Key Immunogenicity Endpoints in Elasomeran Studies

What are the key immunogenicity endpoints reported for Elasomeran clinical studies?

The key immunogenicity endpoints for Elasomeran clinical studies were anti-Spike IgG antibody levels and seroconversion rates for humoral immunity (primary endpoints) and SARS-CoV-2 specific T-cell responses for cellular immunity (secondary endpoints), assessed from 2 weeks to 12 months post-vaccination.

Abstract

Four observational studies evaluated mRNA-1273 (Elasomeran) immunogenicity in immunocompromised populations including inflammatory bowel disease, multiple myeloma, hematologic malignancies, and autoimmune rheumatic diseases. The primary immunogenicity endpoints were humoral responses measured by anti-Spike IgG antibodies targeting the receptor binding domain using electrochemiluminescence assays, with seropositivity thresholds defined as ≥0.80 U/ml or ≥0 AU/ml. Secondary endpoints included cellular immunity assessed through SARS-CoV-2 specific T-cell responses measured by interferon-gamma release assays and cytokine production (TNF-α, IFN-γ). Assessment timepoints ranged from 2 weeks to 12 months post-vaccination. Seroconversion rates were consistently high across populations (91.7-100%), though absolute antibody titers varied substantially. Titers in multiple myeloma patients (median 435 U/ml) were significantly lower than healthy controls (1040.5 U/ml, p=0.008), and mRNA-1273 produced higher titers than Ad26.CoV2.S in IBD patients at both week 2 (log10 4.20 vs 1.96) and week 8 (3.72 vs 2.65, p<0.001). Immunosuppressive therapies, particularly anti-CD20 and anti-CD38 antibodies, substantially reduced humoral responses, while disease remission status, autologous stem-cell transplantation, and lenalidomide maintenance independently predicted higher antibody titers. Notably, cellular responses were preserved in patients receiving anti-CD20 therapy despite impaired humoral immunity, and antibody levels demonstrated temporal decay across all populations from peak responses to 4-12 month follow-up.

Methods

We analyzed 4 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

Records from Elicit search

• n = 200

• Papers screened using: Human Participants with Elasomeran, Immunogenicity Endpoints, Quantitative Immunogenicity Measures, Appropriate Study Design, Clinical Study Type, Primary Focus on Immunogenicity, Adequate Sample Size, Attributable Immunogenicity Data

• n = 200

• Papers screened out

• n = 196

• Papers included for extraction

• n = 4

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

Screening

We screened in sources based on their abstracts that met these criteria:

• Human Participants with Elasomeran: Does this study involve human participants who received Elasomeran (mRNA-1273)?
• Immunogenicity Endpoints: Does this study report immunogenicity endpoints or outcomes?
• Quantitative Immunogenicity Measures: Does this study report quantitative immunogenicity measures (e.g., antibody titers, neutralizing antibody levels, T-cell responses with numerical data)?
• Appropriate Study Design: Is this study a randomized controlled trial, single-arm clinical trial, observational study, systematic review, or meta-analysis?
• Clinical Study Type: Is this a clinical study involving human participants (not a preclinical, in vitro, or animal study)?
• Primary Focus on Immunogenicity: Does this study report immunogenicity outcomes as a primary or secondary endpoint (not exclusively focused on safety, efficacy, or other non-immunogenicity outcomes)?
• Adequate Sample Size: Does this study include 10 or more participants (i.e., is it not a case report or case series with fewer than 10 participants)?
• Attributable Immunogenicity Data: Can the immunogenicity data in this study be attributed specifically to Elasomeran (i.e., can the data be separated from other interventions if multiple interventions were given)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• Study Design:
  Extract study design and population details for Elasomeran immunogenicity studies, including:

  • Study type (RCT, observational, cohort, etc.)
  • Sample size for Elasomeran recipients
  • Population characteristics (age, disease status, immunocompromised conditions, prior infections)
  • Comparison groups if any (other vaccines, placebo, healthy controls)
  • Study setting and duration

• Immunogenicity Endpoints:
  Extract all immunogenicity endpoints reported for Elasomeran, including:

  • Humoral immunity measures (anti-Spike IgG, neutralizing antibodies, binding antibodies, etc.)
  • Cellular immunity measures (T-cell responses, cytokine production, etc.)
  • Seroconversion/seropositivity rates
  • Endpoint definitions and thresholds used (e.g., positive cutoff values)
  • Primary vs secondary endpoints
  • Any composite immunogenicity measures

• Measurement Methods:
  Extract details about how immunogenicity endpoints were measured for Elasomeran, including:

  • Laboratory assays used (ELISA, ECLIA, neutralization assays, etc.)
  • Specific platforms or kits (e.g., Elecsys®, MSD, etc.)
  • Measurement units (U/ml, titers, fold-change, etc.)
  • Validation status of assays
  • Laboratory performing the analysis

• Timing Points:
  Extract all time points when immunogenicity was assessed for Elasomeran recipients, including:

  • Baseline (pre-vaccination) measurements
  • Post-dose 1 time points
  • Post-dose 2 time points (days/weeks/months after completion)
  • Long-term follow-up time points
  • Any booster dose time points
  • Specific timing descriptions (e.g., ‘14-29 days after dose 2’)

• Immunogenicity Results:
  Extract quantitative and qualitative immunogenicity results for Elasomeran, including:

  • Seroconversion rates with percentages and confidence intervals
  • Antibody levels/titers (median, geometric mean, ranges)
  • Fold-change from baseline
  • Response rates by endpoint
  • Durability of responses over time
  • Statistical significance values
  • Comparison results if other vaccines included

• Modifying Factors:
  Extract factors that influenced Elasomeran immunogenicity responses, including:

  • Impact of immunosuppressive medications/therapies
  • Age-related differences in response
  • Disease status effects (active vs remission, disease severity)
  • Prior COVID-19 infection impact
  • Comorbidity effects
  • Dose interval effects
  • Any identified predictors of poor response
  • Multivariable analysis results for response predictors

Results

Characteristics of Included Studies

Four studies evaluated the immunogenicity of mRNA-1273 (Elasomeran) across diverse immunocompromised populations.

The studies enrolled immunocompromised patients with varying underlying conditions. The IBD cohort had extensive use of immune-modifying therapies including biologics, JAK inhibitors, immunomodulators, and corticosteroids. The multiple myeloma cohort included patients with relapse/refractory disease, many having received autologous stem-cell transplantation and various treatment regimens including immunomodulatory drugs and proteasome inhibitors. The rheumatic disease population had varying disease durations and immunosuppressive exposures. All studies excluded participants with prior COVID-19 infection.

Immunogenicity Endpoints and Measurement Methods

The studies assessed both humoral and cellular immunity using standardized assays. Humoral immunity was measured through anti-Spike IgG antibodies targeting the receptor binding domain. Pozdnyakova et al. used the SARS-CoV-2 IgG-II assay from Abbott Labs, Mancuso et al. employed the Elecsys® Anti-SARS-CoV-2 ECLIA platform, and Szebeni et al. utilized the Siemens Advia Centaur XPT system with Siemens Healthineers SARS-CoV-2 IgG assay. The Siemens assay showed good correlation with virus neutralization titers (r = 0.84).

Cellular immunity assessment varied by study. Mancuso et al. evaluated SARS-CoV-2 specific IFNγ T cell responses using IGRA tests, while Szebeni et al. measured T-cell responses including TNF-α and IFN-γ production by CD4+ and CD8+ T-cells using the SARS-CoV-2 T-Cell Analysis Kit from Miltenyi Biotec. Jiménez et al. reported preserved cellular responses in patients under anti-CD20 therapy despite impaired humoral responses.

Seropositivity thresholds were defined as IgG anti-Spike RBD ≥0.80 U/ml in the Mancuso study and ≥0 AU/ml in the Pozdnyakova study. Szebeni et al. used a diagnostic cut-off of 400 reactive cells per 10^6 parental population for T-cell responses.

Timing of Immunogenicity Assessment

Assessment time points varied considerably across studies. Pozdnyakova et al. measured antibody responses at three post-vaccination time points: after regimen completion (2-13 days), week 2 (14-29 days), and week 8 (42-84 days). Mancuso et al. conducted more extensive longitudinal follow-up, measuring humoral responses at 1, 3, 6, 9, and 12 months post-second dose, with cellular immunity evaluated at 3 and 12 months. The primary analysis in Mancuso’s study focused on 1 month post-vaccination (median 30 days, IQR 28-32). Szebeni et al. assessed responses at 1 and 4 months after the second dose.

Immunogenicity Results

Seroconversion Rates

Seroconversion rates were consistently high for mRNA-1273, ranging from 91.7% to 100% depending on population and time point. In the IBD cohort, mRNA-1273 achieved 100% seropositivity, comparable to BNT162b2 (99%) and superior to Ad26.CoV2.S (90%). The multiple myeloma cohort showed slightly lower seroconversion (91.7%) compared to healthy controls (100%, p=0.05). In rheumatologic disease patients, mRNA-1273 recipients achieved 81% seropositivity at 4 months, higher than inactivated or adenovirus-based vaccines.

Antibody Titers

Antibody titers showed substantial variation across populations and time points. In IBD patients, mRNA-1273 produced log10 titers of 4.20 at week 2, declining to 3.72 by week 8. Multiple myeloma patients achieved median titers of 435 U/ml at 1 month, significantly lower than healthy controls (1040.5 U/ml, p=0.008). Szebeni et al. reported that mRNA-1273 achieved higher antibody levels at 4 months compared to BBIBP-CorV or AZD1222 (p=0.0107).

Factors Influencing Immunogenicity

Impact of Immunosuppressive Medications

Immunosuppressive therapies substantially affected humoral responses across multiple studies. In IBD patients, receipt of immune-modifying therapies (biologics, JAK inhibitors, immunomodulators, corticosteroids) was independently associated with lower antibody titers (β=-0.308, 95% CI -0.52 to -0.10, p=0.004). In multiple myeloma, patients receiving proteasome inhibitors had median antibody titers of 156 U/ml compared to higher levels in other patients (p=0.003). Anti-CD38 monoclonal antibodies reduced median titers to 265 U/ml (p<0.001). Similarly, anti-CD20 therapy and B-cell inhibitory treatments reduced immunogenicity in rheumatic disease patients and impaired humoral responses in hematologic malignancy patients, though cellular responses remained preserved.

Disease Status Effects

Disease control significantly influenced antibody production. In multiple myeloma, patients achieving complete response (≥CR) had median antibody titers of 1242 U/ml versus 221.5 U/ml in those with <CR (p<0.001). Multivariable analysis confirmed CR as an independent predictor of better humoral response (OR 2.54, 95% CI 93-756). First-line treatment was also independently associated with improved responses (OR 2.10, 95% CI 22-722). In rheumatic diseases, longer disease duration impaired antibody responses even in patients with low disease activity or remission. Conversely, rheumatic disease patients in remission showed differential responses by disease type, with spondylarthropathies achieving higher antibody levels at 4 months compared to rheumatoid arthritis and other autoimmune RMDs (p=0.0048).

Treatment-Specific Factors

Certain therapeutic interventions enhanced immunogenicity. Multiple myeloma patients who received autologous stem-cell transplantation had median antibody titers of 1042 U/ml versus 160 U/ml in non-transplanted patients (p<0.001). Lenalidomide maintenance therapy was particularly beneficial, with median titers of 1681.2 U/ml versus 529.5 U/ml without maintenance (p<0.001), and multivariable analysis confirmed lenalidomide maintenance as an independent predictor (OR 4.53, 95% CI 484-1233). Immunoparesis negatively impacted responses, with patients having 2-immunoglobulin class reductions showing median titers of 272 U/ml versus 2500 U/ml in those without immunoparesis (p=0.0037). Immunosuppressive therapy for graft-versus-host disease reduced cellular responses without affecting humoral immunogenicity.

Temporal Dynamics

Antibody levels demonstrated durability over time, though with gradual decay. In IBD patients, log10 antibody titers decreased from 4.20 at week 2 to 3.72 at week 8. Multivariable analysis at week 8 showed that longer duration between vaccine completion and blood sampling was independently associated with lower titers (β=-0.009, 95% CI -0.02 to -0.001, p=0.032). In rheumatic disease patients, antibody levels decreased from 1 month to 4 months post-vaccination in some groups.

Synthesis

The evidence demonstrates consistently high seroconversion rates for mRNA-1273 across diverse immunocompromised populations (91.7-100%), though absolute antibody titers varied substantially based on underlying disease, immunosuppressive regimen, and disease control status. The apparent heterogeneity in antibody magnitudes is explained by three key contextual factors.

First, disease activity and treatment response emerge as major determinants of immunogenicity. The multiple myeloma data reveal a dose-response relationship between disease control and antibody production: complete responders achieved titers nearly 6-fold higher than partial responders (1242 vs 221.5 U/ml), and this effect persisted in multivariable analysis adjusting for treatment type. This pattern likely reflects the relationship between plasma cell burden, bone marrow function, and capacity for antibody production. Similarly, in rheumatic diseases, longer disease duration—even with clinical remission—predicted impaired responses, suggesting cumulative immune dysregulation beyond current inflammation measures.

Second, specific immunosuppressive mechanisms produce distinct immunogenicity profiles. B-cell depleting or inhibiting therapies (anti-CD20, anti-CD38 antibodies) profoundly impaired humoral responses across multiple studies, with anti-CD38 therapy reducing median titers by >60% in myeloma patients. However, these agents showed divergent effects on cellular immunity: anti-CD20 therapy preserved cellular responses in hematologic malignancies, while anti-CD38 antibodies likely impair both arms given their broader immunomodulatory effects. Conversely, lenalidomide maintenance amplified responses 3-fold, consistent with its immunostimulatory properties on T cells and NK cells. The preservation of cellular responses under anti-CD20 therapy despite impaired antibody production suggests that patients on B-cell depleting agents may retain vaccine benefit through T-cell mediated immunity, though the clinical implications remain undefined.

Third, platform-specific characteristics influenced comparative immunogenicity. mRNA-1273 consistently produced higher antibody titers than Ad26.CoV2.S at all timepoints in IBD patients (log10 4.20 vs 1.96 at week 2, p<0.001), and outperformed inactivated and adenovirus-based vaccines in rheumatic disease patients at 4 months. The superior performance of mRNA vaccines likely reflects their more robust antigen expression, innate immune activation, and prime-boost dosing strategy. However, the clinical significance of these titer differences remains unclear absent correlates of protection. The observation that 90% of Ad26.CoV2.S recipients and 91.7% of mRNA-1273 recipients in the most immunosuppressed populations achieved seropositivity suggests qualitative immune engagement across platforms, though quantitative thresholds for protection are undefined.

The temporal dynamics reveal antibody decay across all populations, with log10 titers declining from 4.20 to 3.72 over 6 weeks in IBD patients and continued decreases from 1 to 4 months in rheumatic disease patients. This decay occurred independently of immunosuppression, suggesting natural antibody kinetics rather than therapy-specific effects. The preservation of high seroconversion rates despite declining titers (100% at week 2 maintained through week 8) indicates that most patients retain detectable antibodies even as absolute levels wane.

Critically, all studies assessed only SARS-CoV-2 spike variants circulating in 2021, prior to Omicron emergence. The reported antibody levels may not predict responses to contemporary variants. Additionally, the correlation between antibody titers and clinical protection from infection or severe disease remains undefined in immunocompromised populations, limiting interpretation of quantitative differences. The preservation of T-cell responses in patients with impaired humoral immunity underscores that antibody titers represent only one component of vaccine-induced protection.