key: cord-0912909-v54f59vg
authors: Chan, Wei Yee; Howells, Lara; Wilson, William; Sanchez, Emilie; Ainley, Louise; Chavda, Selina J.; Dowling, Emma; Correia, Nuno; Lecat, Catherine S. Y.; McMillan, Annabel; Wisniowski, Brendan; Mahmood, Shameem; Papanikolaou, Xenofon; Lee, Lydia; Sive, Jonathan; Kyriakou, Charalampia; Wechalekar, Ashutosh; Popat, Rakesh; Rabin, Neil; Nastouli, Eleni; Yong, Kwee L.; Xu, Ke
title: Serological response to the BNT162b2 mRNA or ChAdOx1 nCoV‐19 COVID‐19 vaccine after first and second doses in patients with plasma cell disorders: influence of host and disease factors
date: 2021-10-10
journal: Br J Haematol
DOI: 10.1111/bjh.17864
sha: b12e1a419052a233fffb3b9c0c264a89d6cba9ca
doc_id: 912909
cord_uid: v54f59vg

nan

We read with interest Avivi et al. 1 evaluating humoral response to two doses of BNT162b2 mRNA vaccine in multiple myeloma (MM) at manufacturer's dosing interval. Suboptimal response to one [2] [3] [4] and both doses 5 of coronavirus disease 2019 (COVID-19) vaccines in MM have also been reported elsewhere. Administration of COVID-19 vaccines is important to protect this vulnerable cohort. Recognised humoral and cellular immune dysfunction in plasma cell disorders (PCDs), which is multi-factorial and related to the disease itself, age, comorbidities and immunosuppressive therapies, may reduce vaccination protection. The UK experience differs as a substantial proportion of the population received ChAdOx1 nCoV-19, and intervals were extended to 12 weeks in December 2020. 6 With emergence of the Delta variant, from May 2021, identified immunosuppressed individuals had their second doses brought forward to 8 weeks. We report findings in PCD receiving both doses of COVID-19 vaccines within the UK vaccination programme, and the influence of dosing interval.

A clinical audit was conducted at University College London Hospitals between December 2020 and July 2021 of anti-spike protein antibody testing in patients with PCDs after each vaccine dose. Some had routine nucleocapsid antibody monitoring, 7 those receiving chemo-immunotherapy (CIT) have 4-weekly routine swabs. Patient and treatment characteristics were retrieved from medical records (Table SI) . Full methods are described in Data S1.

A total of 188 patients [monoclonal gammopathy of undetermined significance/smouldering MM (10), MM (155), systemic AL amyloid (18), other PCD (5) The seropositivity rate after the first dose was 67% (70/ 104); of those with available negative baseline antibody test, 68% (30/44) seroconverted. After the second dose, 89% (154/174) were seropositive; of those with negative baseline antibody, 90% (61/68) seroconverted. Analysing paired samples, median titres were higher after the second dose than after the first dose ( Fig 1A) .

Active CIT, four lines of therapy, a less than partial response (PR) disease response, light-chain (LC) disease, male gender and not responding to first dose were significant factors for not responding to the second dose and remained significant after adjusting for disease response (Table I) . No difference in response was found by CIT type, vaccine type, dosing intervals (>42 vs. 42 days) or time to serology sample. Dosing interval analysis showed no difference when re-categorised (28 AE 14, 43-69 and 84 AE14 days), nor was there difference in titres with both categorisations (Fig 1C,  D) . Significantly higher titres occurred in females, non-LC isotype and four lines of treatment ( Figure S1 ). Eligibility for booster dosing in the OCTAVE-DUO study will utilise 400 u/ml as cut-off based on lower third titres of the OCTAVE study. 8 We explored disease and patient-related factors associated with suboptimal response (defined here as 400 u/ml) after a second dose, found in 43% (75/174) of patients. Age ≥70 years, male gender, four lines of treatment were significant independent risk factors (anti-CD38 therapy of borderline significance) ( Figure S2 , Table SII ). No difference was observed with vaccine interval, vaccine type or active CIT. We analysed patients with PCDs altogether ( Figure S3A shows post second dose titres by underlying diagnosis), as future vaccination policy will be unlikely to discriminate between them. A larger cohort with similar dose-interval and vaccine-type analyses, by subgroups of patients with PCDs will help us understand differences in immune response and hence disease risks amongst these patients.

In all, 19 of 34 (56%) patients who were seronegative after the first dose, seroconverted after the second dose; however, antibody titres were significantly lower than in those who seroconverted after the first dose ( Fig 1B) . A total of 27 patients were tested twice after their second doses; titres declined over time ( Fig 1E) . Titres in 14 patients with previous COVID-19 infection, were over a 100-times higher after the first dose and remained significantly higher after the second dose, compared to those without previous infection ( Fig 1F; Figure S3B ). correspondence This real-world analysis of opportunistic testing in patients with PCDs reports a 67% seropositive response rate after the first dose, 3 rising to 89% after the second dose despite extended dosing in our present cohort. Response rates and median titres remained lower than in healthy adults. 1, 5 Nearly two-thirds of those seronegative after the first dose 5 We describe association of age ≥70 years, male gender, four lines of treatment with suboptimal humoral response. Lower humoral and cellular responses with older age have been reported. 9 Association with male gender and older age may be related to higher frequency of autoantibodies to type-1 interferons that impair their ability to block severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. 10, 11 We found no association of anti-myeloma agent types with serological response in contrast to reports of B-cell maturation antigen (BCMA)-targeted 5 and anti-CD38 therapies. 4,5 A borderline significant effect on optimal response was observed in patients receiving anti-CD38 therapy. Only 36% of our present patients were exposed to anti-CD38 and even less to BCMA-targeted therapies (1Á6%), as the latter are not yet widely available in the UK. We found no difference in response or titres with vaccine types, although BNT162b2 mRNA has shown higher vaccine effectiveness against the delta variant compared to ChAdOx1 nCoV-19 elsewhere. 12 We did not assess cellular immunity, an important aspect of vaccine immunogenicity. Further studies of cellular and ASCT, autologous stem cell transplantation; CD, cluster of differentiation; CI, confidence interval; CIT, chemo-immunotherapy; CR, complete response; Ig, immunoglobulin; IMiD, immunomodulatory imide drug; LC, light-chain; N/A, not available; OR, odds ratio; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response. Disease response variable used for adjusted OR was CR/VGPR/PR versus SD/PD. *The reported P value is from a likelihood ratio test comparing a logistic regression model with lines of treatment as a covariate to one without. **There is a borderline association between presence of a post-dose 1 response and response post-dose 2 (P = 0Á05), with patients with missing dose 1 responses being more likely to respond post-dose 2. A sensitivity analysis assuming all missing data shows the opposite association to the observed data has an OR of 2Á44 (95% CI 0Á84-7Á03), P = 0Á1. While not significant, still provides some evidence of a positive association between post-dose 1 and post-dose 2 response. One patient tested borderline above the defined positive cut-off for response post first dose (0Á81 u/ml) and subsequently tested negative post second dose.

Correspondence humoral responses to vaccination are awaited as correlates of humoral response and immunogenicity markers with disease protection from COVID-19 in PCDs are unknown. 13, 14 A third of our present seropositive patients with PCDs had a suboptimal response (<400 u/ml) and may be at risk of reduced protection despite measurable humoral response. Patients with PCDs are at 33% estimated risk of death from SARS-CoV-2, 15 hence should be prioritised for shorter dosing intervals. Significant predictors of seronegative and suboptimal response after two doses can be utilised to select patients for booster doses; timing doses for when particular risk factors have been eliminated. Prophylactic strategies (e.g. anti-spike monoclonal antibodies) in patients identified at high-risk of vaccine response failure or in whom vaccination response is suboptimal should be explored. Results of these trials alongside correlates of protection applicable to PCDs will be eagerly awaited.

coronavirus-2, vaccination response, plasma cell disorders, humoral response

Additional supporting information may be found online in the Supporting Information section at the end of the article. Fig S1. Comparison of post second dose titres based on patient or disease-related factors. Fig S2. Forest plot of univariate analysis of optimal response (defined as titres ≥400 u/ml). Fig S3. Anti-SARS-CoV-2 S titre comparisons based on plasma cell diagnosis and available baseline anti-SARS-CoV-2 S Titres in patients with previous COVID-19 infection. Table SI . Baseline patient and plasma cell disorder characteristics after first and second dose of a COVID-19 vaccine. Table SII . Multivariate analysis of optimal response to second vaccine dose.

Data S1. Supplementary Methods.

Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma

Low neutralizing antibody responses against SARS-CoV-2 in elderly myeloma patients after the first BNT162b2 vaccine dose

Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma

Fifth-week immunogenicity and safety of anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and myeloproliferative malignancies on active treatment: preliminary data from a single institution

Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma

COVID-19 greenbook chapter 14a (homepage on the Internet)

Development of antibody response to SARS-CoV-2 following asymptomatic infection in patients with plasma cell disorders on immunomodulatory therapy

Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity -the OCTAVE trial

Differential immunogenicity of BNT162b2 or ChAdOx1 vaccines after extended-interval homologous dual vaccination in older people

Autoantibodies neutralizing type I IFNs are present in~4% of uninfected individuals over 70 years old and account for~20% of COVID-19 deaths

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Effectiveness of COVID-19 vaccines against the B.1.617.2 (Delta) variant

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study

Immunological surrogate endpoints of COVID-2019 vaccines: the evidence we have versus the evidence we need

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set

Kwee L. Yong has received honoraria from Janssen, Takeda, Sanofi, GSK and Amgen. Kwee L. Yong receives research funding from Sanofi, Celgene, Takeda, Janssen and Autolus. Neil Rabin has received Janssen consultancy, travel support for meetings and Speakers Bureau outside the submitted work.