Prevention of Vaccine Failure in Haemophilus influenzae Type B Vaccines

A Haemophilus influenzae type b (Hib) vaccine, PRP-CRM197, may be more immunogenic than another Hib vaccine, PRP-T (polyribosylribitol phosphate conjugated with tetanus toxoid), due to the stimulation of a higher level of anti-PRP-specific antibodies and a higher serum bactericidal activity (SBA) titer after the primary series, according to a study published in Vaccine.

In a previous phase 3 study, the immunogenicity of 2 Hib conjugate vaccines, Vaxem™ Hib (PRP conjugated with a nontoxic diphtheria toxin mutant, PRP-CRM197, containing aluminum phosphate adjuvant [PRP-CRM197]) and PRP-T were compared and shown to have no significant differences in Hib PRP-specific immunoglobulin (Ig) G antibody titers. These vaccines differ in the carrier proteins conjugated with Hib PRP and in containing aluminum phosphate adjuvant.

Protection against Hib infection has relied on SBA antibodies; however, licensure has relied on measuring the induction of antibodies to PRP as a surrogate for SBA. It has been suggested that measurement of SBA is the more reliable predictor for successful immunization against Hib as vaccine failure in an infant showed sufficient anti-PRP antibody levels but low SBA titer levels. In the hope of reinforcing the conclusion of the previously mentioned study, this phase 3 randomized double-blind study (ClinicalTrials.gov identifier: NCT01379846) conducted in Japanese infants compared SBA titers between PRP-T and PRP-CRM197.

A total of 415 children between the age of 3 and 6 months were immunized with a 3-dose primary series of either PRP-CRM197 or PRP-T and a booster approximately 1 year after primary series completion. The anti-PRP specific IgG level was increased after the primary series with PRP-CRM197 (18.0 mg/ml) and PRP-T (8.67 mg/ml). In addition, 99.3% of patients in the PRP-CRM197 group, and 95.6% of patients in the PRP-T group had titers above the threshold for long-term seroprotection. Using the same sera, a significantly higher SBA titer was found in the PRP-CRM197 group than in the PRP-T group (geometric mean ratio, 2.88 (PRP-CRM197/PRP-T)). Mean SBA titers post-immunization were 201.7 for PRP-CRM197 and 69.9 for PRP-T groups.

A moderate positive correlation between anti-PRP antibody levels and SBA titers was found in the PRP-CRM197 (n=263; P <.0001) and PRP-T (n=115; P =.0003) groups. Conversely, a few patients with >1.0 µg/mL (long-term) in both vaccination groups had SBA titers <16; these patients may provide an explanation for vaccine failure and Hib infection breakthrough.

To study this further, subjects with anti-PRP IgG antibody titers ³0.15 mg/mL for short-term or ³1.0 mg/mL for long-term were categorized as non-responders if they had SBA <16 or responders if they had SBA ³16 and were compared in each group. Results indicated that PRP-CRM197 immunization had significantly fewer non-responders than patients who received PRP-T immunization with antibody levels exceeding short-term (97.8% vs 87.9%, respectively) and long-term (98.5% vs 91.3%, respectively) seroprotective thresholds.

Therefore, the higher SBA titers found post-immunization with PRP-CRM197 showed that this vaccine has superior seroprotective effects short-term and long-term when compared with PRP-T immunization. Based on these results, the study investigators concluded that “PRP-CRM197 administration can decrease the incidence of vaccine failures.”

Disclosure: This clinical trial was funded by Takeda Pharmaceutical Company Limited.

Reference

Akeda Y, Koizumi Y, Takanami Y, et al. Comparison of serum bactericidal and antibody titers induced by two Haemophilus influenzae type b conjugate vaccines: a phase III randomized double-blind study. Vaccine. 2018;36:1528-1532.