Emerging data suggest that the effects of infection with SARS-CoV-2 are far reaching extending beyond those with severe acute disease. Specifically, the presence of persistent symptoms after apparent resolution from COVID-19 have frequently been reported throughout the pandemic by individuals labeled as "long-haulers". The purpose of this study was to assess for symptoms at days 0-10 and 61+ among subjects with PCR-confirmed SARS-CoV-2 infection. The University of California COvid Research Data Set (UC CORDS) was used to identify 1407 records that met inclusion criteria. Symptoms attributable to COVID-19 were extracted from the electronic health record. Symptoms reported over the previous year prior to COVID-19 were excluded, using nonnegative matrix factorization (NMF) followed by graph lasso to assess relationships between symptoms. A model was developed predictive for becoming a long-hauler based on symptoms. 27% reported persistent symptoms after 60 days. Women were more likely to become long-haulers, and all age groups were represented with those aged 50 ± 20 years comprising 72% of cases. Presenting symptoms included palpitations, chronic rhinitis, dysgeusia, chills, insomnia, hyperhidrosis, anxiety, sore throat, and headache among others. We identified 5 symptom clusters at day 61+: chest pain-cough, dyspnea-cough, anxiety-tachycardia, abdominal pain-nausea, and low back pain-joint pain. Long-haulers represent a very significant public health concern, and there are no guidelines to address their diagnosis and management. Additional studies are urgently needed that focus on the physical, mental, and emotional impact of long-term COVID-19 survivors who become long-haulers.
Thanks to a drug that was originally developed to combat heart disease, a team of doctors at the Eye Clinic (Director: Prof. Dr. Friedrich E. Kruse) at the Erlangen University Hospital has now succeeded for the first time in an individual attempt at healing a 59-year-old man with Long COVID Syndrome became symptom-free. Whether the active ingredient BC 007 also helps other sufferers will soon be examined in a clinical study. "At the moment, unfortunately, we can no longer treat people with the drug because it has not yet passed all approval studies," says Prof. Dr. Christian Mardin, senior physician in charge of the eye clinic.
The images of the OCT angiography show: The blood flow to the retina of a patient after corona infection (left) is reduced compared to that of a healthy person (right). Photo: Eye Clinic / University Clinic Erlangen
The doctors of the Eye Clinic and Medical Clinic 1 - Gastroenterology, Pneumology and Endocrinology (Director: Prof. Dr. Markus F. Neurath) and Medical Clinic 3 - Rheumatology and Immunology (Director: Prof. Dr. med. Univ. Georg Schett) of the University Hospital Erlangen had already found out in advance as part of the ReCOVer study: If you have a COVID-19 infection, the blood flow to the eyes is still significantly restricted many months later. The background thought to the attempted healing was that the changed blood flow is certainly not limited to the eye, but can be seen as an example for the entire body.
In the blood of former COVID-19 patients, the team of doctors, together with a long-term cooperation partner and former employee of the Max Delbrück Center for Molecular Medicine in Berlin, Dr. Gerd Wallukat, months after the infection, certain proteins that you have been dealing with for many years in connection with glaucoma (green star): autoantibodies against G-protein-coupled receptors “This means that the immune defense, which is good per se, is directed against the own body and forms substances that can be harmful. This has serious consequences in some cases, ”explains Dr. Dr. Bettina Hohberger, specialist at the Erlangen Eye Clinic. If the body increasingly forms autoantibodies, these may attack different body structures. The interdisciplinary medical and scientific team found out during the blood tests that patients have several of these proteins after a corona infection. "We already know one of these autoantibodies from glaucoma and know that it has a bad effect on the blood circulation in the eye," explains Dr. Hohberger.
Through the long-term cooperation with Dr. Wallukat had heard from the ophthalmologist about a preparation that binds these harmful autoantibodies. This would make it possible to render the autoantibodies harmless and possibly to improve the circulatory disorders. The drug was specially developed for patients with severe heart disease a few years ago by Dr. Wallukat, his colleague Dr. Annekathrin Haberland and former cardiac surgeon of the German Heart Center Berlin in a registration study. "Originally, I wanted to use it to help my glaucoma patients," recalls Dr. Hohberger. “When we then saw the results that arose from cooperation projects on Long COVID, it was like many small pieces of the puzzle that fit together for us. It was quite conceivable
Blood circulation improved significantly
When a long-time patient with glaucoma in the Erlangen glaucoma registry reported his symptoms after surviving corona infection - loss of taste, severe concentration disorders and fatigue that severely restricted him in his professional and private life - the team at the eye clinic wanted to offer him help. As part of an individual attempt at healing with the Berlin drug, BC 007, the 59-year-old received the preparation via infusion and stayed three days as an inpatient at the University Clinic Erlangen. “There was an improvement within a few hours. When he was discharged, our patient felt much more relaxed than before the administration and his autoantibody values confirmed this impression, ”the team of doctors describes the process. The difficulty concentrating also disappeared, the performance of the 59-year-old increased again and the sense of taste returned. "Overall, the blood flow to the capillaries, which we can measure on the eye, has improved significantly." The team at the Erlangen Eye Clinic therefore assumes that the patient's long COVID symptoms have disappeared thanks to the improved blood flow. For the approach to render these autoantibodies harmless with a drug in patients with glaucoma, Dr. Hohberger 2020 nominated for the Galenus von Pergamon Prize in the basic research category. that the patient's long COVID complaints have disappeared thanks to the improved blood circulation. For the approach to render these autoantibodies harmless with a drug in patients with glaucoma, Dr. Hohberger 2020 nominated for the Galenus von Pergamon Prize in the basic research category. that the patient's long COVID complaints have disappeared thanks to the improved blood circulation. For the approach to render these autoantibodies harmless with a drug in patients with glaucoma, Dr. Hohberger 2020 nominated for the Galenus von Pergamon Prize in the basic research category.
ReCOVer study
In cooperation with the intensive care unit of Medicine 1, where corona patients have also been treated since spring 2020, and Medicine 3, the research team at the eye clinic examined the blood flow in the smallest vessels, the capillaries, in COVID-19 patients. They made the blood flow visible with the help of an innovative, painless and non-invasive method: OCT angiography (optical coherence angiography). Only in the eye and at the nail fold - the transition between the nail bed and the finger - is it possible to make the blood flow visible without injecting contrast media, for example. As part of the clinical study, the ophthalmologists at the University Hospital Erlangen have been able to offer this examination method specifically to patients after their COVID-19 infection since 2020. First evaluations show: Even months after the disease, the blood flow within the retina is clearly restricted, even if those affected have no visual problems. The clinical study with patients after a COVID-19 infection will continue. Together with the scientists at the Max Planck Center for Physics and Medicine in Erlangen and the team led by Dr. Wallukat, mechanisms are now being investigated that can lead to the restricted blood flow and explain the mechanism of action of the successful healing attempt. Together with the scientists at the Max Planck Center for Physics and Medicine in Erlangen and the team led by Dr. Wallukat, mechanisms are now being investigated that can lead to the restricted blood flow and explain the mechanism of action of the successful healing attempt. Together with the scientists at the Max Planck Center for Physics and Medicine in Erlangen and the team led by Dr. Wallukat, mechanisms are now being investigated that can lead to the restricted blood flow and explain the mechanism of action of the successful healing attempt.
During June, as the Delta variant of COVID-19 took hold in Missouri, the seven-day average of new cases doubled.
And now that the easily spread mutation has reached every corner of the state, July will be a repeat of June, or worse, according to the University of Missouri professor monitoring wastewater for the coronavirus.
“Pretty much everywhere we have seen the Delta variant appear we have seen a spike in cases in two or three weeks,” Marc Johnson, professor of molecular microbiology and immunology, said on Thursday.
The variant was first identified in Branson in May and has since spread throughout the state. It was identified in every one of 36 samples from large and small sewage systems collected between June 14 and June 20.
“I am assuming our overall state case numbers are going to double or triple in the next few weeks,” Johnson said.
Missouri reported more than 1,000 additional COVID-19 cases on Wednesday and Thursday, the first time since Feb. 12 with consecutive days of more than 1,000 cases. The last date with 3,000 or more cases was Jan. 15.
The seven-day average of reported cases, 400 per day on June 1, was 886 per day on Wednesday.
The highest number reported on a single day was 6,606 on Nov. 14. The lowest number since Jan. 1 other than on a holiday weekend was 189 on May 24.
Missouri has recorded 620,025 cases of COVID-19 since the first was identified in March 2020. The Department of Health and Senior Services (DHSS) has reported 9,350 deaths, 1.5 percent of the total cases confirmed by testing.
Because of the spike in cases, the state is asking for federal help from newly formed surge response teams, DHSS spokeswoman Lisa Cox wrote in an email. She had few other details.
“I’ll provide more as I’m able, but I don’t believe we have firm dates yet,” Cox wrote.
The Kansas City Star reported that the team will focus on vaccine confidence efforts, epidemiology, surveillance and sequencing support related to the Delta variant.
Missouri is 39th of the 50 states and District of Columbia in vaccine delivery, according to the Centers for Disease Control. Statewide, 44.5 percent of the state’s population has received at least one dose of vaccine, compared to 54.6 percent nationwide. Only one of the state’s 117 local health department jurisdictions, Boone County, tops 50 percent.
There are 34 jurisdictions with fewer than 25 percent initiating vaccination, including seven with less than 20 percent.
A vaccine is the only tool available that can stop the spread, said Scott Clardy, assistant director of the Columbia-Boone County Department of Public Health and Human Services.
“This vaccine is not 100 percent effective to keep you from getting COVID-19,” Clardy said. “But what it is very effective at is keeping you out of the hospital and keeping you from dying of COVID-19.”
Where it’s been
Since January, Missouri seemed to be firmly on the downside of the COVID-19 curve.
From almost 90,000 cases to start the year, new infections fell below 30,000 in February and below 20,000 in March.
In May, it was fewer than 15,000.
But by the end of May, the first hints that a new wave was coming were clear. Linn and Livingston counties in northwest Missouri had a combined 488 new cases, a 17 percent increase in total infections.
At that time, Johnson’s analysis showed the Delta variant only in Branson, Brookfield in Linn County and Licking in Texas County.
The variant spread out of Branson along the highway corridors leading to Springfield and the Lake of the Ozarks and soon most of southwest Missouri was showing spikes in cases. From 774 cases in May, Greene County recorded 2,524 COVID-19 cases in June, according to state data. The highest total came on June 30, with 204 additional cases.
The move from rural areas to more populated centers reversed the path used by the Alpha variant, first identified in Great Britain, which first appeared in more populated areas of the state, Johnson said.
Studies suggest the Delta variant is 40 to 60 percent more transmissible than the Alpha variant, which is 50 percent more easily spread than the original coronavirus that emerged in China in 2019.
By the time samples were taken in early June, 18 of the wastewater systems being tested showed the Delta variant, some in combination with the Alpha variant. The map used to illustrate the wastewater results identifies the variant with a color-coded symbol.
The most recent data, posted Tuesday, has 19 purple boxes, from tiny Memphis in northeast Missouri, population 1,822, to the Metropolitan Sewer District serving the homes and businesses of St. Louis.
Where it’s going
This map, a screenshot from a website maintained by the Department of Health and Senior Services, shows the purple boxes where the Delta variant is dominant in wastewater.
Now that the Delta variant is established throughout the state, there is a lot of uncertainty, Johnson said.
“All the larger places it has hit have had the same pattern,” he said. “I don’t know what it will look like because the only place that has gotten to the end is Brookfield and they may have run out of people to infect.”
There are 11,920 people in Linn County and 13.4 percent have had COVID-19 infections identified by a test.
The increase in new cases is clear in Boone and Buchanan counties, which each had more than 425 cases in June and more than 200 in the final week of the month.
Columbia Public Schools in Boone County has 384 students and 13 faculty and staff home with a positive COVID-19 case or in quarantine due to exposure from the summer session that began June 14. The district has 8,900 students enrolled in summer courses, the Columbia Missourian reported.
All the indicators for Boone County show a rapid increase in cases is likely. The positive rate for COVID-19 tests performed by Columbia’s three hospital systems, below 3 percent in the first weeks of May, is 13.3 percent during the seven day period ending Thursday.
From a seven-day average of 4 cases per day on May 31, the rate was 36 per day on Thursday. On April 19, only five people, including four from Boone County, were hospitalized with COVID-19. On Thursday, there were 53, all but 5 from the rural region of about 25 counties served by the city’s hospitals.
The health department moved its hospital status to yellow, meaning steps have been taken either to delay transfers from other facilities or reduce other operations to focus on COVID-19 patients.
“I am hopeful things don’t get as bad as they were back in November when we had nobody vaccinated,” Clardy said.
The department is collecting the data that will show how many of those hospitalized were not vaccinated, Clardy said.
“Just anything to make people understand this is serious,” he said.
The vaccines are a tool that wasn’t available when the virus was raging late last year, Clardy said. While the county leads the state in shots administered, he said, it isn’t enough.
“We’ve got the ability to keep this from going up now,” Clardy said. “We’ve got vaccines. We’ve still got things like masking, social distancing and staying home, but we have to keep pushing to get as many people vaccinated as we possibly can.”
The department is not considering recommendations against gatherings for Independence Day and the city has a full celebration planned downtown for its bicentennial.
Johnson’s project is a collaboration between the university, the Department of Natural Resources, which regulates sewage and collects the samples, and the state health department, which reports the data to local health departments.
Jeff Wenzel, chief of the state health department’s Bureau of Environmental Epidemiology, said the connection between the results from wastewater sampling and the advent of new cases is very strong.
“With our tool, when we have seen an increase in the viral load of 40 percent or greater in one week, it is followed by a 25 percent increase in cases, at least,” Wenzel said.
One aspect of how the coronavirus is spread that was evident early on is that people who do not show symptoms can infect others.
“We’re not done fighting COVID yet,” Wenzel said. “We continue to see these variants, Alpha, Delta. We still need to have good hygiene and stay home if you are sick. You still need to become vaccinated if you are not already.”
Hospitalizations statewide were up more than 40 percent in June, above 900 on June 28 for the first time since March 16. Hospitalizations peaked at 2,862 in late December.
The greatest increase has been in southwest Missouri and Steve Edwards, CEO of CoxHealth in Springfield, has been outspoken in his contempt for people who doubt the effectiveness of the vaccine or the danger from COVID-19.
32% symptomatic pos. rate, very concerning! (From 4%) 4 pediatric Covid inpatients yesterday. Age…a few weeks old to 18 y/o
If you are making wildly disparaging comments about the vaccine, and have no public health expertise, you may be responsible for someone’s death. Shut up.
His hospitals are treating 74 COVID-19 cases, including four pediatric patients, he tweeted Thursday. The children range in age from a few weeks old to 18.
“If you are making wildly disparaging comments about the vaccine, and have no public health expertise, you may be responsible for someone’s death,” Edwards wrote. “Shut up.”
The Army has directed commands to prepare to administermandatory COVID-19 vaccinesas early as Sept. 1, pending full Food and Drug Administration licensure, Army Times has learned.
The directive came from an execute order sent to the force by Department of the Army Headquarters.
Army Times obtained a portion of a recent update to HQDA EXORD 225-21, COVID-19 Steady State Operations.
“Commanders will continue COVID-19 vaccination operations and prepare for a directive to mandate COVID-19 vaccination for service members [on or around] 01 September 2021, pending full FDA licensure,” the order said. “Commands will be prepared to provide a backbrief on servicemember vaccination status and way ahead for completion once the vaccine is mandated.”
EXORDS are utilized when the president directs the defense secretary to execute a military operation.
“As a matter of policy we do not comment on leaked documents. The vaccine continues to be voluntary,” said Maj. Jackie Wren, an Army spokesperson. “If we are directed by DoD to change our posture, we are prepared to do so.”
The Pentagon has not put out any guidance to the services to prepare for a mandatory vaccine roll-out in September, a defense official separately told Army Times.
It was not immediately clear whether the vaccines would even be approved in time for a Sept. 1 mandatory rollout. And an FDA spokesperson did not have an exact timeline available.
The ”timelines for vaccine approval may vary depending on a number of factors, but as Pfizerand Moderna announced, they have initiated rolling submissions of their biologics license applications for their COVID-19 vaccines,” said Alison Hunt, an FDA spokesperson. “As a general matter, FDA cannot comment on particular applications.”
Once the companies finish collecting biologics license application data on their vaccines, the FDA will take 60 days to review the applications for full approval, in accordance with the agency’s guidelines for priority review.
The Army currently has around 70 percent of its force vaccinated against the coronavirus, according to Army Lt. Gen. Ronald Place, director of the Defense Health Agency.
However, demand for the vaccine has fallen off in recent months across the military, roughly following a similar drop in demand among the American people.
The Veterans Affairs administration is currently weighing a plan to require all VA staffers to receive the vaccine, amid growing worry worldwide about the more severe Delta variant of the virus.
The Navy also recently told sailors to expect a mandatory vaccination program despite having the highest vaccine acceptance rate thus far.
Other than running a placebo-controlled, clinical trial lasting many months and involving tens of thousands of people, is there any way to be sure a COVID-19 vaccine will work? Many researchers contend that the success of several vaccines now widely in use offers a shortcut: Simply gauge a vaccine’s ability to elicit so-called neutralizing antibodies, which bind to the virus and prevent it from entering cells. But several recent studies, the latest published as a preprint on 24 June, point to other “correlates of protection”: “binding” antibodies—which latch on to the virus but don’t block entry—and another set of immune warriors called T cells.
Vaccine decisions may soon depend on a better understanding of these supporting actors. Several companies are developing updates of their COVID-19 vaccines tailored to protect against new viral variants, and they hope regulatory agencies won’t require that they show efficacy in big clinical trials, which are not only time-consuming and expensive, but also increasingly ethically fraught because some of the participants receive a placebo even though proven vaccines are now available.
With an established correlate of protection, trials can give an updated vaccine to a much smaller group of participants and then check whether they produce the telltale immune responses. (That’s how the annual updates of flu vaccines are approved.) Health officials may also turn to correlates when they consider prioritizing existing COVID-19 vaccines, authorizing new “mix and match” combinations, or even when making decisions about entirely new vaccines.
But finding robust correlates has been challenging. During the megatrials that led to the authorization of COVID-19 vaccines, investigators monitored antibody responses and tried to correlate them with their odds of participants getting sick. Different trials, however, used different antibody assays and different definitions of mild COVID-19, the main endpoint in the trials. “It’s anarchy because it’s always been anarchy,” says John Moore, an immunologist at Weill Cornell Medicine. “You’re dealing with different academic labs and different companies, and companies tend not to talk to each other.” Many trials also lacked the statistical power to measure protection from hospitalization and death, arguably a COVID-19 vaccine’s most important task. And few trials even looked carefully at T cells, which are far more cumbersome to measure.
Still, two studies—first published as preprints in March here and here—confirmed the prediction by Moore and many other scientists that neutralizing antibodies (“neuts”) play a key role. To “normalize” the different assays used in the trials, they compared levels of antibody elicited by each vaccine with antibodies found in people who naturally became infected in the trial’s placebo group. In both analyses, the vaccines that triggered higher levels of neuts than the ones typically seen in recovered people offered the best protection—strong evidence of a correlation, Moore says.
“That’s a great relief to me,” says Penny Moore, a virologist at the National Health Laboratory Service in South Africa, who helped measure protective immune responses in different vaccine trials and was “really puzzled” by the results. But she and others suspected neuts are far from the whole story. “I just cannot work out for the life of me how much [other immune responses] are contributing and where they’re contributing,” she says.
During the efficacy trials of the messenger RNA (mRNA) vaccines made by the Pfizer-BioNTech collaboration and Moderna, for example, the first shot of both vaccines triggered barely measurable levels of neutralizing antibodies, but still offered substantial protection. “It suggests there’s more than neutralizing antibodies going on here,” says David Montefiori, an immunologist at Duke University who runs a lab that measures neuts for a handful of COVID-19 vaccine trials sponsored by the U.S. government. Neuts skyrocketed only after the second mRNA shot, when protection rose to more than 90%.
T cells, which coordinate the B cells that produce antibodies but also clear infected cells when neuts falter, appear to bolster the defense. In a study published in February that included 12 patients whose COVID-19 ranged from mild to fatal, a team led by immunologist Antonio Bertoletti of the Duke–National University of Singapore Medical School reported that patients who early on had the highest levels of immune system messengers that kick T cells into action—an indirect, but relatively simple, way to measure their presence—had milder disease because they cleared the infection faster.
Penny Moore and colleagues also found support for a role for T cells. In an 11 June preprint, they reported that 96% of participants in an efficacy trial of the COVID-19 vaccine produced by Johnson & Johnson (J&J) made antibodies that neutralized a viral strain from early in the pandemic but only 19% had antibodies that neutralized the Beta variant, which is widespread in South Africa and infamous for dodging neuts. Yet despite the variant, the vaccine remained protective against moderate and severe COVID-19. “I think it’s entirely plausible … that T cells are doing something really useful here,” Penny Moore says. A monkey study with this vaccine, published in Nature last year, also showed that T cells contributed substantially to control of the virus if neut levels weren’t high enough to do the job.
Binding antibodies may also be more important than researchers assumed. The 24 June preprint, by researchers from the University of Oxford, found that high levels of neuts correlated with the 80% protection achieved 28 days after participants in the United Kingdom received two shots of the vaccine the team developed with AstraZeneca. But digging more deeply into the data revealed that binding antibodies were as good as a correlate—if not better.
It’s not clear exactly why, because binding antibodies don’t directly block the infection process. One possibility is that they make the virus more susceptible to being gobbled up by macrophages or other cells that ingest intruders. This mechanism, called phagocytosis, protected children from severe COVID-19, immunologist Galit Alter of the Ragon Institute of MGH, MIT and Harvard reported in Nature Medicine in March. Then again, it may be that binding antibodies are produced in lockstep with neuts, but at higher levels, and are simply a surrogate marker.
Work by virologist Shane Crotty and Alessandro Sette of the La Jolla Institute for Immunology has shown that people handle SARS-CoV-2 most effectively if they have T cells and antibodies working in sync, as they showed in a study of the immune reactions of 24 COVID-19 patients whose disease ranged from mild to fatal. “The immune system figures out how to use all the weapons at its disposal,” Crotty says.
South Africa, which has fewer than 1% of its population fully vaccinated amid an exploding epidemic, has shown the potential pitfalls of overemphasizing neuts. In February, the country abandoned the AstraZeneca-Oxford vaccine after it had a disappointing 22% efficacy against mild disease in a large trial. Test tube analyses seemed to support the decision: Antibodies triggered by the vaccine had far less neutralizing power against the Beta variant, which then accounted for nearly all infections. But Penny Moore’s study of the J&J vaccine has subsequently shown that disappointing levels of neutralizing antibodies don’t keep a vaccine from providing good protection against severe disease. “Our obsession with neuts may mean that we missed an opportunity here for AstraZeneca,” she says.
Other scientists counter that it makes sense to use neuts as a gauge to rank the relative powers of different vaccines, but acknowledge that this will require standardized assays. Chinese researchers in the 23 June issue of Vaccine published national standards for SARS-CoV-2 neutralization assays. “This has not been the most important priority, but it’s going to become one if we move away from phase 3 trials,” John Moore says.
With the picture still muddy, regulators need to decide whether correlates of protection should offer vaccinemakers a shortcut to bringing improved products to market. Pfizer and Moderna are developing next generation candidates designed to create high levels of neutralizing antibodies against the Beta variant, and the U.S. Food and Drug Administration (FDA) has signaled that it will accept this correlate of protection for approval decisions. “Even though we might not get the perfect surrogate—it might mediate partial protection—that could be good enough,” says Peter Gilbert, a biostatistician who designs clinical trials at the Fred Hutchinson Cancer Research Center. “We don’t need perfection here.”
But Alter worries regulators relying on neuts might approve unnecessary booster shots simply because they outdo existing shots on that measure. “If [regulators] don’t adapt, we’re going to end up overboosting, and we’re going to be making the drug companies really happy,” she says.
It’s also unclear whether a convincing correlate from a vaccine that uses, say, mRNA, applies to one that uses a different platform like a viral vector. “We’re hoping to have more immune correlate of protection information before updates on that,” says Peter Marks, who heads FDA’s vaccine division.
With more than a dozen vaccines now in use, that information may arrive soon, Sette says. Although companies typically control the data from clinical trials, academic labs can now compare recipients of different vaccines, he says. “In the next few months, all the different labs will be generating analyses of what different vaccines do and a large amount of data will be generated in academic labs,” Sette says. “There’s going to be a fundamental wealth of information.”
