Infectious Disease · Medical Literature
Immunogenicity and safety of co-administered Escherichia coli-produced bivalent HPV-16/18 vaccine and hepatitis E vaccine.
Abstract
Human papillomavirus (HPV) and Hepatitis E virus (HEV) infections are major health concerns for women of reproductive age. Administration of HPV and HEV vaccines serves as primary prevention strategies. Our study aimed to demonstrate the immunogenicity and safety of co-administering Escherichia coli-produced bivalent HPV-16/18 vaccine and HEV vaccine compared to HPV-alone/HEV-alone. This randomized, multicenter, open-label trial was conducted at 4 clinical study sites in Zhejiang Province, China. Participants were enrolled and randomly assigned into three groups to receive bivalent HPV vaccine co-administered with HEV vaccine, HPV vaccine alone and HEV vaccine alone following a 0, 1, 6-month vaccination schedule. The geometric mean concentrations (GMC) and seroconversion rates were measured at months 0 and 7 to evaluate immunogenicity. Non-inferiority was met if the lower bound of the two-sided 95% CI for the seroconversion rate difference exceeded -5%, or that for the GMC ratio exceeded 0.5. Safety outcomes were assessed post-vaccination. Of the 480 women aged 18-25 years enrolled, 462 (96.3%) completed the full vaccination regimen and follow-up and were included in the per-protocol set (PPS), whereas all 480 participants (100%) were included in the safety set (SS). The GMC ratio for HPV-16 (HPV+HEV group vs. HPV-alone group) was 0.82 (95% CI 0.68-0.98), with corresponding GMCs of 433.16 IU/mL and 529.20 IU/mL, respectively. For HPV-18, the GMC ratio (HPV+HEV vs. HPV-alone) was 0.78 (95% CI 0.64-0.96), based on concentrations of 318.30 and 407.54 IU/mL, respectively. HEV GMCs were 10.51 WU/mL for the co-administration group and 11.18 WU/mL for the HEV-alone group (ratio 0.94; 95% CI 0.81-1.09). All groups achieved 100% seroconversion. Most adverse reactions were Grade 1, and no vaccine-related serious adverse events (SAEs) occurred. Co-administration of HPV vaccine and HEV vaccine elicited high seroconversion rates and met non-inferiority criteria compared to administration of each vaccine alone, with a similar safety profile, supporting the feasibility of concomitant vaccination.
Clinical relevance
In women aged 18–25 years, does co-administration of an Escherichia coli-produced bivalent HPV-16/18 vaccine with a hepatitis E vaccine (HEV239, Hecolin®) produce non-inferior immunogenicity and an acceptable safety profile compared to administration of each vaccine alone? __SNAPSHOT__ {"studyDesign":"Randomized, multicenter, open-label, three-arm parallel-group non-inferiority trial","setting":"Four clinical study sites in Zhejiang Province, China","sampleSize":"n=480 enrolled (safety set); n=462 (96.3%) included in per-protocol set (PPS). Arm allocation not reported individually per group.","population":"Healthy women aged 18–25 years; baseline seronegative individuals assessed for primary immunogenicity outcomes. Pregnant, immunocompromised, or previously vaccinated individuals were excluded per standard trial criteria (specific exclusion criteria beyond age not detailed in the available abstract).","intervention":"Bivalent HPV-16/18 vaccine (E. coli-produced; Cecolin®) co-administered with HEV vaccine (Hecolin®) at months 0, 1, and 6","comparator":"HPV vaccine alone (months 0, 1, 6) and HEV vaccine alone (months 0, 1, 6) administered as separate monovalent groups","primaryOutcome":"Geometric mean concentrations (GMC) and seroconversion rates for anti-HPV-16 IgG, anti-HPV-18 IgG, and anti-HEV IgG at month 7 (one month after the third dose); non-inferiority criteria: lower bound of 95% CI for seroconversion rate difference > −5% OR lower bound of 95% CI for GMC ratio > 0.5","followUp":"7 months (immunogenicity assessment at months 0 and 7); safety assessed post-each vaccination through the study period","fundingSource":"Not reported in the available abstract or retrieved full-text excerpt"}
Key findings
All three groups achieved 100% seroconversion for their respective vaccine antigens (HPV-16, HPV-18, and HEV IgG) at month 7, meeting the seroconversion rate non-inferiority criterion (lower bound of 95% CI for difference > −5%) across all comparisons. For HPV-16, the GMC in the co-administration group was 433.16 IU/mL vs. 529.20 IU/mL in the HPV-alone group, yielding a GMC ratio of 0.82 (95% CI: 0.68–0.98); the lower bound (0.68) exceeded the pre-specified non-inferiority margin of 0.5, satisfying that criterion. For HPV-18, GMC was 318.30 IU/mL (co-administration) vs. 407.54 IU/mL (HPV-alone), GMC ratio 0.78 (95% CI: 0.64–0.96); lower bound 0.64, above the 0.5 threshold. For HEV, GMC was 10.51 WU/mL (co-administration) vs. 11.18 WU/mL (HEV-alone), GMC ratio 0.94 (95% CI: 0.81–1.09), indicating minimal attenuation of HEV immunogenicity. Notably, while all GMC ratio lower bounds exceeded the 0.5 non-inferiority margin, the absolute GMCs for HPV-16 and HPV-18 in the co-administration group were approximately 18–22% lower than in the respective monovalent arms; the clinical significance of this magnitude of reduction is not established in the study. P-values for comparisons were not reported in the available data. NNT/NNH are not calculable from the reported immunogenicity data. Regarding safety, most adverse reactions were Grade 1; Grade 2 and 3 adverse reactions were rare but rates were not reported numerically. No vaccine-related serious adverse events (SAEs) occurred in any group.
Practice implications
This trial establishes that co-administration of the E. coli-produced bivalent HPV-16/18 vaccine with the HEV vaccine meets pre-specified immunogenicity non-inferiority criteria and is well tolerated in young women aged 18–25 years in China. The study does NOT establish equivalence of antibody titers—GMCs for HPV-16 and HPV-18 were measurably lower in the co-administration arm, though both remained above the non-inferiority threshold of 0.5 GMC ratio. The clinical relevance of the observed ~18–22% GMC attenuation for HPV antigens is uncertain, as the study was not powered or designed to assess protective efficacy outcomes (e.g., persistent infection, CIN). Findings apply specifically to the E. coli-produced bivalent HPV vaccine (Cecolin®) and Hecolin® HEV vaccine on a 0, 1, 6-month schedule; they cannot be generalized to other HPV vaccine platforms (e.g., AS04-adjuvanted or yeast-produced vaccines) or to other HEV vaccine candidates. The study was restricted to women aged 18–25 in Zhejiang Province, China; generalizability to older age groups, males, immunocompromised populations, or non-Chinese settings is not established. The open-label design limits control of performance and detection bias for subjective safety outcomes. Practice change is premature based on this single trial; however, these results are encouraging for vaccination programs in settings where co-administration would improve coverage and compliance. Only the abstract and select data points from the full publication were available for this summary, which may limit completeness of this assessment. __LIMITATIONS__ Open-label design introduces potential performance and detection bias, particularly for subjective safety and tolerability outcomes; participants and investigators were aware of group assignment,Non-inferiority trial powered for immunogenicity endpoints only; no clinical efficacy outcomes (persistent HPV or HEV infection, disease prevention) were assessed,Short follow-up (7 months for immunogenicity); antibody persistence, long-term protection, and potential immune waning from GMC attenuation are unknown,Restrictive and homogeneous study population (healthy women aged 18–25, single province in China) limits generalizability to other age groups, sexes, ethnicities, comorbid populations, or global settings,Approximately 18–22% lower absolute HPV GMCs in the co-administration group versus monovalent HPV arm; correlation of this magnitude of reduction with long-term protective efficacy has not been established for this vaccine platform,Funding source is not reported, precluding assessment of industry sponsorship or conflict-of-interest risk,Grade 2 and 3 adverse reaction rates not reported numerically; limits quantitative safety characterization,Individual per-arm sample sizes not reported in available data, limiting assessment of group balance and statistical power per comparison,Single-country trial with a culturally and geographically specific vaccine (Hecolin® HEV vaccine licensed in China and Pakistan only); findings not directly transferable to global immunization programs __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In 462 women aged 18–25 years, co-administration of the E. coli-produced bivalent HPV-16/18 vaccine (Cecolin®) with the HEV vaccine (Hecolin®) met pre-specified non-inferiority criteria for both seroconversion rates and GMC ratios, with 100% seroconversion across all groups and no vaccine-related serious adverse events. HPV-16 and HPV-18 GMCs were approximately 18–22% lower in the co-administration arm compared to HPV alone, exceeding the non-inferiority threshold but not achieving equivalent titers; the clinical significance of this attenuation requires further study. These results support the immunologic feasibility of co-administration to improve program efficiency, but should not be considered practice-changing until clinical efficacy data and longer follow-up are available.