Posted on by Dr. Francis Collins
A key issue as we move closer to ending the pandemic is determining more precisely how long people exposed to SARS-CoV-2, the COVID-19 virus, will make neutralizing antibodies against this dangerous coronavirus. Finding the answer is also potentially complicated with new SARS-CoV-2 “variants of concern” appearing around the world that could find ways to evade acquired immunity, increasing the chances of new outbreaks.
Now, a new NIH-supported study shows that the answer to this question will vary based on how an individual’s antibodies against SARS-CoV-2 were generated: over the course of a naturally acquired infection or from a COVID-19 vaccine. The new evidence shows that protective antibodies generated in response to an mRNA vaccine will target a broader range of SARS-CoV-2 variants carrying “single letter” changes in a key portion of their spike protein compared to antibodies acquired from an infection.
These results add to evidence that people with acquired immunity may have differing levels of protection to emerging SARS-CoV-2 variants. More importantly, the data provide further documentation that those who’ve had and recovered from a COVID-19 infection still stand to benefit from getting vaccinated.
These latest findings come from Jesse Bloom, Allison Greaney, and their team at Fred Hutchinson Cancer Research Center, Seattle. In an earlier study, this same team focused on the receptor binding domain (RBD), a key region of the spike protein that studs SARS-CoV-2’s outer surface. This RBD is especially important because the virus uses this part of its spike protein to anchor to another protein called ACE2 on human cells before infecting them. That makes RBD a prime target for both naturally acquired antibodies and those generated by vaccines. Using a method called deep mutational scanning, the Seattle group’s previous study mapped out all possible mutations in the RBD that would change the ability of the virus to bind ACE2 and/or for RBD-directed antibodies to strike their targets.
In their new study, published in the journal Science Translational Medicine, Bloom, Greaney, and colleagues looked again to the thousands of possible RBD variants to understand how antibodies might be expected to hit their targets there . This time, they wanted to explore any differences between RBD-directed antibodies based on how they were acquired.
Again, they turned to deep mutational scanning. First, they created libraries of all 3,800 possible RBD single amino acid mutants and exposed the libraries to samples taken from vaccinated individuals and unvaccinated individuals who’d been previously infected. All vaccinated individuals had received two doses of the Moderna mRNA vaccine. This vaccine works by prompting a person’s cells to produce the spike protein, thereby launching an immune response and the production of antibodies.
By closely examining the results, the researchers uncovered important differences between acquired immunity in people who’d been vaccinated and unvaccinated people who’d been previously infected with SARS-CoV-2. Specifically, antibodies elicited by the mRNA vaccine were more focused to the RBD compared to antibodies elicited by an infection, which more often targeted other portions of the spike protein. Importantly, the vaccine-elicited antibodies targeted a broader range of places on the RBD than those elicited by natural infection.
These findings suggest that natural immunity and vaccine-generated immunity to SARS-CoV-2 will differ in how they recognize new viral variants. What’s more, antibodies acquired with the help of a vaccine may be more likely to target new SARS-CoV-2 variants potently, even when the variants carry new mutations in the RBD.
It’s not entirely clear why these differences in vaccine- and infection-elicited antibody responses exist. In both cases, RBD-directed antibodies are acquired from the immune system’s recognition and response to viral spike proteins. The Seattle team suggests these differences may arise because the vaccine presents the viral protein in slightly different conformations.
Also, it’s possible that mRNA delivery may change the way antigens are presented to the immune system, leading to differences in the antibodies that get produced. A third difference is that natural infection only exposes the body to the virus in the respiratory tract (unless the illness is very severe), while the vaccine is delivered to muscle, where the immune system may have an even better chance of seeing it and responding vigorously.
Whatever the underlying reasons turn out to be, it’s important to consider that humans are routinely infected and re-infected with other common coronaviruses, which are responsible for the common cold. It’s not at all unusual to catch a cold from seasonal coronaviruses year after year. That’s at least in part because those viruses tend to evolve to escape acquired immunity, much as SARS-CoV-2 is now in the process of doing.
The good news so far is that, unlike the situation for the common cold, we have now developed multiple COVID-19 vaccines. The evidence continues to suggest that acquired immunity from vaccines still offers substantial protection against the new variants now circulating around the globe.
The hope is that acquired immunity from the vaccines will indeed produce long-lasting protection against SARS-CoV-2 and bring an end to the pandemic. These new findings point encouragingly in that direction. They also serve as an important reminder to roll up your sleeve for the vaccine if you haven’t already done so, whether or not you’ve had COVID-19. Our best hope of winning this contest with the virus is to get as many people immunized now as possible. That will save lives, and reduce the likelihood of even more variants appearing that might evade protection from the current vaccines.
 Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Greaney AJ, Loes AN, Gentles LE, Crawford KHD, Starr TN, Malone KD, Chu HY, Bloom JD. Sci Transl Med. 2021 Jun 8.
COVID-19 Research (NIH)
Bloom Lab (Fred Hutchinson Cancer Research Center, Seattle)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
While primarily a respiratory disease, COVID-19 can also lead to neurological problems. The first of these symptoms might be the loss of smell and taste, while some people also may later battle headaches, debilitating fatigue, and trouble thinking clearly, sometimes referred to as “brain fog.” All of these symptoms have researchers wondering how exactly the coronavirus that causes COVID-19, SARS-CoV-2, affects the human brain.
In search of clues, researchers at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have now conducted the first in-depth examinations of human brain tissue samples from people who died after contracting COVID-19. Their findings, published in the New England Journal of Medicine, suggest that COVID-19’s many neurological symptoms are likely explained by the body’s widespread inflammatory response to infection and associated blood vessel injury—not by infection of the brain tissue itself .
The NIH team, led by Avindra Nath, used a high-powered magnetic resonance imaging (MRI) scanner (up to 10 times as sensitive as a typical MRI) to examine postmortem brain tissue from 19 patients. They ranged in age from 5 to 73, and some had preexisting conditions, such as diabetes, obesity, and cardiovascular disease.
The team focused on the brain’s olfactory bulb that controls our ability to smell and the brainstem, which regulates breathing and heart rate. Based on earlier evidence, both areas are thought to be highly susceptible to COVID-19.
Indeed, the MRI images revealed in both regions an unusual number of bright spots, a sign of inflammation. They also showed dark spots, which indicate bleeding. A closer look at the bright spots showed that tiny blood vessels in those areas were thinner than normal and, in some cases, leaked blood proteins into the brain. This leakage appeared to trigger an immune reaction that included T cells from the blood and the brain’s scavenging microglia. The dark spots showed a different pattern, with leaky vessels and clots but no evidence of an immune reaction.
While those findings are certainly interesting, perhaps equally noteworthy is what Nath and colleagues didn’t see in those samples. They could find no evidence in the brain tissue samples that SARS-CoV-2 had invaded the brain tissue. In fact, several methods to detect genetic material or proteins from the virus all turned up empty.
The findings are especially intriguing because there has been some suggestion based on studies in mice that SARS-CoV-2 might cross the blood-brain barrier and invade the brain. Indeed, a recent report by NIH-funded researchers in Nature Neuroscience showed that the viral spike protein, when injected into mice, readily entered the brain along with many other organs .
Another recent report in the Journal of Experimental Medicine, which used mouse and human brain tissue, suggests that SARS-CoV-2 may indeed directly infect the central nervous system, including the brain . In autopsies of three people who died from complications of COVID-19, the NIH-supported researchers detected signs of SARS-CoV-2 in neurons in the brain’s cerebral cortex. This work was done using the microscopy-based technique of immunohistochemistry, which uses antibodies to bind to a target, in this case, the virus’s spike protein. Also last month, in a study published in the journal Neurobiology of Disease, another NIH-supported team demonstrated in a series of experiments in cell culture that the SARS-CoV-2 spike protein could cross a 3D model of the blood-brain barrier and infect the endothelial cells that line blood vessels in the brain .
Clearly, more research is needed, and NIH’s National Institute of Neurological Disorders and Stroke has just launched the COVID-19 Neuro Databank/Biobank (NeuroCOVID) to collect more clinical information, primarily about COVID-19-related neurological symptoms, complications, and outcomes. Meanwhile, Nath and colleagues continue to explore how COVID-19 affects the brain and triggers the neurological symptoms often seen in people with COVID-19. As we learn more about the many ways COVID-19 wreaks havoc on the body, understanding the neurological symptoms will be critical in helping people, including the so-called Long Haulers bounce back from this terrible viral infection.
 Microvascular Injury in the Brains of Patients with Covid-19. Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. N Engl J Med. 2020 Dec 30.
 The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice. Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA. Nat Neurosci. 2020 Dec 16.
 Neuroinvasion of SARS-CoV-2 in human and mouse brain. Song E, Zhang C, Israelow B, et al. J Exp Med (2021) 218 (3): e20202135.
 The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, Bullock TA, McGary HM, Khan JA, Razmpour R, Hale JF, Galie PA, Potula R, Andrews AM, Ramirez SH. Neurobiol Dis. 2020 Dec;146:105131.
COVID-19 Research (NIH)
Avindra Nath (National Institute of Neurological Disorders and Stroke/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging; National Institute of General Medical Sciences; National Cancer Institute; National Institute of Mental Health
Posted on by Dr. Francis Collins
Throughout the COVID-19 pandemic, healthcare workers around the world have shown willingness to put their own lives on the line for their patients and communities. Unfortunately, many have also contracted SARS-CoV-2, the coronavirus that causes of COVID-19, while caring for patients. That makes these frontline heroes helpful in another way in the fight against SARS-CoV-2: determining whether people who have recovered from COVID-19 can be reinfected by the virus.
New findings from a study of thousands of healthcare workers in England show that those who got COVID-19 and produced antibodies against the virus are highly unlikely to become infected again, at least over the several months that the study was conducted. In the rare instances in which someone with acquired immunity for SARS-CoV-2 subsequently tested positive for the virus within a six month period, they never showed any signs of being ill.
Some earlier studies have shown that people who survive a COVID-19 infection continue to produce protective antibodies against key parts of the virus for several months. But how long those antibodies last and whether they are enough to protect against reinfection have remained open questions.
In search of answers, researchers led by David Eyre, University of Oxford, England, looked to more than 12,000 healthcare workers at Oxford University Hospitals from April to November 2020. At the start of the study, 11,052 of them tested negative for antibodies against SARS-CoV-2, suggesting they hadn’t had COVID-19. But the other 1,246 tested positive for antibodies, evidence that they’d already been infected.
After this initial testing, all participants received antibody tests once every two months and diagnostic tests for an active COVID-19 infection at least every other week. What the researchers discovered was rather interesting. Eighty-nine of the 11,052 healthcare workers who tested negative at the outset later got a symptomatic COVID-19 infection. Another 76 individuals who originally tested negative for antibodies tested positive for COVID-19, despite having no symptoms.
Here’s the good news: Just three of these more than 1400 antibody-positive individuals subsequently tested positive for SARS-CoV-2. What’s more, not one of them had any symptoms of COVID-19.
The findings, which were posted as a pre-print on medRxiv, suggest that acquired immunity from an initial COVID-19 infection offers protection against reinfection for six months or maybe longer. Questions remain about whether the acquired immunity is due to the observed antibodies alone or their interplay with other immune cells. It will be important to continue to follow these healthcare workers even longer, to learn just how long their immune protection might last.
Meanwhile, more than 15 million people in the United States have now tested positive for COVID-19, leading to more than 285,000 deaths. Last week, the U.S. reported for the first time more than 200,000 new infections, with hospitalizations and deaths also on the rise.
While the new findings on reinfection come as good news to be sure, it’s important to remember that the vast majority of the 328 million Americans still remain susceptible to this life-threatening virus. So, throughout this holiday season and beyond—as we eagerly await the approval and widespread distribution of vaccines—we must all continue to do absolutely everything we can to protect ourselves, our loved ones, and our communities from COVID-19.
 Antibodies to SARS-CoV-2 are associated with protection against reinfection. Lumley, S.F. et al. MedRxiv. 19 November 2020.
Coronavirus (COVID) (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
David Eyre (University of Oxford, England)