What is immunogenicity?

Understanding Immunogenicity

Immunogenicity is the ability of a substance to provoke an immune response in the body, which can be measured by the production of antibodies or cellular immune responses against that substance. 1, 2

Key Components of Immunogenicity

Definition and Measurement

• Immunogenicity refers to the capacity of proteins, peptides, vaccines, or therapeutic agents to trigger immune responses 1, 3
• It can be measured through:
  • Antibody production (humoral immunity)
  • T-cell responses (cellular immunity)
  • Seroconversion rates (percentage of individuals developing antibodies)
  • Antibody titers (concentration of antibodies)

Types of Immunogenicity

1. Beneficial immunogenicity:

   • Desired in vaccines where the goal is to generate protective immunity 4
   • Measured as seroprotection (antibody levels sufficient to protect against infection)

2. Unwanted immunogenicity:

   • Occurs with therapeutic proteins/biologics where immune responses may reduce efficacy or cause adverse effects 2, 5
   • Results in anti-drug antibodies (ADAs) that can neutralize the therapeutic effect

Factors Affecting Immunogenicity

Product-Related Factors

• Structural characteristics of the molecule (sequence, glycosylation patterns)
• Presence of aggregates or contaminants
• Manufacturing processes and formulation 5

Patient-Related Factors

• Genetic factors (HLA type)
• Underlying disease state
• Concomitant medications (especially immunosuppressants)
• Route of administration and dosing regimen 1

Treatment-Related Factors

• Disease-modifying antirheumatic drugs (DMARDs) can significantly impact immunogenicity:
  • Rituximab (anti-CD20) substantially decreases vaccine immunogenicity 1
  • Methotrexate reduces antibody responses to vaccines 1
  • TNF inhibitors may decrease absolute antibody titers but often maintain seroprotection rates 1
  • IL-6R, IL-12/23, and IL-17 inhibitors have minimal impact on vaccine immunogenicity 1

Clinical Significance of Immunogenicity

In Vaccine Development

• Immunogenicity is essential for vaccine efficacy
• Surrogate markers of protection include:
  • Seroconversion rates (percentage developing antibodies)
  • Antibody titers against specific antigens
  • For some vaccines, there is a clear correlation between antibody levels and protection (measles, rubella, tetanus, hepatitis) 1
  • For others, this correlation is less clear (HPV, pertussis) 1

In Biologic Therapeutics

• Immunogenicity can lead to:
  • Reduced drug efficacy through neutralizing antibodies
  • Altered pharmacokinetics (increased clearance)
  • Hypersensitivity reactions
  • Cross-reactivity with endogenous proteins 2, 5
• Monitoring immunogenicity is critical for biologics, especially in long-term treatments 2

Assessment of Immunogenicity

Laboratory Methods

• Enzyme-linked immunosorbent assays (ELISAs)
• Cell-based assays
• Neutralization assays to detect functional antibodies
• FluoroSpot-based assays for T-cell responses 6

Clinical Assessment

• Monitoring for loss of therapeutic response
• Evaluating unexpected adverse events
• Measuring drug levels in conjunction with anti-drug antibody testing 3

Mitigating Immunogenicity

For Therapeutic Proteins

• Protein engineering to remove immunogenic epitopes
• Optimization of formulation to prevent aggregation
• Appropriate dosing regimens
• Concomitant immunosuppression when appropriate 5

For Vaccines

• Timing of vaccination relative to immunosuppressive therapy:
  • Vaccinate before starting rituximab when possible
  • Consider holding methotrexate temporarily around vaccination 1
  • Live vaccines should be avoided in patients on significant immunosuppression 1

Common Pitfalls in Assessing Immunogenicity

• Confusing immunogenicity (ability to provoke immune response) with efficacy (clinical protection)
• Relying solely on antibody titers without considering functional neutralizing capacity
• Not accounting for the impact of immunosuppressive medications when interpreting vaccine responses
• Failing to recognize that immunogenicity assays vary in sensitivity and specificity, making direct comparisons between studies difficult 1, 3

Immunogenicity assessment is critical for both vaccine development and biologic therapy management, requiring careful consideration of multiple factors that influence immune responses and their clinical relevance.