key: cord-0945775-bc7i6z6u authors: Zeng, Q.; Yang, X.; Gao, Q.; Lin, B.-y.; Li, Y.-z.; Huang, G.; Xu, Y. title: Interpretation of non-responders to SARS-CoV-2 vaccines using WHO International Standard date: 2022-04-01 journal: nan DOI: 10.1101/2022.03.31.22273272 sha: 2a686f2c0cb63c302746dd523c1b9b5397e977e1 doc_id: 945775 cord_uid: bc7i6z6u Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with more than 485 millions infected. Questions about non-responders to SARS-CoV-2 vaccines remain unaddressed. Here, we report data from people after administering the complete dose of SARS-CoV-2 vaccines using the World Health Organization International Standard for anti-SARS-CoV-2 immunoglobulin. Our study showed that immune cells such as CD4 cells, CD8 cells, and B cells and anti-spike immunoglobulin G levels were significantly reduced in the elderly. There were 7.5% non-responders among the 18-59 yr group and 11.7% in the [≥]60 yr group. A titer of anti-SARS-CoV-2 spike immunoglobulin G is blew 50 BAU/mL to be considered as non-responders at intervals of 30 to 90 days after the last vaccine dose. Booster vaccination may be recommended for non-responders to reduce the disease severity and mortality. In order to bring the COVID-19 pandemic under control as soon as possible and ensure that the To date, more than 5 billion people have been vaccinated against COVID-19. 9 In clinical trials 86 associated with COVID-19 vaccines, the effective COVID-19 vaccination reportedly elicits 87 specific antibody responses. An effective humoral immune response is defined as a ≥ 4-fold 88 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.31.22273272 doi: medRxiv preprint 4 increase in antibody titers from baseline within 1-3 months of the vaccination procedure and is 89 considered gold standard for assessing antibody protection in vaccinated recipients. [10] [11] [12] In 90 contrast, a non-responder is an individual who demonstrates no effective humoral immune 91 response despite the completion of the suggested vaccination procedure. 13 To this end, in December 2020, WHO issued an international standard (IS) for the quantification 100 of anti-SARS-CoV-2 immunoglobulin for post-vaccination testing. [26] [27] This standard provides a 101 unified benchmark for effective antibody protective concentrations after vaccination. In this 102 clinical study, we analyzed 627 people that volunteered to participate in COVID-19 vaccination 103 and subsequent assessment of antibody titers. After two doses of vaccination, the antibody titer 104 was evidently increased by ≥ 4 times from baseline as the gold standard. Furthermore, the data 105 using the WHO IS was comprehensively analyzed to provide insights for improving the efficacy 106 of vaccines, help in reduction of breakthrough infections after vaccines, and ultimately to reduce 107 the disease severity and mortality. (Table 1 ). In fact, the number of naïve 117 lymphocytes, CD4 cells, CD8 cells, and B cells were significantly reduced in the elderly 118 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Anti-spike IgG levels in the 627 cases after complete vaccination 123 We analyzed the anti-spike immunoglobulin (Ig)G levels after complete vaccination of the 627 124 cases ( Characteristics of seroconversion after the complete dose 134 Thereafter, we evaluated the vaccine-induced responses, based on the post-second-dose and pre-135 second-dose titers, using the 4-fold increase parameter (fold-index <4 or ≥4) ( Table 2) . 136 Remarkably, there were 7.5% non-responders (fold-index < 4) among the 18-59 yr group and 137 11.7% in the ≥60 yr group (Table 2, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We further observed that the seroconversion rate was significantly related to the proportion of 151 certain naïve immune cells (Table 2) However, the CD8 cell count in the ≥60 yr group and NK cell count in both the age groups did 170 not portray any significant differences. To the best of our knowledge, this is the first clinical study to report non-responders after 175 administering the complete dose of inactivated SARS-CoV-2 vaccines using WHO International (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. The WHO IS has demonstrated to be enabled to comparison between different types of vaccines. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.31.22273272 doi: medRxiv preprint 8 proves this phenomenon. [29] [30] If this theory turns out to be correct, then it is possible that SARS-212 CoV-2 vaccine responders have a strong ability to produce antibodies against variants through 213 asymptomatic infections. This may support the Government-issued "immunity passports" to (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. There are several potential strategies that can be employed to reduce the COVID-19 mortality 271 rate below 0.13 % of that caused by influenza virus. These include the following measures: (1) Increase the vaccination rate of the population; 2 (2) Develop vaccines against emerging and 273 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 390 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 1, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 2. World Health Organization. COVID-19 advice for the public: Getting vaccinated Centers for Disease Control and Prevention. 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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Lymphocytes, mean (95% CI) 1,130 CD4 cells, mean (95% CI) B cells, mean (95% CI) NK cells, mean (95% CI) *Post-vaccination testing was done at intervals of 14 to 90 days after the second vaccine dose. The reference ranges were defined as the 2.5-97.5 603 percentile in the study. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.31.22273272 doi: medRxiv preprint