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This Is Why NIH Invests in Global Health Research

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Young girl getting immunized
Caption: Global partnerships fostered by NIH’s Fogarty International Center speed translation of scientific discoveries into lifesaving biomedical products. Credit: Gabe Bienczycki, PATH, Seattle

Efforts over the past few years to end the COVID-19 pandemic clearly reveal how global health impacts individual wellbeing and national security. At NIH, the Fogarty International Center helps the other institutes become engaged with global health research, which investigates the dual burden of infectious disease and non-communicable disease.

Global health research also encompasses data science, economics, genetics, climate change science, and many other disciplines. For more than 50 years, Fogarty has been building partnerships among institutions in the U.S. and abroad, while training the next generation of scientists focused on universal health needs.

America’s investment in Fogarty has paid rich dividends

During the pandemic, in particular, we’ve seen researchers trained by our programs make scientific discoveries that contributed to international security. Take Jessica Manning, a former Fogarty fellow who now conducts malaria research in Phnom Penh, Cambodia. Her team at the Ministry of Health sequenced the viral strain of SARS-CoV-2, the cause of COVID-19, infecting the first Cambodian patient and documented early the spread of this novel coronavirus outside of China.

Similarly, Christian Happi, director of the African Centre of Excellence for the Genomics of Infectious Disease, Ede, Nigeria, sequenced the first SARS-CoV-2 genome in Africa. Happi was able to do it by adapting the sequencing and analytical pipelines that he’d created back when he was a Fogarty grantee studying Ebola.

In Botswana, Sikhulile Moyo leveraged the skills he’d acquired while supported by a Fogarty HIV research training grant with Max Essex, Harvard School of Public Health, Cambridge, MA, to track COVID-19 mutations for his country’s Ministry of Health. Last November, he alerted the world of a new Omicron variant. Within six weeks, Omicron became the dominant global strain, challenging the ability of COVID vaccines to control its spread. In the Dominican Republic, William Duke, a national commission member, used what he’d learned as a Fogarty trainee to help create a national COVID-19 intervention plan to prevent and control the disease.

Fogarty’s fostering of global health leaders is one way we advance scientific expertise while ensuring our nation’s biosecurity. Another is by finding effective ways to study abroad the same health conditions that affect our own population.

Research conducted in Colombia, for example, may provide clues for preventing Alzheimer’s disease in the U.S. Fogarty support brought together neuroscientists Kenneth Kosik, University of California, Santa Barbara, and Francisco Lopera, University of Antioquia, Colombia, to study members of the largest-known family with an early-onset, rapidly progressive form of the disease. Over the years, Kosik and Lopera have trained local scientists, explored gene therapy targets, investigated biomarkers to monitor disease progression, and conducted drug trials in search of a cure for Alzheimer’s.

Researchers in other fields also discover unique opportunities to investigate populations with high rates of disease. Siana Nkya, a Fogarty grantee based in Tanzania, has devoted her career to studying the genetic determinants of sickle cell disease, which affects many people around the world, including in the U.S. We hope that US-African partnerships might develop improved, affordable treatments and a cure for all patients with this devastating disease. Similarly, people in the U.S. have access to state-of-the-art HIV treatment studies in places around the globe where incidence rates are higher.

Fogarty has supported many milestone achievements in HIV research over the years. Among them is a study that took place in nine countries. The research, led by Myron Cohen of the University of North Carolina at Chapel Hill, established that antiretroviral therapy can prevent sexual transmission of HIV-1 among couples in which one person is infected and the other is not. In fact, this research informs current HIV treatment recommendations worldwide, including in the U.S.

Americans will also undoubtedly benefit from projects funded by Fogarty’s Global Brain and Nervous System Disorders Research across the Lifespan program. For example, psychologist Tatiana Balachova, University of Oklahoma, Oklahoma City, has designed an intervention for women in Russia to prevent fetal alcohol spectrum disorders. In another project in South Africa, Sandra and Joseph Jacobson, Wayne State University, Detroit, conducted the first-ever prospective longitudinal study of the syndrome. Findings from both projects are ripe for translation within an American context.

Other examples of Global Brain program investigations with broad implications in our own country include studying early psychosis in China; capacity building for schizophrenia research in Macedonia; exploring family consequences from the Zika virus in Brazil; and studying dementia and related health and social challenges in Lebanon.

These are just a few examples of Fogarty’s work and its unique mission. What is most remarkable about Fogarty is that just under 90 percent of our grants are co-funded by at least one other NIH institute, center, or office. Collaboration, both within borders and across them, is Fogarty’s formula for success.

Links:

Fogarty International Center (NIH)

Overview of Brain Disorders: Research Across the Lifespan (Fogarty)

Former Fogarty Scholar Dr Jessica Manning Helps Cambodia Respond to COVID (Fogarty)

Christian Happi: Former Fogarty Grantee Leads COVID-19 Genomics Work in Africa (Fogarty)

Sikhulile Moyo: Fogarty Fellow Recognized for Omicron Discovery (Fogarty)

William Duke: Former Fogarty HIV Trainee Helps Lead Dominican Republic’s COVID Response (Fogarty)

Kenneth Kosic and Francisco Lopera: NIH Support Spurs Alzheimer’s Research in Colombia (Fogarty)

Former Fogarty fellow Siana Nkya Tackles Sickle Cell Disease in Tanzania (Fogarty)

Tatiana Balachova: Researchers Tackle Fetal Alcohol Syndrome in Russia (Fogarty)

Sandra and Joseph Jacobson: Fetal Alcohol Exposure Research Supported by NIAAA in South Africa, Ukraine and Russia Improves Prevention, Outcomes (Fogarty)

Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 22nd in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.


Experimental mRNA Vaccine May Protect Against All 20 Influenza Virus Subtypes

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mRNA-lipid Nanoparticle Vaccine. Half sphere filled with more half spheres containing RNA
Caption: Messenger RNA (mRNA)– nanoparticle vaccine encoding hemagglutinin antigens (H with number) from all 20 known influenza subtypes.

Flu season is now upon us, and protecting yourself and loved ones is still as easy as heading to the nearest pharmacy for your annual flu shot. These vaccines are formulated each year to protect against up to four circulating strains of influenza virus, and they generally do a good job of this. What they can’t do is prevent future outbreaks of more novel flu viruses that occasionally spill over from other species into humans, thereby avoiding a future influenza pandemic.

On this latter and more-challenging front, there’s some encouraging news that was published recently in the journal Science [1]. An NIH-funded team has developed a unique “universal flu vaccine” that, with one seasonal shot, that has the potential to build immune protection against any of the 20 known subtypes of influenza virus and protect against future outbreaks.

While this experimental flu vaccine hasn’t yet been tested in people, the concept has shown great promise in advanced pre-clinical studies. Human clinical trials will hopefully start in the coming year. The researchers don’t expect that this universal flu vaccine will prevent influenza infection altogether. But, like COVID-19 vaccines, the new flu vaccine should help to reduce severe influenza illnesses and deaths when a person does get sick.

So, how does one develop a 20-in-1“multivalent” flu vaccine? It turns out that the key is the same messenger RNA (mRNA) technology that’s enabled two of the safe and effective vaccines against COVID-19, which have been so instrumental in fighting the pandemic. This includes the latest boosters from both Pfizer and Moderna, which now offer updated protection against currently circulating Omicron variants.

While this isn’t the first attempt to develop a universal flu vaccine, past attempts had primarily focused on a limited number of conserved antigens. An antigen is a protein or other substance that produces an immune response. Conserved antigens are those that tend to stay the same over time.

Because conserved antigens will look similar in many different influenza viruses, the hope was that vaccines targeting a small number of them would afford some broad influenza protection. But the focus on a strategy involving few antigens was driven largely by practical limitations. Using traditional methods to produce vaccines by growing flu viruses in eggs and isolating proteins, it simply isn’t feasible to include more than about four targets.

That’s where recent advances in mRNA technology come in. What makes mRNA so nifty for vaccines is that all you need to know is the letters, or sequence, that encodes the genetic material of a virus, including the sequences that get translated into proteins.

A research team led by Scott Hensley, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, recognized that the ease of designing and manufacturing mRNA vaccines opened the door to an alternate approach to developing a universal flu vaccine. Rather than limiting themselves to a few antigens, the researchers could make an all-in-one influenza vaccine, encoding antigens from every known influenza virus subtype.

Influenza vaccines generally target portions of a plentiful protein on the viral surface known as hemagglutinin (H). In earlier work, Hensley’s team, in collaboration with Perelman’s mRNA vaccine pioneer Drew Weissman, showed they could use mRNA technology to produce vaccines with H antigens from single influenza viruses [2, 3]. To protect the fragile mRNA molecules that encode a selected H antigen, researchers deliver them to cells inside well-tolerated microscopic lipid shells, or nanoparticles. The same is true of mRNA COVID-19 vaccines. In their earlier studies, the researchers found that when an mRNA vaccine aimed at one flu virus subtype was given to mice and ferrets in the lab, their cells made the encoded H antigen, eliciting protective antibodies.

In this latest study, they threw antigens from all 20 known flu viruses into the mix. This included H antigens from 18 known types of influenza A and two lineages of influenza B. The goal was to develop a vaccine that could teach the immune system to recognize and respond to any of them.

More study is needed, of course, but early indications are encouraging. The vaccine generated strong and broad antibody responses in animals. Importantly, it worked both in animals with no previous immunity to the flu and in those previously infected with flu viruses. That came as good news because past infections and resulting antibodies sometimes can interfere with the development of new antibodies against related viral subtypes.

In more good news, the researchers found that vaccinated mice and ferrets were protected against severe illness when later challenged with flu viruses. Those viruses included some that were closely matched to antigens in the vaccine, along with some that weren’t.

The findings offer proof-of-principle that mRNA vaccines containing a wide range of antigens can offer broad protection against influenza and likely other viruses as well, including the coronavirus strains responsible for COVID-19. The researchers report that they’re moving toward clinical trials in people, with the goal of beginning an early phase 1 trial in the coming year. The hope is that these developments—driven in part by technological advances and lessons learned over the course of the COVID-19 pandemic—will help to mitigate or perhaps even prevent future pandemics.

References:

[1] A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Arevalo CP, Bolton MJ, Le Sage V, Ye N, Furey C, Muramatsu H, Alameh MG, Pardi N, Drapeau EM, Parkhouse K, Garretson T, Morris JS, Moncla LH, Tam YK, Fan SHY, Lakdawala SS, Weissman D, Hensley SE. Science. 2022 Nov 25;378(6622):899-904.

[2] Nucleoside-modified mRNA vaccination partially overcomes maternal antibody inhibition of de novo immune responses in mice. Willis E, Pardi N, Parkhouse K, Mui BL, Tam YK, Weissman D, Hensley SE. Sci Transl Med. 2020 Jan 8;12(525):eaav5701.

[3] Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Pardi N, Parkhouse K, Kirkpatrick E, McMahon M, Zost SJ, Mui BL, Tam YK, Karikó K, Barbosa CJ, Madden TD, Hope MJ, Krammer F, Hensley SE, Weissman D. Nat Commun. 2018 Aug 22;9(1):3361.

Links:

Understanding Flu Viruses (Centers for Disease Control and Prevention, Atlanta)

COVID Research (NIH)

Decades in the Making: mRNA COVID-19 Vaccines (NIH)

Video: mRNA Flu Vaccines: Preventing the Next Pandemic (Penn Medicine, Philadelphia)

Scott Hensley (Perelman School of Medicine at the University of Pennsylvania, Philadelphia)

Weissman Lab (Perelman School of Medicine)

Video: The Story Behind mRNA COVID Vaccines: Katalin Karikó and Drew Weissman (Penn Medicine, Philadelphia)

NIH Support: National Institute for Allergy and Infectious Diseases


Clinical Center Doctors Testing 3D-Printed Miniature Ventilator

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Small plastic device next to a thumbdrive
Caption: A USB flash drive (front) next to the 3D-printed miniature ventilator (back). Credit: William Pritchard, Clinical Center, NIH

Here at the NIH Clinical Center, we are proud to be considered a world-renowned research hospital that provides hope through pioneering clinical research to improve human health. But what you may not know is that our doctors are constantly partnering with public and private sectors to come up with innovative technologies that will help to advance health outcomes.

I’m excited to bring to you a story that is perfect example of the ingenuity of our NIH doctors working with global strategic partners to create potentially life-saving technologies. This story begins during the COVID-19 pandemic with the global shortage of ventilators to help patients breathe. Hospitals had a profound need for inexpensive, easy-to-use, rapidly mass-produced resuscitation devices that could be quickly distributed in areas of critical need.

Through strategic partnerships, our Clinical Center doctors learned about and joined an international group of engineers, physicians, respiratory therapists, and patient advocates using their engineering skills to create a ventilator that was functional, affordable, and intuitive. After several iterations and bench testing, they devised a user-friendly ventilator.

Transparent plastic mini ventilator
Caption: The miniature ventilator connected to an oxygen line (asterisk) and the breathing tube to the patient (crosshatch). The exhaust (dagger) is recessed to prevent accidental blockage. Credit: William Pritchard, Clinical Center, NIH

Then, with the assistance of 3D-printing technology, they improved the original design and did something pretty incredible: the team created the smallest single-patient ventilator seen to date. The device is just 2.4 centimeters (about 1 inch) in diameter with a length of 7.4 centimeters (about 3 inches).

A typical ventilator in a hospital obviously is much larger and has a bellows system. It fills with oxygen and then forces it into the lungs followed by the patient passively exhaling. These systems have multiple moving parts, valves, hoses, and electronic or mechanical controls to manage all aspects of the oxygen flow into the lungs.

But our miniature, 3D-printed ventilator is single use, disposable, and has no moving parts. It’s based on principles of fluidics to ventilate patients by automatically oscillating between forced inspiration and assisted expiration as airway pressure changes. It requires only a continuous supply of pressurized oxygen.

The possibilities of this 3D-printed miniature ventilator are broad. The ventilators could be easily used in emergency transport, potentially treating battlefield casualties or responding to disasters and mass casualty events like earthquakes.

While refining a concept is important, the key is converting it to actual use, which our doctors are doing admirably in their preclinical and clinical studies. NIH’s William Pritchard, Andrew Mannes, Brad Wood, John Karanian, Ivane Bakhutashvili, Matthew Starost, David Eckstein, and medical student Sheridan Reed studied and have already tested the ventilators in swine with acute lung injury, a common severe outcome in a number of respiratory threats including COVID-19.

In the study, the doctors tested three versions of the device built to correspond to mild, moderate, and severe lung injury. The respirators provided adequate support for moderate and mild lung injuries, and the doctors recall how amazing it was initially to witness a 190-pound swine ventilated by this miniature ventilator.

The doctors believe that the 3D-printed miniature ventilator is a potential “game changer” from start to finish since it is lifesaving, small, simple to use, can be easily and inexpensively printed and stored, and does not require additional maintenance. They recently published their preclinical trial results in the journal Science Translational Medicine [1].

The NIH team is preparing to initiate first-in-human trials here at the Clinical Center in the coming months. Perhaps, in the not-too-distant future, a device designed to help people breathe could fit into your pocket next to your phone and keys.

Reference:

[1] In-line miniature 3D-printed pressure-cycled ventilator maintains respiratory homeostasis in swine with induced acute pulmonary injury. Pritchard WF, Karanian JW, Jung C, Bakhutashvili I, Reed SL, Starost MF, Froelke BR, Barnes TR, Stevenson D, Mendoza A, Eckstein DJ, Wood BJ, Walsh BK, Mannes AJ. Sci Transl Med. 2022 Oct 12;14(666):eabm8351.

Links:

Clinical Center (NIH)

Andrew Mannes (Clinical Center)

Bradford Wood (Clinical Center)

David Eckstein (Clinical Center)

Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 21st in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.


Gratitude for Biomedical Progress and All Those Who Make It Possible

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Group of people holding hands around a dinner table
Credit: Shutterstock/Rawpixel.com

It’s good for our health to eat right, exercise, and get plenty of rest. Still, many other things contribute to our sense of wellbeing, including making it a point to practice gratitude whenever we can. With this in mind, I can’t think of a better time than Thanksgiving to recognize just a few of the many reasons that I—and everyone who believes in the mission of the National Institutes of Health (NIH)—have to be grateful.

First, I’m thankful for the many enormously talented people with whom I’ve worked over the past year while performing the duties of the NIH Director. Particular thanks go to those on my immediate team within the Office of the Director. I could not have taken on this challenge without their dedicated support.

I’m also gratified by the continued enthusiasm and support for biomedical research from so many different corners of our society. This includes the many thousands of unsung, patient partners who put their time, effort, and, in some cases, even their lives on the line for the sake of medical progress and promising treatment advances. Without them, clinical research—including the most pivotal clinical trials—simply wouldn’t be possible.

I am most appreciative of the continuing efforts at NIH and across the broader biomedical community to further enable diversity, equity, inclusion, and accessibility within the biomedical research workforce and in all the work that NIH supports.

High on my Thanksgiving list is the widespread availability of COVID-19 bivalent booster shots. These boosters not only guard against older strains of the coronavirus, but also broaden immunity to the newer Omicron variant and its many subvariants. I’m also tremendously grateful for everyone who has—or soon will—get boosted to protect yourself, your loved ones, and your communities as the winter months fast approach.

Another big “thank you” goes out to all the researchers studying Long COVID, the complex and potentially debilitating constellation of symptoms that strikes some people after recovery from COVID-19. I look forward to more answers as this work continues and we certainly couldn’t do it without our patient partners.

I’d also like to express my appreciation for the NIH’s institute and center directors who’ve contributed to the NIH Director’s Blog to showcase NIH’s broad and diverse portfolio of promising research.

Finally, a special thanks to all of you who read this blog. As you gather with family and friends to celebrate this Thanksgiving holiday, I hope the time you spend here gives you a few more reasons to feel grateful and appreciate the importance of NIH in turning scientific discovery into better health for all.


Study Shows Benefits of COVID-19 Vaccines and Boosters

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Diverse group of smiling adults with band-aids on their shoulders
Credit: Shutterstock/Semanche

As colder temperatures settle in and people spend more time gathered indoors, cases of COVID-19 and other respiratory illnesses almost certainly will rise. That’s why, along with scheduling your annual flu shot, it’s now recommended that those age 5 and up should get an updated COVID-19 booster shot [1,2]. Not only will these new boosters guard against the original strain of the coronavirus that started the pandemic, they will heighten your immunity to the Omicron variant and several of the subvariants that continue to circulate in the U.S. with devastating effects.

At last count, about 14.8 million people in the U.S.—including me—have rolled up their sleeves to receive an updated booster shot [3]. It’s a good start, but it also means that most Americans aren’t fully up to date on their COVID-19 vaccines. If you or your loved ones are among them, a new study may provide some needed encouragement to make an appointment at a nearby pharmacy or clinic to get boosted [4].

A team of NIH-supported researchers found a remarkably low incidence of severe COVID-19 illness last fall, winter, and spring among more than 1.6 million veterans who’d been vaccinated and boosted. Severe illness was also quite low in individuals without immune-compromising conditions.

These latest findings, published in the journal JAMA, come from a research group led by Dan Kelly, University of California, San Francisco. He and his team conducted their study drawing on existing health data from the Veterans Health Administration (VA) within a time window of July 2021 and May 2022.

They identified 1.6 million people who’d had a primary-care visit within the last two years and were fully vaccinated for COVID-19, which included receiving a booster shot. Almost three-quarters of those identified were 65 and older. Nearly all were male, and more than 70 percent had another pre-existing health condition that put them at greater risk of becoming seriously ill from a COVID-19 infection.

Over a 24-week follow-up period for each fully vaccinated individual, 125 per 10,000 people had a breakthrough infection. That’s about 1 percent. Just 8.9 in 10,000 fully vaccinated people—less than 0.1 percent—died or were hospitalized from COVID-19 pneumonia. Drilling down deeper into the data:

• Individuals with an immune-compromising condition had a very low rate of hospitalization or death. In this group, 39.6 per 10,000 people had a serious breakthrough infection. That translates to 0.3 percent.

• For people with other preexisting health conditions, including diabetes and heart disease, hospitalization or death totaled 0.07 percent, or 6.7 per 10,000 people.

• For otherwise healthy adults aged 65 and older, the incidence of hospitalization or death was 1.9 per 10,000 people, or 0.02 percent.

• For boosted participants 65 or younger with no high-risk conditions, hospitalization or death came to less than 1 per 10,000 people. That comes to less than 0.01 percent.

It’s worth noting that these results reflect a period when the Delta and Omicron variants were circulating, and available boosters still were based solely on the original variant. Heading into this winter, the hope is that the updated “bivalent” boosters from Pfizer and Moderna will offer even broader protection as this terrible virus continues to evolve.

The Centers for Disease Control and Prevention continues to recommend that everyone stay up to date with their COVID-19 vaccines. That means all adults and kids 5 and older are encouraged to get boosted if it has been at least two months since their last COVID-19 vaccine dose. For older people and those with other health conditions, it’s even more important given their elevated risk for severe illness.

What if you’ve had a COVID-19 infection recently? Getting vaccinated or boosted a few months after you’ve had a COVID-19 infection will offer you even better protection in the future.

So, if you are among the millions of Americans who’ve been vaccinated for COVID-19 but are now due for a booster, don’t delay. Get yourself boosted to protect your own health and the health of your loved ones as the holidays approach.

References:

[1] CDC recommends the first updated COVID-19 booster. Centers for Disease Control and Prevention. September 1, 2022.

[2] CDC expands updated COVID-19 vaccines to include children ages 5 through 11. Centers for Disease Control and Prevention, October 12, 2022.

[3] COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.

[4] Incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines. Kelly JD, Leonard S, Hoggatt KJ, Boscardin WJ, Lum EN, Moss-Vazquez TA, Andino R, Wong JK, Byers A, Bravata DM, Tien PC, Keyhani S. JAMA. 2022 Oct 11;328(14):1427-1437.

Links:

COVID-19 Research (NIH)

Dan Kelly (University of California, San Francisco)

NIH Support: National Institute of Allergy and Infectious Diseases


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