robust induction of b cell and t cell responses by a third dose of inactivated sars cov 2 CORD-Papers-2021-10-25 (Version 1)

Title: Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine
Abstract: SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a non-randomized trial among the healthcare professionals (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccine and the potential need for a third booster dose for the HCWs. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 31.2 AU/ml to 9.2 AU/ml 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 66.8 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to 2 doses were not truly no responders but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term immunological memory by the inactivated vaccine, which has implications for future booster strategies that the frontline HCWs, individuals with low serological response to 2 dose of vaccine and immune compromised patients could benefit from a third dose of inactivated vaccine.
Published: 9/15/2021
DOI: 10.1101/2021.09.12.21263373
DOI_URL: http://doi.org/10.1101/2021.09.12.21263373
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Zeng, Q
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zeng_q
Author Name: Deng, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/deng_c
Author Name: Li, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_m
Author Name: Li, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_l
Author Name: Liu, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_d
Author Name: Mei, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mei_j
Author Name: Mo, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mo_r
Author Name: Zhou, Q
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhou_q
Author Name: Liu, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_m
Author Name: Peng, S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/peng_s
Author Name: Wang, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_j
Author Name: Zhang, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhang_h
Author Name: Xiao, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/xiao_h
sha: 7fd6914169c25c3057810838aab27d707b03e9ff
license: medrxiv
source_x: MedRxiv
url: http://medrxiv.org/cgi/content/short/2021.09.12.21263373v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: CD4 immune memory medRxiv T cells medRxiv preprint 4 spike-specific memory B spike-specific SARS-CoV-2 patients follicular helper T cells HCWs SARS-CoV-2-specific B cells https://doi.org/10.1101/2021.09.12.21263373 doi CD8 COVID-19 Fig. 2F, 2G S. peripheral blood 6 Guangzhou, FBS vaccine CoronaVac ChiCTR2100042222 sera spike-or RBD-specific memory B 1μg/ml CD45RA S. Fig. 2, 3) peripheral blood 5 S. Fig. 1 IgA + B cells COVID-19 8 CD4 -CD8 -T cells StemCell Antigen-specific T cell extracellular SARS-CoV-2-specific memory B cells treatment-induced B cell CD4 vaccine medRxiv individuals SARS-CoV-2 vaccine BBIBP-CorV FACS spike-or RBD-specific BCR human Fig. 2D, 2E SARS-CoV-2 structure proteins SARS-CoV-2 spike protein (2 RBD-specific B cells AIM + T cells SARS-CoV-2-specific B cells coronavirus 2 Avidin-HRP SARS-CoV-2-specific NAb SARS-CoV-2-specific memory B Peripheral blood mononuclear cells d194 SARS-CoV-2 S1 antigen-specific T cells memory B cells OX40 + 4-1BB Antigen-specific memory B cells S. Table 1 ChiCTR2100048665 NTD SARS-CoV-2-specific CD8 serum SARS-CoV-2 NAb immune memory Falcon tubes lymph nodes SARS-CoV-2-specific T cell B cell SARS-CoV-2-specific CD4 RPMI 1640 IgM + B cells RBD-specific memory B cells herd cellular COVID-19 patients 26 d187 blood samples IFN-γ u.f.c/10 6 SARS-CoV-2 nucleocapsid CD8 B cells SARS-CoV-2 vaccines SARS-CoV-2 vaccine ACE2 layer naïve B cells YHLO globe SARS-CoV-2 [3] [4] [ heparinized tubes anti-CD3/CD28 dynabeads cells Blood samples SARS-CoV-2 participants CD3 SARS-CoV-2-specific CD4 + T cells IgG BBIBP-CorV SARS-CoV-2 receptor LymphoprepTM PBMCs Spike-or RBD-specific memory B SARS-CoV-2 antigens T EMRA d180 T cell IgG + SARS-CoV-2-specific CD3 tubes spike-specific T cells streptomycin patients penicillin IgD -CD27 -) B cells ACE serum samples CD69 + 4-1BB d28 T EM medRxiv preprint 7 Fig. 5G HCWs SARS-CoV-2-specific cTFH cells FAH-SYSU medRxiv preprint Convalescent patients BNT162b2 convalescent COVID-19 patients S. Fig. 7 https://doi.org/10.1101/2021.09.12.21263373 doi coronavirus disease 2019 medRxiv preprint 6 T cells B, C 5I CD45RA -CCR7effector memory T cells u.f.c/10 6 PBMCs anti-CD3/CD28 CD4 d201 d194 medRxiv preprint medRxiv Spike-specific BCR d187 Caparisons https://doi.org/10.1101/2021.09.12.21263373 doi
Extracted Text Content in Record: First 5000 Characters:SARS-CoV-2 inactivated vaccines have shown remarkable efficacy in clinical trials, especially in reducing severe illness and casualty. However, the waning of humoral immunity over time has raised concern over the durability of immune memory following vaccination. Thus, we conducted a non-randomized trial among the healthcare professionals (HCWs) to investigate the long-term sustainability of SARS-CoV-2-specific B cells and T cells stimulated by inactivated vaccine and the potential need for a third booster dose for the HCWs. Although neutralizing antibodies elicited by the standard two-dose vaccination schedule dropped from a peak of 31.2 AU/ml to 9.2 AU/ml 5 months after the second vaccination, spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 66.8 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4 + and CD8 + T cells were also robustly elevated by 5.9 and 2.7 folds respectively. Robust expansion of memory pools by the third dose potentiated greater durability of protective immune responses. Another key finding in this trial was that HCWs with low serological response to 2 doses were not truly "no responders" but fully equipped with immune memory that could be quickly recalled by a third dose even 5 months after the second vaccination. Collectively, these data provide insights into the generation of long-term . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263373 doi: medRxiv preprint 4 immunological memory by the inactivated vaccine, which has implications for future booster strategies that the frontline HCWs, individuals with low serological response to 2 dose of vaccine and immune compromised patients could benefit from a third dose of inactivated vaccine. The coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread across the globe currently 1,2 . The pandemic has brought profound casualties of human life and socioeconomic issues. The establishment of herd immunity by effective and sustainable vaccines represents the best strategy to prevent COVID-19. The rapid spreading of COVID-19 has urged the governments to authorize the emergent use of vaccines against SARS-CoV-2 [3] [4] [5] . The presence of neutralizing antibodies (NAbs) against SARS-CoV-2 is an indicator of protective immunity after vaccination or infection 6, 7 . NAbs capable of blocking the interaction between the spike protein and its receptor angiotensin converting enzyme 2 (ACE2) are particularly important for protection from COVID-19 8 . Therefore, inducing potent NAbs and long-lasting memory B cells are the primary goal of SARS-CoV-2 vaccines. Two doses of mRNA or inactivated vaccines are capable of inducing potent neutralizing antibody responses 9, 3, 10 . Our previous study further demonstrated that inactivated vaccines elicited SARS-CoV-2 specific memory B cells 11 , which is important for a rapid and robust recall of protective responses against viral infection. However, little is known how long can these immune responses sustain. A rapid decline of neutralizing antibodies has been observed among infected healthcare workers (HCWs) 12 . Neutralizing antibodies also waned over time after the second dose of BNT162b2 or ChAdOx1 13 , which indicates . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 15, 2021. ; https://doi.org/10.1101/2021.09.12.21263373 doi: medRxiv preprint 6 weakened protection from SARS-CoV-2 infection. In addition, the rapid emergence of novel SARS-CoV-2 variants of concern dampens the efficacy of SARS-CoV-2 vaccines, since vaccine-induced antibodies were always less effective in neutralizing emerging variants of concern (VOCs) 14 . Moreover, cross-reactive antibodies decayed even faster than antibodies against wild-type strain 15 . Besides humoral immune responses, T cells also play a pivotal role in coordinating the adaptive immune responses and as effectors against viral infection. In some cases, patients with inherited or treatment-induced B cell deficiency were able to recover from COVID-19 16, 17 , suggesting a potential role of cellular responses in fighting against SARS-CoV-2 infection. Induction of CD8 + T cell responses was documented in both SARS-CoV-2 infection and vaccination 18, 19 . On the other hand, rapid induction of CD
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