Virus World

Vaccination, infection with SARS-CoV-2 infection and a combination of both provide varying degrees of protection against infection. Three years into the pandemic, the immune systems of the vast majority of humans have learnt to recognize SARS-CoV-2 through vaccination, infection or, in many cases, both. But just how quickly do these types of immunity fade? New evidence suggests that ‘hybrid’ immunity, the result of both vaccination and a bout of COVID-19, can provide partial protection against reinfection for at least eight months1. It also offers greater than 95% protection against severe disease or hospitalization for between six months and a year after an infection or vaccination, according to estimates from a meta-analysis2. Immunity acquired by booster vaccination alone seems to fade somewhat faster. But the durability of immunity is much more complex than the numbers suggest. How long the immune system can fend off SARS-CoV-2 infection depends not only on how much immunity wanes over time but also on how well immune cells recognize their target. “And that has more to do with the virus and how much it mutates,” says Deepta Bhattacharya, an immunologist at the University of Arizona College of Medicine in Tucson. If a new variant finds ways to escape the existing immune response, then even a recent infection might not guarantee protection.

Omicron era

Omicron has presented just such a scenario. In late 2021 and early 2022, the main Omicron subvariants that were causing infections were BA.1 and BA.2. By mid-2022, the BA.5 wave was gathering strength in some countries, raising the prospect that those who’d already had one round of Omicron could soon be exposed to another. Data are now providing a sense of the risk of reinfection over time. In one study1, researchers looking at Portugal’s national database of infections studied vaccinated people who became infected during the BA.1/BA.2 wave. Analysis showed that 90 days after an infection, this population had high immune protection — their risk of becoming infected with BA.5 was just one-sixteenth that of people who had been vaccinated but never infected. After that, hybrid immunity against infection declined steeply for a few months and then stabilized, ultimately providing protection for eight months after infection, the duration of the study. Another study3 looked at 338 vaccinated health-care workers in Sweden, some of whom had also had a prior SARS-CoV-2 infection. The authors found that workers with hybrid immunity had some level of protection against infection with BA.1, BA.2 and BA.5 for at least eight months. Swabbing of these workers’ noses revealed high levels of ‘mucosal’ antibodies, which are thought to be a better shield against infection than antibodies that circulate in the blood. A study4 in Qatar compared the infection risks of people who had never caught SARS-CoV-2 with those of people who’d had a previous infection with Omicron or an earlier variant. Both groups included vaccinated and unvaccinated individuals. The results show that more recent infections provide greater protection than older ones in all cases. But because the virus kept evolving, the authors couldn’t untangle whether those differences were because of waning immunity, the virus’s growing ability to evade the immune response or, more likely, a combination of the two.

Infection reprieve

Taken together, the studies suggest that hybrid immunity provides some protection against infection for at least seven or eight months, and probably longer. “That’s pretty good,” says Charlotte Thålin, an immunologist at the Karolinska Institute in Stockholm and an author of the Swedish study. Other data suggest that in people whose immunity arises only from vaccination, a booster dose provides relatively short-lived protection against infection. Researchers in Israel studied more than 10,000 health-care workers who had not previously been infected; all received either three or four doses of the vaccine made by Pfizer and BioNTech5. The authors found that the fourth dose’s efficacy against infection fell rapidly. In fact, after four months, the fourth dose was no better than three doses at preventing infection. However, “we are talking just about what we call relatively mild disease”, says study co-author Gili Regev-Yochay, an epidemiologist at Sheba Medical Center Tel Hashomer in Ramat Gan, Israel. None of the people in the study developed severe COVID-19. What about those who haven’t been vaccinated? Another study6 in Qatar suggests that if the virus doesn’t change, infection-based immunity against reinfection can last up to three years. But that immunity can fade faster if the virus mutates. The authors studied data from unvaccinated people who were infected with a pre-Omicron variant. Fifteen months later, those infections were less than 10% effective at protecting against Omicron infection. And it is much riskier to rely on immunity from infection than to get immunized. But it’s nearly impossible to apply the study results to predict an individual’s risk of becoming infected in future. Immunity depends on a variety of factors, including genetics, age and sex. And past risk of infection isn’t necessarily a good predictor of the risk of future infection, because new variants are continually arising.

Publiished in Nature (Feb. 2, 2023)

https://doi.org/10.1038/d41586-023-00124-y 

Findings from Brazil, Sweden and the United Kingdom show that before the advent of Omicron, vaccination benefited even those who had had a bout of COVID-19.  Even people who have had COVID-19 receive long-lasting benefits from a full course of vaccination, according to three recent studies1–3. What's more, one of the studies3 found that the ‘hybrid’ immunity caused by vaccination and infection is long-lasting, conferring highly effective protection against symptomatic disease for at least six to eight months after vaccination. The data were collected before the Omicron variant emerged, casting some doubt on the studies’ relevance today. But if the findings hold up, they could inform vaccination schemes and vaccine passports, which some countries require for entry to places such as restaurants. The work also counters high-profile claims that people who have had COVID-19 don’t benefit from vaccination. Just such a claim helped to launch some of the research. Brazilian President Jair Bolsonaro “said that he already had COVID-19, and for this reason, it is not necessary to take a vaccination”, says Julio Croda, an infectious-disease doctor and epidemiologist at the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Croda and his colleagues drew on Brazilian vaccination and infection databases to test such assertions. The researchers found that between February 2020 and November 2021, people who had previously been infected with SARS-CoV-2 and then received one vaccine dose — made by either Pfizer–BioNTech, Oxford–AstraZeneca, SinoVac or Johnson & Johnson — avoided as many as 45% of the COVID-19 cases that the group would have been expected to contract without vaccination1. Full courses of two-dose vaccines prevented as many as 65% of expected infections and more than 80% of expected cases of severe COVID-19. “The big message is this: you need to have a full vaccination scheme for COVID-19,” Croda said.

‘Immunity’ passports?

Some authorities consider previous infections when deciding who should have entry to public places such as concerts and restaurants, but others consider only vaccination status. Peter Nordström, an epidemiologist at Umeå University in Sweden, says this dichotomy prompted him and his colleagues to perform another of the studies. Using records collected by the Public Health Agency of Sweden between March 2020 and October 2021, the researchers showed that Swedish residents who had been infected with SARS-CoV-2 had a 95% reduction in their risk of contracting COVID-19 compared with people who had no immunity — and protection grew over the three months following infection and lasted until at least 20 months after infection2. One dose of vaccine reduced the risk of infection by about an additional 50%, and a second dose stabilized the additional protection over the six months following vaccination. Although vaccination increases protection, Nordström thinks the immunity offered by infection alone is worthy of consideration. “Perhaps we should have immunity passports instead of vaccination passports. So you are considered immune — and less likely to transmit the disease — if you have been fully vaccinated, or you have had a documented previous infection,” he says.  Epidemiologist Victoria Hall at the UK Health Security Agency in London and her colleagues performed the third study by tracking infections in thousands of health-care workers from March 2020 to September 2021. The researchers found that previous infections prevented more than 80% of the COVID-19 cases that otherwise would have been expected in the year after infection, but protection waned to around 70% after a year3. Study participants who received two doses of the Pfizer–BioNTech or Oxford–AstraZeneca vaccine after an infection had near 100% protection for at least six to eight months following the second dose. “Protection declined over time after vaccination, and also after infection, but remained persistently high in those with hybrid immunity,” Hall wrote in an e-mail to Nature. Miguel Hernan, an epidemiologist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, says the studies show the near-universal benefit of full vaccination. Some nations have issued guidelines that encourage people who have had COVID-19 to receive only a single vaccine dose: a move that “may be justified in a setting of vaccine scarcity, but not otherwise”, Hernan wrote in an e-mail to Nature.

Variant might change the game

Dan Barouch, a virologist at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, says the findings are in line with previous research. “Vaccination following infection, or infection following vaccination, results in particularly robust antibody responses” he wrote in an e-mail to Nature. But Barouch notes that all three studies draw on data collected before the Omicron variant emerged. He and others caution that past infections will provide imperfect protection against emerging strains. Dan Kelly, an infectious-disease epidemiologist at the University of California, San Francisco, underscores that concern. Omicron is so different from the strains analysed in the studies that the findings might not apply to people who were infected with Omicron after being vaccinated. His advice to people who fall into this category: “Just be really careful.”

Published in Nature (April 6, 2022):

https://doi.org/10.1038/d41586-022-00961-3

This article updates our perspectives on when the coronavirus pandemic will end to reflect the latest information on vaccine rollout, variants of concern, and disease progression. In the United Kingdom and the United States, we see progress toward a transition to normalcy during the second quarter of 2021. The new wave of cases in the European Union means that a similar transition is likely to come later there, in the late second or third quarter. Improved vaccine availability makes herd immunity most likely in the third quarter for the United Kingdom and the United States and in the fourth quarter for the European Union, but risks threaten that timeline. The timeline in other countries will depend on seven crucial variables. And when herd immunity is reached, the risks will not vanish; herd immunity may prove temporary or be limited to regions in a country....

New evidence suggests that people who have had COVID-19 may be immune to SARS-CoV-2, the virus that causes it, for at least 5–7 months, if not longer. Recent alleged cases of reinfection with SARS-CoV-2, the coronavirus that causes COVID-19, have raised concerns that the human immune system may only provide short-term protection against the virus. In addition, scarce research has suggested that the number of antibodies in a person’s bloodstream that is capable of disabling the virus declines sharply after an initial infection. However, scientists at the University of Arizona (UArizona) College of Medicine in Tucson have now found evidence of long lasting immunity in people who have had COVID-19. 

They tested for the presence of antibodies to the virus in nearly 6,000 individuals and then followed them up for several months. “We clearly see high quality antibodies still being produced 5–7 months after SARS-CoV-2 infection,” says Dr. Deepta Bhattacharya, an associate professor of immunobiology at the university, who co-led the research.  “Many concerns have been expressed about immunity against COVID-19 not lasting. We used this study to investigate that question and found immunity is stable for at least 5 months.”  Bhattacharya points out that people who contracted the SARS-CoV virus responsible for the 2002–2004 outbreak of SARS were still immune 12–17 years after infection. This virus is very similar to SARS-CoV-2.  “If SARS-CoV-2 is anything like the first one, we expect antibodies to last at least 2 years, and it would be unlikely for anything much shorter,” he says.  In their paper, published in the journal Immunity, the scientists also note that out of nearly 30 million cases of COVID-19 since December 2019, there have been only about 10 confirmed cases of reinfection...

Study published in Immunity (Oct. 13, 2020):

https://doi.org/10.1016/j.immuni.2020.10.004

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.”...

A rare peek into the bone marrow after vaccination shows key antibodymaking cells have a short life span. The annual influenza vaccine saves lives and spares many people from severe disease, which is why governments and employers promote and subsidize its use. But it’s hardly an ideal vaccine, offering so-so protection that wears off rapidly. A new, one-of-its-kind study, published today in Science, helps explain those shortcomings: A key cell type hidden in bone marrow that quickly kicks into activity after vaccination fades within a few months, researchers found. The discovery could lead to new strategies to increase the vaccine’s durability. The best vaccines—such as the ones for measles, rubella, and diphtheria—provide almost 100% protection for life. Flu vaccines, however, often don’t exactly match the rapidly evolving influenza virus, so their effectiveness changes each year: In the United States between 2009 and 2019, it ranged from a low of 19% to a high of 60%. And protection wanes quickly: If you live in a temperate region of the world and receive the shot in the early fall, immunity can disappear before the end of that winter. To better understand the durability problem, Rafi Ahmed, an immunologist at Emory University School of Medicine, homed in on a type of B cell that resides in the bone marrow and whose role Ahmed helped uncover in 1996. B cells make antibodies that can attach to and disable viruses. Ahmed focused on a type of B cell called bone marrow plasma cells (BMPCs), which continuously produce antibodies after an infection or vaccination. So-called memory B cells also produce antibodies and are created the same way, but in contrast to BMPCs, they do not steadily pump out the protective proteins. Instead, as their name implies, memory B cells that are trained to recognize a specific virus kick into gear only when they’re re-exposed to it. It takes them several days after an infection to produce high levels of antibodies—a disadvantage in influenza, which can cause disease rapidly.

To the surprise and disbelief of many, Ahmed’s group showed in 1996 that some BMPCs can live for many years, meaning they could, in theory, confer long-lasting immunity. Whether influenza vaccines trigger high levels of BMPCs and if so, whether the cells are the long-lived variety was a mystery, however. Ahmed and colleagues repeatedly examined the bone marrow and blood of 53 volunteers aged between 20 and 45 years old in the weeks and months before and after they received influenza vaccines. (Some people participated over more than one flu season.) The study was no fun for the participants: Removing fluid from within a bone is a challenging and painful procedure that involves piercing the pelvic bone with a special needle. “The logistics … were very difficult, and I think nobody will ever try to do the same thing again,” Ahmed says. Rino Rappuoli, chief scientist at GlaxoSmithKline Vaccines, says he knows of no other study that sampled bone marrow for vaccine research. “Rafi’s work is great and pioneering,” Rappuoli says. The researchers found spikes of BMPCs specific for influenza 4 weeks after immunization. But after 1 year, the new cells were virtually gone. Rappuoli and others aren’t particularly surprised by this but welcome the evidence. “This finding tracks nicely with the observed rapidly waning [blood] antibody titers and decreasing protection in humans after getting the flu vaccine,” says Adam Wheatley, an immunologist at the University of Melbourne. “It’s a really nice piece of work.” The study “helps define the landscape” of the flu vaccine’s lousy durability, says Mark Slifka, an immunologist at Oregon National Primate Research Center who earned his Ph.D. with Ahmed more than 20 years ago but was not involved with this work. “They chipped away at the stone in terms of understanding why the immune response is short-lived,” Slifka says....

Original study published in Science (August 13, 2020):

https://doi.org/10.1126/science.aaz8432

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 19,860 individuals screened at Mount Sinai Health System in New York City.

We also show that titers are stable for at least a period approximating three months, and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses and that these titers are stable for at least the near-term future...

Preprint available at medRxiv (July 17, 2020):

 https://doi.org/10.1101/2020.07.14.20151126

Those with SARS-CoV-2 are often advised to isolate for only a few days. But evidence is mounting that some people can continue to pass on the virus for much longer.  When the US Centers for Disease Control and Prevention (CDC) halved its recommended isolation time for people with COVID-19 to five days back in December, it said that the change was motivated by science. Specifically, the CDC said that most SARS-CoV-2 transmission occurs early in the course of the illness, in the one to two days before the onset of symptoms and for two to three days after. Many scientists disputed that decision then and they continue to do so. Such dissent is bolstered by a series of studies confirming that many people with COVID-19 remain infectious well into the second week after they first experience symptoms. Reductions in the length of the recommended isolation period — now common around the world — are driven by politics, they say, rather than any reassuring new data. “The facts of how long people are infectious for have not really changed,” says Amy Barczak, an infectious-disease specialist at Massachusetts General Hospital in Boston. “There is not data to support five days or anything shorter than ten days [of isolation].” Barczak’s own research, published on the medRxiv preprint server, suggests that one-quarter of people who have caught the Omicron variant of SARS-CoV-2 could still be infectious after eight days.

A numbers game

Although the question is simple — for how long is someone with COVID-19 contagious? — experts caution that the answer is complicated. “We always think of it as a black and white thing … if somebody’s infectious or not infectious — but in reality, it’s a numbers game and a probability,” says Benjamin Meyer, a virologist at the University of Geneva in Switzerland.  And that numbers game has shifting rules and baselines. Emerging variants, vaccination and varying levels of natural immunity provoked by previous infection can all influence how quickly someone can clear the virus from their system, Meyer says, and this ultimately dictates when they stop being infectious. Behavioural factors matter as well. People who feel unwell tend to mix less with others, he adds, so the severity of someone’s symptoms can influence how likely they are to infect others. Something most scientists are confident about is that PCR tests can return a positive result even after someone is no longer infectious. This probably occurs when the tests, which detect viral RNA, pick up non-infectious remnants left behind after most of the live virus has been eliminated.By contrast, lateral flow (or ‘rapid  antigen’) tests offer a better guide to infectiousness, because they detect proteins produced by actively replicating virus. “There’s still all of these things that we’re not exactly sure about, but if I had to sum it up in one very concise message, it would be that if you’re antigen positive, you shouldn't go out and interact closely with people who you don’t want to be infected,” says Emily Bruce, a microbiologist and molecular geneticist at the University of Vermont in Burlington. What about somebody who has tested negative on a lateral flow test for a few days but still has a fever and a hacking cough? Bruce says it’s important to remember that although lingering symptoms might look and sound serious, they do not indicate continued infectiousness. “You can definitely have symptoms for longer than you test positive on lateral flow,” she says. “And I think that’s because many of the symptoms are caused by the immune system and not directly by the virus itself.”

Transmission tests

In countries such as the United Kingdom, the relaxation of the isolation guidelines coincided with the withdrawal of free lateral flow tests. So, assuming that many of the people who follow the new recommendations are going to stop isolating after five days without testing, scientists have been investigating in particular how many people with COVID-19 are likely to remain infectious after this point. It’s not practical to track direct onward transmission of the virus from large numbers of people and to measure how it reduces over time, so researchers instead rely on proxy measurements to determine the point at which they would expect people to stop being contagious.  Researchers with access to a high-security biosafety level 3 laboratory — as Barczak has — can do this by running experiments to test whether live SARS-CoV-2 can be cultured from samples taken from patients over several consecutive days. “If you’re still shedding virus that we can culture out of your nose, there’s at least a good chance you’re still infectious to other people,” she says. As different variants have emerged and various research groups have done these experiments, Barczak says, a consensus has emerged that it’s very unusual for people to shed culturable virus after ten days. “So, it’s very unusual for people to stay infectious after ten days,” she says. Other studies take a step further away from the real world, and use levels of viral RNA measured by PCR tests to infer whether someone is infectious. This makes it easier to work with large sample sizes. For example, a project run by the Crick Institute and University College Hospital, both in London, can draw on PCR tests carried out on more than 700 participants, obtained from when symptoms developed. A study based on this group suggests that significant numbers of people retain viral loads high enough to trigger onward infection at days seven to ten, irrespective of the variant type or how many vaccine doses people had received. The study was published on the medRxiv preprint server on 10 July. “We’re not measuring live virus, but there is now a huge amount of work in the literature that provides a pretty good mapping of what constitutes a viral load likely to yield infectious virus,” says David LV Bauer, a virologist at the Crick Institute who is co-investigator on that study. “So while it’s not a perfect picture, it’s a reasonable one.”

‘Rebound phenomenon’

Yonatan Grad, an infectious-disease specialist at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts, who has worked on similar PCR-based studies of infectiousness, agrees that ten days is a useful rule of thumb for when people should no longer be contagious. But he cautions that a small number of people could still be infectious beyond that point.  Some such cases in the United States have been linked to the common antiviral drug Paxlovid (nirmatrelvir–ritonavir), he says. “There’s a rebound phenomenon where people will see that their symptoms seem to resolve and they may even test negative on a rapid test, but then a few days later symptoms and the virus come back.” Barczak says this is one of the key questions that researchers are now studying. “Antivirals change the dynamics of symptoms, change the dynamics of the immune response and change the dynamics of how you shed,” she says. “I think this is really important, because people are out in the world thinking they're not infectious after ten days. But if they have Paxlovid rebound they might be.”

Published in Nature  (July 26, 2022):

https://doi.org/10.1038/d41586-022-02026-x 

Two doses of COVID vaccine cut the risk of infection and mild illness from the rising BA.2 subvariant, although protection wanes quickly.  The Omicron subvariant BA.2 is replacing its sister version, BA.1, as the dominant form of SARS-CoV-2 in many countries, which has led scientists to wonder whether the COVID-19 pandemic is about to throw these regions into disarray yet again. But a study1 published on 13 March shows that mRNA vaccines offer a similar degree of protection against the two strains — although protection against SARS-CoV-2 infection and symptomatic disease wanes within months of a third dose.

The study, published on the preprint server medRxiv, has not yet been peer reviewed. Researchers have known for months that the BA.1 subvariant evades much of the protection that mRNA vaccines offer against mild-to-moderate disease. Scientists quickly realized that BA.2 spreads more rapidly than BA.1, but it wasn’t immediately clear whether the newcomer would also prove to be more adept at evading vaccines.  “BA.2 could be even worse than BA.1 — this was the fear,” says Laith Abu-Raddad, an infectious-diseases epidemiologist at Weill Cornell Medicine–Qatar in Doha and a co-author of the study.

Abu-Raddad and his colleagues performed a massive observational study using vaccination records and SARS-CoV-2 test results from Qatar’s health-care system. They found that Qatari residents who received two doses of either the Pfizer–BioNTech or Moderna mRNA-based vaccine enjoyed several months of substantial protection against symptomatic disease caused by either BA.1 or BA.2. But protection waned to around 10% after only 4–6 months, meaning that the vaccines prevented only 10% of the cases that would have occurred if all of the individuals had been unvaccinated. Protection against BA.2 did not seem to wane any faster than protection against BA.1, and a booster shot brought the protection against symptomatic infection by either subvariant back to 30–60%. Surveillance data collected in the United Kingdom reveal a similar trend: vaccine effectiveness against symptomatic COVID-19 is less than 20% for both subvariants 25 weeks or more after a second dose, but rises to roughly 70% 2–4 weeks after a third dose. The researchers also analysed the degree of protection that mRNA vaccines offer against severe disease, but to do so they had to pool the data on BA.1 and BA.2 cases — a measure that was necessary because Qatar’s population is strongly skewed towards young people, making severe COVID-19 cases rare. Only after pooling did the researchers have enough cases to achieve meaningful results. This analysis showed that protection against severe disease remained at 68% or higher for at least 7 months, even in people who had only received two vaccine doses, and shot up to over 80% after a booster dose. Abu-Raddad says that because 70-80% of the pooled cases were BA.2, he suspects that vaccines still offer a high level of protection against severe disease in the face of surging BA.2 levels. 

Promising results

In an e-mail to Nature, virologist Andrew Pekosz at Johns Hopkins University in Baltimore, Maryland, wrote that, overall, the work is “a very sound study. Qatar has been at the lead when it comes to reporting data on COVID-19 vaccine effectiveness in a very rapid manner.” Abu-Raddad says the results give him hope because vaccines prevent many of the worst COVID-19 cases, even in response to BA.2. “The vaccines are actually working remarkably well, given the challenges of evolution,” he said. Pekosz agrees, adding in his e-mail that the results emphasize the importance of booster doses. “Focusing on the primary vaccination schedule isn’t enough any more. There have to be plans to effectively get populations vaccinated through a booster,” he wrote. But going forwards, Abu-Raddad thinks researchers should move away from designing vaccines against single variants and instead focus on pan-coronavirus vaccines. “This would be a more fundamental solution for the future,” he says.

Research cited available inn medRxiv (March 13, 2022):

https://doi.org/10.1101/2022.03.13.22272308 

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

Antibodies that people make to fight the new coronavirus last for at least four months after diagnosis and do not fade quickly as some earlier reports suggested, scientists have found. Tuesday’s report, from tests on more than 30,000 people in Iceland, is the most extensive work yet on the immune system’s response to the virus over time, and is good news for efforts to develop vaccines. If a vaccine can spur production of long-lasting antibodies as natural infection seems to do, it gives hope that “immunity to this unpredictable and highly contagious virus may not be fleeting,” scientists from Harvard University and the U.S. National Institutes of Health wrote in a commentary published with the study in the New England Journal of Medicine. One of the big mysteries of the pandemic is whether having had the coronavirus helps protect against future infection, and for how long. Some smaller studies previously suggested that antibodies may disappear quickly and that some people with few or no symptoms may not make many at all.

The new study was done by Reykjavik-based deCODE Genetics, a subsidiary of the U.S. biotech company Amgen, with several hospitals, universities and health officials in Iceland. The country tested 15% of its population since late February, when its first COVID-19 cases were detected, giving a solid base for comparisons. Scientists used two different types of coronavirus testing: the kind from nose swabs or other samples that detects bits of the virus, indicating infection, and tests that measure antibodies in the blood, which can show whether someone was infected now or in the past. Blood samples were analyzed from 30,576 people using various methods, and someone was counted as a case if at least two of the antibody tests were positive. These included a range of people, from those without symptoms to people hospitalized with signs of COVID-19. In a subgroup who tested positive, further testing found that antibodies rose for two months after their infection initially was diagnosed and then plateaued and remained stable for four months. Previous studies suggesting antibodies faded quickly may have been just looking at the first wave of antibodies the immune system makes in response to infection; those studies mostly looked 28 days after diagnosis. A second wave of antibodies forms after a month or two into infection, and this seems more stable and long-lasting, the researchers report. The results don’t necessarily mean that all countries’ populations will be the same, or that every person has this sort of response. Other scientists recently documented at least two cases where people seem to have been reinfected with the coronavirus months after their first bout. The new study does not establish how much or which type of antibody confers immunity or protection — that remains unknown.

The study also found:

— Testing through the bits-of-virus method that’s commonly done in community settings missed nearly half of people who were found to have had the virus by blood antibody testing. That means the blood tests are far more reliable and better for tracking spread of the disease in a region and for guiding decisions and returning to work or school, researchers say.

— Nearly a third of infections were in people who reported no symptoms.

— Nearly 1% of Iceland’s population was infected in this first wave of the pandemic, meaning the other 99% are still vulnerable to the virus.

— The infection fatality rate was 0.3%. That’s about three times the fatality rate of seasonal flu and in keeping with some other more recent estimates, said Dr. Derek Angus, critical care chief at the University of Pittsburgh Medical Center.

Although many studies have been reporting death rates based on specific groups such as hospitalized patients, the rate of death among all infected with the coronavirus has been unknown. The news that natural antibodies don’t quickly disappear “will be encouraging for people working on vaccines,” Angus said.

Study in NEJM (September 1, 2020):

https://doi.org/10.1056/NEJMoa2026116 

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

Scientists are examining the role of T cells, which are likely crucial for long-term protection against SARS-CoV-2. When COVID-19 began spreading like wildfire in the Northeast United States this spring, critical care doctor Nuala Meyer could barely believe what she was seeing. “The number of patients who were presenting with critical illness all at the same time was staggering,” remembers Meyer, a professor of medicine at the Hospital of the University of Pennsylvania. But it wasn’t just that these patients were really sick—it was that they were sick in a startling variety of ways. Some had cardiac issues. Others had blood clots in their legs. Then there were those who developed pneumonia and related respiratory problems. Organ failure affected some. The list went on and on. When Meyer and colleagues profiled the ways in which hospitalized patients’ bodies had tried to combat the virus, they found a variety of different immune responses. T and B cells were highly activated in some but not others, for instance. Their work joins a swath of recent publications aiming to decipher the role of these crucial cells in fending off SARS-CoV-2. To understand how vaccines and long-term immunity function, scientists say, they’ll need to uncover how T and B cells fight this most challenging of infections. In pursuit of this goal, Meyer and her colleagues examined immune responses in a sample of 125 patients. Their findings were published in Science July 15.

The researchers found that some patients had very unbalanced immune cell activity and that this imbalance could manifest in multiple ways. For instance, some produced lots of CD4+ T cells—helper cells that assist other parts of the immune system to block or destroy the virus—but very few CD8+ T “killer” cells, which destroy infected cells in the body. Meanwhile, some patients generated lots of B cells, which churn out antibodies, but not in concert with the two main types of T cell. Getting these cells to work together is important, explains coauthor Michael Betts, an immunologist at the Penn Institute for Immunology, because it helps fight infection on several fronts at once. Some T cells, for instance, help B cells to produce antibodies—it’s a joint effort. In some patients studied by the group, there was a worrying lack of T and B cells in general. Severely ill patients, notably, experienced “the spectrum” of responses, says Betts—from hardly any T and B cell activation to excessive amounts. He says it’s still not clear what drives severe illness in many patients. Scientists also don’t yet know precisely what kind of T and B cell response occurs in patients who have mild or no symptoms....