Antibody avidity, persistence, and response to antigen recall: comparison of vaccine adjuvants

Differences in innate immune ‘imprinting’ between vaccine adjuvants may mediate dissimilar effects on the quantity/quality of persisting adaptive responses. We compared antibody avidity maturation, antibody/memory B cell/CD4+ T cell response durability, and recall responses to non-adjuvanted fractional-dose antigen administered 1-year post-immunization (Day [D]360), between hepatitis B vaccines containing Adjuvant System (AS)01B, AS01E, AS03, AS04, or Alum (NCT00805389). Both the antibody and B cell levels ranked similarly (AS01B/E/AS03 > AS04 > Alum) at peak response, at D360, and following their increases post-antigen recall (D390). Proportions of high-avidity antibodies increased post-dose 2 across all groups and persisted at D360, but avidity maturation appeared to be more strongly promoted by AS vs. Alum. Post-antigen recall, frequencies of subjects with high-avidity antibodies increased only markedly in the AS groups. Among the AS, total antibody responses were lowest for AS04. However, proportions of high-avidity antibodies were similar between groups, suggesting that MPL in AS04 contributes to avidity maturation. Specific combinations of immunoenhancers in the AS, regardless of their individual nature, increase antibody persistence and avidity maturation.

The serological response to SARS corona virus-2 is characterized by frequent incomplete maturation of functional affinity (avidity)

The humoral immune systems controls viral infections through recognition of critical viral target structures, selective proliferation stimulation of IgM-presenting B cells, class switch to IgG-generating B cells and subsequent affinity maturation of IgG. Affinity maturation is achieved through proliferation, hypermutation and clonal selection of IgG-generating B cells (1-4). The establishment of high affinity IgG is essential for sustained protective antiviral effects (5-10). While analyzing the maturation of functional affinity (avidity) of IgG towards SARS CoV-2 nucleoprotein, surface protein and its receptor-binding domain, we realized that avidity maturation was frequently not completed after infection. This finding gives insight into the biological strategy of SARS CoV-2 and is important for serodiagnosis. Incomplete avidity maturation might explain the observed decline of the humoral response (11-14), allow for secondary SARS CoV-2 infections and prevent the establishment of herd immunity. Therefore, future immunization strategies should achieve the goal to induce neutralizing IgG of high avidity.

Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Avidity Maturation and Association with Disease Severity

The kinetics of IgG avidity maturation during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was studied. The IgG avidity assay, using a novel label-free immunoassay technology, revealed a strong correlation between IgG avidity and days since symptom onset. Peak readings were significantly higher in severe than mild disease cases.

Kinetics of SARS-CoV-2 Antibody Avidity Maturation and Association with Disease Severity

The kinetics of IgG avidity maturation during SARS-CoV-2 infection was studied. The IgG avidity assay used a novel label-free immunoassay technology. It was found that there was a strong correlation between IgG avidity and days since symptom onset, and peak readings were significantly higher in severe than mild disease cases.

Development and Use of an Endpoint Titration Assay To Characterize Mumps IgG Avidity following Measles, Mumps, and Rubella Vaccination and Wild-Type Mumps Infection

ABSTRACTWaning mumps IgG antibody and incomplete IgG avidity maturation may increase susceptibility to mumps virus infection in some vaccinees. To measure mumps IgG avidity, serum specimens serially diluted to the endpoint were incubated on a commercial mumps-specific IgG enzyme immunoassay and treated with the protein denaturant diethylamine (60 mM, pH 10). End titer avidity indices (etAIs [percent ratio of detected diethylamine-resistant IgG at endpoint]) were calculated. Unpaired serum specimens (n= 108) from 15-month-old children living in a low-incidence setting were collected 1 month and 2 years after the first measles, mumps, and rubella vaccine dose (MMR1) and tested for mumps avidity. Per the receiver operating characteristic curve, the avidity assay is accurate (area under the curve, 0.994; 95% confidence interval [CI], 0.956 to 1.000), 96.5% sensitive (95% CI, 87.9 to 99.6%), and 92.2% specific (95% CI, 81.1 to 97.8%) at an etAI of 30%. When 9 sets of paired serum specimens collected 1 to 60 months post-MMR1 were tested for mumps and measles IgG avidity using comparable methods, the mumps etAI increased from 11% to 40 to 60% in 6 months. From 6 to 60 months, avidity was sustained at a mean etAI of 50% (95% CI, 46 to 54%), significantly lower (P < 0.0001) than the mean measles etAI of 80% (95% CI, 74 to 86%). Mean etAIs in children 2 years post-MMR1 (n= 51), unvaccinated adults with distant mumps disease (n= 29), and confirmed mumps cases (n= 23) were 54, 62, and 57%, respectively. A mumps-specific endpoint avidity assay was developed and validated, and mumps avidity was determined to be generally sustained at etAIs of 40 to 60%, reaching etAIs of >80% in some individuals.IMPORTANCENumerous outbreaks of mumps have occurred in the United States among two-dose measles-mumps-rubella (MMR)-vaccinated populations since 2006. The avidity of mumps-specific IgG antibodies may affect susceptibility to mumps virus infection in some vaccinated individuals. To accurately measure mumps avidity, we developed and validated a mumps-specific IgG avidity assay that determines avidity at the endpoint titer of serially diluted serum specimens, providing results that are independent of IgG concentration. At low antibody titers, endpoint methods are considered more accurate than methods that determine avidity at a single dilution. We determined that 6 months after the first MMR dose, mumps IgG avidity is high and generally sustained at avidity indices of 40 to 60%, reaching values of >80% in some individuals. Additionally, 4% (4/103) of individuals had avidity indices of ≤30% (low avidity) 2 years after vaccination. Inadequate mumps avidity maturation may be one factor influencing susceptibility to mumps virus infection among previously vaccinated or naturally infected individuals.

pMHC affinity controls duration of CD8+ T cell–DC interactions and imprints timing of effector differentiation versus expansion

During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC) affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulated factor 4) induction and timing of effector differentiation, as low affinity–primed T cells acquired cytotoxic activity earlier than high affinity–primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity–stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.