Virus World

n 2017, three leading vaccine researchers submitted a grant application with an ambitious goal. At the time, no one had proved a vaccine could stop even a single beta coronavirus—the notorious viral group then known to include the lethal agents of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as several causes of the common cold and many bat viruses. But these researchers wanted to develop a vaccine against them all. Grant reviewers at the National Institute of Allergy and Infectious Diseases (NIAID) deemed the plan “outstanding.” But they gave the proposal a low priority score, dooming its bid for funding. “The significance for developing a pan-coronavirus vaccine may not be high,” they wrote, apparently unconvinced that the viruses pose a global threat. How things have changed. As the world nears 3 million deaths from the latest coronavirus in the spotlight, SARS-CoV-2, NIAID and other funders have had a major change of heart. In November 2020, the agency solicited applications for “emergency awards” to pursue pancoronavirus vaccine development. And in March, the Coalition for Epidemic Preparedness Innovations (CEPI), an international nonprofit launched in 2017, announced it would spend up to $200 million on a new program to accelerate the creation of vaccines against beta coronaviruses, a family that now includes SARS-CoV-2.

The threat of another coronavirus pandemic now seems very real. Beyond bats, coronaviruses infect camels, birds, cats, horses, mink, pigs, rabbits, pangolins, and other animals from which they could jump into human populations with little to no immunity, as most researchers suspect SARS-CoV-2 did. “Chances are, in the next 10 to 50 years, we may have another outbreak like SARS-CoV-2,” says structural biologist Andrew Ward of Scripps Research, one of the scientists who submitted the 2017 proposal NIAID rejected. The agency has not given out any of its new awards yet, but Ward’s lab is already pursuing a vaccine targeting a subset of beta coronaviruses. Some two dozen other research groups around the world have similar pancoronavirus vaccine projects underway. Their approaches include novel nanocages arrayed with viral particles, the cutting-edge messenger RNA (mRNA) technique at the heart of proven COVID-19 vaccines, and cocktails of inactivated viruses, the mainstay of past vaccines. A few teams have even published promising results from animal tests of early candidates. No pancoronavirus vaccine has entered human trials, and how to evaluate a candidate’s protection against diseases that have not yet emerged remains a challenge. Nor is it clear how such a vaccine might be used. One possibility: keeping it in reserve until a new human threat emerges. “We might be able to prime everybody to get a basic level of immunity” against the emerging virus, buying time to make a more specific vaccine, Ward says. Despite the many unknowns, the rapid success of vaccines against SARS-CoV-2 has sparked optimism. This coronavirus doesn’t seem particularly difficult to foil with a vaccine, which raises hopes that the immune system can be trained to outwit its relatives, too. Survivors of SARS years ago provide more encouragement: Some of their antibodies—an immune memory of that viral encounter—can also stymie the infectivity of SARS-CoV-2 in lab dishes. NIAID’s Barney Graham, who helped develop Moderna’s mRNA COVID-19 vaccine, shares the optimism about pancoronavirus vaccines. “Compared to flu and HIV, this is going to be relatively easy to accomplish,” he predicts.

EARLIER THIS YEAR, Hannah Turner, a technician at Scripps Research who works with Ward, took a cold, hard look at a now infamous protein: SARS-CoV-2’s spike, which enables the virus to infect cells and is at the heart of several successful COVID-19 vaccines. All coronaviruses have these spikes, which create the distinctive crownlike appearance that earned them their name, and most pancoronavirus vaccine efforts aim to rouse an immune response to some part of the spike protein. On this February morning, Turner mixes labmade copies of the SARS-CoV-2 spike with “broadly neutralizing” antibodies harvested from COVID-19 patients. These antibodies powerfully prevent multiple variants of SARS-CoV-2, as well as the original SARS virus, SARS-CoV, from infecting susceptible cells in test tube studies. Turner then freezes the spike-antibody mixtures with liquid nitrogen and places the resulting crystals in a $4 million microscope the size of three refrigerators. It begins bombarding the samples with up to 200 kilovolts of electrons to map the spike-antibody complexes at atomic resolution—an increasingly popular technique called cryo–electron microscopy (cryo-EM). What resembles a telescope view of lunar landscapes unfolds across four monitors. Turner’s trained eye spots the crystallized spike proteins, clumped together in groups of three called trimers and studded with antibodies. She points out one of the fanlike structures. “It’s pretty cool,” she says. “This is what you want to see.” The computers over the next few days will sort through 1100 different angles of her sample, migrating the best views into software that creates a gorgeous “final map” of spike with an attached antibody, at a resolution that approaches 3 angstroms, just a tad thicker than a strand of DNA. By creating similar portraits of spikes from many different coronaviruses with broadly neutralizing antibodies bound to them, Ward hopes to identify short segments of the protein—so-called epitopes—key to that binding for all the pathogens. Those epitopes, Ward believes, are the key to designing a vaccine that can trigger a broad immune attack on coronaviruses....

Published in Science (April 15, 2021):

https://doi.org/10.1126/science.abi9939

The world is in uncharted waters for the 2020 respiratory virus season. For the first time in modern history, the Northern Hemisphere faces the prospect of the coronavirus disease 2019 (COVID-19) pandemic and a simultaneous epidemic of seasonal influenza. Each causes life-threatening illness and death, especially in older adults, people with chronic diseases, and other vulnerable populations. How can we prepare for this convergence?

The timing and severity of a COVID-19 wave in the fall and winter are uncertain, but past experiences with the 1918 and 1957 influenza pandemics point to the possibility of a resurgence. Almost nothing is known about the interaction of influenza virus and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, the cause of COVID-19) within individuals. Does coinfection increase the risk of severe illness or amplify virus shedding? Few coinfections have been reported from China during the early phase of the pandemic. The Southern Hemisphere influenza season is just beginning, and it may provide some clues as to what can be expected in the Northern Hemisphere later this year.

Much of the population remains susceptible to SARS-CoV-2, and the stress on hospitals will be greatest if the COVID-19 and influenza epidemics overlap and peak around the same time. It is possible that the number of individuals infected with each virus will peak at different times, reducing the peak demand for hospital beds. If a surge in COVID-19 cases occurs this fall, tightening mitigation strategies will be necessary. Social distancing and stay-at-home orders are socially and economically disruptive, but can reduce demand on hospitals and protect vulnerable populations. They will also reduce transmission of other respiratory viruses, including influenza and respiratory syncytial virus. Supplies of personal protective equipment must sufficiently meet the projected demand of a severe influenza season along with COVID-19....

Published in Science (June 12, 2020):

https://doi.org/10.1126/science.abd2220

On 22 January, Dave O’Connor and Tom Friedrich invited several dozen colleagues around the United States to join a new workspace on the instant messaging platform Slack. The scientists, both at the Wisconsin National Primate Research Center, had seen news about a new disease emerging in China and realized researchers would need a primate model if they were going to answer some important questions about its biology. “We put out a call to a bunch of investigators and basically said: ‘Hey, let’s talk,’” O’Connor says. The idea is to coordinate research and make sure results are comparable, Friedrich adds. (They named the Slack workspace the Wu-han Clan, a play on the hip-hop group Wu-Tang Clan.)

The Wu-han Clan is just one example of how the COVID-19 outbreak is transforming how scientists communicate about fast-moving health crises. A torrent of data is being released daily by preprint servers that didn’t even exist a decade ago, then dissected on platforms such as Slack and Twitter, and in the media, before formal peer review begins. Journal staffers are working overtime to get manuscripts reviewed, edited, and published at record speeds. The venerable New England Journal of Medicine (NEJM) posted one COVID-19 paper within 48 hours of submission. Viral genomes posted on a platform named GISAID, more than 200 so far, are analyzed instantaneously by a phalanx of evolutionary biologists who share their phylogenetic trees in preprints and on social media.

“This is a very different experience from any outbreak that I’ve been a part of,” says epidemiologist Marc Lipsitch of the Harvard T.H. Chan School of Public Health. The intense communication has catalyzed an unusual level of collaboration among scientists that, combined with scientific advances, has enabled research to move faster than during any previous outbreak. “An unprecedented amount of knowledge has been generated in 6 weeks,” says Jeremy Farrar, head of the Wellcome Trust....

Primate centers band together for study rejected by Operation Warp Speed. Primate researchers in the United States have banded together in a push for an ambitious monkey study that would do head-to-head comparisons of the leading COVID-19 vaccine candidates. Although 10 candidates are already undergoing large-scale tests in people, proponents of the monkey plan say those clinical trials may not deliver the comprehensive data needed to choose the safest and most effective vaccines. The comparison trial in monkeys, in contrast, could shed light in a matter of weeks on how the candidates stack up on measures including potential side effects, the strength of immune responses they trigger, and how well they protect against infection and disease. “We should take a cold, hard look at all of the data and ask ourselves, ‘What appears to work best?’” says Nancy Haigwood, who directs the Oregon National Primate Research Center and is a key advocate for the comparative monkey study.

The proposed monkey vaccine comparison faces hurdles: It would add to the pressure on the dwindling U.S. supply of research monkeys, potentially delaying research on other diseases, and it does not yet have funding. Haigwood says she expected the U.S. government would gladly support the effort, which would cost an estimated $10 million, compared with the $10 billion the Trump administration’s Operation Warp Speed has already devoted to a COVID-19 vaccine push. But facing a lack of interest by current Warp Speed officials, Haigwood and colleagues at the six other national primate research centers are now turning to the National Institutes of Health (NIH) for support. Most developers of the vaccine candidates in efficacy trials have already published how well each works in monkeys against a “challenge” with SARS-CoV-2—a deliberate exposure to the pandemic coronavirus that causes COVID-19. But the details of how the experiments were conducted and the ways the results were analyzed differ so profoundly that immunologist John Moore of Weill Cornell Medicine says he can’t make sense of how the candidates compare. “It’s comparing apples to oranges and bananas,” says Moore, who has co-authored a review, on preprint.org, that compares the various monkey studies. 

The human vaccine trials, for their part, are likely to yield only preliminary signals of efficacy over the next few months, not clear-cut evidence that one or more is safe and protects people. “We’re going to get data dribbling in from clinical trials,” says Haigwood, a veteran AIDS vaccine researcher. The data from the many human trials, some in multiple countries, will also be tough to compare. Jay Rappaport, who heads the Tulane National Primate Research Center, notes the trial populations differ and are infected by different variants of SARS-CoV-2. In addition, the human trials—as with the monkey experiments—often use different assays to measure immune responses. “There’s so much variation in the primate studies, but there’s even more variation in the human studies,” Rappaport says. In contrast to the human trials that must wait for enough participants to become naturally infected to gauge a vaccine’s worth, Haigwood says, monkey challenge studies could deliver definitive results quickly. She says the monkey comparison could start as soon as this month and would require only about 6 weeks to vaccinate animals, challenge them, and assess their immune responses and levels of protection...

This video explains how SARS-CoV-2, the virus that causes COVID-19, can severely damage lungs, but in serious cases it doesn’t stop there. Clinicians have observed body-wide damage due to the coronavirus. As researchers begin to better understand the pathology of the disease, new treatments can be deployed to help save lives.