Antibody Responses to an Additional Dose of SARS-CoV-2 mRNA Vaccine in Solid Organ Transplant Recipients with and without HIV

Purpose: Solid organ transplant (SOT) recipients mount suboptimal immune responses to a two-dose SARS-CoV-2 mRNA vaccine series. Data regarding antibody responses in HIV and SOT remains limited. We characterized spike binding antibody responses before and after an additional mRNA vaccine dose in SOT recipients, including in people with HIV (PWH). Method(s): Spike binding antibody titers were assessed before and one month after an additional vaccine dose using a quantitative ELISA. An additional vaccine dose was defined as a third dose of a mRNA vaccine primary series, as recommended by the CDC. Result(s): Antibody titers were assessed in 64 SOT recipients (58% kidney, 34% liver, 8% other). Participants had a median age of 57 and 47% were women. PWH comprised 14% of the cohort (9/64, 78% kidney). 70% (45/64) of SOT recipients developed antibodies after a two-dose vaccine series (62% kidney, 33% liver). The additional dose was given a median of 169 days (IQR 144.75-185.75 days) after the second vaccine dose, and 72% received three doses of BNT162b2 (Pfizer-BioNTech) while 28% received three doses of mRNA-1273 vaccine (Moderna). The median time between transplantation and an additional vaccine dose was 2.8 years (IQR, 0.6-8.9). 32% (6/19) of SOT recipients who had no detectable antibody seroconverted after receiving an additional vaccine dose. The 45 participants who were seropositive prior to the third dose displayed a median 4.4-fold increase in antibody titers. SOT recipients with HIV had comparable antibody responses to those without HIV. Conclusion(s): Our data indicate that SOT recipients benefit from an additional SARS-CoV-2 mRNA vaccine dose. SOT recipients with and without HIV appear to mount comparable antibody responses upon vaccination, although larger numbers are needed.

Assessing vulnerability of patients with lung cancer to SARS-CoV-2 infection based on serological antibody analyses

COVID-19 presents a unique threat to patients with lung cancer, with mortality rates as high as ∼32%. Given the convergence of these two deadly diseases, the lung cancer research and advocacy communities rapidly mobilized in early 2020 to create the COVID Lung Cancer Consortium (CLCC), a global assembly of leading experts in thoracic oncology, immunology, virology, vaccines and patient advocacy. With ongoing robust exchange of data and shared learning and rational planning for clinical and laboratory investigations, the CLCC is bringing its collective expertise to bear on beginning to address the question of why patients with lung cancer are at such elevated risk of worse outcomes from COVID-19. These efforts led to a recently funded U54 CA260560 grant as part of the National Cancer Institute's SeroNet initiative to study the magnitude, quality and duration of antibody responses to SARS-CoV-2 infection in patients with lung cancer compared to healthy controls. In the first project, our Mt. Sinai U54 Serological Center of Excellence will follow a prospective lung cancer cohort (750 patients) and a matched non-lung cancer control group (750 individuals) to determine if there are differences in antibody responses related to age, gender, tobacco history, and race/ethnicity. Given that effective SARS-CoV-2 vaccines are now being deployed, the study will also analyze antibody responses to vaccination across these two patient cohorts. The second project will examine biological determinants correlating with susceptibility to infection, including analysis of both ACE2 and TMPRSS2 levels, and antibody-mediated neutralization in pre-clinical models of established lung cancer and normal lung epithelial cell lines. In order to capture a diverse and inclusive patient population, this effort will be supported by GO2 Foundation for Lung Cancer through its national network of Centers of Excellence. This rapid global mobilization of the lung cancer community through the CLCC and the resulting Serological Center of Excellence is positioned to answer fundamental questions regarding the susceptibility of patients with lung cancer to SARS-CoV-2 infection and severe COVID-19 disease and provide information to allow assessment of the value of vaccination and the utility of specifically designed vaccine programs for this high-risk patient population.

Suboptimal Humoral and Cellular Immune Response to SARS-CoV-2 RNA Vaccination in Myeloma Patients Is Associated with Anti-CD38 and BCMA-Targeted Treatment

Background: Multiple myeloma (MM) patients are immunocompromised due to defects in humoral/cellular immunity and immunosuppressive therapy. Reports indicate that the antibody (Ab) response in MM after 1 dose of SARS-CoV-2 RNA vaccine is attenuated. The impact of treatment on cellular immunity after vaccination remains unknown. Methods: We analyzed SARS-CoV-2 spike-binding (anti-S) IgG level in 320 MM patients receiving SARS-CoV-2 RNA vaccination. Blood and saliva were taken at multiple time points and compared with serology data of 69 age-matched vaccinated healthcare workers. We profiled SARS-CoV-2-specific T cell responses in a subset of 45 MM patients and 12 age-matched healthy controls by flow cytometry and ELIspot. All subjects were enrolled in studies approved by the Institutional Review Board at the Icahn School of Medicine at Mount Sinai. Results: The 320 patients (median age 68 year) received two-dose RNA vaccines (69.1% BNT162b2, 27.2% mRNA-1273). Median time to diagnosis was 60 months with a median of 2 prior treatment lines (range 0-16). We included 23 patients with smoldering MM. Patients received various treatments at vaccination with 148 (43.8%) on anti-CD38-containing treatment, 36 (11.3%) on BCMA-targeted therapy and 59 (18.4%) not on active treatment (incl. SMM patients). At the last available evaluation prior to vaccination, 131 (40.9%) exhibited a complete response. At data cutoff, a total of 260 patients (81.3%) had anti-S IgG measured >10 days after the second vaccine (median 51 days). Of these, 84.2% mounted measurable anti-S IgG levels (median 149 AU/mL). In the control group, Ab levels were significantly higher (median 300 AU/mL). Ab levels in the vaccinated MM patients with prior COVID-19 were 10-fold higher than those of patients without prior COVID-19 (p<0.001). Repeat Ab measurements up to 60 days after second vaccination confirm delayed and suboptimal IgG kinetics, particularly in patients receiving anti-MM treatment compared to controls (Figure 1). MM patients on active treatment had lower anti-S IgG levels (p=0.004) compared to patients not on therapy (median 70 vs 183 AU/mL). Notably, 41 patients (15.8%) failed to develop detectable anti-S IgG: 24/41 (58.5%) were on anti-CD38, 13/41 (31.7%) on anti-BCMA bispecific Ab therapy and 4/41 (9.8%) >3 months after CAR T. Univariate analysis showed an association of disease-related factors with absence of anti-S IgG: more previous lines of treatment (>3 lines, p=0.035;>5 lines, p=0.009), receiving active MM treatment (p=0.005), grade 3 lymphopenia (p=0.018), receiving anti-CD38 therapy (p=0.042) and receiving BCMA-targeted therapy (p<0.001). Multivariate analysis (corrected for age, vaccine type, lines of treatment, time since diagnosis, response status and lymphopenia) confirmed that anti-CD38 (p=0.005) and BCMA-targeted treatment (p<0.001) are associated with not developing detectable anti-S IgG. Clinical relevance is emphasized by 10 cases of COVID-19 after 1 (n=7) or 2 vaccine doses (n=3, all without anti-S IgG) with 1 patient passing due to respiratory failure. We studied SARS-CoV-2-specific T cell responses >2 weeks after the second vaccine in 18 MM patients with undetectable anti-S IgG (seronegative), 27 with detectable anti-S IgG (seropositive) and 12 healthy seropositive controls. We found that seropositive MM patients had CD4+CD154+ T cells producing IFNg, TNFa and IL-2 at similar levels as controls, whereas in the seronegative MM cohort CD4 T cell responses were significantly reduced (p<0.005). SARS-CoV-2-specific CD8 T cell responses were overall weaker and not different across cohorts. This data suggests that absence of detectable IgG is associated with suboptimal response of humoral and cellular immunity. Conclusion: MM patients mount a suboptimal IgG response after SARS-CoV-2 vaccination, with 15.8% of patients without detectable anti-S IgG. Ongoing analyses will highlight durability of serological protection against COVID-19. Additional data on T cell responses and immunophenotyping in the context of vaccination will be upda ed at the meeting. Implications are continuation of non-pharmacological interventions, e.g. masking/social distancing, for vulnerable patients. The findings underscore a need for serological monitoring of MM patients after vaccination and for trials assessing use of prophylactic strategies or studies exploring additional immunization strategies. [Formula presented] Disclosures: Wang: Sanofi Genzyme: Consultancy. Chari: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees;Pharmacyclics: Research Funding;GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees;Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding;Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Research Funding;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cordon-Cardo: Kantaro: Patents & Royalties. Krammer: Kantaro: Patents & Royalties;Merck: Consultancy;Pfizer: Consultancy;Avimex: Consultancy;Seqirus: Consultancy. Jagannath: Legend Biotech: Consultancy;Karyopharm Therapeutics: Consultancy;Janssen Pharmaceuticals: Consultancy;Bristol Myers Squibb: Consultancy;Sanofi: Consultancy;Takeda: Consultancy. Simon: Kantaro: Patents & Royalties. Parekh: Foundation Medicine Inc: Consultancy;Amgen: Research Funding;PFIZER: Research Funding;CELGENE: Research Funding;Karyopharm Inv: Research Funding.

Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains

[Figure: see text].

Analysis of Lung Cancer Patients Receiving SARS-CoV-2 Vaccines Revealed a Minority Subset With Poor Antibody Responses Relative to Controls

Introduction: Patients with lung cancer (LC) were reported to have a high case fatality rate (30-40%) from SARS-CoV-2 infection, raising the question of whether LC patients mount a weaker antibody response to natural infection and/or vaccination, compared to healthy controls (HCs). We previously analyzed antibody responses to SARS-CoV-2 mRNA vaccination in several hundred healthy individuals, stratified by previous SARS-CoV-2 infection status. Using a validated enzyme-linked immunosorbent assay (ELISA) to the full-length spike protein (PMC8183627, PMC7235504), we found strong responses to infection and a robust neutralizing antibody response to vaccination. We compare these results to data from individuals diagnosed with LC undergoing different types of cancer treatment. Methods: This is an ongoing, prospective, control-matched longitudinal cohort study of 750 LC patients in all stages with or without previous SARS-CoV-2 infection and/or vaccination, comparing SARS-CoV-2 antibody titers at baseline (time of enrollment) and at 3-, 6-, 12- and 24-month intervals. We examine the quality, magnitude, and duration of the SARS-CoV-2 antibody titers against the full-length spike protein compared to the matched (age, tobacco history, sex and ethnicity) HC cohort. Types of Analysis and Data Reporting: ELISAs are performed in a CLIA-certified laboratory using an FDA-approved antibody assay along with other well-established, research-grade assays. We hypothesized that LC patients have a weaker antibody response to SARS-Cov-2 infection and/or vaccination due to cancer or its treatment compared to matched HCs. The non-parametric Kruskal–Wallis test was used to test this hypothesis. If confirmed, a tailored vaccination program would be necessary to ensure immune protection in patient with LC. Results: 111 LC patients have been enrolled to date;with 78 receiving at least one vaccination and 33 unvaccinated. Median age is 69, with 58% female. 39 patients were fully vaccinated (defined as 14+ days after second vaccination). Partially vaccinated (after 1st vaccine dose) LC patients had a lower median antibody level than partially vaccinated HCs (p=0.01). Fully vaccinated LC patients had substantial antibody titers but a lower median antibody level than fully vaccinated HCs (p=0.01) with a subset not raising large antibody titers. Especially important were the 30% of partially vaccinated LC patients who did not develop neutralizing antibodies. To date, there were no significant differences in median antibody levels in LC patients by gender, smoking status, age (< or > 65 years old), or treatment (with or without chemotherapy, immune checkpoint inhibitors, or targeted therapy). Conclusion: While most (∼70%+) of LC patients mounted a good antibody response to vaccination, a subgroup had significantly lower anti-spike antibody/neutralizing levels compared to controls. Further studies are required to evaluate the role of further boost vaccinations in this patient population with a particular focus on patients not producing neutralizing antibodies to further understand the lack of response. We will continue to analyze the effect of systemic anti-cancer therapies as more data becomes available. Keywords: SARS-CoV-2, lung cancer, covid-19

Transfusion reactions associated with COVID-19 convalescent plasma therapy for SARSCoV-2 across the Mount Sinai Health System in New York City

Background/Case Studies: To date, convalescent plasma for the treatment of SARS-CoV-2 has shown effectiveness in severely ill patients in reducing mortality. While studies have demonstrated a low risk of serious adverse events, the comprehensive incidence and nature of the spectrum of transfusion reactions to convalescent plasma is unknown. Here, we retrospectively examine 427 inpatient convalescent plasma transfusions to determine incidence and types of reactions, as well as clinical parameters and risk factors associated with transfusion reactions. Study Design/Methods: Retrospective analysis was performed for 427 transfusions to 215 COVID-19 patients within the Mount Sinai Health System (MSHS), through eIND and EAP approval pathways by the FDA. Transfusions were blindly evaluated by two reviewers and adjudicated by a third reviewer in discordant cases. Patient demographics, clinical, and laboratory parameters were compared and analyzed. Statistical analysis was performed determine the significance of these parameters and univariate logistic regression analysis was performed to assess which independent variables were correlated with a transfusion reaction. Results/Findings: Fifty-five reactions from 427 transfusion events were identified (12.9% incidence), thirteen of which were attributed to transfusion (3.1% incidence). Reactions were classified as underlying COVID-19 (76%), febrile non-hemolytic (10.9%), transfusion-associated circulatory overload (9.1%), allergic (1.8%), and hypotensive (1.8%) reactions. Statistical analysis identified increased transfusion reaction risk for ABO blood group B, Sequential Organ Failure Assessment scores of 12-13, or a cancer diagnosis. A decreased risk was identified for patients in the age group of 80-89 years. Conclusions: Our findings support the use of convalescent plasma as a safe therapeutic option from a transfusion reaction perspective, in the setting of COVID-19. Further studies are needed to confirm the clinical significance of ABO group B, cancer diagnosis, age, and predisposing disease severity in the incidence of transfusion reaction events.