Immunogenicity and safety of a fully liquid aluminum phosphate adjuvanted Haemophilus influenzae type b PRP-CRM197-conjugate vaccine in healthy Japanese children: A phase III, randomized, observer-blind, multicenter, parallel-group study.
Broad use of monovalent Haemophilus influenzae type b (Hib) conjugate vaccines based on the capsular polysaccharide polyribosyl-ribitol phosphate (PRP), has significantly reduced invasive Hib disease burden in children worldwide, particularly in children aged <1year. In Japan, PRP conjugated to tetanus toxoid (PRP-T) vaccine has been widely used since the initiation of public funding programs followed by a routine vaccination designation in 2013.



We compared the immunogenicity and safety of PRP conjugated to a non-toxic diphtheria toxin mutant (PRP-CRM197) vaccine with the PRP-T vaccine when administered subcutaneously to healthy Japanese children in a phase III study. Additionally, we evaluated the immunogenicity and safety profiles of a diphtheria-tetanus acellular pertussis (DTaP) combination vaccine when concomitantly administered with either PRP-CRM197 or PRP-T vaccines. The primary endpoint was the "long-term seroprotection rate", defined as the group proportion with anti-PRP antibody titers ⩾1.0μg/mL, after the primary series.



Long-term seroprotection rates were 99.3% in the PRP-CRM197 group and 95.6% in the PRP-T group. The intergroup difference (PRP-CRM197 group - PRP-T group) was 3.7% (95% confidence interval: 0.099-7.336), demonstrating that PRP-CRM197 vaccine was non-inferior to PRP-T vaccine (p<0.0001). Furthermore, the "short-term seroprotection rate" (anti-PRP antibody titer ⩾0.15μg/mL) before booster vaccination was higher in the PRP-CRM197 group than in PRP-T. Concomitant administration of PRP-CRM197 vaccine with DTaP vaccine showed no differences in terms of immunogenicity compared with concomitant vaccination with PRP-T vaccine and DTaP vaccine. Although CRM197 vaccine had higher local reactogenicity, overall, both Hib vaccines had acceptable safety and tolerability profiles.



The immunogenicity of PRP-CRM197 vaccine administered subcutaneously as a three-dose primary series in children followed by a booster vaccination 1year after the primary series induced protective levels of Hib antibodies with no safety or tolerability concerns.



Registered on ClinicalTrials.gov: NCT01379846.
Hokkaido Anti-Tuberculosis Assoiciation, Kita 8, Nishi 3-28, Kita-ku, Sapporo 060-0808, Japan.
Takehiro
T
Togashi
Takeda Pharmaceutical Company Limited, 1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan. Electronic address: nodoka.mitsuya@takeda.com.
Nodoka
N
Mitsuya
Takeda Pharmaceutical Company Limited, 1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan.
Osamu
O
Kogawara
Takeda Pharmaceutical Company Limited, 1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan.
Shuji
S
Sumino
Takeda Pharmaceutical Company Limited, 1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan.
Yohei
Y
Takanami
Takeda Pharmaceutical Company Limited, 1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645, Japan.
Kayoko
K
Sugizaki
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D017607:Aluminum Compounds / Q000008:administration & dosage*; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000276:immunology*; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage; D005260:Female; D018073:Haemophilus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007117:Immunization, Secondary; D000071497:Immunogenicity, Vaccine; D007223:Infant; D007564:Japan; D008297:Male; D010710:Phosphates / Q000008:administration & dosage*; D013745:Tetanus Toxoid / Q000276:immunology / Q000627:therapeutic use*; D018074:Vaccines, Conjugate / Q000276:immunology / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D017607:Aluminum Compounds; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D015721:Diphtheria-Tetanus-Pertussis Vaccine; D018073:Haemophilus Vaccines; C055753:Haemophilus influenza type b polysaccharide vaccine-tetanus toxin conjugate; D010710:Phosphates; D013745:Tetanus Toxoid; D018074:Vaccines, Conjugate; C028581:CRM197 (non-toxic variant of diphtheria toxin); C012714:aluminum phosphate
Haemophilus influenzae type b; Immunogenicity; Japan; Phase III trial; Safety; Vaccine