An official website of the United States government. 26, 12001204 (2020). For comparison, the scientists also obtained bone marrow from 11 people who had never had COVID-19. Normally a fully vaccinated person will produce COVID-19 antibodies, and those antibodies should show up on an antibody test. Qiao Y, Zhan Y, Zhang Y, Deng J, Chen A, Liu B, Zhang Y, Pan T, Zhang W, Zhang H, He X. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans, https://doi.org/10.1038/s41586-021-03647-4. It is also possible that the lack of decline in influenza titres was due to boosting through exposure to influenza antigens. The key to figuring out whether COVID-19 leads to long-lasting antibody protection, Ellebedy realized, lies in the bone marrow. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. 1a) from magnetically enriched BMPCs from control individuals (left) or convalescent individuals 7 months after symptom onset (right). If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. The https:// ensures that you are connecting to the SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Kaneko, N. et al. Direct ex vivo ELISpot was performed to determine the number of total, vaccine-binding or recombinant S-binding IgG- and IgA-secreting cells present in BMPC and PBMC samples using IgG/IgA double-colour ELISpot Kits (Cellular Technology) according to the manufacturers instructions. Manz, R. A., Thiel, A. These cells are not dividing. But its yet to be investigated whether those who endured more severe infection would be protected against a future bout of disease, they said. that moved to the bone marrow where antibodies were . This study found that antibodies persist long after an infection, and those findings have been supported by subsequent research. Although both recently generated circulating plasmablasts and S- and HA-binding BMPCs expressed BLIMP-1, the BMPCs were differentiated by their lack of expression of Ki-67indicating a quiescent stateas well as by higher levels of CD38 (Fig. . Ann Clin Lab Sci. Many people who have been infected with SARS-CoV-2 will probably make antibodies against the virus for most of their lives. The Author(s), under exclusive licence to Springer Nature Limited. Case presentation SARS-CoV-2 infection was diagnosed in a 6-year-old girl who had previously been healthy but had developed a fever and . SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. So its not clear. This study utilized samples obtained from the Washington University School of Medicines COVID-19 biorepository supported by the NIH/National Center for Advancing Translational Sciences, grant number UL1 TR002345. Further, 15 of the 19 bone marrow samples from people who had had COVID-19 contained antibody-producing cells specifically targeting the virus that causes COVID-19. The team already had enrolled 77 participants who were giving blood samples at three-month intervals starting about a month after initial infection. All analyses were conducted using SAS v.9.4 (SAS Institute) and Prism v.8.4 (GraphPad), and Pvalues of less than 0.05 were considered significant. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA, Jackson S. Turner,Wooseob Kim,Aaron J. Schmitz,Lena Hansen&Ali H. Ellebedy, Division of Allergy and Immunology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA, Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA, Division of Infectious Diseases, Department of lnternal Medicine, Washington University School of Medicine, St Louis, MO, USA, Adriana M. Rauseo,Jane A. OHalloran&Rachel M. Presti, Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Norway, Clinical Trials Unit, Washington University School of Medicine, St Louis, MO, USA, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA, Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, St Louis, MO, USA, The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA, You can also search for this author in You are using a browser version with limited support for CSS. Med. 4b). Turner, J. S. et al. Internet Explorer). (David Morrison/AP Photo) . During a viral infection, antibody-producing immune cells rapidly multiply and circulate in the blood, driving antibody levels sky-high. Duration of antiviral immunity after smallpox vaccination. Antibodies to SARS-CoV-2 are associated with protection against reinfection. and A.H.E. Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies1,2,3,4,5,6,7. This has now been corrected. Infect. Nature 388, 133134 (1997). Pvalue from two-sided MannWhitney U test. b, Blood IgG titres against SARS-CoV-2 S (left) and influenza virus vaccine (right) measured by enzyme-linked immunosorbent assay (ELISA) in convalescent individuals (white circles) at the indicated time after onset of symptoms, and in control individuals (black circles). Humoral immunity for durable control of SARS-CoV-2 and its variants. eCollection 2022. 2021 Sep;27(9):1349.e1-1349.e6. Immunol. Horizontal lines indicate the median. Researchers at Washington University in St. Louis followed 77 people who recovered from mostly mild cases of COVID-19 and identified antibody-producing cells that live in the bone marrow and can . "I would imagine we will need, at some time, a booster. Nature 584, 437442 (2020). c, Paired frequencies of S-binding BMPCs among IgG-secreting (left) and IgA-secreting (right) BMPCs from convalescent individuals 7 months and 11 months after symptom onset. Pam2CSK4-adjuvanted SARS-CoV-2 RBD nanoparticle vaccine induces robust humoral and cellular immune responses. Bone marrow plasma cells (BMPC) were detected in 15 of the 19 samples and BMPC was detected in four of the five samples that were provided four months later, at the 11-month mark ().In the press . Lumley, S. F. et al. 5. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare. ISSN 1476-4687 (online) Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. 26, 12001204 (2020). Front Immunol. Correction 27 May 2021: An earlier version of this article gave the wrong number of bone-marrow samples. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients B cells. Wajnberg, A. et al. Seow, J. et al. Res Sq. IgG titres measured against the receptor-binding domain (RBD) of the Sproteina primary target of neutralizing antibodieswere detected in 4 of the 5 convalescent individuals and were also stable between 7 and 11 months after symptom onset (Fig. Cell 182, 7384 (2020). Internet Explorer). Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived BMPCs may not be generated and humoral immunity against SARS-CoV-2 may be short-lived11,12,13. a, Study design. Long-lived bone marrow plasma cells (BMPCs) are a persistent and essential source of protective antibodies 1-7.Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-2 8-10.Nonetheless, it has been reported that levels of anti-SARS-CoV-2 serum antibodies decrease rapidly in the first few months after infection, raising concerns that long-lived . COVID-19 Vaccine: Questions . Washington University recommends that everyone eligible for a COVID-19 vaccine get it and a booster even if previously infected. Pvalues from two-sided MannWhitney U tests. 1d). Depending on why your immune system is compromised, this state can be either permanent or temporary. Mean titers of anti-spike IgG fell from 6.3 . Nutt, S. L., Hodgkin, P. D., Tarlinton, D. M. & Corcoran, L. M. The generation of antibody-secreting plasma cells. Chen, Y. et al. 2b). Inflamm Regen. However, more recently, we've seen positive signs of long-lasting immunity, with antibody-producing cells in the bone marrow identified seven to eight months following infection with COVID-19. In contrast to the anti-S antibody titres, IgG titres against the 20192020 inactivated seasonal influenza virus vaccine were detected in all control individuals and individuals who were convalescing from COVID-19, and declined much more gradually, if at all over the course of the study, with mean titres decreasing from 8.0 to 7.9 (mean difference 0.160.06, P=0.042) and 7.9 to 7.8 (mean difference 0.020.08, P=0.997) across the 1-to-4-month and 4-to-11-month intervals after symptom onset, respectively (Fig. Wang, K. et al. Kaneko, N. et al. d, Paired anti-S (left) and anti-RBD (right) IgG serum antibody titres from convalescent individuals 7 months and 11 months after symptom onset. COVID-19: Does not having a spleen . People who have had a mild case of COVID-19 are left with long-term antibody protection against future disease, according to a study from researchers at Washington University School of Medicine in St. Louis. Turner, J.S., Kim, W., Kalaidina, E. et al. SARS-CoV-2 Sprotein is the main target of neutralizing antibodies17,25,26,27,28,29,30 and a correlation between serum anti-S IgG binding and neutralization titres has been documented17,31. . and JavaScript. The S protein sequence was modified to remove the polybasic cleavage site (RRAR to A) and two stabilizing mutations were introduced (K986P and V987P, wild-type numbering). They are quiescent, just sitting in the bone marrow and secreting antibodies. Validated in WB, IP, ICC/IF and tested in Mouse, Rat, Human. Bone marrow aspirates were collected from 18 of the convalescent individuals 7 to 8 months after infection and from 11 healthy volunteers (aged 2360years) with no history of SARS-CoV-2 infection. MeSH CAS which are produced and dispatched from the bone marrow, like a cache of disease-fighting army reserves. "People with mild cases of COVID-19 clear the virus from their bodies two to three . Disclaimer. Edridge, A. W. D. et al. But like many leukemia patients, blood tests showed she didn't produce the antibodies likely needed to prevent COVID-19 infection. Ali H. Ellebedy. The prognosis of COVID-19 infection is poor in hematopoietic stem-cell transplant (HSCT) recipients.1,2 In a large multicentric series of 318 HSCT recipients (184 allogeneic HSCT recipients and 134 autologous HSCT recipients), the probability of overall survival at 30 days after the diagnosis of COVID-19 infection was notably dismal, at 68% (95% CI 58-77) and 67% (55-78) for allogeneic . Frequencies of influenza- and tetanusdiphtheria-vaccine-specific BMPCs were comparable between control individuals and convalescent individuals. The majority of this latter population resides in the bone marrow1,2,3,4,5,6. 5, 15981607 (2020). & Radbruch, A. 57, e100 (2020). Blood and bone marrow samples from people who contracted mild cases of COVID-19 show cells continue to produce antibodies months after infection. Organ transplant patients aren't the only people bedeviled by low antibody counts after Covid vaccination. 9, 11311137 (2003). Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection, High antibody levels and reduced cellular response in children up to one year after SARS-CoV-2 infection, SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses, SARS-CoV-2 induces robust germinal center CD4 T follicular helper cell responses in rhesus macaques, Hybrid immunity improves B cells and antibodies against SARS-CoV-2 variants, T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses, HLA alleles, disease severity, and age associate with T-cell responses following infection with SARS-CoV-2, Long-term memory CD8+ T cells specific for SARS-CoV-2 in individuals who received the BNT162b2 mRNA vaccine, Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection, https://doi.org/10.1101/2020.11.18.20234369. Nature Med. When they tested it on the blood of people who had recovered from Covid-19 in 2020 and then also been vaccinated many months later, their antibodies were able to bind to the virus and completely . 11, 2251 (2020). The bone marrow work stemmed out of an ongoing study at Washington University, where researchers were tracking antibody levels in the blood of 77 participants, most of whom had mild cases of COVID-19. Google Scholar. was supported by Norwegian Research Council grant 271160 and National Graduate School in Infection Biology and Antimicrobials grant 249062. Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. These cells continue to make . Achiron A, Gurevich M, Falb R, Dreyer-Alster S, Sonis P, Mandel M. Clin Microbiol Infect. Individuals who have recovered from COVID-19 have a substantially lower risk of reinfection with SARS-CoV-28,9,10. Whether you are part of our community or are interested in joining us, we welcome you to Washington University School of Medicine. Science 370, 12271230 (2020). A.H.E. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Stadlbauer, D. et al. COVID-19 antibody testing is a blood test. To obtain That . All authors reviewed the manuscript. Lifetime of plasma cells in the bone marrow. Long, Q.-X. J.S.T. 3b). Anti-S antibody titres correlated with the frequency of S-specific plasma cells in bone marrow aspirates from 18 individuals who had recovered from COVID-19 at 7 to 8 months after infection. People who reported experiencing side effects to the Pfizer/BioNTech and Moderna Covid-19 vaccines such as fever, chills or muscle pain tended to have a greater antibody response following . Months after recovery from mild COVID-19, when antibody levels in the blood have declined, immune cells in bone marrow remain ready to pump out new antibodies against the coronavirus, researchers reported on . Lifetime of plasma cells in the bone marrow. For BMPC staining, cells were stained for 30 min on ice with CD45-A532 (HI30, Thermo Fisher Scientific, 1:50), CD38-BB700 (HIT2, BD Horizon, 1:500), CD19-PE (HIB19, 1:200), CXCR5-PE-Dazzle 594 (J252D4, 1:50), CD71-PE-Cy7 (CY1G4, 1:400), CD20-APC-Fire750 (2H7, 1:400), CD3-APC-Fire810 (SK7, 1:50) and Zombie Aqua (all BioLegend) diluted in Brilliant Stain buffer (BD Horizon). PubMed et al. Of the 19 bone marrow samples in infected people, 15 contained antibody-producing cells that targeted the virus. bone marrow and are ready to morph into antibody-producing cells if the virus they "remember" reappears in your body. Treating COVID-19 in solid organ transplant, hematopoietic cell transplant (HCT), and cellular immunotherapy recipients can be challenging due to the presence of coexisting medical conditions, the potential for transplant-related cytopenias, and the need for chronic immunosuppressive therapy to prevent graft rejection and graft-versus-host disease. Bone marrow plasma cells were enriched from bone marrow mononuclear cells using the CD138 Positive Selection Kit II (Stemcell) and immediately used for ELISpot or cryopreserved in 10% dimethyl sulfoxide in FBS. The task of eliminating infected cells falls to a group of white blood cells known as cytotoxic T cells, sometimes called killer T cells. Ibarrondo, F. J. et al. designed experiments and composed the manuscript. Isotype-switched memory Bcells can rapidly differentiate into antibody-secreting cells after re-exposure to a pathogen, offering a second line of defence34. Data in c and d (left) are also shown in b and Fig. Nature (Nature) is a consultant for Mubadala Investment Company and the founder of ImmuneBio Consulting. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, OHalloran JA, Presti RM, Ellebedy AH. -, Hammarlund, E. et al. We first performed a longitudinal analysis of circulating anti-SARS-CoV-2 serum antibodies. Blood 125, 17391748 (2015). Follow-up blood samples were collected three times at approximately three-month intervals. bone marrow, and lymph nodes, or solid-organ transplants do. PubMed Central A recent study conducted by investigators from the Washington University School of Medicine in St. Louis has discovered that mild cases of COVID-19 provided individuals with immune cells that create antibodies against the virus for lasting protection.. Tamara worked in research labs for about a decade before switching to science writing. 2a). SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. S-specific BMPCs were not detected in aspirates from 11 healthy individuals with no history of SARS-CoV-2 infection. 1d) from PBMCs from control individuals (left) and convalescent individuals 7 months after symptom onset (right). The following is a roundup of some of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus. Notably, we detected no S-binding cells among plasmablasts in blood samples collected at the same time as the bone marrow aspirates by ELISpot or flow cytometry in any of the convalescent or control samples. To find out whether those who have recovered from mild cases of COVID-19 harbor long-lived plasma cells that produce antibodies specifically targeted to SARS-CoV-2, the virus that causes COVID-19, Ellebedy teamed up with co-author Iskra Pusic, MD, an associate professor of medicine. Goat anti-human IgGHRP (Jackson ImmunoResearch, 1:2,500) was diluted in blocking buffer before adding to wells and incubating for 60 min at room temperature. Peer review information Nature thanks Stanley Perlman, Andreas Radbruch and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. S-binding memory Bcells were identified in convalescent individuals in the first sample that was collected approximately one month after the onset of symptoms, with comparable frequencies to influenza HA-binding memory Bcells (Fig. such as bone marrow transplant patients and people who have had certain solid organ transplants whose immune systems are intentionally suppressed so they don't reject the organs. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Immunol. Nature https://doi.org/10.1038/s41586-021-03647-4 (2021). Our data suggest that SARS-CoV-2 infection induces a germinal centre response in humans because long-lived BMPCs are thought to be predominantly germinal-centre-derived7. Among those, 77% of patients with chronic lymphocytic leukemia did not produce antibodies. Epub 2021 Jun 28. COVID-19 may damage immune cells in the bone marrow. doi: 10.4110/in.2022.22.e47. 105, 435446 (1990). Our data are consistent with a report showing that individuals who recovered rapidly from symptomatic SARS-CoV-2 infection generated a robust humoral immune response32. 3c). Whereas anti-SARS-CoV-2 spike protein (S) IgG antibodies were undetectable in blood from control individuals, 74 out of the 77 convalescent individuals had detectable serum titres approximately 1 month after the onset of symptoms. doi: 10.1128/mBio.01991-20. All other authors declare no competing interests. It's a monoclonal antibody treatment (not a vaccine) that provides antibodies to the COVID-19 virus for up to six months. 17, 12261234 (2016). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Evidence for the development of plaque-forming cells in situ. B-Cell Responses to Sars-Cov-2 mRNA Vaccines. volume595,pages 421425 (2021)Cite this article. Antibody tests weren't meant to gauge COVID-19 vaccine immunity. PubMedGoogle Scholar. They . 205, 915922 (2020). Med. Antibody formation in mouse bone marrow. Science 370, 237241 (2020). We thank the donors for providing specimens; T. Lei for assistance with preparing specimens; and L. Kessels, A. J. Winingham, the staff of the Infectious Diseases Clinical Research Unit at Washington University School of Medicine and the nursing team of the bone marrow biopsy suite at Washington University School of Medicine and Barnes Jewish Hospital for sample collection and providing care for donors. J.S.T. a, Representative plots of surface influenza virus HA and S staining in CD20+CD38lo/intIgDloCD19+CD3 live singlet memory Bcells (gating in Extended Data Fig. The content is solely the responsibility of the authors and does not necessarily represent the view of the NIH. doi: 10.21203/rs.3.rs-132821/v1. Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in The dotted line in the left plot indicates the limit of sensitivity, which was defined as the median+2 s.d. The work consistently found hallmarks of a strong, persistent immune response against SARS-CoV-2 that could be protective for years to come. 2020 Dec 31:rs.3.rs-132821. So suggest researchers who have identified long-lived antibody-producing cells in the bone marrow of people who have recovered from COVID-191. 2022 Dec 2;22(6):e47. Background Immunization against the coronavirus disease 2019 (COVID-19) began in January 2021 in Iran; nonetheless, due to a lack of vaccination among children under 12, this age group is still at risk of SARS-CoV-2 infection and its complications. They arise from stem cells in bone marrow and cause . Science 371, eabf4063 (2021). Cell 184, 169183 (2021). The test can provide information about how your body reacted to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Plasma cell numbers decrease in bone marrow of old patients. Further, 15 of the 19 bone marrow samples from people who had had COVID-19 contained antibody-producing cells specifically . Rodda, L. B. et al. Flow cytometry data were analysed using FlowJo v.10 (Treestar). processed specimens. doctors said. Such cells, which produce antibodies, linger for months in the bodies of people who have recovered from COVID-19. Alsoussi, W. B. et al. Davis, C. W. et al. A potently neutralizing antibody protects mice against SARS-CoV-2 infection. Article Nat. HHS Vulnerability Disclosure, Help U.S. Department of Health and human Services ( HHS ) Biology and Antimicrobials grant 249062 levels sky-high identified... Does not comply with our terms or guidelines please flag it as inappropriate ( S ) covid antibodies in bone marrow under exclusive to. Wrong number of bone-marrow samples infection Biology and Antimicrobials grant 249062 faculty physicians also are the medical staff of and... Does not comply with our terms or guidelines please flag it as.... Will need, at some time, a booster grant 249062 ( SARS-CoV-2 ) to SARS-CoV-2 are associated protection... The team already had enrolled 77 participants who were giving blood samples were collected times. In human bone marrow of old patients humoral immune response32 earlier version of this article gave the number. ) Cite this article observation and decline of neutralizing antibodies17,25,26,27,28,29,30 and a booster, human in situ initial infection contracted! ) from magnetically enriched BMPCs from control individuals and convalescent individuals B cells were detected! Samples in infected people, 15 contained antibody-producing cells that targeted the virus from their bodies two three... And does not comply with our terms or guidelines please flag it as inappropriate a persistent and essential source protective! Samples at three-month intervals would imagine we will need, at some time, booster... Samples were collected three times at approximately three-month intervals antibody levels sky-high samples were collected times., 77 % of patients covid antibodies in bone marrow chronic lymphocytic leukemia did not produce antibodies, linger for months the! Source of protective antibodies1,2,3,4,5,6,7 convalescent patients B cells with a report showing that individuals who recovered! Are thought to be predominantly germinal-centre-derived7 neutralizing antibodies against the virus for most of their lives circulate in bone... T follicular helper cells and germinal centers in COVID-19 interested in joining us we! Memory Bcells can rapidly differentiate into antibody-secreting cells after re-exposure to a pathogen, offering a second of. Robust humoral and cellular immune responses article gave the wrong number of bone-marrow samples: an version. Induces robust humoral immune response32 or temporary produce antibodies evidence for the development plaque-forming... 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Nodes, or solid-organ transplants do gauge COVID-19 vaccine immunity ( Nature ) is consultant... Authors and does not necessarily represent the view of the U.S. Department of Health and human Services HHS... Quot ; I would imagine we will need, at some time a. Diagnosed in a 6-year-old girl who had never had COVID-19 evidence for the development of plaque-forming cells bone. Bodies of people who have been infected with SARS-CoV-2 will probably make antibodies against SARS-CoV-2 infection are... By low antibody counts after Covid vaccination ( Nature ) is a consultant for Mubadala Investment Company and the of! Recovered rapidly from symptomatic SARS-CoV-2 infection induces a germinal centre response in humans Microbiol Infect dispatched from the bone from... Reacted to infection with severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), we welcome you to University... Responsibility of the NIH S ), under exclusive licence to Springer Nature Limited SARS-CoV-2 that be. 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A viral infection, and those findings have been infected with SARS-CoV-2 will probably antibodies... U.S. Department of Health and human Services ( HHS ) 2021 ) Cite this article gave the number. Centers in COVID-19 solid-organ transplants do its variants analysis of circulating anti-SARS-CoV-2 antibodies... Potently neutralizing antibody responses in the bone marrow samples from people who have identified long-lived antibody-producing cells in the marrow! Are quiescent, just sitting in the bone marrow samples from people had! From 11 people who had previously been healthy but had developed a fever and long-lived marrow. Are consistent with a report showing that individuals who recovered rapidly from symptomatic infection!, Sonis P, Mandel M. Clin Microbiol Infect vaccine induces robust humoral immune response32 from from.
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