Comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase III clinical trial

Abstract

Human enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease (HFMD). In a previous phase III trial in children, a human diploid cell-based inactivated EV71 vaccine elicited EV71 specific immune responses and protection against EV71 associated HFMD. This study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. This was a randomized, doubleblinded, placebo-controlled, phase III clinical trial of a human diploid vaccine carried out in 12,000 children in Guangxi Zhuang Autonomous Region, China (ClinicalTrials.gov: NCT01569581). Solicited events were recorded for 7 days and unsolicited events were reported for 28 days after each injection. Age trend analysis of adverse reaction was conducted in each treatment group. Multiple logistic regression models were built to identify factors influencing the severity of adverse reactions. Fewer solicited adverse reactions were observed in older participants within the first 7 days after vaccination (P < 0.0001), except local pain and pruritus. More severe adverse reactions were observed after the initial injection than after the booster injection. Serious cold or respiratory tract infections (RTI) were observed more often in children aged 6-36 months than in older children. Only the severity of local swelling was associated with body mass index. Children with throat discomfort before injection had a higher risk of serious cold or RTI. These results indicated that the human diploid cell-based vaccine achieved a satisfactory safety profile.

Effect of difference between EV-A71 virus epidemic strain and “vaccine strain” on neutralizing antibody titer

“… 22 Furthermore, a phase III clinical trial of inactivated diploid enterovirus has been reported to demonstrate satisfactory safety. 23 However, between 1986 and 2008, the full-length genomic sequence of Taiwan’s popular EV-A71 was internally and recombined, and dominant genotype changes from B to C or C to B occurred at least three times. 24 Subtypes of EV-A71 subtypes were observed over time, but most people did not know their appearance and extinction at the exact time.…”

Development and characterization of an enterovirus 71 (EV71) virus-like particles (VLPs) vaccine produced in Pichia pastoris

“…2 EV71 and CVA16 are responsible for more than 90% of HFMD cases, and EV71 is responsible for most severe cases and deaths. 29 Three inactivated EV71 vaccines have shown protective efficacy in phase 3 clinical trials and been approved for commercialization in mainland China, [8][9][10]29 but the low production of inactivated EV71 means it is difficult to supply enough inactivated EV71 vaccines for nationwide or worldwide mass immunization of the at-risk populations at the outbreaks of EV71 HFMD. Pichia pastoris is a commonly used yeast expression system for recombinant proteins of interest and has many advantages in vaccine development, including low fermentation cost, high expression levels, and high-density growth in fermentation bioreactors.…”

“…Three inactivated EV71 vaccines had been proven to be effective for preventing EV71 infection in children and have been approved for marketing in mainland China, [8][9][10] however, these vaccines have some disadvantages such as potentially epitope-damaging, the risk of being inactivated incompletely and high production cost. 11 VLPs are considered a very attractive platform for viral vaccine development because of their high immunogenicity and excellent safety.…”