Posted on by Dr. Francis Collins
About 20,000 people in the U.S. live with hemophilia A. It’s a rare X-linked genetic disorder that affects predominantly males and causes their blood to clot poorly when healing wounds. For some, routine daily activities can turn into painful medical emergencies to stop internal bleeding, all because of changes in a single gene that disables an essential clotting protein.
Now, results of an early-stage clinical trial, published recently in the New England Journal of Medicine, demonstrate that gene therapy is within reach to produce the essential clotting factor in people with hemophilia A. The results show that, in most of the 18 adult participants, a refined gene therapy strategy produced lasting expression of factor VIII (FVIII), the missing clotting factor in hemophilia A . In fact, gene therapy helped most participants reduce—or, in some cases, completely eliminate—bleeding events.
Currently, the most-common treatment option for males with hemophilia A is intravenous infusion of FVIII concentrate. Though infused FVIII becomes immediately available in the bloodstream, these treatments aren’t a cure and must be repeated, often weekly or every other day, to prevent or control bleeding.
Gene therapy, however, represents a possible cure for hemophilia A. Earlier clinical trials reported some success using benign adeno-associated viruses (AAVs) as the vector to deliver the therapeutic FVIII gene to cells in the liver, where the clotting protein is made. But after a year, those trial participants had a marked decline in FVIII expression. Follow-up studies then found that the decline continued over time, thought to be at least in part because of an immune response to the AAV vector.
In the new study, an NIH-funded team led by Lindsey George and Katherine High of the Children’s Hospital of Philadelphia and the University of Pennsylvania, tested their refined delivery system. High is also currently with Asklepios BioPharmaceutical, Inc., Chapel Hill, NC. (Back in the 1970s, she and I were medical students in the same class at the University of North Carolina.) The study was also supported by Spark Therapeutics, Philadelphia.
Trial participants received a single infusion of the novel recombinant AAV-based gene therapy called SPK-8011. It is specifically designed to produce FVIII expression in the liver. In this phase 1/2 clinical trial, which evaluates the safety and initial efficacy of a treatment, participants received one of four different doses of SPK-8011. Most also received steroids to prevent or treat the presumed counterproductive immune response to the therapy.
The researchers followed participants for a year after the experimental treatment, and all enrolled in a follow-up trial for continued observation. During this time, researchers detected no major safety concerns, though several patients had increases in blood levels of a liver enzyme.
The great news is all participants produced the missing FVIII after gene therapy. Twelve of the 16 participants were followed for more than two years and had no apparent decrease in clotting factor activity. This is especially noteworthy because it offers the first demonstration of multiyear stable and durable FVIII expression in individuals with hemophilia A following gene transfer.
Even more encouraging, the men in the trial had more than a 92 percent reduction in bleeding episodes on average. Before treatment, most of the men had 8.5 bleeding episodes per year. After treatment, those events dropped to an average of less than one per year. However, two study participants lost FVIII expression within a year of treatment, presumably due to an immune response to the therapeutic AAV. This finding shows that, while steroids help, they don’t always prevent loss of a therapeutic gene’s expression.
Overall, the findings suggest that AAV-based gene therapy can lead to the durable production of FVIII over several years and significantly reduce bleeding events. The researchers are now exploring possibly more effective ways to control the immune response to AAV in expansion of this phase 1/2 investigation before pursuing a larger phase 3 trial. They’re continuing to monitor participants closely to establish safety and efficacy in the months and years to come.
On a related note, the recently announced Bespoke Gene Therapy Consortium (BGTC), a partnership between NIH and industry, will expand the refined gene therapy approach demonstrated here to more rare and ultrarare diseases. That should make these latest findings extremely encouraging news for the millions of people born with other rare genetic conditions caused by known alterations to a single gene.
 Multiyear Factor VIII expression after AAV Gene transfer for Hemophilia A. George LA, Monahan PE, Eyster ME, Sullivan SK, Ragni MV, Croteau SE, Rasko JEJ, Recht M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. N Engl J Med. 2021 Nov 18;385(21):1961-1973.
Hemophilia A (National Center for Advancing Translational Sciences/NIH)
FAQ About Rare Diseases (National Center for Advancing Translational Sciences/NIH)
Lindsey George (University of Pennsylvania, Philadelphia)
Katherine High (University of Pennsylvania)
NIH Support: National Heart, Lung, and Blood Institute
Posted on by Dr. Francis Collins
More than 8 million people in the United States have now tested positive for COVID-19. For those who’ve recovered, many wonder if fending off SARS-CoV-2—the coronavirus that causes COVID-19—one time means their immune systems will protect them from reinfection. And, if so, how long will this “acquired immunity” last?
The early data brought hope that acquired immunity was possible. But some subsequent studies have suggested that immune protection might be short-lived. Though more research is needed, the results of two recent studies, published in the journal Science Immunology, support the early data and provide greater insight into the nature of the human immune response to this coronavirus [1,2].
The new findings show that people who survive a COVID-19 infection continue to produce protective antibodies against key parts of the virus for at least three to four months after developing their first symptoms. In contrast, some other antibody types decline more quickly. The findings offer hope that people infected with the virus will have some lasting antibody protection against re-infection, though for how long still remains to be determined.
In one of the two studies, partly funded by NIH, researchers led by Richelle Charles, Massachusetts General Hospital, Boston, sought a more detailed understanding of antibody responses following infection with SARS-CoV-2. To get a closer look, they enrolled 343 patients, most of whom had severe COVID-19 requiring hospitalization. They examined their antibody responses for up to 122 days after symptoms developed and compared them to antibodies in more than 1,500 blood samples collected before the pandemic began.
The researchers characterized the development of three types of antibodies in the blood samples. The first type was immunoglobulin G (IgG), which has the potential to confer sustained immunity. The second type was immunoglobulin A (IgA), which protects against infection on the body’s mucosal surfaces, such as those found in the respiratory and gastrointestinal tracts, and are found in high levels in tears, mucus, and other bodily secretions. The third type is immunoglobulin M (IgM), which the body produces first when fighting an infection.
They found that all three types were present by about 12 days after infection. IgA and IgM antibodies were short-lived against the spike protein that crowns SARS-CoV-2, vanishing within about two months.
The good news is that the longer-lasting IgG antibodies persisted in these same patients for up to four months, which is as long as the researchers were able to look. Levels of those IgG antibodies also served as an indicator for the presence of protective antibodies capable of neutralizing SARS-CoV-2 in the lab. Even better, that ability didn’t decline in the 75 days after the onset of symptoms. While longer-term study is needed, the findings lend support to evidence that protective antibody responses against the novel virus do persist.
The other study came to very similar conclusions. The team, led by Jennifer Gommerman and Anne-Claude Gingras, University of Toronto, Canada, profiled the same three types of antibody responses against the SARS-CoV-2 spike protein, They created the profiles using both blood and saliva taken from 439 people, not all of whom required hospitalization, who had developed COVID-19 symptoms from 3 to 115 days prior. The team then compared antibody profiles of the COVID-19 patients to those of people negative for COVID-19.
The researchers found that the antibodies against SARS-CoV-2 were readily detected in blood and saliva. IgG levels peaked about two weeks to one month after infection, and then remained stable for more than three months. Similar to the Boston team, the Canadian group saw IgA and IgM antibody levels drop rapidly.
The findings suggest that antibody tests can serve as an important tool for tracking the spread of SARS-CoV-2 through our communities. Unlike tests for the virus itself, antibody tests provide a means to detect infections that occurred sometime in the past, including those that may have been asymptomatic. The findings from the Canadian team further suggest that tests of IgG antibodies in saliva may be a convenient way to track a person’s acquired immunity to COVID-19.
Because IgA and IgM antibodies decline more quickly, testing for these different antibody types also could help to distinguish between an infection within the last two months and one that more likely occurred even earlier. Such details are important for filling in gaps in our understanding COVID-19 infections and tracking their spread in our communities.
Still, there are rare reports of individuals who survived one bout with COVID-19 and were infected with a different SARS-CoV-2 strain a few weeks later . The infrequency of such reports, however, suggests that acquired immunity after SARS-CoV-2 infection is generally protective.
There remain many open questions, and answering them will require conducting larger studies with greater diversity of COVID-19 survivors. So, I’m pleased to note that the NIH’s National Cancer Institute (NCI) recently launched the NCI Serological Sciences Network for COVID19 (SeroNet), now the nation’s largest coordinated effort to characterize the immune response to COVID-19 .
The network was established using funds from an emergency Congressional appropriation of more than $300 million to develop, validate, improve, and implement antibody testing for COVID-19 and related technologies. With help from this network and ongoing research around the world, a clearer picture will emerge of acquired immunity that will help to control future outbreaks of COVID-19.
 Persistence and decay of human antibody responses to the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 patients. Iyer AS, Jones FK, Nodoushani A, Ryan ET, Harris JB, Charles RC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe0367.
 Persistence of serum and saliva antibody responses to SARS-CoV-2 spike antigens in COVID-19 patients. Isho B, Abe KT, Zuo M, Durocher Y, McGeer AJ, Gommerman JL, Gingras AC, et al. Sci Immunol. 2020 Oct 8;5(52):eabe5511.
 What reinfections mean for COVID-19. Iwasaki A. Lancet Infect Dis, 2020 October 12. [Epub ahead of print]
 NIH to launch the Serological Sciences Network for COVID-19, announce grant and contract awardees. National Institutes of Health. 2020 October 8.
Coronavirus (COVID-19) (NIH)
Charles Lab (Massachusetts General Hospital, Boston)
Gingras Lab (University of Toronto, Canada)
Jennifer Gommerman (University of Toronto, Canada)
NCI Serological Sciences Network for COVID-19 (SeroNet) (National Cancer Institute/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Cancer Institute
Posted on by Dr. Francis Collins
The pandemic has already claimed far too many lives in the United States and around the world. Fortunately, as doctors have gained more experience in treating coronavirus disease 2019 (COVID-19), more people who’ve been hospitalized eventually will recover. This raises an important question: what does recovery look like for them?
Because COVID-19 is still a new condition, there aren’t a lot of data out there yet to answer that question. But a recent study of 55 people recovering from COVID-19 in China offers some early insight into the recovery of lung function . The results make clear that—even in those with a mild-to-moderate infection—the effects of COVID-19 can persist in the lungs for months. In fact, three months after leaving the hospital about 70 percent of those in the study continued to have abnormal lung scans, an indication that the lungs are still damaged and trying to heal.
The findings in EClinicalMedicine come from a team in Henan Province, China, led by Aiguo Xu, The First Affiliated Hospital of Zhengzhou University; Yanfeng Gao, Zhengzhou University; and Hong Luo, Guangshan People’s Hospital. They’d heard about reports of lung abnormalities in patients discharged from the hospital. But it wasn’t clear how long those problems stuck around.
To find out, the researchers enrolled 55 men and women who’d been admitted to the hospital with COVID-19 three months earlier. Some of the participants, whose average age was 48, had other health conditions, such as diabetes or heart disease. But none had any pre-existing lung problems.
Most of the patients had mild or moderate respiratory illness while hospitalized. Only four of the 55 had been classified as severely ill. Fourteen patients required supplemental oxygen while in the hospital, but none needed mechanical ventilation.
Three months after discharge from the hospital, all of the patients were able to return to work. But they continued to have lingering symptoms of COVID-19, including shortness of breath, cough, gastrointestinal problems, headache, or fatigue.
Evidence of this continued trouble also showed up in their lungs. Thirty-nine of the study’s participants had an abnormal result in their computed tomography (CT) lung scan, which creates cross-sectional images of the lungs. Fourteen individuals (1 in 4) also showed reduced lung function in breathing tests.
Interestingly, the researchers found that those who went on to have more lasting lung problems also had elevated levels of D-dimer, a protein fragment that arises when a blood clot dissolves. They suggest that a D-dimer test might help to identify those with COVID-19 who would benefit from pulmonary rehabilitation to rebuild their lung function, even in the absence of severe respiratory symptoms.
This finding also points to the way in which the SARS-CoV-2 virus seems to enhance a tendency toward blood clotting—a problem addressed in our Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership. The partnership recently initiated a trial of blood thinners. That trial will start out by focusing on newly diagnosed outpatients and hospitalized patients, but will go on to include a component related to convalescence.
Moving forward, it will be important to conduct larger and longer-term studies of COVID-19 recovery in people of diverse backgrounds to continue to learn more about what it means to survive COVID-19. The new findings certainly indicate that for many people who’ve been hospitalized with COVID-19, regaining normal lung function may take a while. As we learn even more about the underlying causes and long-term consequences of this new infectious disease, let’s hope it will soon lead to insights that will help many more COVID-19 long-haulers and their concerned loved ones breathe easier.
 Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG. EClinicalMedicine.2020 Aug 25:100463
Coronavirus (COVID-19) (NIH)
How the Lungs Work (National Heart, Lung, and Blood Institute/NIH)
Computed Tomography (CT) (National Institute of Biomedical Imaging and Bioengineering/NIH)
Zhengzhou University (Zhengzhou City, Henan Province, China)