Safety and immunogenicity of an Escherichia coli-produced bivalent human papillomavirus type 6/11 vaccine: A dose-escalation, randomized, double-blind, placebo-controlled phase 1 trial

Abstract

A dose-escalation, randomized, double-blind, placebo-controlled phase 1 clinical trial enrolled 145 eligible participants aged 18-55 years in March 2015 in Liuzhou, China. Stratified by age and sex, the participants were randomly assigned to receive either 30, 60, or 90 μg of the HPV-6/11 vaccine (n = 41/40/40) or the parallel placebo vaccine (n = 8/8/8) with a 0/1/6-month dose-escalation schedule. Participants were actively followed-up to record local and systemic AEs occurring within 30 days after each vaccination, and SAEs occurred in 7 months. Blood and urine samples of each participant were collected before and 2 days after the first and third vaccination to determine changes in routine blood, serum biochemical, and urine indexes. Serum HPV-6/11-specific IgG and neutralizing antibody levels at month 7 were analyzed. A total of 79 adverse events were reported, and no SAEs occurred. The incidences of total adverse reactions in the 30 μg, 60 μg, and 90 μg HPV vaccine groups and the control group were 31.7%, 50.0%, 42.5%, and 62.5%, respectively. All but one of the adverse reactions was mild or moderate with grade 1 or 2. No vaccine-related changes with clinical significance were found in paired blood and urine indexes before and after vaccinations. All the participants in the per-protocol set seroconverted at month 7 for both IgG and neutralizing antibodies. The candidate novel Escherichia-coli-produced bivalent HPV-6/11 vaccine has been preliminarily proven to be well tolerated and with robust immunogenicity in a phase 1 clinical study, supporting further trials with larger sample size. The study has been registered at ClinicalTrials.gov (NCT02405520).

Keywords: Human papillomavirus; genital warts; immunogenicity; phase 1 clinical trial; safety; vaccine.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: Zhao-Jun Mo, Zhao-Feng Bi, Wei Sheng, Qi Chen, Teng Huang, Ming-Qiang Li, Xue-Lian Cui, Ya-Hui Wangjiang, Ya-Fei Li, Ya Zheng, Si-Jie Zhuang, Ying-Ying Su, Shou-Jie Huang, Ting Wu, Jun Zhang, and Ning-Shao Xia reported no potential conflicts of interest relevant to this article. The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: The study funder, Xiamen Innovax, prepared the vaccines in the phase I trial. Bi-Zhen Lin, Feng-Zhu Zheng, Guang Sun, and Hui-Rong Pan are current employees of Xiamen Innovax.

Figures

Figure 1.

Trial profile. The dose-escalation phase 1 study was carried out in three stages. Seven days after the first dose of vaccination in each stage, total adverse reactions and events that occurred during the first week were collected and analyzed. If no vaccine-related serious adverse events occurred within the first week, the next stage of study was started. All the participants received three doses of the allocated vaccine according to the protocol.

Figure 2.

Changes in routine paired blood, serum biochemical, and urine indexes before and 2 days after the first and third vaccinations. The fluctuations were classified into three categories: “maintaining” indicated no grade change observed; “worsening” indicated a change from normal to abnormal or an increase in grade; and “improving” indicated a change from abnormal to normal or a decrease in grade. a) Six routine blood indexes were measured: white blood cell count (WBC), lymphocytes (LY), absolute neutrophil count (ANC), eosinophils (EOS), platelets (PLT), and hemoglobin (HGB). b) Four serum biochemical indexes were measured: total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glucose (GLU). c) Three routine urine indexes were measured: urinary protein (PRO), urinary glucose (UGLU) and urine occult blood (BLD).

Figure 3.

HPV-6/11 antibody levels at one month post three doses of vaccine (month 7) in the per-protocol set. Antibody level of each participant is shown (A: HPV-6 IgG; B: HPV-11 IgG; C: HPV-6 nAb; D: HPV-11 nAb). The black lines indicate the GMC/GMT and 95%CI. *: Significant difference between the two dose groups; **: Significant differences between this group and all the other dose groups. nAb: neutralizing antibody. ID50: the highest dilution which blocked 50% of green fluorescent protein (GFP) expression (50% neutralization).

Figure 4.

Reverse cumulative distribution curves of the HPV-6/11 antibodies in the per-protocol set for immunogenicity (PPS-I). A: HPV-6 IgG; B: HPV-11 IgG; C: HPV-6 nAb; D: HPV-11 nAb. nAb: neutralizing antibody. ID50: the highest dilution which blocked 50% of green fluorescent protein (GFP) expression (50% neutralization).