key: cord-0428540-z0itsalx authors: Fox, T. A.; Kirkwood, A. A.; Enfield, L.; O'Reilly, M.; Arulogun, S.; D'Sa, S.; O'Nions, J.; Kavi, J.; Vitsaras, E.; Townsend, W.; Burns, S. O.; Gohil, S. H.; Cwynarski, K.; Thomson, K. J.; Noursadeghi, M.; Heyderman, R. S.; Rampling, T.; Ardeshna, K. M.; McCoy, L. E.; Morris, E. C. title: Low seropositivity and sub-optimal neutralisation rates in patients fully vaccinated against COVID-19 with B cell malignancies. date: 2021-07-19 journal: nan DOI: 10.1101/2021.07.19.21260762 sha: edad8eea904bd12c9835b3a4dbae05bc9ed2e384 doc_id: 428540 cord_uid: z0itsalx Patients with haematological malignancies are at increased risk of severe disease and death from COVID-19 and are less likely to mount humoral immune responses to COVID-19 vaccination, with the B cell malignancies a particularly high-risk group. Our COV-VACC study is evaluating the immune response to COVID-19 vaccination in patients with B cell malignancies. Eligible patients were either receiving active treatment or had received treatment within the last 24 months. Patients were vaccinated with either the BNT162b2 (Pfizer-BioNTech) (n=41) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) (n=14) vaccines. The median age of participants was 60 years (range: 27-82) and 50% were receiving systemic anti-cancer therapy (SACT) at the time of vaccination. This interim analysis from the first 55 participants describes anti-S seropositivity rates, neutralising antibody activity and association with peripheral lymphocyte subsets. After the first vaccine dose, 36% overall had detectable anti-S antibodies rising to 42% after the second dose. Sera from seropositive patients was assessed for neutralisation activity in vitro. Of the seropositive patients after first dose (n=17), only 41% were able to neutralise SARS-CoV-2 pseudotyped virus with a 50% inhibitory dilution factor (ID50) of >1:50. After two doses (n=21) 57% of the seropositive patients had detectable neutralisation activity (median ID50 of 1:469, range 1:70 - 1:3056). Total blood lymphocyte, CD19, CD4 and CD56 counts were significantly associated with seropositivity. Patients vaccinated more than 6 months after completing therapy were significantly more likely to develop antibodies than those within 6 months of treatment or on active treatment; OR: 5.93 (1.29 - 27.28). Our data has important implications for patients with B cell malignancies as we demonstrate a disconnect between anti-S seropositivity and virus neutralisation in vitro following vaccination against COVID-19. Urgent consideration should be given to revaccinating patients with B-cell malignancies after completion of anti-cancer treatment as large numbers currently remain at high risk of infection with the increasing transmission of SARS-CoV-2 in many countries. Patients with haematological malignancies are at increased risk of severe disease and death from COVID-19 and are less likely to mount humoral immune responses to COVID-19 vaccination, with the B cell malignancies a particularly high-risk group. Our COV-VACC study is evaluating the immune response to COVID-19 vaccination in patients with B cell malignancies. Eligible patients were either receiving active treatment or had received treatment within the last 24 months. Patients were vaccinated with either the BNT162b2 (Pfizer-BioNTech) (n=41) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) (n=14) vaccines. The median age of participants was 60 years (range: 27-82) and 50% were receiving systemic anti-cancer therapy (SACT) at the time of vaccination. This interim analysis from the first 55 participants describes anti-S seropositivity rates, neutralising antibody activity and association with peripheral lymphocyte subsets. After the first vaccine dose, 36% overall had detectable anti-S antibodies rising to 42% after the second dose. Sera from seropositive patients was assessed for neutralisation activity in vitro. Of the seropositive patients after first dose (n=17), only 41% were able to neutralise SARS-CoV-2 pseudotyped virus with a 50% inhibitory dilution factor (ID50) of >1:50. After two doses (n=21) 57% of the seropositive patients had detectable neutralisation activity (median ID50 of 1:469, range 1:70 -1:3056). Total blood lymphocyte, CD19, CD4 and CD56 counts were significantly associated with seropositivity. Patients vaccinated more than 6 months after completing therapy were significantly more likely to develop antibodies than those within 6 months of treatment or on active treatment; OR: 5.93 (1.29 -27.28). Our data has important implications for patients with B cell malignancies as we demonstrate a disconnect between anti-S seropositivity and virus neutralisation in vitro following vaccination against COVID-19. Urgent consideration should be given to revaccinating patients with B-cell malignancies after completion of anti-cancer treatment as large numbers currently remain at high risk of infection with the increasing transmission of SARS-CoV-2 in many countries. Patients with haematological malignancies are at increased risk of severe disease and death from COVID-19. 1 Vaccination is essential to increase population immunity and decrease disease burden. The first COVID-19 vaccines were authorised in the United Kingdom (UK) after phase III trials which showed that both the BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines were highly effective at preventing symptomatic disease and hospitalisation. 2,3 Real-world vaccine efficacy studies have subsequently shown that both vaccines confer protection against the Delta variant of concern (VOC) (B 1.617.2) which is currently dominant in the UK and elsewhere. 4 Whilst both vaccines have demonstrated robust immune responses in healthy volunteers, patients with haematological malignancies were excluded from the large immunogenicity and efficacy clinical trials. Emerging data suggests such patients are less likely to mount a humoral immune response to COVID-19 vaccination. [5] [6] [7] Data has shown that patients who have recently received Bruton's Tyrosine Kinase inhibitors (BTKi) or CD20-directed therapies for B cell malignancies were the least likely to generate SARS-CoV-2S antibodies following vaccination. 8, 9 With the increasing transmission of SARS-CoV-2 in many countries there is an urgent need to understand the risk this poses to vaccinated patients with B cell malignancies. We report interim results from the first 55 participants recruited to our ongoing COV-VACC Blood samples were taken prior to vaccination where possible, and 1 month after both first and second vaccine doses. At each time point, a full blood count, and immunoglobulin levels, 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 July 19, 2021. Where available, sera from seropositive participants after first or second dose were then used to assess neutralisation activity in vitro. Of the seropositive patients after first dose (n=17), just 41% were able to neutralise SARS-CoV-2 pseudotyped virus with a 50% inhibitory dilution factor (ID50) of >1:50. After two doses (n=21) 57% of the seropositive patients had detectable neutralisation activity (median ID50 of 1:469, range 1:70 -1:3056) ( Figure 1D ). Total blood lymphocyte, CD19, CD4, and CD56 counts all showed a significant association with seropositivity ( Figures 1E, F, G, H) . For a 1 log increase in each lymphocyte subset, the odds of developing antibodies in response to vaccination were 1.32 (95% CI: 1.05 -1.66, p= 0.013), 2.5 (95% CI: 1.12 -5.55, p = 0.025) and 4.47 (95% CI: 1.46 -13.06, p = 0.0008) times higher, respectively for CD19, CD4 and CD56 counts ( Table 1) . Timing of vaccination in relation to SACT was important (p=0.0126), with participants vaccinated more than 6 months after completing therapy more likely to develop antibodies; OR: 5.33 (1.14 -24.90). No difference in seropositivity was seen between those vaccinated within 6 months of treatment or on active treatment; OR: 0.68 (0.18 -2.55). We could not show any impact of therapy type (BTKi or anti-CD20 antibodies), but numbers not treated with CD20 antibodies were very small. 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. Patients on or within 6 months of treatment had significantly lower CD56 and CD19 counts (p= 0.003 and p= 0.014) and a trend towards lower CD4 (p = 0.11). CAR-T cell therapy recipients had very low rates of seropositivity (2/9, 22.2%) ( Table 1) . Nine of ten CAR-T therapy patients were within 6 months of infusion. Seropositive patients could be divided into those whose sera did or did not demonstrate neutralising activity. Neutralising activity was associated with higher median anti-S antibody levels (p=0.0005). Further, both higher CD56 and CD19 counts showed trends towards This interim analysis adds to a growing body of evidence that immunocompromised patients are less likely to produce robust immune response following COVID-19 vaccination. [5] [6] [7] 9 In our cohort 42% had detectable anti-S antibodies following two doses of an approved vaccine compared to 91%-100% in healthy individuals in phase I/II trials. 2, 12 What is striking from the neutralisation data, is that even when seroconversion occurs the protective humoral response may be limited. Just 23% of the cohort (n=56) (57% of seropositive participants) neutralised virus in vitro. Others have shown neutralising antibody levels to be highly predictive of immune protection from symptomatic infection. 13, 14 Our data identifies several factors associated with vaccine response such as peripheral blood lymphocyte, CD19, CD4 and CD56 counts, which if validated in larger cohorts may enable the identification of patients unlikely to respond to vaccination based on their individual immune profile. This data has important implications for patients with B-cell malignancies and other severely immunocompromised groups, providing further evidence that patients on SACT are less likely to produce antibodies following COVID-19 vaccination. 7 Firstly, anti-S seropositivity does not necessarily correlate with serum neutralisation and is unlikely predictive of an effective antibody response based on current estimates of correlates of protection. 14 Urgent validation in larger cohorts is required as many patients with B cell malignancies may remain at high risk 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 July 19, 2021. ; https://doi.org/10.1101/2021.07.19.21260762 doi: medRxiv preprint of infection, regardless of anti-S antibody status, when community prevalence of COVID-19 is high or increasing. Secondly, all clinically vulnerable patients regardless of vaccination status, should be considered for neutralising monoclonal antibody therapies if they develop COVID-19. 15, 16 Urgent consideration needs to be given to provision of booster doses or full revaccination to this group of patients, particularly if they have been vaccinated within 6 months of active therapy. A third vaccination dose has been shown to be beneficial in solid organ transplant recipients 17 , although low CD19 and CD4 counts were also associated with poor responses. The correlation between peripheral blood lymphocyte, CD19, CD4 and CD56 counts suggest that booster doses or vaccination may be most effective if given when an individual has recovered lymphocytes and are at least 6 months following SACT. This interim analysis is limited by cohort size and heterogeneity. However, we demonstrate a disconnect between seropositivity and virus neutralisation in vitro, following vaccination against COVID-19. (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 July 19, 2021. ; https://doi.org/10.1101/2021.07.19.21260762 doi: medRxiv preprint 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. The copyright holder for this preprint this version posted July 19, 2021. ; https://doi.org/10.1101/2021.07.19.21260762 doi: medRxiv preprint Outcomes of patients with hematologic malignancies and COVID-19: A systematic review and meta-analysis of 3377 patients Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. 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Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19 Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients This study is supported by the NIHR UCLH Biomedical Research Centre and Blood Cancer UK.RSH is a NIHR Senior Investigator. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.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 July 19, 2021.