Low intrinsic killing activity and no impact of its positivity on phase 3 pneumococcal vaccine adult studies.

Abstract

BACKGROUND The opsonophagocytic assay (OPA) is the gold standard for measuring functional antibody responses to bacterial vaccines. However, antibody-independent bactericidal activities, such as those by antibiotics, could contribute to the killing and thus inflate the measured antibody titer. Because of this, an intrinsic killing (IK) assay is currently required to screen and exclude samples with antibody-independent bactericidal activities. METHODS Here, we utilized multiple Phase 3 studies of V116 (Capvaxive), as well as in vitro antibiotic spiked samples with known OPA titers, to gain in-depth insights regarding the impact and necessity of the IK screening testing. RESULTS Our results show that even at the highest clinically relevant blood concentration, an antibiotic such as amoxicillin only contributes to a titer of about 50 in the antibody-depleted serum sample. Consistent with this, IK-positivity in V116 Phase 3 studies only showed higher geometric mean titers (GMTs) in the pre-vaccinated, baseline population when the GMTs are lower than 320. After vaccination, no significant differences in OPA titers were observed between IK-positive and IK-negative samples. This, combined with the low rate of IK positivity in healthy adults of V116 clinical studies (≤2 % in each study), demonstrated that including IK-positive samples did not alter the relevant clinical assessments of opsonophagocytic activity. CONCLUSION Thus, eliminating the IK assay as a requirement for OPA testing could be considered in healthy adult populations where antibiotic use is well-regulated.