies continue to stand in our way, placing the public at risk for infection, hospitalization, and even death during times of uncertainty and danger. Moreover, disruptive effects of system hesitancies are not shared equally across populations, with disproportionate clinical and economic burdens for the elderly, communities of color, those living with poverty, and children who were forced to see a safe return to school politicized,” the co-authors state.

These systemic hesitancies included:

• Hesitancy to comprehend and act on warnings
• Hesitancy to share, integrate, and learn from diverse data streams across sectors
• Hesitancy to coordinate
• Hesitancy to enable and empower local leadership

Newer technology has made near real-time disease surveillance possible on wide scales, but wider adoption is needed. Many lessons learned about coordinated response to natural disasters still need to be translated to public health responses to disease outbreaks.

System improvements should not focus only on top-down command and control, but rather top-down and bottom-up organizational approaches that support flexible, adaptive, and timely responses, the co-authors say.

In previous research about COVID response, several of the co-authors on the Health Affairs Forefront article also co-authored a report in April 2021 in the Mayo Clinic Proceedings that described how a number of organizations collaborated in southwest Ohio to rapidly build a “regional learning health system” to respond to the pandemic.

In southwest Ohio, a history of routine meetings between otherwise disconnected and often competitive hospitals, health departments and other agencies helped cut red tape, speed data sharing, and smooth resource sharing. That experience may serve as a model for other communities, the co-authors suggest.

“We can design a resilient public health system resistant to hesitancies, a system capable of detecting dynamic public health emergencies, and responding nimbly and efficiently,” the co-authors say. “To do so, we need an integrated system that works across sectors, approaches leadership in a new way, and enables rapid learning from the top-down and bottom-up.”

Co-authors included Peter Margolis, MD, PhD, and Robert Kahn, MD, MPH, from Cincinnati Children’s; Steve Miff, PhD, president and CEO at the Parkland Center for Clinical Innovation; Muhammad Zafar, MD, University of Cincinnati; Kate Schroder, president and CEO at Interact for Health in Cincinnati; Tiffany Mattingly, vice president, clinical strategies at The Health Collaborative in Cincinnati; and Pierre Barker, MD, MBChB, chief global partnerships and programs officer for the Institute for Healthcare Improvement in Boston.

More than 1.2 million people have died in the United States during the COVID-19 pandemic to date, more documented deaths than any other nation on Earth.

While many have attributed the high death toll on widespread personal hesitancy to wear masks, avoid crowded places or receive vaccines once they were developed, there were several “system hesitancies” that contributed to the tragic outcomes that need addressing, according to an analysis published Dec. 6, 2023, in Health Affairs Forefront.

The analysis was written by first author David Hartley, PhD, MPH, and corresponding author Andrew Beck, MD, MPH, at Cincinnati Children’s and several co-authors based in Cincinnati and Boston.

“Such hesitancies continue to stand in our way, placing the public at risk for infection, hospitalization, and even death during times of uncertainty and danger. Moreover, disruptive effects of system hesitancies are not shared equally across populations, with disproportionate clinical and economic burdens for the elderly, communities of color, those living with poverty, and children who were forced to see a safe return to school politicized,” the co-authors state.

These systemic hesitancies included:

• Hesitancy to comprehend and act on warnings
• Hesitancy to share, integrate, and learn from diverse data streams across sectors
• Hesitancy to coordinate
• Hesitancy to enable and empower local leadership

Newer technology has made near real-time disease surveillance possible on wide scales, but wider adoption is needed. Many lessons learned about coordinated response to natural disasters still need to be translated to public health responses to disease outbreaks.

System improvements should not focus only on top-down command and control, but rather top-down and bottom-up organizational approaches that support flexible, adaptive, and timely responses, the co-authors say.

In previous research about COVID response, several of the co-authors on the Health Affairs Forefront article also co-authored a report in April 2021 in the Mayo Clinic Proceedings that described how a number of organizations collaborated in southwest Ohio to rapidly build a “regional learning health system” to respond to the pandemic.

In southwest Ohio, a history of routine meetings between otherwise disconnected and often competitive hospitals, health departments and other agencies helped cut red tape, speed data sharing, and smooth resource sharing. That experience may serve as a model for other communities, the co-authors suggest.

“We can design a resilient public health system resistant to hesitancies, a system capable of detecting dynamic public health emergencies, and responding nimbly and efficiently,” the co-authors say. “To do so, we need an integrated system that works across sectors, approaches leadership in a new way, and enables rapid learning from the top-down and bottom-up.”

Co-authors included Peter Margolis, MD, PhD, and Robert Kahn, MD, MPH, from Cincinnati Children’s; Steve Miff, PhD, president and CEO at the Parkland Center for Clinical Innovation; Muhammad Zafar, MD, University of Cincinnati; Kate Schroder, president and CEO at Interact for Health in Cincinnati; Tiffany Mattingly, vice president, clinical strategies at The Health Collaborative in Cincinnati; and Pierre Barker, MD, MBChB, chief global partnerships and programs officer for the Institute for Healthcare Improvement in Boston.

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JOURNAL

Health Affairs Forefront

DOI

10.1377/forefront.20231205.622677 

ARTICLE TITLE

Learning From COVID-19 To Overcome System Hesitancies In Public Health Preparedness And Response

ARTICLE PUBLICATION DATE

6-Dec-2023

 

Study reveals Zika’s shape-shifting machinery—and a possible vulnerability

Zika’s crucial enzyme performs multiple tasks, but a wrench in the system could bring it to a screeching halt

Peer-Reviewed Publication

SANFORD-BURNHAM PREBYS

 

IMAGE: 

ALEXEY TERSKIKH, PH.D.

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CREDIT: SANFORD BURNHAM PREBYS

Viruses have limited genetic material—and few proteins—so all the pieces must work extra hard. Zika is a great example; the virus only produces 10 proteins. Now, in a study published in the journal PLOS Pathogens, researchers at Sanford Burnham Prebys have shown how the virus does so much with so little and may have identified a therapeutic vulnerability.

 

In the study, the research team showed that Zika’s enzyme—NS2B-NS3—is a multipurpose tool with two essential functions: breaking up proteins (a protease) and dividing its own double-stranded RNA into single strands (a helicase).

 

“We found that Zika’s enzyme complex changes function based on how it’s shaped,” says Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys and senior author of the paper. “When in the closed conformation, it acts as a classic protease. But then it cycles between open and super-open conformations, which allows it to grab and then release a single strand of RNA—and these functions are essential for viral replication.”

 

Zika is an RNA virus that’s part of a family of deadly pathogens called flaviviruses, which include West Nile, dengue fever, yellow fever, Japanese encephalitis and others. The virus is transmitted by mosquitoes and infects uterine and placental cells (among other cell types), making it particularly dangerous for pregnant women. Once inside host cells, the virus re-engineers them to produce more Zika.

 

Understanding Zika on the molecular level could have an enormous payoff: a therapeutic target. It would be difficult to create safe drugs that target the domains of the enzyme needed for protease or helicase functions, as human cells have many similar molecules. However, a drug that blocks Zika’s conformational changes could be effective. If the complex can’t shape-shift, it can’t perform its critical functions, and no new Zika particles would be produced.

 

 

An efficient machine

Researchers have long known that Zika’s essential enzyme was composed of two units: NS2B-NS3pro and NS3hel. NS2B-NS3pro carries out protease functions, cutting long polypeptides into Zika proteins. However, NS2B-NS3pro’s abilities to bind single-stranded RNA and help separate the double-stranded RNA during viral replication were only recently discovered.

 

In this study, the researchers leaned on recent crystal structures and used protein biochemistry, fluorescence polarization and computer modeling to dissect NS2B-NS3pro’s life cycle. NS3pro is connected to NS3hel (the helicase) by a short amino acid linker and becomes active when the complex is in its closed conformation, like a closed accordion. The RNA binding happens when the complex is open, whereas the complex must transition through the super-open conformation to release RNA.

 

These conformational changes are driven by the dynamics of NS3hel activity, which extends the linker and eventually “yanks” the NS3pro to release RNA. NS3pro is anchored to the inside of the host cell’s endoplasmic reticulum (ER)—a key organelle that helps shepherd cellular proteins to their appropriate destinations—via NS2B and, while in the closed conformation, cuts up the Zika polypeptide, helping generate all viral proteins.

 

On the other side of the linker, NS3hel separates Zika’s double-stranded RNA and conveniently hands a strand over to NS3pro, which has positively charged “forks” to grab on to the negatively charged RNA.

 

“There’s a very nice groove of positive charges,” says Terskikh. “So, RNA just naturally follows that groove. Then the complex shifts to the closed conformation and releases the RNA.”

 

As NS3hel reaches forward to grab the double-stranded RNA, it pulls the complex with it; however, since the NS3pro is anchored in the ER membrane, and the linker can only extend so far, the complex snaps into the super-open conformation and releases RNA. The complex then relaxes back to the open conformation, ready for a new cycle.

 

Meanwhile, when NS3pro detects a viral polypeptide to cut, it forces the complex into the closed conformation, becoming a protease. The authors call this process “reverse inchworm,” because grabbing and releasing the single-stranded RNA resembles inchworm movements, but backward, with the jaws (the protease) trailing behind.

 

In addition to providing a possible therapeutic target for Zika, this detailed understanding could be applied to other flaviviruses, which share similar molecular machinery.

 

“Versions of the NS2B-NS3pro complex are found throughout the flaviviruses,” says Terskikh. “It could potentially constitute a whole new class of drug targets for multiple viruses.”

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JOURNAL

PLoS Pathogens

DOI

10.1371/journal.ppat.1011795 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Dual function of Zika virus NS2B-NS3 protease

 

New study reveals latest data on global burden of cardiovascular disease

Cardiovascular disease remains leading cause of death; urgent action is needed for a heart-healthy world

Peer-Reviewed Publication

AMERICAN COLLEGE OF CARDIOLOGY

A world without cardiovascular disease (CVD) is possible, yet millions of lives are lost prematurely to heart disease each year, according to the new Global Burden of Disease (GBD) special report published today in the Journal of the American College of Cardiology. The report provides an update of health estimates for the global, regional and national burden and trends of CVD from 1990-2022 by analyzing the impact of cardiovascular conditions and risk factors across 21 global regions.

Research from this study reflects an urgent need for countries to establish public-health strategies aimed at preventing cardiovascular diseases by underscoring the global action needed to disseminate information and implement health programs, especially in hard-to-reach countries. While cardiovascular disease rates are high globally, regions of Asia, Europe, Africa and the Middle East were estimated to have the highest burden of CVD mortality. High blood pressure, high cholesterol, dietary risks and air pollution remain its leading causes.

“Cardiovascular diseases are a persistent challenge that lead to an enormous number of premature and preventable deaths,” said Gregory A. Roth, MD, MPH, senior author of the paper and associate professor in the Division of Cardiology and director of the Program in Cardiovascular Health Metrics at the Institute for Health Metrics and Evaluation at the University of Washington. “There are many inexpensive, effective treatments. We know what risk factors we need to identify and treat. There are simple healthy choices that people can make to improve their health. This atlas provides detailed information on where countries stand in their efforts to prevent and treat cardiovascular diseases.”

The mortality rates are broken down by location, along with age, sex and time categories. The report identifies disability-adjusted life years (DALYs), the years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs). The results presented include several updates to previously published estimates, reflecting new data and new disease modelling methods.

The paper specifically addresses 18 cardiovascular conditions and provides estimates for 15 leading risk factors for cardiovascular disease: environmental (air pollution, household air pollution, lead exposure, low temperature, high temperature), metabolic (systolic blood pressure, LDL-C, body mass index, fasting plasma glucose, kidney dysfunction) and behavioral (dietary, smoking, secondhand smoke, alcohol use, physical activity.

“We formed the Global Burden of Cardiovascular Diseases Collaboration three years ago to help bring state-of-the-art research to the forefront of the global cardiovascular community,” said Valentin Fuster, MD, PhD, an author of the paper, President of Mount Sinai Fuster Heart Hospital, physician-in-chief of The Mount Sinai Hospital, and editor-in-chief of JACC. “We are excited to publish this 2023 Almanac as a dedicated issue of the Journal to inform the realities of CVD risk and inspire strategies for a heart-healthy world.”

Key takeaways from the report:

• Ischemic heart disease remains the leading cause of global CVD mortality with an age-standardized rate per 100,000 of 108.8 deaths, followed by intracerebral hemorrhage and ischemic stroke.
• High systolic blood pressure accounted for the largest contribution to attributable age-standardized CVD disability-adjusted life years (DALYs) at 2,564.9 per 100,000 globally.
• Dietary risks were the leading contributor to age-standardized CVD DALYs among the behavioral risks, while ambient particulate matter pollution led the environmental risks.
• Between 2015-2022, age-standardized CVD mortality increased in 27 out of 204 locations.
• Global death counts due to CVD increased from 12.4 million in 1990 to 19.8 million in 2022 reflecting global population growth and aging and the contributions from preventable metabolic, environmental, and behavioral risks.
• Eastern Europe had the highest age-standardized total CVD mortality at 553 deaths per 100,000. In contrast, countries in Australasia had the lowest age-standardized total CVD mortality at 122.5 deaths per 100,000 people.
• Central Asia, Eastern Europe, North Africa and the Middle East had the highest age-standardized mortality rate per 100,000 people attributable to high systolic blood pressure. The regions with the highest rates of CVD burden attributable to dietary risk were Central Asia, Oceania, and parts of North Africa and the Middle East.

 

“Identifying sustainable ways to work with communities to take action to prevent and control modifiable risk factors for heart disease is essential for reducing the global burden of heart disease,” said George A. Mensah, M.D., F.A.C.C., F.A.H.A., director of the Center for Translation Research and Implementation Science at the National Heart, Lung, and Blood Institute (NHLBI). “The 2023 Almanac represents an important resource for using locally relevant data to inform local-level actions for heart-healthy and thriving communities.”

Launched in 2020, the Global Burden of Cardiovascular Diseases Collaboration is an alliance between the Journals of the American College of Cardiology, the Institute for Health Metrics and Evaluation at the University of Washington, and the National Heart, Lung, and Blood Institute. Serving as an update to 2022’s GBD Study, the 2023 publication includes data from 204 countries and territories, highlighting the leading global modifiable cardiovascular risk factors, their contribution to disease burden and recent prevention advancements.

The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at www.ACC.org or follow @ACCinTouch.

The ACC’s family of JACC Journals rank among the top cardiovascular journals in the world for scientific impact. The flagship journal, the Journal of the American College of Cardiology (JACC) — and family of specialty journals consisting of JACC: Advances, JACC: Asia, JACC: Basic to Translational Science, JACC: CardioOncology, JACC: Cardiovascular Imaging, JACC: Cardiovascular Interventions, JACC: Case Reports, JACC: Clinical Electrophysiology and JACC: Heart Failure — pride themselves on publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.org.

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JOURNAL

Journal of the American College of Cardiology

ARTICLE TITLE

New Study Reveals Latest Data on Global Burden of Cardiovascular Disease

ARTICLE PUBLICATION DATE

11-Dec-2023

 

Boston Medical Center to offer first FDA-approved gene therapy treatment program for sickle cell disease

Renowned, expert care team to deliver transformative new therapy to eligible adult patients suffering from sickle cell disease

Business Announcement

BOSTON MEDICAL CENTER

Boston Medical Center to Offer First FDA-Approved Gene Therapies for Sickle Cell Disease

Renowned, Expert Care Team to Deliver Transformative New Therapies to Eligible Adult Patients Suffering from Sickle Cell Disease

DECEMBER 8, 2023 (Boston) – Boston Medical Center (BMC), a national leader in the treatment of sickle cell disease for more than 50 years, announced today that it will offer the first-ever gene therapies for sickle cell disease, including one that uses a type of novel genome editing technology. The new therapies leverage the latest advances in medical science to alleviate the severe painful vaso-occlusive crises (VOCs) associated with sickle cell disease, in a long-awaited step toward equity for a disproportionally impacted Black patient population.

The announcement comes as the FDA today granted approval of a new gene editing therapy, jointly developed by Boston-based Vertex Pharmaceuticals and CRISPR Therapeutics of Switzerland, along with approval of a separate gene therapy developed by bluebird bio of Somerville, Mass., for sickle cell disease. BMC is the only hospital in New England to offer the therapies to eligible adults with sickle cell disease.

“Boston Medical Center has a longstanding commitment to providing advanced clinical care to those with sickle cell disease,” said Dr. Jean-Antoine Ribeil, MD, PhD, Clinical Director of the Center of Excellence in Sickle Cell Disease at Boston Medical Center and an internationally renowned hematologist who has dedicated his career to the development of gene therapies for patients with sickle cell disease and beta thalassemia. “The new gene therapies can be life changing for eligible patients who are impacted by sickle cell disease and the extreme pain that it causes, with previously limited treatment options.”

Sickle cell disease is a debilitating and chronic disease that afflicts more than 100,000 Americans and predominantly impacts people of African descent, representing 1 out of every 365 births[1]. The disease is caused by a gene mutation that makes blood cells misshapen which can lead to strokes, organ damage and episodes of agonizing pain. Those with sickle cell disease often rely on regular blood transfusions to ease pain and reduce risk of additional complications.

The new Vertex Pharmaceuticals treatment is the first therapy to treat a genetic disease with the CRISPR gene-editing technique. Vertex began clinical trials on the therapy in the United States in 2018. The SCD clinical trial enrolled a patient population that was predominantly of African ancestry. The FDA reviewed the safety and effectiveness of the treatment in that trial before today’s approval.

Bluebird bio’s new therapy, also approved by the FDA following clinical trials, is a one-time gene therapy that has the potential to resolve vaso-occlusive events and is custom-designed to treat the underlying cause of sickle cell disease.

Both treatments will be offered to select, eligible adult sickle cell patients at BMC as part of its Center of Excellence in Sickle Cell Disease, which is the largest center of its kind in New England, serving approximately 600 adult and pediatric patients annually. The introduction of these therapies gives those with sickle cell disease more options to try to achieve a life without chronic pain.

The BMC Center of Excellence in Sickle Cell Disease has long taken an innovative and multidisciplinary approach to caring for patients suffering from this debilitating disease. The Center pairs hematologists with specialists, such as pulmonologists, nephrologists, and primary care doctors who understand the needs and many complications of patients with sickle cell disease. The addition of cutting-edge gene therapy to its suite of services reflects BMC’s ongoing commitment to this population and to being a leader in offering advanced, equitable care to its patients.

For more information on BMC’s Center of Excellence in Sickle Cell Disease visit their website or connect on Facebook, Instagram, X (formerly Twitter), and LinkedIn.

 

# # #

 

About Boston Medical Center

Boston Medical Center models a new kind of excellence in healthcare, where innovative and equitable care empowers all patients to thrive. We combine world-class clinicians and cutting-edge treatments with compassionate, quality care that extends beyond our walls. As an award-winning health equity leader, our diverse clinicians and staff interrogate racial disparities in care and partner with our community to dismantle systemic inequities. And as a national leader in research and the teaching affiliate for Boston University Chobanian & Avedisian School of Medicine, we’re driving the future of care.

 

 

 

 

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[1]https://www.cdc.gov/ncbddd/sicklecell/data.html#:~:text=SCD%20affects%20approximately%20100%2C000%20Americans,sickle%20cell%20trait%20(SCT).

 

Milestones in Europe: First results in using new tools to tackle respiratory syncytial virus

Protecting infants from respiratory syncytial virus (RSV) with new tools: vaccines for pregnant women and use of monoclonal antibodies have been approved for use in the European Union to prevent RSV among young children. Are those tools working?

Peer-Reviewed Publication

EUROPEAN CENTRE FOR DISEASE PREVENTION AND CONTROL (ECDC)

 

IMAGE: 

PHYLOGENETIC TREE OF RESPIRATORY SYNCYTIAL VIRUS G AND F SEQUENCES PUBLISHED IN GISAID (N = 2,314 RSV A; N = 2,875 RSV B)

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CREDIT: EUROSURVEILLANCE

Each year, an estimated 101,000 children below the age of 5 years die across the globe due to infections caused by respiratory syncytial virus (RSV). Worldwide, RSV is a main cause of hospitalisation among young children. [1]

It took more than 60 years to develop and approve vaccines against RSV that can now be used to immunise both elderly people and pregnant women in the European Union (EU). In addition, a long-acting monoclonal antibody (nirsevimab) was licensed in the EU for use in infants end of 2022. Both events marked a milestone in the attempt to prevent RSV infections especially in very young children.

In an editorial in Eurosurveillance, Eeva Broberg and Hanna Nohynek [2] look at these recent advances and which supporting measures might be needed to understand the actual burden of RSV, its annual circulation patterns and genomic evolution.

For that understanding to improve, Broberg and Nohynek argue that “sequencing data need to be collected and reported to publicly accessible databases. As for other respiratory viruses and most infectious diseases, under-ascertainment will remain an issue for RSV surveillance in general as patients may present late for testing after the infection or not even be tested if they present with mild symptoms.”

Overcoming the challenges of sequencing RSV
To illustrate the current changes in tackling RSV infections across Europe, Broberg and Nohynek relate to the rapid communication in the same Eurosurveillance issue. Iglesias-Caballero et al. describe two PCR-based sequencing systems for RSV that can be used as methods to monitor the genetic diversity of the virus and with that inform molecular epidemiology, vaccine effectiveness and treatment strategies.

The authors show that their approach is less labour-intensive and less costly and presents the opportunity to increase laboratory capacities and probably also shorten throughput times. According to Broberg and Nohynek, the study from Spain demonstrates that the method outlined by Iglesias-Caballero et al. “can be used in retrospective molecular epidemiological studies of RSV and even with the simplified approach to sequence only the G and F gene genome, molecular evolution of RSV could be assessed.”

Complementing this RSV article from Spain, Martinón-Torres et al. [3] review first experiences in the autonomous community Galicia (northern Spain) following the implementation of universal RSV prophylaxis in infants with long-acting monoclonal antibodies. Both Spain and France have already introduced nirsevimab in their national immunisation programmes.

Based on the findings in Galicia, the early uptake of nirsevimab, which had a range of 81–98% in this region according to the study, has exceeded expectations. This immunisation achievement is the result of successful targeting and rationally designed immunisation logistics. According to the authors, the implementation and motivation of parents to immunise their children was likely facilitated by the quite intense RSV epidemic in Europe during the autumn 2022 in combination with awareness raising campaigns.

As Broberg and Nohynek put it, “the value of the work of Martinón-Torres et al. lies not only in the clear and meticulous description of how implementation challenges were approached, i.e. by distinguishing infants belonging to the seasonal and catch-up or high-risk groups, which provides an excellent example to other European countries, but also in the fact that Galicia will be able to answer the burning question on whether universal introduction of nirsevimab in the real- world setting is a cost-effective intervention on the short as well as the long run. If preventing RSV infection in early life can reduce asthma later in life, the impact of the intervention will be manifold.”

The European Centre for Disease Prevention and Control and the World Health Organization Regional Office for Europe have agreed on an integrated respiratory surveillance, which also includes RSV, and the weekly results are published in the European Respiratory Virus Surveillance Summary

 

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References/notes to editors:
[1] Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, Gill CJ, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. 2022;399(10340):2047-64.  https://doi.org/10.1016/S0140-6736(22)00478-0  PMID: 35598608

[2] Broberg Eeva K, Nohynek Hanna. Respiratory syncytial virus infections – recent developments providing promising new tools for disease prevention. Euro Surveill. 2023;28(49):pii=2300686. https://doi.org/10.2807/1560-7917.ES.2023.28.49.2300686

[3] Martinón-Torres Federico, Mirás-Carballal Susana, Durán-Parrondo Carmen. Early lessons from the implementation of universal respiratory syncytial virus prophylaxis in infants with long-acting monoclonal antibodies, Galicia, Spain, September and October 2023. Euro Surveill. 2023;28(49):pii=2300606. https://doi.org/10.2807/1560-7917.ES.2023.28.49.2300606

[4] Respiratory syncytial virus (RSV) is a common respiratory virus that causes mild, cold-like symptoms. People who contract RSV usually recover in around a week without the need for medical treatment. However, in infants under six months of age, people over 65, and people with a compromised immune system, RSV can cause severe illness and death. Symptoms usually appear two to eight days after being infected. Read more: https://www.ecdc.europa.eu/en/respiratory-syncytial-virus-rsv

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JOURNAL

Eurosurveillance

DOI

10.2807/1560-7917.ES.2023.28.49.2300606 

METHOD OF RESEARCH

Commentary/editorial

ARTICLE TITLE

Respiratory syncytial virus infections – recent developments providing promising new tools for disease prevention

ARTICLE PUBLICATION DATE

7-Dec-2023

COI STATEMENT

Hanna Nohynek: Co-lead of Work package 2 of the Innovate Health Initiative’s Preparing for RSV Immunisation and Surveillance in Europe (PROMISE) project (https://imi-promise.eu), member of the National Immunization Technical Advisory Group of the Finnish Institute for Health and Welfare, and chair of the Strategic Advisory Group of Experts of the World Health Organization.

 

40 years after the discovery of HIV, research raises hopes of remission

Meeting Announcement

INSTITUT PASTEUR

 

IMAGE: 

ONE OF THE VERY FIRST PHOTOGRAPHS OF THE HIV-1 VIRUS (COLORIZED BLUE) TAKEN ON FEBRUARY 4, 1983.

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CREDIT: © INSTITUT PASTEUR/CHARLES DAUGUET

Nearly 39 million people worldwide are carriers of human immunodeficiency virus (HIV), and 1.3 million people contracted HIV in 2022[1]. Forty years after the virus was discovered at the Institut Pasteur, HIV research is still active – the aim is to elucidate the mechanisms of infection so that the virus can be eradicated. A concerted global effort has led to considerable progress in knowledge. The conference "40 years of HIV science," which took place from November 29 to December 1 at the Institut Pasteur in collaboration with ANRS | Emerging Infectious Diseases, was an opportunity to look back at the major advances that are now raising hopes of remission and a cure for HIV.

For the past 40 years, since HIV was identified at the Institut Pasteur, scientists have been working to describe the virus and to understand the different stages from initial infection to integration in the host cell genome. This knowledge has led to considerable scientific and medical progress to slow infection, and has also improved the life expectancy and quality of life of people living with HIV. The participants in the opening session of the conference "40 years of HIV science" share the observation that although there have been major breakthroughs, the battle against HIV is not over, even if they have high hopes of finding avenues for remission and a cure: "I salute all these years of research, medical progress and activism, but there are still many challenges to overcome. Despite all the progress made, 630,000 people died from AIDS in 20221 and new infections continue to occur. The fight against HIV is not over. This international battle continues, and no one will be left behind!" said Stewart Cole, President of the Institut Pasteur.

Forty years after the discovery of HIV, basic research continues to shed light on mechanisms of infection

In response to these challenges, several different fields of investigation are being actively explored, especially to elucidate the molecular mechanisms that underpin HIV replication and viral integration into the host cell genome. State-of-the-art techniques have led to the surprising discovery that the virus targets the cell nucleus. It exploits host cell mechanisms to multiply its genome and produce viral particles that infect other cells. This discovery that HIV targets the cell nucleus opens new avenues for tackling viral replication and persistence. Another approach under exploration is innate immunity, in other words the body's defenses, which can be harnessed to block the virus as soon as it enters the cell. It may be possible to stimulate this natural response by developing immunotherapy treatments.

Removing the virus from all the cells in the body where it is present is crucial to avoid viral persistence. Scientists are using new technologies to understand how the virus evades the immune system and antiretroviral treatments to remain in reservoirs, and to determine the location of these viral reservoirs. Lymph nodes and intestines are among the reservoirs that scientists are investigating closely.

Analyzing the natural ability of some individuals to suppress the virus

How is it that some people are able to suppress HIV without antiretroviral treatment, by slowing its progression or preventing the reactivation of viral reservoirs? These people are able to control HIV infection because of an optimal immune response that neutralizes the virus. One strategy that is being explored as a novel therapeutic solution to overcome HIV infection is to attempt to reproduce the particularities of the immune cells responsible for this optimal response.

"The identification of HIV control in some individuals has significantly boosted hopes of remission and cure and has given us a unique opportunity to study the underlying mechanisms," explains Asier Sáez-Cirión, Head of the Institut Pasteur's Viral Reservoirs and Immune Control Unit.

Scientists are also interested in people who, despite repeated exposure to HIV, have never been infected because they have a genetic mutation that stops the virus from entering their cells. This mutation could be induced by gene therapy. Developing molecular scissors to make the body resistant or targeting the virus to eliminate it after its integration in the cell are fields of study that might pave the way to a long-term cure.

Using social sciences to make sure therapeutic innovation is accessible to everyone

As well as the challenges in medical research to improve our understanding of the mechanism of action of HIV infection, there are also societal challenges. Patient organizations, scientists and researchers in social sciences have been working together for the past 40 years to change attitudes to HIV and AIDS by tackling discrimination and the stigma attached to people living with HIV and by calling on authorities to help improve prevention and early diagnosis. The availability of rapid diagnostic tests is one of the tangible results of this collective effort. Therapeutic innovation alone is not enough – it needs to go hand in hand with targeted, relevant programs that will reach people at risk of HIV infection. The aim of the community-based research that has developed as part of the fight against HIV is to complement existing knowledge to reduce inequalities in access and to tailor strategies to patients' real-life circumstances. 9.2 million people living with HIV still did not have access to antiretroviral treatment in 2022. Access to antiretroviral treatment and infection prevention methods like PrEP (pre-exposure prophylaxis) is also a social battle that is being fought by stakeholders in the war against HIV.

To achieve the goal of eradicating HIV, the members of the international community that attended the conference confirmed that we need to double down on our efforts to explore all the scientific avenues that are opened with each new discovery related to the virus, and to step up work on prevention and access to therapies.

Finally, it is worth noting that the expertise that has developed in the field of HIV research over the past 40 years has also helped us tackle other diseases, including the recent COVID pandemic.

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[1] UNAIDS

Engaging heterosexual men more effectively could slash HIV infections in Uganda

Peer-Reviewed Publication

IMPERIAL COLLEGE LONDON

 

IMAGE: 

COMMUNITY LEADERS IN SOUTHERN UGANDA AND RAKAI HEALTH SCIENCES PROGRAM RESEARCH STAFF PARTICIPATE IN A COMMUNITY FOOTBALL TOURNAMENT TO RAISE AWARENESS FOR HIV

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CREDIT: RAKAI HEALTH SCIENCES PROGRAM

A study looking at 15 years of HIV transmission and suppression in Uganda reveals how closing gender gaps in treatment could slash infection rates.

Providing more heterosexual men with easy access to HIV treatment and care could help to suppress the virus and rapidly cut transmission to their female partners, shows a new study published in Nature Microbiology.

The research, led by scientists from Imperial College London and the Rakai Health Sciences Program in Uganda, analysed 15 years of data from 2003-2018, during which the US President’s Emergency Plan For AIDS Relief (PEPFAR) has delivered an extensive programme of HIV/AIDS testing, prevention, and treatment.

This included distributing Antiretroviral Therapy (ART) drugs, which supress the virus so a person is no longer infectious. The analysis shows that the PEPFAR program and other services have greatly reduced new infections among young women and heterosexual men, but that reductions were less substantial in women aged 25 and above.

This is thought to be because women are more likely to reach viral suppression through uptake and effective use of HIV treatment, preventing them from passing HIV to their male partners, but that the same is not true the other way around.

Gender disparity

The analysis showed that the number of women reaching and maintaining undetectable (non-transmissible) levels of HIV infection were 1.5 to 2 times higher than men across all ages by the year 2018. The analysis shows that had men reached the same levels of virus suppression as women, around half the new infections that occurred between 2016 and 2018 could have been avoided.

The team also reconstructed transmission networks based on the genetic code of the virus from thousands of participants, which confirmed that overall, the proportion of transmissions from men is increasing and is now at 63% of all transmissions in the area – even though a greater number of women are living with HIV than men.

The team say the disparity could be because men need to travel for work, that clinics are closed when they are back home, or for other reasons, including social stigma.

Dr Oliver Ratmann, senior author of the study from the Department of Mathematics at Imperial, said: “In this evolving battle against HIV, it is critical we adapt our strategies, bridge gaps in care, and ensure that individuals, regardless of their gender, have access to the lifesaving benefits of ART.

“It is important to design services in a way that everybody who would like to use them is able and feels empowered to do so. By routinely monitoring the changing dynamics of the epidemic and striving for equity in HIV care, we can move closer to the ultimate goal of controlling and, one day, eliminating HIV transmission.”

Dr Kate Grabowski, a co-author of the study from the Johns Hopkins School of Medicine, added: “The continued success of the President's Emergency Plan for AIDS Relief (PEPFAR) in reducing infections and saving lives is crucial for ending HIV transmission. With United States Congress currently evaluating PEPFAR funding, our evidence strongly supports the program's efficacy and provides a clear roadmap to ending the pandemic through enhanced HIV treatment coverage, particularly among men.”

Closing the gap in transmission

The team used data from the Rakai Community Cohort Study (RCCS) in southern Uganda, a region where more than 9% of adults are living with HIV – approximately 20 times higher than in the US. Since 2003, a period predating the widespread availability of ART in Africa, RCCS has enrolled nearly 37,000 individuals, tracking changes in HIV infection as new interventions came on board.

The analysis tracked evolving heterosexual HIV epidemic dynamics in 36 communities over a 15-year span of RCCS surveillance data, including records of new infections, deep sequence HIV genomic data, HIV treatment uptake, viral suppression, and behavioural information.

Analyses in earlier years showed that the highest number of new HIV cases in southern Uganda was among adolescent girls and young women aged 15-24 years. In more recent years tracked in the new study, women 25-34 years old have become a new focal group, experiencing a slower decline in new infections than other age groups. This is alongside a significant difference in the declines in new infections between men and women, with those among boys and men declining much faster.

To estimate the likely impact of getting men to the same level of viral suppression, the team applied statistical models based on the data about transmission dynamics. The resulting projections indicate that closing the viral suppression gap in men could have effectively halved rates of new infections among women and eliminated gender disparities in acquiring HIV.

Dr Joseph Kagaayi, previous director of the Rakai Health Sciences program and senior co-author of the study, said: “Our study findings emphasise the importance of addressing disparities in ART uptake and viral suppression between men and women. By doing so, we can not only reduce HIV infections among women but also work towards closing the gender gap in HIV transmission. Achieving these goals will require concerted efforts, informed policies, and strengthened healthcare services.”

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JOURNAL

Nature Microbiology

DOI

10.1038/s41564-023-01530-8 

ARTICLE TITLE

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda

ARTICLE PUBLICATION DATE

5-Dec-2023