Virus World

Hope for a future without fear of COVID-19 comes down to circulating antibodies and memory B cells. Unlike circulating antibodies, which peak soon after vaccination or infection only to fade a few months later, memory B cells can stick around to prevent severe disease for decades. And they evolve over time, learning to produce successively more potent "memory antibodies" that are better at neutralizing the virus and more capable of adapting to variants. Vaccination produces greater amounts of circulating antibodies than natural infection. But a new study suggests that not all memory B cells are created equal. While vaccination gives rise to memory B cells that evolve over a few weeks, natural infection births memory B cells that continue to evolve over several months, producing highly potent antibodies adept at eliminating even viral variants.  The findings highlight an advantage bestowed by natural infection rather than vaccination, but the authors caution that the benefits of stronger memory B cells do not outweigh the risk of disability and death from COVID-19. "While a natural infection may induce maturation of antibodies with broader activity than a vaccine does—a natural infection can also kill you," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman professor and head of Rockefeller's Laboratory of Molecular Immunology. "A vaccine won't do that and, in fact, protects against the risk of serious illness or death from infection."

Your body on COVID-19

When any virus enters the body, immune cells immediately churn out hordes of circulating antibodies. Foot soldiers of the immune system, these antibodies burn bright but decay at variable rates depending on the vaccine or infection—they may protect us for months or years but then dwindle in number, allowing possible reinfection. The immune system has a backup plan: an elite cadre of memory B cells that outlive circulating antibodies to produce so-called memory antibodies that provide long-term protection. Studies suggest that memory B cells for smallpox last at least 60 years after vaccination; those for Spanish flu, nearly a century. And while memory B cells don't necessarily block reinfection, they can prevent severe disease. Recent studies have suggested that within five months of receiving a vaccine or recovering from a natural infection, some of us no longer retain sufficient circulating antibodies to keep the novel coronavirus at bay, but our memory B cells stand vigilant. Until now, however, scientists did not know whether the vaccines could be expected to provide the sort of robust memory B cell response seen after natural infection.

The convalescent advantage

Nussenzweig and colleagues resolved to tease out any differences in memory B cell evolution by comparing blood samples from convalescent COVID-19 patients to those from mRNA-vaccinated individuals who had never suffered natural infection. Vaccination and natural infection elicited similar numbers of memory B cells. Memory B cells rapidly evolved between the first and second dose of the Pfizer and Moderna vaccines, producing increasingly potent memory antibodies. But after two months, progress stalled. The memory B cells were present in large numbers and expressed potent antibodies, but the antibodies were not getting any stronger. Also, although some of these antibodies were able to neutralize Delta and other variants, there was no overall improvement in breadth. With convalescent patients, on the other hand, memory B cells continued to evolve and improve up to one year after infection. More potent and more broadly neutralizing memory antibodies were coming out with every memory B cell update.

To boost or not to boost

There are several potential reasons that memory B cells produced by natural infection might be expected to outperform those produced by mRNA vaccines, the researchers say. It is possible that the body responds differently to viruses that enter through the respiratory tract than those that are injected into our upper arms. Or perhaps an intact virus goads the immune system in a way that the lone spike protein represented by the vaccines simply cannot. Then again, maybe it's that the virus persists in the naturally infected for weeks, giving the body more time to mount a robust response. The vaccine, on the other hand, is flushed out of the body mere days after triggering the desired immune response. Regardless of the cause, the implications are clear. We can expect memory B cells to undergo limited volleys of evolution in response to mRNA vaccines, a finding that may have significant implications for the design and rollout of booster shots. A booster with the currently available mRNA vaccine would be expected to engage memory cells to produce circulating antibodies that are strongly protective against the original virus and somewhat less so against the variants, Nussenzweig says. "When to administer the booster depends on the object of boosting," he says. "If the goal is to prevent infection, then boosting will need to be done after 6 to 18 months depending on the immune status of the individual. If the goal is to prevent serious disease boosting may not be necessary for years."

See findings published in Nature (October 7, 2021):

https://doi.org/10.1038/s41586-021-04060-7

The Pfizer/BioNTech and Moderna Covid-19 vaccines are effective in pregnant and lactating women, who can pass protective antibodies to newborns, according to research published Thursday in the American Journal of Obstetrics and Gynecology. Researchers at Massachusetts General Hospital, Brigham and Women's Hospital and the Ragon Institute of MGH, MIT and Harvard looked at 131 women who received either the Pfizer/BioNTech or Moderna Covid-19 vaccine. Among the participants, 84 were pregnant, 31 were lactating and 16 were not pregnant. Samples were collected between December 17, 2020 and March 2, 2021.  The vaccine-induced antibody levels were equivalent in pregnant and lactating women, compared to non-pregnant women. The antibody levels were "strikingly higher" than those resulting from coronavirus infection during pregnancy, the team noted. "These vaccines seem to work incredibly effectively in these women," said one of the researchers, Galit Alter, a professor of medicine at the Ragon Institute.

The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa) and B.1.1.248 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of UK, South Africa and Brazil variant into human cells is susceptible to blockade by entry inhibitors. In contrast, entry of the South Africa and Brazil variant was partially (Casirivimab) or fully (Bamlanivimab) resistant to antibodies used for COVID-19 treatment and was less efficiently inhibited by serum/plasma from convalescent or BNT162b2 vaccinated individuals. These results suggest that SARS-CoV-2 may escape antibody responses, which has important implications for efforts to contain the pandemic.

Preprint available (Feb. 11. 2021):

https://doi.org/10.1101/2021.02.11.430787 

Background: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness.

Methods: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible.

Results: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P=0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed.

Conclusions: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163. opens in new tab.)

Published in NEJM (Jan. 6, 2021):

https://doi.org/10.1056/NEJMoa2033700

Antibody levels stayed elevated in the 90 days after people received the second dose of Moderna’s COVID-19 vaccine, raising hopes that the prophylactic can provide protection for one year. With Moderna and Pfizer, in partnership with BioNTech, showing mRNA vaccines provide protection against symptomatic COVID-19 in the short term, attention has turned to durability. The full picture of the durability of protection will only become clear over time, but immunogenicity data from the phase 1/2 trial of Moderna’s mRNA-1273 offer encouragement.  In a letter to The New England Journal of Medicine, scientists at the National Institute of Allergy and Infectious Diseases and other research centers presented updated data on 34 people who received the 100-μg dose of mRNA-1273 in the early-phase trial. The phase 3 trial used the same 100-μg dose. The researchers tracked a slight decline in levels of binding and neutralizing antibodies over the 90 days after the administration of the second dose. However, the geometric mean titers for both types of antibody remained above the median of a panel of 41 convalescent COVID-19 patients. The median time from diagnosis of contributors to the convalescent panel was 34 days. 

Researchers are yet to show what immune characteristics an individual needs to be protected against the coronavirus, limiting our ability to infer the real-world consequences of the antibody increases associated with any vaccine. However, the authors of the NEJM letter said the data show mRNA-1273 “has the potential to provide durable humoral immunity.” Analysts concurred with that assessment.    In a note to investors, analysts at Jefferies wrote, “mRNA-1273 induced neutralizing antibody levels stay relatively high and decline only modestly over the initial 3 months suggesting the trajectory of protection from symptomatic disease could last for at least 6 mos (though unclear), so an annual boost would seem good." The NEJM update also touched on the safety of the vaccine. No serious adverse events were seen in the small trial, and no new adverse events deemed related to the vaccine occurred after Day 57.  Moderna shared details of the NEJM letter alongside an update on its effort to scale up production. As previously disclosed, Moderna expects to make around 20 million doses available in the U.S. by the end of the year. That early delivery is set to be followed by the shipment of up to 125 million vaccines globally in the first quarter. The U.S. will get around 80% of the vaccines available in the first quarter...

Research cited published in NEJM (December 3, 2020):

https://doi.org/10.1056/NEJMc2032195

The evolution of SARS-CoV-2 humoral response in infected individuals remains poorly characterized. Here, we performed a longitudinal study of sera from 308 RT-qPCR+ individuals with mild disease, collected at two time-points, up to 6 months post-onset of symptoms (POS). We performed two anti-S and one anti-N serology assays and quantified neutralizing antibodies (NAbs). At month 1 (M1), males, individuals > 50 years of age or with a body mass index (BMI) > 25 exhibited higher levels of antibodies. Antibody levels decreased over time. At M3-6, anti-S antibodies persisted in 99% of individuals while anti-N IgG were measurable in only 59% of individuals. The decline in anti-S and NAbs was faster in males than in females, independently of age and BMI. Our results show that some serology tests are less reliable overtime and suggest that the duration of protection after SARS-CoV-2 infection or vaccination will be different in women and men.

Preprint available in medRxiv (Nov. 15, 2020):

https://doi.org/10.1101/2020.11.12.20230466

Clinical setbacks reported this past week by Regeneron Pharmaceuticals and Eli Lilly have raised questions about the effectiveness of antibody therapies in patients with severe COVID-19 compared to patients with mild-to-moderate forms of the virus. Regeneron said Friday it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing its two-antibody “cocktail” REGN-COV2 in hospitalized adult patients with COVID-19. In pausing enrollment of the sickest patients, Regeneron said it is following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment—but did say it would inform the FDA of its findings, since the agency is evaluating the company’s request for an emergency use authorization (EUA) of REGN-COV2 for in mild-to-moderate outpatients at high risk for poor outcomes. Regeneron is the second developer of a leading antibody candidate against COVID-19 to suffer a clinical setback this past week. On October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury™ (remdesivir) and placebo in people who have been hospitalized with COVID-19.

“Disappointing replication”

“A disappointing replication: monoclonal antibodies to #SARSCoV2 don’t provide benefit to hospitalized patients w/ moderate-severe illness,” tweeted Eric Topol, MD, founder and director of the Scripps Translational Research Institute, on Friday.  Topol, who is also professor, molecular medicine and executive vice president of Scripps Research, added that the Regeneron and Lilly disappointments reflected “the need to treat #COVID19 early or preventatively.” Florian Krammer, PhD, professor at the department of microbiology, Icahn School of Medicine at Mount Sinai, also noted in a Twitter thread that early in COVID-19, monoclonal antibodies and other antivirals are likely to help infected patients.  “Late in infection, our own immune system does the damage, and immunomodulatory drugs likely help at this stage (like dexamethasone),” Krammer said. “Using mAbs late (like in the trials stopped by Eli Lilly and Regeneron) was unlikely to work. But using them early is very promising.” Reflecting that promise, the IDMC in Regeneron’s hospitalized patient trial of REGN-COV2 also recommended continuing enrollment of the less severely injured hospitalized patients—namely those requiring either no or low-flow oxygen, “as the risk/benefit remains acceptable in these cohorts.” The trial has an estimated enrollment of 2,970 participants....

AstraZeneca’s long-acting antibody (LAAB) combination, AZD7442, will advance into two Phase III clinical trials in more than 6,000 participants at sites in and outside the US that are due to begin in the next weeks. The LAABs have been engineered with AstraZeneca’s proprietary half-life extension technology to increase the durability of the therapy for six to 12 months following a single administration. The combination of two LAABs is also designed to reduce the risk of resistance developed by the SARS-CoV-2 virus. The Company has received support of around $486m from the US Government for the development and supply of AZD7442 under an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the US Department of Health and Human Services, and the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense.

One trial will evaluate the safety and efficacy of AZD7442 to prevent infection for up to 12 months, in approximately 5,000 participants. The second trial will evaluate post-exposure prophylaxis and pre-emptive treatment in approximately 1,100 participants. AstraZeneca is planning additional trials to evaluate AZD7442 in approximately 4,000 patients for the treatment of COVID-19. AstraZeneca plans to supply up to 100,000 doses starting towards the end of 2020 and the US Government can acquire up to an additional one million doses in 2021 under a separate agreement. Pascal Soriot, Chief Executive Officer, said: “This agreement with the US Government will help accelerate the development of our long-acting antibody combination which has the potential to provide immediate and long-lasting effect in both preventing and treating COVID-19 infections. We will be evaluating the LAAB combination in different settings from prophylaxis, to outpatient treatment to hospitalisation, with a focus on helping the most vulnerable people.”

LAABs mimic natural antibodies and have the potential to treat and prevent disease progression in patients already infected with the virus, as well as to be given as a preventative intervention prior to exposure to the virus. A LAAB combination could be complementary to vaccines as a prophylactic agent, e.g. for people for whom a vaccine may not be appropriate or to provide added protection for high-risk populations. It could also be used to treat people who have been infected. Today’s agreement builds on previous funding of more than $25m from US government agencies BARDA and the Defense Advanced Research Projects Agency for the discovery and evaluation of the monoclonal antibodies, as well as the Phase I clinical trial started in August 2020 to assess safety, tolerability and pharmacokinetics of AZD7442 in healthy individuals.

The company said that doses of the unproven treatment would be available for 50,000 patients. It’s impossible to know whether it helped the president. The drugmaker Regeneron said on Wednesday that it had submitted an application to the Food and Drug Administration for emergency approval of the experimental antibody cocktail that President Trump had praised just hours earlier without evidence as a “cure” for the coronavirus. The company said access to the treatment would be extremely limited at first, with only enough doses for 50,000 patients, a far cry from the “hundreds of thousands” of doses that Mr. Trump, in a video released on Wednesday, said he would soon be making available to Americans free of charge. In the five-minute video, Mr. Trump said that it was a “blessing from God” that he had been infected with the coronavirus and that the Regeneron cocktail had suddenly made him feel better. “I felt unbelievable,” he said. “I felt good immediately.”  There is no evidence that the treatment is the reason he was feeling better, and his doctors have said he has taken other drugs as well. 

Mr. Trump gave the impression that he would push the F.D.A. to approve Regeneron’s treatment, even though the agency’s scientists are supposed to make independent decisions about approvals. “I have emergency-use authorization all set, and we’ve got to get it signed now,” Mr. Trump said. A spokeswoman for the F.D.A. declined to comment on Wednesday, saying the agency does not confirm or deny product applications. The news of Regeneron’s application on the same day that Mr. Trump effusively praised the unproven drug is likely to intensify fears that the president is pressuring federal health agencies to make decisions aimed at benefiting him politically. In the video, Mr. Trump repeated his desire to get a vaccine approved before the election on Nov. 3, even though the vaccine makers themselves have said that is highly unlikely...

During the first wave of the COVID-19 pandemic, fewer than 10% of the US adult population formed antibodies against SARS-CoV-2, and fewer than 10% of those with antibodie swere diagnosed. Public health efforts to limit SARS-CoV-2 spread need to especially
target racial and ethnic minority and densely populated communities. Many patients receiving dialysis in the USA share the socioeconomic characteristics of underserved communities, and undergo routine monthly laboratory testing, facilitating a practical, unbiased, and repeatable assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence.

The biotech company’s small preliminary study indicates the vaccine produced similar levels of antibodies for younger people and those aged 56 and older. Massachusetts-based biotech company Moderna said Wednesday that in a small trial, its experimental coronavirus vaccine produced a similar number of antibodies for people aged 56 years and older as younger adults in a preliminary study, a promising sign for the high-risk age group amid concern that vaccines wouldn’t offer as much protection for older adults. Older adults are at higher risk of hospitalization and death from Covid-19 than younger people and, because the immune system usually weakens with age, it can be harder for a vaccine to be effective, according to the U.S. Centers for Disease Control and Prevention. Moderna, which reported in July that its vaccine induced immune response and was generally safe and well tolerated in adults aged 18 to 55, said during a presentation to medical experts and advisors that it had expanded its study to a small group of older adults. Moderna tested its vaccine on 10 adults between the ages of 56 and 70 and 10 adults aged 71 and older and found that the older volunteers developed antibodies in a similar range as the younger volunteers; Moderna said the vaccine was well-tolerated with no serious side effects reported. Moderna presented the data, which has yet to be peer reviewed, Wednesday to a committee of outside experts to advise the U.S. Centers for Disease Control and Prevention on vaccine practices.

Earlier this month, President Trump said the U.S. government will purchase 100 million doses of Moderna’s coronavirus vaccine candidate for $1.5 billion as part of Operation Warp Speed which hopes to find at least one safe, effective vaccine by the end of the year. The goal of the federal government’s Operation Warp Speed initiative is to spur the production of promising vaccine candidates and to buy initial batches so they can be distributed as soon as a candidate is approved. The White House has made similar deals over the last few months with other companies developing vaccines, including Johnson & Johnson, Pfizer, Novavax, AstraZeneca and GlaxoSmithKline and Sanofi. The U.S. had already given $955 million to help Moderna research develop its vaccine through the Biomedical Advanced Research and Development Authority. Although a vaccine might be proven safe and effective by early next year, Dr. Anthony Fauci said last month he doesn’t anticipate widespread availability with hundreds of millions of doses until “several months” into 2021. $2.1 billion. That’s Moderna CEO Stéphane Bancel’s net worth, according to Forbes estimates. He became a billionaire in April as Moderna stock jumped after announcing it expected to begin Phase 2 human trials for its Covid-19 vaccine.

A massive COVID-19 outbreak on a US fishing boat spared crew members who already had antibodies against the new coronavirus, providing what scientists say is the first direct evidence that these antibodies protect people against being reinfected. After a viral infection, the immune system makes compounds called neutralizing antibodies that can attack the virus if it invades again. But previous research had not determined whether such antibodies can shield humans from SARS-CoV-2 reinfection. Alexander Greninger at the University of Washington School of Medicine in Seattle and his colleagues tested the crew of a US fishing vessel for SARS-CoV-2 and for antibodies to the virus (A. Addetia et al. Preprint at medRxiv http://doi.org/d6qm; 2020). Just before the ship’s departure, the researchers tested 120 of the 122 crew members and found that all were negative for SARS-CoV2, but an outbreak hit the ship soon after it left shore.

Post-voyage testing showed that 104 members of the 122-person crew were infected. None of those who were infected and had been tested before embarking had shown neutralizing antibodies against SARS-CoV-2. But all three crew members who did have such antibodies before departure escaped infection, providing statistically significant evidence that neutralizing antibodies acquired during SARS-CoV-2 infection protect against reinfection, the authors say. The findings have not yet been peer reviewed.

Preprint in medRxiv (August 14, 2020):

https://doi.org/10.1101/2020.08.13.20173161

Long-term antibody responses and neutralizing activities following SARS-CoV-2 infections have not yet been elucidated. We quantified immunoglobulin M (IgM) and G (IgG) antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) of the spike (S) or the nucleocapsid (N) protein, and neutralizing antibodies during a period of six months following COVID-19 disease onset in 349 symptomatic COVID-19 patients, which were among the first world-wide being infected.

The positivity rate and magnitude of IgM-S and IgG-N responses increased rapidly. High levels of IgM-S/N and IgG-S/N at 2-3 weeks after disease onset were associated with virus control and IgG-S titers correlated closely with the capacity to neutralize SARS-CoV-2. While specific IgM-S/N became undetectable 12 weeks after disease onset in most patients, IgG-S/N titers showed an intermediate contraction phase, but stabilized at relatively high levels over the six months observation period. At late time points the positivity rates for binding and neutralizing SARS-CoV-2-specific antibodies was still over 70%. Taken together, our data indicate sustained humoral immunity in recovered patients who suffer from symptomatic COVID-19, suggesting prolonged immunity.

Preprint available at medRxiv (July 24, 2020):

https://doi.org/10.1101/2020.07.21.20159178

Knowing which signatures in the blood predict protection against COVID-19 could speed the development of new vaccines.  Researchers developing the Oxford–AstraZeneca COVID-19 vaccine have identified biomarkers that can help to predict whether someone will be protected by the jab they receive. The team at the University of Oxford, UK, identified a ‘correlate of protection’ from the immune responses of trial participants — the first found by any COVID-19 vaccine developer. Identifying such blood markers, scientists say, will improve existing vaccines and speed the development of new ones by reducing the need for costly large-scale efficacy trials. “We would like to have an antibody measure that is a reliable guide to protection because it could speed up the licensure of new vaccines,” says David Goldblatt, a vaccinologist at University College London.  New formulations of influenza vaccines, for instance, are generally judged by whether they trigger a strong enough antibody response against a viral protein in a relatively small number of people, instead of in large trials that look for reductions in rates of infection. Researchers and regulators hope to do the same with COVID-19 vaccines. “The power of a correlate in vaccines is profound,” says Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “If there’s a reliable correlate, then it can be used in clinical trials to make decisions as to what vaccines are likely to work, what form of vaccines are likely to work, or how durable the vaccines are going to be.” The findings are reported in a preprint study posted to medRxiv on 24 June1.

Searching for markers

Correlates of protection are typically determined by comparing the immune responses of trial participants who were protected by a vaccine to those of ‘breakthrough cases’ — volunteers who got a vaccine but still became infected. But owing to the high efficacy of many COVID-19 vaccines, it has taken longer than expected for developers to determine markers of vaccine protection on the basis of breakthrough cases, says Peter Dull, deputy director for Integrated Clinical Vaccine Development at the Bill & Melinda Gates Foundation in Seattle, Washington. In the absence of studies of breakthrough cases, several teams have attempted to determine a correlate of protection for COVID-19 vaccines by comparing published data on vaccine efficacy with those from earlier trials measuring immune responses to the jabs2,3.  These studies suggest that virus-blocking ‘neutralizing’ antibodies are a good predictor of a vaccine’s success. Those that trigger high levels of these antibodies, such as the Pfizer–BioNTech and Moderna jabs, are more effective than the Oxford–AstraZeneca and Johnson & Johnson vaccines, which generated relatively low levels of neutralizing antibodies. The Oxford–AstraZeneca study confirms the relationship between higher neutralizing-antibody levels and protection. The analysis, led by Oxford biostatistician Merryn Voysey, compared the immune responses in 171 breakthrough cases with those of more than 1,404 people who got the vaccine and did not develop a symptomatic infection. Participants who had higher levels of neutralizing antibodies — as well as ‘binding’ antibodies, which recognize the SARS-CoV-2 spike protein — tended to gain stronger, but not total, protection from a symptomatic infection, the Oxford team determined. The team used a model to estimate the antibody levels that corresponded to different levels of vaccine protection against COVID-19 in trials, ranging from 50% to 90% protection. Other vaccines that trigger similar antibody responses can be expected to generate similar levels of protection against symptomatic infections, the Oxford team says.

Miles Davenport, an immunologist at the University of New South Wales in Sydney, Australia, notes that there was no significant difference in the neutralizing antibody responses of breakthrough infections and controls. This could occur if young people at greater risk of infection — because they have more social contacts, for example — also had higher antibody levels. The Oxford team accounted for this overlap in their model by estimating participants’ risk of infection. However, Davenport says that it's a challenge to identify protective antibody levels based on estimated risk, rather than observed differences in antibody levels — which would have been possible only if there were clear differences between breakthroughs and controls.  It’s not certain whether the antibody levels established in the study will be able to predict the success of other vaccines, Goldblatt says, particularly those based on different technologies. “We don’t want to develop something just for one vaccine or one kind of vaccine,” says Goldblatt. “We’ve got all these manufacturers around the world, developing vaccines based on different platforms.” The Oxford vaccine uses a harmless chimpanzee adenovirus to instruct cells to make the SARS-CoV-2 spike protein, whereas those developed by Moderna and Pfizer–BioNTech use RNA molecules to do this. Other COVID-19 vaccines deliver the protein itself or inactivated versions of the entire SARS-CoV-2 virus. Another team is working out correlates of protection for vaccines supported by the US government, including those from Moderna and Johnson & Johnson. The Moderna analysis is expected soon. 

Predicting protection

Philip Dormitzer, vice-president and chief scientific officer of viral vaccines at Pfizer, says it’s not clear whether the high levels of neutralizing antibodies explain the protection the company’s vaccine offers. Their levels are undetectable in most people before they receive a second dose, but clinical trials and real-world studies suggest that the vaccine offers strong protection after one dose. Neutralizing antibodies also do a poor job at predicting vaccine efficacy against variants, he says, and their levels wane over time. Dormitizer and other researchers say it’s important to distinguish between biomarkers that can simply predict the success of vaccines and those that are responsible for their protective effects. In addition to neutralizing antibodies that block infection in laboratory assays, vaccines trigger antibodies with other properties, as well as T cells that kill off infected cells and support other immune responses. All of these parts of the immune response could have a role in protection.  Ultimately, it will be up to regulators to decide how to apply correlates of protection for COVID-19 vaccines, says Dull. This is already starting to happen. The UK’s medicines regulator has signalled that it could approve a vaccine using inactivated SARS-CoV-2, developed by French biotech company Valneva, if it triggers higher levels of antibodies than does the Oxford–AstraZeneca vaccine in a trial of 4,000 participants. Dull says it’s important to move carefully when determining and applying correlates of protection to COVID-19 vaccines. If vaccines approved on the basis of a biomarker turn out to perform poorly in the real world, it could undermine immunization efforts. But he hopes that developers, regulators and stakeholders can soon settle on some answers. “We are in an era where there is limited capacity to run new efficacy studies,” he says. “Let’s get some more vaccines moving forward.”

Published in Nature (July 1, 2021):

https://doi.org/10.1038/d41586-021-01778-2

Research cited available in medRxiv (June 24, 2021):

https://www.medrxiv.org/content/10.1101/2021.06.21.21258528v1

New research at Washington University School of Medicine in St. Louis indicates that three new, fast-spreading variants of the virus that cause COVID-19 can evade antibodies that work against the original form of the virus that sparked the pandemic. With few exceptions, whether such antibodies were produced in response to vaccination or natural infection, or were purified antibodies intended for use as drugs, the researchers found more antibody is needed to neutralize the new variants.  The findings, from laboratory-based experiments and published March 4 in Nature Medicine, suggest that COVID-19 drugs and vaccines developed thus far may become less effective as the new variants become dominant, as experts say they inevitably will. The researchers looked at variants from South Africa, the United Kingdom and Brazil. "We're concerned that people whom we'd expect to have a protective level of antibodies because they have had COVID-19 or been vaccinated against it, might not be protected against the new variants," said senior author Michael S. Diamond, MD, Ph.D., the Herbert S. Gasser Professor of Medicine. "There's wide variation in how much antibody a person produces in response to vaccination or natural infection. Some people produce very high levels, and they would still likely be protected against the new, worrisome variants. But some people, especially older and immunocompromised people, may not make such high levels of antibodies. If the level of antibody needed for protection goes up tenfold, as our data indicate it does, they may not have enough. The concern is that the people who need protection the most are the ones least likely to have it."

The virus that causes COVID-19, known as SARS-CoV-2, uses a protein called spike to latch onto and get inside cells. People infected with SARS-CoV-2 generate the most protective antibodies against the spike protein. Consequently, spike became the prime target for COVID-19 drug and vaccine developers. The three vaccines authorized by the Food and Drug Administration (FDA) for emergency use in the U.S.—made by Pfizer/BioNTech, Moderna and Johnson & Johnson—both target spike. And potent anti-spike antibodies were selected for development into antibody-based drugs for COVID-19. Viruses are always mutating, but for nearly a year the mutations that arose in SARS-CoV-2 did not threaten this spike-based strategy. Then, this winter, fast-spreading variants were detected in the United Kingdom, South Africa, Brazil and elsewhere. Sparking concern, the new variants all carry multiple mutations in their spike genes, which could lessen the effectiveness of spike-targeted drugs and vaccines now being used to prevent or treat COVID-19. The most worrisome new variants were given the names of B.1.1.7 (from the U.K.), B.1.135 (South Africa) and B.1.1.248, also known as P.1 (Brazil).

To assess whether the new variants could evade antibodies made for the original form of the virus, Diamond and colleagues, including first author Rita E. Chen, a graduate student in Diamond's lab, tested the ability of antibodies to neutralize three virus variants in the laboratory. The researchers tested the variants against antibodies in the blood of people who had recovered from SARS-CoV-2 infection or were vaccinated with the Pfizer vaccine. They also tested antibodies in the blood of mice, hamsters and monkeys that had been vaccinated with an experimental COVID-19 vaccine, developed at Washington University School of Medicine, that can be given through the nose. The B.1.1.7 (U.K.) variant could be neutralized with similar levels of antibodies as were needed to neutralize the original virus. But the other two variants required from 3.5 to 10 times as much antibody for neutralization. Then, they tested monoclonal antibodies: mass-produced replicas of individual antibodies that are exceptionally good at neutralizing the original virus. When the researchers tested the new viral variants against a panel of monoclonal antibodies, the results ranged from broadly effective to completely ineffective. Since each virus variant carried multiple mutations in the spike gene, the researchers created a panel of viruses with single mutations so they could parse out the effect of each mutation. Most of the variation in antibody effectiveness could be attributed to a single amino acid change in the spike protein. This change, called E484K, was found in the B.1.135 (South Africa) and B.1.1.248 (Brazil) variants, but not B.1.1.7 (U.K.). The B.1.135 variant is widespread in South Africa, which may explain why one of the vaccines tested in people was less effective in South Africa than in the U.S., where the variant is still rare, Diamond said. "We don't exactly know what the consequences of these new variants are going to be yet," said Diamond, also a professor of molecular microbiology and of pathology & immunology. "Antibodies are not the only measure of protection; other elements of the immune system may be able to compensate for increased resistance to antibodies. That's going to be determined over time, epidemiologically, as we see what happens as these variants spread. Will we see reinfections? Will we see vaccines lose efficacy and drug resistance emerge? I hope not. But it's clear that we will need to continually screen antibodies to make sure they're still working as new variants arise and spread and potentially adjust our vaccine and antibody-treatment strategies."

Original Findings Published in Nature Medicine (March 4, 2021):

https://doi.org/10.1038/s41591-021-01294-w

A study of people in Sierra Leone suggests that the virus can lie in hiding from the immune system before re-emerging later and sparking a new response—although researchers didn't examine whether this could make people infectious again. A substantial proportion of people who survive Ebola may produce a spike in antibody levels more than six months after they’ve recovered from the disease, according to a study published today (January 27) in Nature.   Analyzing multiple plasma samples from 51 survivors of the West African outbreak of 2013–2016, researchers found that the levels of virus-neutralizing antibodies declined, as expected, in the days and weeks following recovery. But these levels shot up again in some survivors around the 200- to 300-day mark before declining again—evidence that Ebola virus may be lingering inside their bodies and re-emerging to trigger immune defenses, the researchers conclude in their paper.  “The idea that there can be a source of virus that could restimulate the immune system isn’t surprising” in itself, says Carl Davis, an immunologist at Emory University who was not involved in the work. “But the fact that they were seeing this so frequently and to such a big magnitude is really pretty shocking Since the West African epidemic, which claimed the lives of more than 11,000 people, there have been multiple reports of viral persistence in survivors. One 2016 study, for example, reported that 24 of 429 men in Liberia who had been infected with Ebola tested positive for viral RNA in their semen more than 12 months after they’d recovered from the disease, with one testing positive more than a year and a half after completing treatment. Viral RNA isn’t necessarily evidence of infectious virus, but based on genomic and epidemiological data, researchers suspect that Ebola can be transmitted sexually by men several months after infection. 

Taking a different approach, University of Liverpool virologists Georgios Pollakis, Bill Paxton, and colleagues focused in the current study on measuring survivors’ immune responses to Ebola virus. Specifically, they analyzed the levels of virus-neutralizing antibodies in 115 healthy people in Sierra Leone who had recovered from prior infections and had volunteered to provide convalescent plasma to be used as an experimental therapy for other patients.   Using a combination of immunological assays, including treating some of the plasma samples with synthetic viral particles bearing specific Ebola virus proteins, the researchers monitored antibody levels between 30 and 500 days after participants were discharged from Ebola treatment units. Among the 51 participants who provided more than one sample, the researchers found that, on the whole, antibody levels seemed to decline following a person’s recovery, as expected. However, in more than half of those participants, the team detected an increase in antibody levels between about six months and a year post-recovery.  Such an antibody spike is unlikely to be the result of people receiving Ebola vaccinations during the study, Pollakis says. Plasma donors reported to clinicians that they hadn’t received vaccines. If they had been immunized, the researchers would have expected to see increased levels of antibodies only against the proteins used in the vaccine; instead, their assays revealed increased levels of antibodies against various viral proteins. Nor is the observation likely to be due to survivors being reinfected by other people, Pollakis adds. The samples were negative for viral RNA, and some of the observed antibody increases occurred after Sierra Leone had stopped reporting new Ebola cases, he explains.

Instead, the researchers hypothesize that the spike is the result of the immune system re-encountering viral antigens already within the body. This could happen if Ebola virus hides in so-called immune-privileged sites such as the eye, the reproductive tract, or the central nervous system—those regions typically better shielded from the immune system than other areas of the body—and then reappears once antibody levels have fallen below a certain threshold.  The findings suggest “that actually, a much larger proportion of individuals than were previously thought carry some form of viral antigens, if not the whole virus,” Pollakis says, “and that as the antibodies decline and reach a nadir around two hundred, two hundred and fifty days, the antigen gets the chance to come back in some form and stimulate the immune system again.” Nathalie MacDermott, an academic clinical lecturer at King’s College London who participated in the medical response to Ebola in West Africa and was not involved in the study, says that the findings seem to confirm something that has long been suggested by other investigations of Ebola survivors, although “the sample size is relatively small.” She adds that it will be important to understand what makes some people more susceptible to a recurrence of the virus than others, and to gather more detailed data on how long recurrent virus may stick around in survivors once it’s reappeared. Davis, who coauthored a 2019 study of B cell responses to Ebola in four survivors treated in the US, notes that it would be interesting to see if the same antibody patterns are present in a more diverse patient population. People selected as potential plasma donors might not be representative of all Ebola survivors—for instance, the authors speculate in their paper that donors are less likely to have viral recurrence, because they have to be healthy to take part in the study and therefore should be better at suppressing Ebola virus than the general population of survivors. But Davis notes that this relationship hasn't been demonstrated. He adds that further work could investigate immune-cell responses in addition to the antibody levels measurable in plasma samples......

Findings published in Nature  (Jan.27,  2021):

https://doi.org/10.1038/s41586-020-03146-y

Commentary in Nature (Jan. 27, 2021):

https://doi.org/10.1038/d41586-020-03044-3

New studies are boosting assessments that immunity to COVID-19 lasts at least 6-8 months after recovery from the disease.

Research published in Science Immunology this week examined 25 patients recovering from the illness. Though antibodies — the immune system proteins that attack virus particles — began dropping in blood samples some 20 days after symptoms appeared, memory B cells that produce antibodies continued to rise in the blood for 150 days and remained high until the 240-day point. This signals subjects’ bodies were primed to fight off the virus for some eight months. Meanwhile, researchers in two other studies found that people who made antibodies to the coronavirus were much less likely to test positive again for up to six months and maybe longer The results bode well for vaccines, which provoke the immune system to make antibodies. A study published Wednesday by the New England Journal of Medicine involved more than 12,500 health workers at Oxford University Hospitals in the United Kingdom. Among the 1,265 who had coronavirus antibodies at the outset, only two had positive results on tests to detect active infection in the following six months and neither developed symptoms. That contrasts with the 11,364 workers who initially did not have antibodies; 223 of them tested positive for infection in the roughly six months that followed.

A third study by the National Cancer Institute study involved more than 3 million people who had antibody tests from two private labs in the United States. Only 0.3% of those who initially had antibodies later tested positive for the coronavirus, compared with 3% of those who lacked such antibodies. The results showed that people with antibodies from natural infections were “at much lower risk… on the order of the same kind of protection you’d get from an effective vaccine,” of getting the virus again, said Dr. Ned Sharpless, director of the US National Cancer Institute.  “It’s very, very rare” to get reinfected, he said.  The institute’s study had nothing to do with cancer — many federal researchers have shifted to coronavirus work because of the pandemic. “It’s very gratifying” to see that the Oxford researchers saw the same risk reduction — 10 times less likely to have a second infection if antibodies were present, Sharpless said. His institute’s report was posted on a website scientists use to share research and is under review at a major medical journal. The findings are “not a surprise … but it’s really reassuring because it tells people that immunity to the virus is common,” said Joshua Wolf, an infectious disease specialist at St. Jude Children’s Research Hospital in Memphis who had no role in either study. “We don’t know how long-lasting this immunity is,” Wolf added. Cases of people getting COVID-19 more than once have been confirmed, so “people still need to protect themselves and others by preventing reinfection.”

Findings Published in Science Immunology (Dec. 22, 2020): 

https://doi.org/10.1126/sciimmunol.abf8891

NEJM (DEc. 23, 2020):

https://doi.org/10.1056/NEJMoa2034545

BACKGROUND

Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials.

METHODS

We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient’s clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death.

RESULTS

A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups.

CONCLUSIONS

No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535. opens in new tab.)

Published in NEJM (November 24, 2020):

https://doi.org/10.1056/NEJMoa2031304

FDA has issued an emergency use authorization (EUA) for the first serology test that detects neutralizing antibodies from recent or prior SARS-CoV-2 infection. These are antibodies that bind to a specific part of a pathogen and have been observed in a laboratory setting to decrease SARS-CoV-2 viral infection of cells. The cPass SARS-CoV-2 Neutralization Antibody Detection Kit from GenScript Biotech, Piscataway, NJ,specifically detects this type of antibody. Although the FDA has previously issued EUAs to more than 50 antibody tests, those tests only detect the presence of binding antibodies. Binding antibodies bind to a pathogen, such as a virus, but do not necessarily decrease the infection and destruction of cells. It’s important to note that the effect of neutralizing antibodies for SARS-CoV-2 in humans is still being researched.

“The ability to detect neutralizing antibodies can help us gain additional insight into what the existence of antibodies may mean for patients as we continue the fight against covid-19,” says Tim Stenzel, MD, PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health. “There are still many unknowns about what the presence of SARS-CoV-2 antibodies may tell us about potential immunity, but today’s authorization gives us another tool to evaluate those antibodies as we continue to research and study this virus. Patients should not interpret results as telling them they are immune, or have any level of immunity, from the virus.” The FDA cautions patients against using the results from this test, or any serology test, as an indication that they can stop taking steps to protect themselves and others, such as stopping social distancing, discontinuing wearing masks, or returning to work. The FDA also wants to remind patients that serology tests should not be used to diagnose an active infection, as they only detect antibodies that the immune system develops in response to the virus, not the virus itself.

FDA authorization letter  (November 6, 2020):

https://www.fda.gov/media/143584/download

Additional Information by GenScript

https://www.genscript.com/covid-19-detection-cpass.html

Research on archived blood does not bear out hopes that antibodies against ‘seasonal’ coronaviruses can protect against severe COVID-19. Paul Bieniasz and Theodora Hatziioannou at the Rockefeller University in New York City and their colleagues analysed 37 blood-serum samples collected before 2020 from people in the United Kingdom (D. Poston et al. Preprint at medRxiv https://doi.org/fc4g; 2020). All of the study participants had tested positive for one of the seasonal human coronaviruses, which can cause the common cold.

The team found that each serum sample contained antibodies that could disable at least one common-cold coronavirus, blocking the virus’s ability to infect human cells in a lab dish. But the serum could not disable a hybrid virus that had been engineered to carry SARS-CoV-2’s spike protein, a crucial player in the virus’s invasion of host cell The results suggest that antibodies to common-cold coronaviruses do not have a major role in determining why some people with COVID-19 fare worse than others, the authors say. The findings have not yet been peer reviewed.

Preprint available at medRxiv (Oct. 11, 2020):

https://doi.org/10.1101/2020.10.08.20209650

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. While the world waits for a COVID-19 vaccine, many researchers are focused on developing effective therapeutics that can be rolled out quickly and cheaply. Monoclonal antibodies—a potentially promising laboratory-manufactured therapy modeled on antibodies extracted from the blood of recovering patients—made headlines recently when President Trump received a not-yet-approved antibody cocktail made by the company Regeneron. And pharmaceutical giant Eli Lilly recently announced that its monoclonal antibody reduced the risk of hospitalization in 300 people who had mild or moderate symptoms of COVID-19, in a small clinical trial. But David Baker, a biochemist at the University of Washington’s Institute for Protein Design, and his colleagues think they can produce an even better therapy. They have designed a synthetic peptide—a short string of amino acids, the building blocks of proteins—20 times smaller than a monoclonal antibody that is designed to bind to the infamous “spike” protein on the surface of the SARS-CoV-2 virus particle. Doing so would directly block the virus from binding to the ACE-2 receptors on human cells, functioning much like an antibody produced by an infected person’s immune system. Baker and his colleagues described these “miniprotein inhibitors” in September in Science. Although the study only tested these synthetic proteins in the lab, mixing viral particles with monkey cells in vitro, he says that unpublished data show they can protect mice and hamsters from SARS-CoV-2 infection. 

“We built these [tiny proteins] from scratch based on ‘first principles,’ using computers to model all the biochemical details of a theoretical protein that could stick to the virus,” explains Baker, who was awarded a $3 million Breakthrough Prize earlier in September for his decades of work pioneering the field of synthetic protein design. His team used computers to digitally design more than two million candidate “miniproteins,” crunched the data using algorithms, sifted out 118,000 candidate genes that encode these proteins, manufactured the proteins from scratch, and tested them directly against the virus in the lab—finding that seven designs could effectively bind to and thus disable the virus. Over the course of 3.5 billion years evolution has produced an incredible array of proteins and peptides. In recent years biochemists have tracked down and used some of these to create new drugs, such as Eptifibatide, an antiplatelet drug administered to prevent heart attacks whose active ingredient is extracted from the venom of the southern pygmy rattlesnake. The Protein Data Bank, an online repository of protein sequences and educational tools, contains the amino acid sequences and full 3-D structures for more than 160,000 peptides and proteins—but the natural world contains hundreds of millions of proteins. 

“It’s very challenging to discover in nature a peptide that does exactly what you want it to do,” explains Gaurav Bhardwaj, also a biochemist at the Institute for Protein Design, but who was not involved in the Science study. He is trying to design a bespoke peptide that would prevent SARS-CoV-2 from replicating within human cells. “Now we can computationally explore the possible design configurations for a peptide in order to perform the exact functions that we want.” Every protein’s function depends on its structure. Interactions between the atoms of the protein’s amino acids cause these chains to self-assemble in less than a second into a complex array of spirals and pleats. As the chain of amino acids grows, these helices and rippled sheets stack on top of and around one another into a dizzyingly complex series of folds, and it is these folds that give proteins their shape and function. Yet figuring out how one amino acid sequence turns into a specific fold has been a torturously difficult task, and it was only in the 1990s—with ever expanding databases of protein information—that scientists could begin to link sequence to form. “We can make up completely new proteins that have never been seen in nature because we now understand the nature of protein folding,” Baker says. “Our ability to use computers to design ‘de novo’ proteins has really only come into its own in the last few years–we might not have been able to apply ourselves to COVID-19 if the pandemic had happened five years ago....

Experts caution more data from larger trials will be needed to know how potentially beneficial monoclonal antibodies are. New data from the biotechnology firm Regeneron seem likely to add to the excitement about drugs called monoclonal antibodies as treatments for Covid-19, but experts caution more data will be needed to know how potentially beneficial the medicines are.  A high dose of the company’s antibody cocktail, REGN-COV2, led levels of the virus to decrease more quickly in infected, non-hospitalized patients, potentially indicating the treatment may help them get better, Regeneron reported Tuesday via press release. Full results will be published at a later date.  “There’s nothing bad about these results, you just can’t say much about how transformative this is going to be,” said Eric Topol, director of the Scripps Research Translational Institute. As with data from a similar antibody, developed by Eli Lilly, he warned that the data so far should not be enough for the Food and Drug Administration to grant an emergency use authorization.   “This doesn’t cut it, but it’s moving in the right direction, that’s for sure,” Topol said. In a notable finding, the data seem to show that the antibody had a bigger effect in patients who tested positive for SARS-CoV-2 but had not created high levels of their own antibodies against the virus. In this group, even a lower dose of the Regeneron antibodies seemed to result in patients getting better faster.

The data add to the early results from Eli Lilly, which showed a reduction in virus levels for patients at some doses and a tantalizing hint that the treatment might help keep patients out of the hospital.  Monoclonal antibodies are synthetic versions of one of the immune system’s own weapons against invaders. From the start of the pandemic, some experts have been most hopeful about this technology to create new medicines to fight SARS-CoV-2, the virus that causes Covid-19. But that potential could be limited by the ability to manufacture large quantities of the treatments. Regeneron has reached an agreement with Roche, the Swiss drug giant, to increase its production capacity. Experts said longer studies, which are ongoing, will be needed to really know if the antibody treatments make patients better. “We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well-tolerated safety profile, and we have begun discussing our findings with regulatory authorities while continuing our ongoing trials,” said George Yancopoulos, Regeneron’s chief scientific officer. 

The data are from a 275-patient portion of Regeneron’s study testing REGN-COV2 in patients who have tested positive for Covid-19 but who are not in the hospital. Patients received either placebo, 2.4 grams of REGN-COV2, or 8 grams of REGN-COV2. (The antibody cocktail is delivered intravenously.) Those who received the high dose saw viral levels decrease by 0.60 log10 copies of the virus per milliliter compared to placebo after seven days, a result that was statistically significant. In the lower dose, there was a 0.23 log10 reduction, which was not statistically significant. Regeneron did not give the total amount of virus detected in its press release. At the beginning of the study, Regeneron tested patients not only to see if they had SARS-CoV-2, but also to see if they created their own antibodies against the virus. The company found that 45% of patients had created antibodies, 41% had not, and 14% had unclear results. Those without antibodies had higher levels of virus in swabs from their noses from the start. And those who had created their own antibodies got better much faster. Patients with their own antibodies in the placebo group saw symptoms disappear in seven days, while in those whom antibodies were not detected, it took 13 days for symptoms to go away. Giving the patients Regeneron’s synthetic antibody had a far greater effect on the amount of virus detected in those who did not have an antibody response before treatment. There was a reduction of 0.6 log10 copies/mL in the patients who received the high dose, and 0.51 in those who received the low dose, both of them statistically significant. The reductions were also greater in patients who had higher levels of virus. And in those patients who did not have detectable antibodies at the study’s outset, Regeneron’s antibody cocktail improved symptoms. In this group, symptoms were alleviated in 13 days on placebo, eight days in the high-dose group, and six days in the low-dose group.  Among the 275 patients for whom data are being reported, 50% were Hispanic, 14% were African American, and the rest of the racial breakdown was not disclosed. On average, they were 45 years old. Forty-nine percent of participants were male and 51% were female...

Regeneron's Press Release:

https://investor.regeneron.com/news-releases/news-release-details/regenerons-regn-cov2-antibody-cocktail-reduced-viral-levels-and 

A study of Nicaraguan children links prior Zika virus infection with aggravated dengue fever symptoms. The 2015–16 Zika virus epidemic that spread through Central and South America was followed last year by a surge in dengue virus cases. While this unfortunate series of diseases battered the region’s populace, it gave scientists, who had been following a cohort of several thousand children in the area, the opportunity to study how these two flaviviruses might jointly affect the immune system. That research has revealed that kids infected with dengue virus are more likely to suffer worse symptoms if they had previously been infected with Zika than if they hadn’t. The findings, reported in Science today (August 27), indicate that antibody-dependent enhancement—a phenomenon known for making a second infection with a virus worse than the first—is not limited to influencing infections by the same pathogen. This raises concerns that such cross-species effects may occur for other types of viruses—including coronaviruses—and may impact vaccine safety, scientists say.

“It’s a pretty amazing story. [It] addresses what I think is the most important question in the field that has emerged following the Zika virus outbreak, and that is, how do Zika virus and dengue virus influence each other?” says virologist Jean Lim of the Icahn School of Medicine at Mount Sinai who was not part of the research team. Dengue and Zika viruses are closely related members of the flavivirus genus and are both transmitted to humans via the bites of infected mosquitoes. Dengue virus infection can be asymptomatic or can cause symptoms such as fever, headache, muscle aches, and rash. In some cases the disease can be severe, causing hemorrhagic fever and even shock (a dangerous drop in blood pressure). Zika virus causes a mostly mild disease—characterized by fever, rash, and joint pain—that resolves within a week, but in adults it can occasionally cause Guillain-Barré syndrome, an autoimmune condition affecting the peripheral nerves, and in pregnant women, the virus can lead to brain defects in the developing fetus including microcephaly. 

There are four strains, or serotypes, of dengue virus and infection by one type has a curious effect on infection by another, explains epidemiologist Isabel Rodriguez-Barraquer of the University of California (UC), San Francisco, who also did not work on the project. While an infection with the same serotype twice will not cause disease the second time around, if a different serotype causes the second infection, the existing antibodies fail to neutralize the virus and actually assist its entry into host cells. “The antibodies that your body builds after that first infection make the second infection worse and that’s often referred to as antibody-dependent enhancement,” Rodriquez-Barraquer says. This phenomenon is also thought to explain the worsening of disease severity seen after dengue vaccination.  Because Zika is closely related to dengue, “when Zika came along there was a question [of whether] there was going to be some sort of immunological interaction,” says UC Berkeley’s Eva Harris. And her group was in a perfect position to provide an answer, she adds, thanks to a long-standing collaboration with scientists in Nicaragua who have been monitoring infections, measuring antibody titers, and collecting other data from a rolling cohort of children since 2004.

In an earlier study, Harris’s group had shown that dengue infections preceding the Zika outbreak that started in 2015 offered a slightly protective effect against Zika severity, at least in children. Then, in 2019, when a major epidemic of dengue infections blew through the region—the worst in Nicaragua’s history—the group looked at the reverse scenario: whether prior Zika infection influenced dengue severity.  A total of 302 children of a cohort of 3,434 were diagnosed with symptomatic dengue fever between 2019 and 2020, confirmed via PCR amplification of the virus’s genetic material. By analyzing the infection history of the cohort, the team then calculated that children who had had a prior Zika infection had a roughly 12 percent chance of developing symptomatic dengue, compared with an only a 3.5 percent chance for children that had had no prior flavivirus exposure. Children who had had one prior dengue infection had a roughly 9 percent chance of later symptomatic disease. Prior Zika or dengue infection also increased the risk that a child would experience the most severe symptoms of dengue—hemorrhagic fever and shock—compared with children who had not previously had flavivirus disease, the team showed...

Published in Science (August 28, 2020):

https://doi.org/10.1126/science.abb6143

Increases in the levels of three cytokines are among the features linked to poor outcomes. study of COVID-19 patients at two London hospitals has identified blood-based immunological changes that are linked to the disease and, in some cases, to symptom severity. The results, reported in Nature Medicine on Monday (August 17) join a growing body of data on how the human immune system responds to SARS-CoV-2 that will hopefully lead to prognostic tools and potential treatments. “The study is a nice comprehensive characterization of the different trajectories of host response against SARS-CoV-2 [and] technically well performed,” Antonio Bertoletti an emerging infectious disease researcher at Duke-National University of Singapore who was not involved in the research, writes in an email to The Scientist. It provides “some specific findings, like the severe drop of dendritic cells and the inflammatory cytokine profile,” he adds, “[that] might predict the worsening of the disease.” Microbiologist and immunologist Stanley Perlman of the University of Iowa who also was not a part of the research team is less optimistic about the potential for prediction. “They came up with parameters that seem to define the different [severity] groups,” he says, “but for an individual [patient] it’s very hard” to make a prediction because “there is so much overlap” between the groups.  He nonetheless praises the efforts of the authors of the paper and similar endeavors, saying such studies provide “a sense for what seems to be happening in people who do worse, which in itself is useful, if not for prognosis . . . it can help you in management [of the disease].”

Since late 2019, the novel coronavirus SARS-CoV-2 has been relentlessly and rampantly spreading from person to person across the globe. While in many people the virus causes no ill effects, in others it ravages the lungs, leaving them hospitalized for weeks, and in some the infection is fatal. More than 780,000 people have died from the disease worldwide to date.  For a disease with such diversity of symptoms and outcomes, and in patients of different ages and sexes with different underlying conditions, finding a common immune signature for COVID-19—a set of immune proteins and cells that define the disease—may seem like an impossibility, but immunologist Adrian Hayday of King’s College London and the Francis Crick Institute was not discouraged by the odds. Despite “extraordinary heterogeneity” within patient populations, he says, “immune responses against potentially lethal pathogens can have very dominant effects that rise above the background and therefore provide you with an immune signature.” Discovering such a signature would be of great value, he explains. For one thing, “you might find things that are unique to COVID-19 and that might give you some very important things to target therapeutically,” he says. And, it might identify “changes that actually could give the doctors a very early indication of which way a patient was going to go.”

For Hayday and his colleagues’ study, the team collected blood samples from 63 patients with mild, moderate, and severe COVID-19 who were admitted to Guys and St. Thomas’s hospitals in London from March to May this year, and from 55 control individuals, including healthy people who had previously tested positive for coronavirus (and had had no or mild symptoms), people with other respiratory tract infections, and healthy individuals with no recent respiratory infections. The researchers performed flow cytometry experiments and protein assays on the blood samples to analyze the presence and characteristics of various immune cell types and to measure antibodies and other immune factors..

Research published in Nature Medicine (August 17, 2020):

https://doi.org/10.1038/s41591-020-1038-6

New research indicates that human immune system cells are storing information about the coronavirus so they can fight it off again. To the immune system, not all germs are equally memorable. But our body’s cells seem to be seriously studying up on the coronavirus. Scientists who have been monitoring immune responses to the virus are now starting to see encouraging signs of strong, lasting immunity, even in people who developed only mild symptoms of Covid-19, a flurry of new studies suggests. Disease-fighting antibodies, as well as immune cells called B cells and T cells that are capable of recognizing the virus, appear to persist months after infections have resolved — an encouraging echo of the body’s enduring response to other viruses. “Things are really working as they’re supposed to,” said Deepta Bhattacharya, an immunologist at the University of Arizona and an author on one of the new studies, which has not yet been peer-reviewed. Although researchers cannot forecast how long these immune responses will last, many experts consider the data a welcome indication that the body’s most studious cells are doing their job — and will have a good chance of fending off the coronavirus, faster and more fervently than before, if exposed to it again. “This is exactly what you would hope for,” said Marion Pepper, an immunologist at the University of Washington and an author on another of the new studies, which is currently under review at the journal Nature. “All the pieces are there to have a totally protective immune response.”

Protection against reinfection cannot be fully confirmed until there is proof that most people who encounter the virus a second time are actually able to keep it at bay, Dr. Pepper said. But the findings could help quell recent concerns over the virus’s ability to dupe the immune system into amnesia, leaving people vulnerable to repeat bouts of disease. Researchers have yet to find unambiguous evidence that coronavirus reinfections are occurring, especially within the few months that the virus has been rippling through the human population. The prospect of immune memory “helps to explain that,” Dr. Pepper said. In discussions about immune responses to the coronavirus, much of the conversation has focused on antibodies — Y-shaped proteins that can latch onto the surfaces of pathogens and block them from infecting cells. But antibodies represent just one wing of a complex and coordinated squadron of immune soldiers, each with their own unique modes of attack. Viruses that have already invaded cells, for instance, are cloaked from antibodies, but are still vulnerable to killer T cells, which force infected cells to self-destruct. Another set of T cells, nicknamed “helpers,” can coax B cells to mature into antibody-making machines. (Yet another sector of the immune system assails pathogens within minutes of their arrival, while sending out signals called cytokines to mobilize forces from elsewhere in the body. Some evidence suggests that severe cases of Covid-19 may stem from this early process going awry.) Antibodies also come with an expiration date: Because they are inanimate proteins and not living cells, they can’t replenish themselves, and so disappear from the blood just weeks or months after they are produced. Hordes of antibodies appear shortly after a virus has breached the body’s barriers, then wane as the threat dissipates. Most of the B cells that produce these early antibodies die off as well. But even when not under siege, the body retains a battalion of longer-lived B cells that can churn out virus-fighting antibodies en masse, should they prove useful again. Some patrol the bloodstream, waiting to be triggered anew; others retreat into the bone marrow, generating small amounts of antibodies that are detectable years, sometimes decades, after an infection is over. Several studies, including those led by Dr. Bhattacharya and Dr. Pepper, have found antibodies capable of incapacitating the coronavirus lingering at low levels in the blood months after people have recovered from Covid-19. “The antibodies decline, but they settle in what looks like a stable nadir,” which is observable about three months after symptoms start, Dr. Bhattacharya said. “The response looks perfectly durable.”...