antibody
Nanoparticle Technology Holds Promise for Protecting Against Many Coronavirus Strains at Once
Posted on by Dr. Francis Collins
It’s truly encouraging to witness people all across our nation rolling up their sleeves to get their COVID-19 vaccines. That is our best chance to end this pandemic. But this is the third coronavirus to emerge and cause serious human illness in the last 20 years, and it’s probably not the last. So, this is also an opportunity to step up our efforts to develop vaccines to combat future strains of disease-causing coronavirus. With this in mind, I’m heartened by a new NIH-funded study showing the potential of a remarkably adaptable, nanoparticle-based approach to coronavirus vaccine development [1].
Both COVID-19 vaccines currently authorized for human use by the Food and Drug Administration (FDA) work by using mRNA to instruct our cells to make an essential portion of the spike protein of SARS-CoV-2, which is the novel coronavirus that causes COVID-19. As our immune system learns to recognize this protein fragment as foreign, it produces antibodies to attack SARS-CoV-2 and prevent COVID-19. What makes the new vaccine technology so powerful is that it raises the possibility of training the immune system to recognize not just one strain of coronavirus—but up to eight—with a single shot.
This approach has not yet been tested in people, but when a research team, led by Pamela Bjorkman, California Institute of Technology, Pasadena, injected this new type of vaccine into mice, it spurred the production of antibodies that react to a variety of different coronaviruses. In fact, some of the mouse antibodies proved to be reactive to related strains of coronavirus that weren’t even represented in the vaccine. These findings suggest that if presented with multiple different fragments of the spike protein’s receptor binding domain (RBD), which is what SARS-like coronaviruses use to infect human cells, the immune system may learn to recognize common features that might protect against as-yet unknown, newly emerging coronaviruses.
This new work, published in the journal Science, utilizes a technology called a mosaic nanoparticle vaccine platform [1]. Originally developed by collaborators at the University of Oxford, United Kingdom, the nanoparticle component of the platform is a “cage” made up of 60 identical proteins. Each of those proteins has a small protein tag that functions much like a piece of Velcro®. In their SARS-CoV-2 work, Bjorkman and her colleagues, including graduate student Alex A. Cohen, engineered multiple different fragments of the spike protein so each had its own Velcro-like tag. When mixed with the nanoparticle, the spike protein fragments stuck to the cage, resulting in a vaccine nanoparticle with spikes representing four to eight distinct coronavirus strains on its surface. In this instance, the researchers chose spike protein fragments from several different strains of SARS-CoV-2, as well as from other related bat coronaviruses thought to pose a threat to humans.
The researchers then injected the vaccine nanoparticles into mice and the results were encouraging. After inoculation, the mice began producing antibodies that could neutralize many different strains of coronavirus. In fact, while more study is needed to understand the mechanisms, the antibodies responded to coronavirus strains that weren’t even represented on the mosaic nanoparticle. Importantly, this broad antibody response came without apparent loss in the antibodies’ ability to respond to any one particular coronavirus strain.
The findings raise the exciting possibility that this new vaccine technology could provide protection against many coronavirus strains with a single shot. Of course, far more study is needed to explore how well such vaccines work to protect animals against infection, and whether they will prove to be safe and effective in people. There will also be significant challenges in scaling up manufacturing. Our goal is not to replace the mRNA COVID-19 vaccines that scientists developed at such a remarkable pace over the last year, but to provide much-needed vaccine strategies and tools to respond swiftly to the emerging coronavirus strains of the future.
As we double down on efforts to combat COVID-19, we must also come to grips with the fact that SARS-CoV-2 isn’t the first—and surely won’t be the last—novel coronavirus to cause disease in humans. With continued research and development of new technologies such as this one, the hope is that we will come out of this terrible pandemic better prepared for future infectious disease threats.
References:
[1] Mosaic RBD nanoparticles elicit neutralizing antibodies against SARS-CoV-2 and zoonotic coronaviruses. Cohen AA, Gnanapragasam PNP, Lee YE, Hoffman PR, Ou S, Kakutani LM, Keeffe JR, Barnes CO, Nussenzweig MC, Bjorkman PJ. Science. 2021 Jan 12.
Links:
COVID-19 Research (NIH)
Bjorkman Lab (California Institute of Technology, Pasadena)
NIH Support: National Institute of Allergy and Infectious Diseases
New Online Resource Shows How You Can Help to Fight COVID-19
Posted on by Dr. Francis Collins
There are lots of useful online resources to learn about COVID-19 and some of the clinical studies taking place across the country. What’s been missing is a one-stop online information portal that pulls together the most current information for people of all groups, races, ethnicities, and backgrounds who want to get involved in fighting the pandemic. So, I’m happy to share that the U.S. Department of Health and Human Services, in coordination with NIH and Operation Warp Speed, has just launched a website called Combat COVID.
This easy-to-navigate portal makes it even easier for you and your loved ones to reach informed decisions about your health and to find out how to help in the fight against COVID-19. Indeed, it shows that no matter your current experience with COVID-19, there are opportunities to get involved to develop vaccines and medicines that will help everyone. Hundreds of thousands of volunteers have already taken this step—but we still need more, so we are seeking your help.
The Combat COVID website, which can also be viewed in Spanish, is organized to guide you to the most relevant information based on your own COVID-19 status:
• If you’ve never had COVID-19, you’ll be directed to information about joining the COVID-19 Prevention Network’s Volunteer Screening Registry. This registry is creating a list of potential volunteers willing to take part in ongoing or future NIH clinical trials focused on preventing COVID-19—like vaccines. Why get involved in a clinical trial now if vaccines will be widely distributed in the future? Well, there’s still a long way to go to get the pandemic under control, and several promising vaccines are still undergoing definitive testing. Your best route to getting access to a vaccine right now might be a clinical trial. And the more vaccines that are found to be safe and effective, the sooner we will be able to immunize all Americans and many others around the world.
• If you have an active COVID-19 infection, you’ll be directed to information about ongoing clinical trials that are studying better ways to treat the infection with promising drugs and other treatments. There are currently at least nine ongoing clinical trials for adults at every stage of COVID-19 illness. That includes five NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership trials. All of these are promising treatments, but need to be rigorously tested to be sure they are safe and effective.
• If you’ve recovered from a confirmed case of COVID-19, you may be able to give the gift of life to someone else. Check out Combat COVID, where you’ll be directed to information about how to donate blood plasma. Once donated, this plasma may be infused into another person to help treat COVID-19 or it may be used to make a potential medicine.
• For doctors treating people with COVID-19, the website also provides a collection of useful information, including details on how to connect patients to ongoing clinical trials and other opportunities to combat COVID-19.
While I’m discussing online resources, NIH’s National Cancer Institute (NCI) also recently launched an interesting website for a critical initiative called the Serological Sciences Network for COVID-19 (SeroNet). A collaboration between several NIH components and 25 of the nation’s top biomedical research institutions, SeroNet will increase the national capacity for antibody testing, while also investigating all aspects of the immune response to SARS-CoV-2, the coronavirus that causes COVID-19. That includes studying variations in the severity of COVID-19 symptoms, the influence of pre-existing conditions for developing severe disease, and the chances of reinfection.
In our efforts to combat COVID-19, we’ve come a long way in a short period of time. But there is still plenty of work to do to get the pandemic under control to protect ourselves, our loved ones, and our communities. Be a hero. Follow the three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often. And, if you’d like to find what else you can do to help, follow your way to Combat COVID.
Links:
Coronavirus (COVID-19) (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Explaining Operation Warp Speed (HHS)
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)
Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)
Antibody Points to Possible Weak Spot on Novel Coronavirus
Posted on by Dr. Francis Collins
Researchers are working hard to produce precise, 3D molecular maps to guide the development of safe, effective ways of combating the coronavirus disease 2019 (COVID-19) pandemic. While there’s been a lot of excitement surrounding the promise of antibody-based tests and treatments, this map you see above highlights another important use of antibodies: to inform efforts to design a vaccine.
This image shows the crystal structure of a human antibody (heavy chain in orange, light chain in yellow), which is a blood protein our immune systems produce to attack viruses and other foreign invaders. This particular antibody, called CR3022, is bound to a key surface protein of the novel coronavirus (white).
The CR3022 antibody actually doesn’t come from someone who has recovered from COVID-19. Instead, it was obtained from a person who, nearly two decades ago, survived a bout of severe acute respiratory syndrome (SARS). The SARS virus, which disappeared in 2004 after a brief outbreak in humans, is closely related to the novel coronavirus that causes COVID-19.
In a recent paper in the journal Science, the NIH-funded lab of Ian Wilson, The Scripps Research Institute, La Jolla, CA, along with colleagues at The University of Hong Kong, sought to understand how the human immune system interacts with and neutralizes this highly infectious virus [1]. The lab did so by employing high-resolution X-ray crystallography tools [2]. They captured the atomic structure of this antibody bound to its target by shooting X-rays through its crystallized form. (An antibody measures about 10 nanometers; a nanometer is 1 billionth of a meter.)
Other researchers had shown previously that CR3022 cross-reacts with the novel coronavirus, although the antibody doesn’t bind tightly enough to neutralize and stop it from infecting cells. So, Wilson’s team went to work to learn precisely where the antibody attaches to the novel virus. Those sites are of special interest because they highlight spots on a virus that are vulnerable to attack—and, as such, potentially good targets for vaccine designers.
A key finding in the new paper is that the antibody binds a highly similar site on both the SARS and novel coronaviruses. Those sites differ in each virus by just four amino acids, the building blocks of a protein.
This is particularly interesting because the antibody pictured above is bound to a spike protein, which is the appendage on both the SARS and novel coronavirus that enables them to bind to a key receptor protein on the surface of human cells, called ACE2. This binding activity marks the first step for these viruses in gaining entry into human cells and infecting them.
The human antibody shown in this image locks onto the virus’s spike protein at a different location than where the human ACE2 protein binds to the novel coronavirus. Intriguingly, the antibody binds to a spot on the novel coronavirus that is usually hidden, except for when virus shapeshifts its structure in order to infect a cell.
The findings suggest that a successful vaccine may be one that elicits antibodies that targets this same spot, but binds more tightly than the one seen above, thereby protecting human cells against the virus that causes COVID-19. However, Wilson notes that this study has just uncovered one potential vulnerability of the novel coronavirus, and it is likely the virus likely has many more that could be revealed with further study.
To continue in this quest to design a safe and effective vaccine, Wilson and his colleagues are now gathering blood samples to collect antibodies from people who’ve recovered from COVID-19. So, we can look forward to seeing some even more revealing images soon.
References:
[1] A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Yuan M, Wu NC, Zhu X, Lee CD, So RTY, Lv H, Mok CKP, Wilson IA. Science. 2020 Apr 3.
[2] 100 Years Later: Celebrating the Contributions of X-ray Crystallography to Allergy and Clinical Immunology. Pomés A, Chruszcz M, Gustchina A, Minor W, Mueller GA, Pedersen LC, Wlodawer A, Chapman MD. J Allergy Clin Immunol. 2015 Jul;136(1):29-37.
Links:
Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)
Coronavirus (COVID-19) (NIH)
Ian Wilson (The Scripps Research Institute, La Jolla, CA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of General Medical Sciences
Celebrating 2019 Biomedical Breakthroughs
Posted on by Dr. Francis Collins
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.
Looking to Llamas for New Ways to Fight the Flu
Posted on by Dr. Francis Collins
Researchers are making tremendous strides toward developing better ways to reduce our risk of getting the flu. And one of the latest ideas for foiling the flu—a “gene mist” that could be sprayed into the nose—comes from a most surprising source: llamas.
Like humans and many other creatures, these fuzzy South American relatives of the camel produce immune molecules, called antibodies, in their blood when exposed to viruses and other foreign substances. Researchers speculated that because the llama’s antibodies are so much smaller than human antibodies, they might be easier to use therapeutically in fending off a wide range of flu viruses. This idea is now being leveraged to design a new type of gene therapy that may someday provide humans with broader protection against the flu [1].
Next Page
