Immunogenicity, efficacy, and safety of human papillomavirus vaccine: Data from China

The incidence rate and mortality rate of cervical cancer have steadily increased in young women in China. Therefore, it is critical to improve HPV vaccination rates, particularly for the younger population. There are currently five types of prophylactic vaccines in China: bivalent HPV vaccine (AS04-HPV-16/18), quadrivalent HPV vaccine, 9-valent HPV vaccine, homemade Escherichia coli-produced HPV bivalent vaccine, and Pichia pastoris produced HPV bivalent vaccine. All these five HPV vaccines have completed relevant clinical trials in China, and have been proven to be generally well-tolerated and immunogenic, efficacious against persistent HPV-related infections and genital precancerous lesions (data for 9-valent HPV vaccine is absent), and have demonstrated acceptable safety profiles, as previously shown in global studies. Given that the HPV vaccination rate in China is still very low, additional HPV vaccine coverage is needed to reduce the incidence and mortality rates of cervical cancer.


Introduction
Cervical cancer is the leading cause of malignant tumors in women. In 2020, there were appropriately 604,000 cases of cervical cancer worldwide, resulting in 342,000 deaths, and making for an 88.1% incidence and 91.4% mortality rate in low-and middle-income countries (1). These rates are expected to rise in China. The annual incidence and mortality rate of cervical cancer in China significantly increased from 2000 to 2016 based on the 2020 International Agency for Research on Cancer report, with 109,741 new cases and 59,060 deaths, accounting for 18.2% of global new cases and 17.3% of global deaths, respectively (2).

Pichia pastoris produced HPV bivalent vaccine
A Phase III-IIIB, randomized, controlled trials (311-HPV-1003 and 311-HPV-1004) of HPV bivalent vaccine in Pichia pastoris ((bv-HPV(P.p)) in 9-30 year aged females showed that the GMT of HPV16 and 18 serum in girls aged 9-17 years was higher than that in women aged 18-30 years, and the neutralizing antibodies of HPV16 and 18 were all above 99.77% in both age groups. The neutralizing antibodies in girls receiving 2 doses were noninferior to that in women aged 18-26 who received 3 doses (the lower limit of 95%CI for GMT ratio was greater than 0.67, and the lower limit of 95%CI for positive difference was greater than -5%) (see instruction book).

Escherichia coli-produced HPV bivalent vaccine
An interim analysis of a randomized clinical trial (NCT01735006) of bv-HPV vaccine (E.c)among 7372 eligible women aged

Women with excisional treatment
A post-hoc analysis focused on intent-to-treat in 168 participants (vaccine, n = 87; placebo, n = 81) who received excisional treatments at baseline and during a follow-up period in a phase II/III, doubleblind, randomized trial (NCT00779766) conducted in Jiangsu Province, China, found that the VE of vaccination on acquiring 14 hrHPV infection after treatment was 27% (95% CI: 4.9, 44.0%).VE against new infections after treatment for 14 hrHPV infection was estimated as 32.0% (95%CI:1.8, 52.8%), and was 41.2% (95%CI:162.7, 86.8%) for HPV16/18 infection. Although no significant evidence demonstrated that the bv-HPV (AS04-HPV-16/18) vaccine could lead to faster viral clearance(vaccine:88.9% vs control: 81.6%) or have any effect on the rates of persistent infection among women who received excision treatments, the post-treatment women could still experience benefits due to the "primary prophylactic" effect (19).

Safety
A phase I trial (NCT00549900) assessing the bv-HPV (AS04-HPV-16/18) vaccine demonstrated that pain at the injection site was the most commonly reported symptom. Two participants reported medically significant adverse incidents, but the investigator found that they were not related to vaccination (20). The per-protocol cohort of bv-HPV (E.c) vaccine study (NCT01735006) showed mild side effects, pain at the injection site (34.0%) and fever (>37.0°C, 35.1%) were the most common reactions that occurred in the vaccine group. No vaccine-related medical adverse incidents were observed (14). The end-of-study analysis also demonstrated a similar rate of serious adverse events between vaccine groups (7.2%, 267 of 3691) and the control (7.9%, 290 of 3681), and was not considered to be vaccination-related (15).
A safety assessment of the qv-HPV vaccine was performed in a clinical trial (NCT03903562) with Chinese women during a 90-month follow-up period and found that injection-site adverse events (AEs) 15 days after vaccination were common among qv-HPV vaccine participants (37.6% vs. 27.8%), and that systemic AEs had a similar frequency between the qv-HPV vaccine and placebo groups (46.8% vs. 45.1%). Pregnancy outcomes, fetal/infant SAEs, and new medical conditions in the qv-HPV vaccine and placebo groups were similar (21). The phase III open-label study (NCT03903562) compared the 9-valent HPV vaccine in 9-45year-old Chinese females demonstrated that injection-site AEs were common such as injection-site pain (39.2%,45.2%, and 39.8%) and injection-site erythema (9.3%, 11.2%, and 7.4%) in the 9-19-year, 20-26-year, and 27-45-year age groups, respectively. No SAEs, or related discontinuations, or deaths were confirmed to be vaccine-related (13).
Although the above clinical trials in China all proved that all HPV vaccines can be tolerated, demonstrate immunogenicity and efficacy against HPV-related infections and genital precancerous lesions (data for 9-valent HPV vaccine is absent), and have acceptable safety profiles as previously shown in global studies, the rate of HPV vaccination in China still must be improved. According to 2021 survey data, only 3% of all Chinese females and 1.9% of females aged 9-14 received the HPV vaccine (22). The Chinese National Health Commission has proposed to gradually launch free HPV vaccinations nationwide to protect women and girls from cervical cancer, starting in pilot regions. At present, many regions in China are actively promoting free HPV vaccination by implementing the 'Healthy China 2030 Program Outline'. For primary prevention, it is necessary to strengthen public health guidance and promote the administration of cervical cancer vaccines. Administering the HPV vaccine to adolescent women is a top priority since effectively preventing cervical cancer requires receiving the HPV vaccine before they become sexually active.

Author contributions
LW designed the study, CZ conducted personnel organization and data collection, YZ and JL reviewed the literature, and ML drafted the manuscript. All authors contributed to the article and approved the submitted version.

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