Two studies have demonstrated that COVID-19 immune responses last as long as 8 months, although the authors focus on different reasons. A third, study by researchers at La Jolla Institute for Immunology in California, predicts that immunity is likely to be long lasting.
The first study followed a small cohort of Australians from day 4 to day 242 after infection. All patients demonstrated the presence of memory B cells – immune cells that "remember" viral proteins and can trigger rapid production of antibodies when re-exposed to the virus – as long as 8 months after initial infection.
The second study investigated antibody responses in 58 confirmed COVID-19 patients in South Korea 8 months after asymptomatic or mild SARS-CoV-2 infection, finding high rates of serum antibodies. These results are contradictory to both the first study's antibody data and previous research that showed antibodies waning after 20 days, but the authors suggest that variations in immunoassay test characteristics and manufacturing may be responsible for the difference.
For the Australian study, researchers obtained blood samples from 25 confirmed COVID-19 patients with a range of disease severities and 36 healthy control patients from March to September, evaluating each patient's antibody status and levels of virus-specific immune cells.
The study authors found that by day 6 post-infection, all patients showed immunoglobulin (Ig) G antibodies for the viral receptor-binding domain – a protein on the viral surface that binds to cell receptors, allowing entry and infection – and the nucleocapsid protein, the protective protein shell of the virus. Patient IgG levels began declining 20 days after symptom onset.
In contrast, the study authors found that memory B cell levels continued to rise up to 150 days post-infection and remained detectable 240 days post-symptom onset, suggesting that patient immune systems were primed to respond to reinfection. Because of their extended presence, the cells may be a better indicator of long-term immune response than serum antibodies, the authors say.
The study results provide hope that vaccines will generate a similar duration of protection, and the authors say cellular immunity may explain why there are few documented cases of reinfection with SARS-CoV-2.
"These results are important because they show, definitively, that patients infected with the COVID-19 virus do in fact retain immunity against the virus and the disease," said senior author Dr Menno van Zelm at Monash University. "This has been a black cloud hanging over the potential protection that could be provided by any COVID-19 vaccine and gives real hope that, once a vaccine or vaccines are developed, they will provide long-term protection."
In the second study, the researchers measured SARS-CoV-2–specific antibodies using four commercial immunoassay tests in isolated patients at a Seoul National University Hospital community treatment centre from 5 March to 9 April. Three of the four assays showed high seropositivity rates (69% to 91.4%; P < 0.01), in contrast to yet another earlier study showing that asymptomatic patients become seronegative by 2 to 3 months post-infection.
"Rates differed according to immunoassay methods or manufacturers, thereby explaining differences in rates between the studies," the authors wrote.
Virus neutralising activity – essential for protection from re-infection – was detected in only 53.4% of study participants at 8 months post-infection, considerably lower than the rate of positivity for immunoassays.
"Despite concerns of waning immunity, appropriate immunoassays can detect antibodies against SARS-CoV-2 at 8 months after infection in most asymptomatic or mildly symptomatic persons," the authors concluded.
Study details (1)
Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence
Gemma E Hartley, Emily SJ Edwards, Pei M Aui, Nirupama Varese, Stephanie Stojanovic, James McMahon, Anton Y Peleg, Irene Boo, Heidi E Drummer, P Mark Hogarth, Robyn E O’Hehir, Menno C van Zelm
Published in Science Immunology on 22 December 2020
Lasting immunity following SARS-CoV-2 infection is questioned because serum antibodies decline in convalescence. However, functional immunity is mediated by long-lived memory T and B (Bmem) cells. Therefore, we generated fluorescently-labeled tetramers of the spike receptor binding domain (RBD) and nucleocapsid protein (NCP) to determine the longevity and immunophenotype of SARS-CoV-2-specific Bmem cells in COVID-19 patients. A total of 36 blood samples were obtained from 25 COVID-19 patients between 4 and 242 days post-symptom onset including 11 paired samples. While serum IgG to RBD and NCP was identified in all patients, antibody levels began declining at 20 days post-symptom onset. RBD- and NCP-specific Bmem cells predominantly expressed IgM+ or IgG1+ and continued to rise until 150 days. RBD-specific IgG+ Bmem were predominantly CD27+, and numbers significantly correlated with circulating follicular helper T cell numbers. Thus, the SARS-CoV-2 antibody response contracts in convalescence with persistence of RBD- and NCP-specific Bmem cells. Flow cytometric detection of SARS-CoV-2-specific Bmem cells enables detection of long-term immune memory following infection or vaccination for COVID-19.
Study details (2)
Antibody Responses 8 Months after Asymptomatic or Mild SARS-CoV-2 Infection
Pyoeng Gyun Choe, Kye-Hyung Kim, Chang Kyung Kang, Hyeon Jeong Suh, EunKyo Kang, Sun Young Lee, Nam Joong Kim, Jongyoun Y, Wan Beom Park, and Myoung-don Oh
Published in Emerging Infectious Diseases on 22 December 2020
Waning humoral immunity in coronavirus disease patients has raised concern over usefulness of serologic testing. We investigated antibody responses of 58 persons 8 months after asymptomatic or mildly symptomatic infection with severe acute respiratory syndrome coronavirus 2. For 3 of 4 immunoassays used, seropositivity rates were high (69.0%–91.4%).
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an antibody response, even in those who are completely asymptomatic. However, the initial immune response is not as strong as in patients with more severe disease, and concerns about waning immunity have been raised (1,2). We evaluated the antibody responses of 58 persons in South Korea 8 months after asymptomatic or mildly symptomatic SARS-CoV-2 infection.
Further research suggests that nearly all COVID-19 survivors have the immune cells necessary to fight re-infection. The findings, based on analyses of blood samples from 188 COVID-19 patients, suggest that responses to the novel coronavirus, SARS-CoV-2, from all major players in the "adaptive" immune system, which learns to fight specific pathogens, can last for at least eight months after the onset of symptoms from the initial infection.
"Our data suggest that the immune response is there – and it stays," La Jolla Institute for Immunology (LJI) in California Professor Alessandro Sette, who co-led the study with LJI Professor Shane Crotty, and LJI research assistant Professor Daniela Weiskopf.
"We measured antibodies, memory B cells, helper T cells and killer T cells all at the same time," says Crotty. "As far as we know, this is the largest study ever, for any acute infection, that has measured all four of those components of immune memory."
The findings could mean that COVID-19 survivors have protective immunity against serious disease from the SARS-CoV-2 virus for months, perhaps years after infection. The new study helps clarify some concerning COVID-19 data from other labs, which showed a dramatic drop-off of COVID-fighting antibodies in the months following infection. Some feared that this decline in antibodies meant that the body wouldn't be equipped to defend itself against reinfection.
Sette explains that a decline in antibodies is very normal. "Of course, the immune response decreases over time to a certain extent, but that's normal. That's what immune responses do. They have a first phase of ramping up, and after that fantastic expansion, eventually the immune response contracts somewhat and gets to a steady state," Sette says.
The researchers found that virus-specific antibodies do persist in the bloodstream months after infection. Importantly the body also has immune cells called memory B cells at the ready. If a person encounters SARS-CoV-2 again, these memory B cells could reactivate and produce SARS-CoV-2 antibodies to fight re-infection.
The SARS-CoV-2 virus uses its "spike" protein to initiate infection of human cells, so the researchers looked for memory B cells specific for the SARS-CoV-2 spike. They found that spike-specific memory B cells actually increased in the blood six months after infection.
COVID-19 survivors also had an army of T cells ready to fight reinfection. Memory CD4+ "helper" T cells lingered, ready to trigger an immune response if they saw SARS-CoV-2 again. Many memory CB8+ "killer" T cells also remained, ready to destroy infected cells and halt a reinfection.
The different parts of the adaptive immune system work together, so seeing COVID-fighting antibodies, memory B cells, memory CD4+ T cells and memory CD8+ T cells in the blood more than eight months following infection is a good sign.
"This implies that there's a good chance people would have protective immunity, at least against serious disease, for that period of time, and probably well beyond that," says Crotty.
The team cautions that protective immunity does vary dramatically from person to person. In fact, the researchers saw a 100-fold range in the magnitude of immune memory. People with a weak immune memory may be vulnerable to a case of recurrent COVID-19 in the future, or they may be more likely to infect others.
"There are some people that are way down at the bottom of how much immune memory they have, and maybe those people are a lot more susceptible to reinfection," says Crotty.
"It looks like people who have been infected are going to have some degree of protective immunity against re-infection," adds Weiskopf. "How much protection remains to be established."
The fact that immune memory against SARS-CoV-2 is possible is also a good sign for vaccine developers. Weiskopf emphasizes that the study tracked responses to natural SARS-CoV-2 infection, not immune memory after vaccination.
"It is possible that immune memory will be similarly long lasting similar following vaccination, but we will have to wait until the data come in to be able to tell for sure," says Weiskopf. "Several months ago, our studies showed that natural infection induced a strong response, and this study now shows that the responses lasts. The vaccine studies are at the initial stages, and so far have been associated with strong protection. We are hopeful that a similar pattern of responses lasting over time will also emerge for the vaccine-induced responses."
The researchers will continue to analyse samples from COVID-19 patients in the coming months and hope to track their responses 12 to 18 months after the onset of symptoms. "We are also doing very detailed analyses at a much, much higher granularity on what pieces of the virus are recognised," says Sette. "And we plan to evaluate the immune response not only following natural infection but following vaccination."
The team is also working to understand how immune memory differs across people of different ages and how that may influence COVID-19 case severity.
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
Jennifer M Dan, Jose Mateus, Yu Kato, Kathryn M Hastie, Esther Dawen Yu, Caterina E Faliti, Alba Grifoni, Sydney I Ramirez, Sonya Haupt, April Frazier, Catherine Nakao, Vamseedhar Rayaprolu, Stephen A Rawlings, Bjoern Peters, Florian Krammer, Viviana Simon, Erica Ollmann Saphire, Davey M Smith, Daniela Weiskopf, Alessandro Sette, Shane Crotty
Published in Science on 6 January, 2021
Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
Technology Review reports that the study contrasts with earlier findings that suggested COVID-19 immunity could be short-lived, putting millions who’ve already recovered at risk of reinfection. That predicament wouldn’t have been a total surprise, since infection by other coronaviruses generates antibodies that fade fairly quickly.
But, the report says, the new study suggests reinfection should only be a problem for a very small percentage of people who’ve developed immunity – whether through an initial infection or by vaccination. In fact, the study does show that a small number of recovered people do not have long-lasting immunity. But vaccination ought to offset that problem by ensuring herd immunity in the larger population.
Technology Review reports that while immunity to other coronaviruses has been less than stellar, it’s worth looking at what happens in people who recovered from SARS, a close cousin of the virus that causes COVID-19.
A study published in August showed that T cells specific to SARS can remain in the blood for at least 17 years, bolstering hopes that COVID-19 immunity could last for decades.
The report says the new study isn’t perfect. It would have been better to collect multiple blood samples from every participant. “Immunity varies from person to person, and uncommon individuals with weak immune memory still may be susceptible to reinfection,” Crotty cautions.
And we can’t make any firm conclusions about COVID-19 immunity until years have passed – it’s simply too early. Nonetheless, this latest result is a good indication that if the vaccination rollout goes well (a big if), we might soon be able to put the pandemic behind us.
Science Immunology study (Open Access)
Emerging Infectious Diseases study (Open Access)
La Jolla Institute for Immunology material
Full Technology Review report