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Celebrating 2019 Biomedical Breakthroughs

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Science 2019 Biomedical Breakthroughs and a Breakdown

Happy New Year! As we say goodbye to the Teens, let’s take a look back at 2019 and some of the groundbreaking scientific discoveries that closed out this remarkable decade.

Each December, the reporters and editors at the journal Science select their breakthrough of the year, and the choice for 2019 is nothing less than spectacular: An international network of radio astronomers published the first image of a black hole, the long-theorized cosmic singularity where gravity is so strong that even light cannot escape [1]. This one resides in a galaxy 53 million light-years from Earth! (A light-year equals about 6 trillion miles.)

Though the competition was certainly stiff in 2019, the biomedical sciences were well represented among Science’s “runner-up” breakthroughs. They include three breakthroughs that have received NIH support. Let’s take a look at them:

In a first, drug treats most cases of cystic fibrosis: Last October, two international research teams reported the results from phase 3 clinical trials of the triple drug therapy Trikafta to treat cystic fibrosis (CF). Their data showed Trikafta effectively compensates for the effects of a mutation carried by about 90 percent of people born with CF. Upon reviewing these impressive data, the Food and Drug Administration (FDA) approved Trikafta, developed by Vertex Pharmaceuticals.

The approval of Trikafta was a wonderful day for me personally, having co-led the team that isolated the CF gene 30 years ago. A few years later, I wrote a song called “Dare to Dream” imagining that wonderful day when “the story of CF is history.” Though we’ve still got more work to do, we’re getting a lot closer to making that dream come true. Indeed, with the approval of Trikafta, most people with CF have for the first time ever a real chance at managing this genetic disease as a chronic condition over the course of their lives. That’s a tremendous accomplishment considering that few with CF lived beyond their teens as recently as the 1980s.

Such progress has been made possible by decades of work involving a vast number of researchers, many funded by NIH, as well as by more than two decades of visionary and collaborative efforts between the Cystic Fibrosis Foundation and Aurora Biosciences (now, Vertex) that built upon that fundamental knowledge of the responsible gene and its protein product. Not only did this innovative approach serve to accelerate the development of therapies for CF, it established a model that may inform efforts to develop therapies for other rare genetic diseases.

Hope for Ebola patients, at last: It was just six years ago that news of a major Ebola outbreak in West Africa sounded a global health emergency of the highest order. Ebola virus disease was then recognized as an untreatable, rapidly fatal illness for the majority of those who contracted it. Though international control efforts ultimately contained the spread of the virus in West Africa within about two years, over 28,600 cases had been confirmed leading to more than 11,000 deaths—marking the largest known Ebola outbreak in human history. Most recently, another major outbreak continues to wreak havoc in northeastern Democratic Republic of Congo (DRC), where violent civil unrest is greatly challenging public health control efforts.

As troubling as this news remains, 2019 brought a needed breakthrough for the millions of people living in areas susceptible to Ebola outbreaks. A randomized clinical trial in the DRC evaluated four different drugs for treating acutely infected individuals, including an antibody against the virus called mAb114, and a cocktail of anti-Ebola antibodies referred to as REGN-EB3. The trial’s preliminary data showed that about 70 percent of the patients who received either mAb114 or the REGN-EB3 antibody cocktail survived, compared with about half of those given either of the other two medicines.

So compelling were these preliminary results that the trial, co-sponsored by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the DRC’s National Institute for Biomedical Research, was halted last August. The results were also promptly made public to help save lives and stem the latest outbreak. All Ebola patients in the DRC treatment centers now are treated with one or the other of these two options. The trial results were recently published.

The NIH-developed mAb114 antibody and the REGN-EB3 cocktail are the first therapeutics to be shown in a scientifically rigorous study to be effective at treating Ebola. This work also demonstrates that ethically sound clinical research can be conducted under difficult conditions in the midst of a disease outbreak. In fact, the halted study was named Pamoja Tulinde Maisha (PALM), which means “together save lives” in Kiswahili.

To top off the life-saving progress in 2019, the FDA just approved the first vaccine for Ebola. Called Ervebo (earlier rVSV-ZEBOV), this single-dose injectable vaccine is a non-infectious version of an animal virus that has been genetically engineered to carry a segment of a gene from the Zaire species of the Ebola virus—the virus responsible for the current DRC outbreak and the West Africa outbreak. Because the vaccine does not contain the whole Zaire virus, it can’t cause Ebola. Results from a large study in Guinea conducted by the WHO indicated that the vaccine offered substantial protection against Ebola virus disease. Ervebo, produced by Merck, has already been given to over 259,000 individuals as part of the response to the DRC outbreak. The NIH has supported numerous clinical trials of the vaccine, including an ongoing study in West Africa.

Microbes combat malnourishment: Researchers discovered a few years ago that abnormal microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. An NIH-supported research team followed up on this lead with a study of kids in Bangladesh, and it published last July its groundbreaking finding: that foods formulated to repair the “gut microbiome” helped malnourished kids rebuild their health. The researchers were able to identify a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. In this month-long study, this bacterial network helped the researchers characterize a child’s microbiome and/or its relative state of repair.

But a month isn’t long enough to determine how the new foods would help children grow and recover. The researchers are conducting a similar study that is much longer and larger. Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development. The hope is that these new foods and others adapted for use around the world soon will help many more kids grow up to be healthy adults.

Measles Resurgent: The staff at Science also listed their less-encouraging 2019 Breakdowns of the Year, and unfortunately the biomedical sciences made the cut with the return of measles in the U.S. Prior to 1963, when the measles vaccine was developed, 3 to 4 million Americans were sickened by measles each year. Each year about 500 children would die from measles, and many more would suffer lifelong complications. As more people were vaccinated, the incidence of measles plummeted. By the year 2000, the disease was even declared eliminated from the U.S.

But, as more parents have chosen not to vaccinate their children, driven by the now debunked claim that vaccines are connected to autism, measles has made a very preventable comeback. Last October, the Centers for Disease Control and Prevention (CDC) reported an estimated 1,250 measles cases in the United States at that point in 2019, surpassing the total number of cases reported annually in each of the past 25 years.

The good news is those numbers can be reduced if more people get the vaccine, which has been shown repeatedly in many large and rigorous studies to be safe and effective. The CDC recommends that children should receive their first dose by 12 to 15 months of age and a second dose between the ages of 4 and 6. Older people who’ve been vaccinated or have had the measles previously should consider being re-vaccinated, especially if they live in places with low vaccination rates or will be traveling to countries where measles are endemic.

Despite this public health breakdown, 2019 closed out a memorable decade of scientific discovery. The Twenties will build on discoveries made during the Teens and bring us even closer to an era of precision medicine to improve the lives of millions of Americans. So, onward to 2020—and happy New Year!

Reference:

[1] 2019 Breakthrough of the Year. Science, December 19, 2019.

NIH Support: These breakthroughs represent the culmination of years of research involving many investigators and the support of multiple NIH institutes.


How Measles Leave the Body Prone to Future Infections

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Boy with measles
Credit: gettyimages/CHBD

As a kid who was home-schooled on a Virginia farm in the 1950s, I wasn’t around other kids very much, and so didn’t get exposed to measles. And there was no vaccine yet. Later on as a medical resident, I didn’t recognize that I wasn’t immune. So when I was hospitalized with a severe febrile illness at age 29, it took a while to figure out the diagnosis. Yes, it was measles. I have never been that sick before or since. I was lucky not to have long-term consequences, and now I’m learning that there may be even more to consider.

With the big push to get kids vaccinated, you’ve probably heard about some of the very serious complications of measles: hearing-threatening ear infections, bronchitis, laryngitis, and even life-threatening forms of pneumonia and encephalitis. But now comes word of yet another way in which the measles can be devastating—one that may also have long-term consequences for a person’s health.

In a new study in the journal Science, a research team, partly funded by NIH, found that the measles virus not only can make children deathly ill, it can cause their immune systems to forget how to ward off other common infections [1]. The virus does this by wiping out up to nearly three-quarters of the protective antibodies that a child’s body has formed in response to past microbial invaders and vaccinations. This immune “amnesia” can leave a child more vulnerable to re-contracting infections, such as influenza or respiratory syncytial virus (RSV), that they may have been protected against before they came down with measles.

The finding comes as yet another reason to feel immensely grateful that, thanks to our highly effective vaccination programs, most people born in the U.S. from the 1960s onward should never have to experience the measles.

There had been hints that the measles virus might somehow suppress a person’s immune system. Epidemiological evidence also had suggested that measles infections might lead to increased susceptibility to infection for years afterwards [2]. Scientists had even suspected this might be explained by a kind of immune amnesia. The trouble was that there wasn’t any direct proof that such a phenomenon actually existed.

In the new work, the researchers, led by Michael Mina, Tomasz Kula, and Stephen Elledge, Howard Hughes Medical Institute and Brigham and Women’s Hospital, Boston, took advantage of a tool developed a few years ago in the Elledge lab called VirScan [3]. VirScan detects antibodies in blood samples acquired as a result of a person’s past encounters with hundreds of viruses, bacteria, or vaccines, providing a comprehensive snapshot of acquired immunity at a particular moment in time.

To look for evidence of immune amnesia following the measles, the research team needed blood samples gathered from people both before and after infection. These types of samples are currently hard to come by in the U.S. thanks to the success of vaccines. By partnering with Rik de Swart, Erasmus University Medical Center, Rotterdam, Netherlands, they found the samples that they needed.

During a recent measles outbreak in the Netherlands, de Swart had gathered blood samples from children living in communities with low vaccination rates. Elledge’s group used VirScan with 77 unvaccinated kids to measure antibodies in samples collected before and about two months after their measles infections.

That included 34 children who had mild infections and 43 who had severe measles. The researchers also examined blood samples from five children who remained uninfected and 110 kids who hadn’t been exposed to the measles virus.

The VirScan data showed that the infected kids, not surprisingly, produced antibodies to the measles virus. But their other antibodies dropped and seemed to be disappearing. In fact, depending on the severity of measles infection, the kids showed on average a loss of around 40 percent of their antibody memory, with greater losses in children with severe cases of the measles. In at least one case, the loss reached a whopping 73 percent.

This all resonates with me. I do recall that after my bout with the measles, I seemed to be coming down with a lot of respiratory infections. I attributed that to the lifestyle of a medical resident—being around lots of sick patients and not getting much sleep. But maybe it was more than that.

The researchers suggest that the loss of immune memory may stem from the measles virus destroying some of the long-lived cells in bone marrow. These cells remember past infections and, based on that immunological memory, churn out needed antibodies to thwart reinvading viruses.

Interestingly, after a measles infection, the children’s immune systems still responded to new infections and could form new immune memories. But it appears the measles caused long term, possibly permanent, losses of a significant portion of previously acquired immunities. This loss of immune memory put the children at a distinct disadvantage should those old bugs circulate again.

It’s important to note that, unlike measles infection, the MMR (measles, mumps, rubella) vaccine does NOT compromise previously acquired immunity. So, these findings come as yet another reminder of the public value of measles vaccination.

Prior to 1963, when the measles vaccine was developed, 3 to 4 million Americans got the measles each year. As more people were vaccinated, the incidence of measles plummeted. By the year 2000, the disease was declared eliminated from the U.S.

Unfortunately, measles has made a come back, fueled by vaccine refusals. In October, the Centers for Disease Control and Prevention (CDC) reported an estimated 1,250 measles cases in the United States so far in 2019, surpassing the total number of cases reported annually in each of the past 25 years [4].

Around the world, measles continues to infect 7 million people each year, leading to an estimated 120,000 deaths. Based on the new findings, Elledge’s team now suspects the actual toll of the measles may be five times greater, due to the effects of immune amnesia.

The good news is those numbers can be reduced if more people get the vaccine, which has been shown repeatedly in many large and rigorous studies to be safe and effective. The CDC recommends that children should receive their first dose by 12 to 15 months of age and a second dose between the ages of 4 and 6. Older people who’ve been vaccinated or have had the measles previously should consider being re-vaccinated, especially if they live in places with low vaccination rates or will be traveling to countries where measles are endemic.

References:

[1] Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Mina MJ, Kula T, Leng Y, Li M, de Vries RD, Knip M, Siljander H, Rewers M, Choy DF, Wilson MS, Larman HB, Nelson AN, Griffin DE, de Swart RL, Elledge SJ. et al. Science. 2019 Nov 1; 366 (6465): 599-606.

[2] Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Mina MJ, Metcalf CJE, De Swart RL, Osterhaus ADME, Grenfell BT. Science. 2015 May 8; 348(6235).

[3] Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung’u T, Ruxrungtham K, Sanchez J, Brander C, Chung RT, O’Connor KC, Walker B, Larman HB, Elledge SJ. Science. 2015 Jun 5;348(6239):aaa0698.

[4] Measles cases and outbreaks. Centers for Disease Control and Prevention. Oct. 11, 2019.

Links:

Measles (MedlinePlus Medical Encyclopedia/National Library of Medicine/NIH)

Measles History (Centers for Disease Control and Prevention)

Vaccines (National Institute of Allergy and Infectious Diseases/NIAID)

Vaccines Protect Your Community (Vaccines.gov)

Elledge Lab (Harvard Medical School, Boston)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases


Resurgence of Measles, Pertussis Fueled by Vaccine Refusals

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Baby getting a vaccine

Credit: Centers for Disease Control and Prevention

I was born in 1950 and was home-schooled until the 6th grade. Thus, I missed exposure to several childhood illnesses that affected most of my generation. I never gave it much thought until, as a medical resident in North Carolina in 1979, I came down with a potentially life-threatening febrile illness that required hospitalization. Only after four days of 105 degree fever did a rash appear, and the diagnosis was made: measles. That was the sickest I have ever been. It turned out that one of my daughter’s school friends had developed measles in a small outbreak of unvaccinated kids in Chapel Hill, and I had been exposed to her. I was born too early to have been vaccinated.

But for most people born in the United States after the 1960s, they have never had to experience the high fever and rash of the measles or the coughing fits of pertussis, commonly known as whooping cough. That’s because these extremely contagious and potentially life-threatening diseases have been controlled with the use of highly effective vaccines and strong vaccination programs. And yet, the number of Americans sickened with measles and pertussis each year has recently crept back up.

Now, an NIH-funded report confirms that many of the recent outbreaks of these vaccine-preventable diseases have been fueled by refusal by some parents to have their children vaccinated [1]. The findings, published recently in JAMA, come as an important reminder that successful eradication of infectious diseases depends not only on the availability of safe and effective vaccines, but also on effective communication about the vaccines and the diseases they prevent.


No Link Between MMR Vaccine and Autism, Even in High-Risk Kids

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Child vaccination

Credit: CDC

Study after study has found no link between autism spectrum disorders (ASD) and the measles-mumps-rubella (MMR) vaccine—or any vaccine for that matter. Yet many parents still refuse or delay vaccinations for their young children based on misplaced fear of ASD, which can be traced back to a small 1998 study that’s since been debunked and retracted [1]. Such decisions can have a major negative impact on public health. With vaccination rates in decline, we’ve recently seen the resurgence of measles and other potentially fatal childhood infectious diseases.

Among the parents most likely to avoid getting their kids vaccinated are those who already have a child with ASD. So, it’s especially important and timely news that researchers have once again found no link between MMR vaccines and ASD—even among children known to be at greater risk for autism because an older sibling has the developmental brain disorder.