key: cord-0758316-18ma7t0x authors: Zeng, Qiang; Yang, Xue; Gao, Qi; Lin, Biao-yang; Li, Yong-zhe; Huang, Gang; Xu, Yang title: Immunological findings in a group of individuals who were non-responders to standard two-dose SARS-CoV-2 vaccines date: 2022-05-06 journal: bioRxiv DOI: 10.1101/2022.05.05.490815 sha: f516511f34f3860fb85b47d2154c31c7c6a2ede7 doc_id: 758316 cord_uid: 18ma7t0x Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic. The virus has infected more than 505 million people and caused more than 6 million deaths. However, data on non-responders to SARS-CoV-2 vaccines in the general population are limited. The objective of the study is to comprehensively compare the immunological characteristics of non-responders to SARS-CoV-2 vaccines in the 18-59 years with that in the 60 years and older using internationally recognized cutoff values. Participants included 627 individuals who received physical examinations and volunteered to participate in COVID-19 vaccination from the general population. The main outcome was an effective seroconversion characterized by anti-SARS-CoV-2 spike IgG level of at least 4-fold increase from baseline. Profiling of naive immune cells was analyzed prior to vaccination to demonstrate baseline immunity. Outcomes of effective seroconversion in the 18-59 years with that in the 60 years and older were compared. The quantitative level of the anti-spike IgG was significantly lower in the 60 years and older and in men among the 18-59 years. There were 7.5% of non-responders among the 18-59 years and 11.7% of non-responders in the 60 years and older using the 4-fold increase parameter. The effective seroconversion rate was significantly related to the level of certain immune cells before vaccination, such as CD4 cells, CD8 cells and B cells and the age. An individual with a titer of anti-SARS-CoV-2 spike IgG that is below 50 BAU/mL might be considered a non-responder between 14-90 days after the last vaccine dose. Booster vaccination or additional protective measures should be recommended for non-responders as soon as possible to reduce 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 vaccination, the effective COVID-19 vaccination reportedly elicits 87 specific antibody responses. An effective humoral immune response is defined as a ≥ 4-fold 88 increase in antibody titers from baseline and is considered gold standard for assessing antibody 89 protection in vaccinated recipients in clinical studies. [10] [11] [12] In contrast, a non-responder is an (Table 1 ). In fact, the number of naïve lymphocytes, CD4 cells, CD8 cells, and B cells 152 were significantly reduced in the elderly (≥60 years) population than that in the 18-59 yr 153 population (P < 0.001). Hence, these naïve immune cells wane significantly, while the NK cell 154 counts increase significantly in the elderly people (Table 1, Figure 1A ). Characteristics of humoral response after complete vaccination 157 We analyzed the anti-spike immunoglobulin (Ig)G levels after complete two doses of vaccination 158 of the 627 cases ( Figure 1B ). The (Table 2) . (Table 2) . Remarkably, there were 7.5% of non-responders (fold-index < 4) among the 18-59 yr 181 group and 11.7% of non-responders in the ≥60 yr group (Table 2, Figure 1C ), indicating that the 182 7 positive rate of anti-spike IgG cannot represent the effective seroconversion rate (fold-index ≥ 4). 183 Therefore, the anti-spike IgG positivity or seroprevalence might not be a suitable predictor of the 184 effective seroconversion. In the 18-59 yr group, the median (IQR) levels of anti-spike IgG and the reference ranges were 187 115.8 (88.6-167.8) and 11.3-266.3 BAU/mL with fold-index < 4, respectively and 420.8 (369.9-188 480.6) and 200.7-576.5 BAU/mL with fold-index ≥ 4, respectively (P < 0.0001) ( Table 2 ). In Relationship between effective seroconversion rate and baseline immunity 197 We further observed that the effective seroconversion rate (fold-index ≥ 4) was significantly 198 related to the level of certain naïve immune cells before vaccination (Table 2) 508-557/mm 3 ), P = 0.0081]. However, the CD8 cell count in the ≥60 yr group and NK cell count 217 in both the age groups did not portray any significant differences. The WHO IS has demonstrated to be enabled to comparison between different types of vaccines. vaccines. An individual with a titer of anti-SARS-CoV-2 spike IgG that is below 50 BAU/mL 373 might be considered a non-responder between 14-90 days after the last vaccine dose. Limitations: Study limitations include small sample size, data was only sourced from a single 376 center, and lack of RBD/spike-specific cellular immune assessments. 2. World Health Organization. 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These naïve 619 immune cells wane significantly, while the natural killer (NK) cell counts increase significantly in the elderly people The anti-spike IgG levels after complete vaccination of the 627 cases. The 621 quantitative level of the anti-spike IgG was significantly lower in the ≥60 yr group There were 7.5% of non-responders (fold-index < 4) among the 18-59 yr group and 625 11.7% in the ≥60 yr group. The level of anti-spike IgG ranges (the 1st-99th percentile) for responders (fold-index ≥ 626 4) were 43.9-592.0 BAU/mL in combination of the 18-59 yr group and the ≥60 yr group. A cutoff line at fold-index 627 4 was shown. (D) In the responder group (fold-index ≥ 4), levels of anti-spike IgG for the 1st Mean and SEM were shown. (B) There 641 was no significant difference in the ≥60 yr group for the quantitative levels of anti-spike IgG 642 between the male group (median 285.4, IQR 113.1-416.3 BAU/mL) and the female group 643 BAU/mL, median (IQR) *The cutoff value for seropositivity was 11.6 BAU/mL. SD, standard deviation; IQR, interquartile range; IgG, immunoglobulin G; CD 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 performed at intervals of 14-90 days after the second vaccine dose. The reference ranges were 691 defined as the 2.5th-97 SARS-CoV-2, severe acute respiratory syndrome coronavirus 2