Review••

Human papillomavirus vaccines developed by Escherichia coli expression system: progress and perspectives from China

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Abstract

Cervical cancer remains a major global public health threat, disproportionately affecting low-income and middle-income countries (LMICs). Prophylactic human papillomavirus (HPV) vaccination is a cornerstone of its prevention but traditional eukaryotic expression systems limit accessibility due to high costs and complex processes. In contrast, China has achieved a pivotal breakthrough by developing HPV vaccines using the Escherichia coli prokaryotic system, which offers rapid scalability, cost-effectiveness and high yield. Building on this foundation, China officially integrated HPV vaccination into its National Immunisation Programme in 2025. This landmark achievement has garnered significant international attention and provides a valuable reference for other LMICs in shaping their immunisation strategies.

This review summarises progress on two E. coli–derived HPV vaccines: bivalent Cecolin (HPV16/18) and nonavalent Cecolin9 (HPV6/11/16/18/31/33/45/52/58). Synthesised clinical evidence shows their favourable safety profiles, robust immunogenicity and high protective efficacy—demonstrating robust humoral immunity, high protection against vaccine-type persistent infections and precancerous lesions and consistent tolerability across age groups and dosing schedules. Notably, Cecolin has obtained WHO prequalification and has been introduced into China’s NIP, while Cecolin9 extends coverage to five additional high-risk genotypes (HPV31/33/45/52/58) that account for a substantial proportion of cervical cancers in China.

The review also addresses the global implications of these vaccines for cervical cancer elimination particularly in resource-limited settings as well as remaining challenges. In conclusion, China’s E. coli-based HPV vaccine platform provides a cost-effective, scalable model that can inform cervical cancer prevention strategies in other LMICs, supporting the WHO’s global elimination goal.

Introduction

Cervical cancer remains a major threat to women’s health worldwide. The disease is primarily caused by persistent infection with high-risk human papillomavirus (HPV), including HPV16/18/31/33/35/39/45/51/52/56/58/59/68, which are also implicated in other malignancies such as anal, vaginal and oropharyngeal cancers.1 In 2022, approximately 660 000 new cases of cervical cancer were diagnosed worldwide, resulting in approximately 350 000 deaths,2 with approximately 84% of new cases occurring in low-income and middle-income countries (LMICs).3 As one of the largest developing countries, China bears a disproportionate share of this burden, reporting approximately 110 000 new cases and 60 000 deaths annually.4 This substantial burden not only threatens women’s health and well-being but also places considerable pressure on public health systems.

Prophylactic HPV vaccination represents the cornerstone of cervical cancer prevention.5 Extensive real-world evidence demonstrates that widespread HPV vaccination leads to a marked decline in infections by vaccine-targeted genotypes and associated conditions while conferring substantial herd-protection benefits.6 As of December 2025, nine prophylactic HPV vaccines have been licensed worldwide, which can be categorised as bivalent, quadrivalent and nonavalent based on the number of targeted genotypes.

To accelerate progress towards disease elimination, the WHO launched a global call to eliminate cervical cancer and proposed achieving 90% HPV vaccination coverage among adolescent girls by 2030.6 The targets have garnered broad international support, with 160 countries having incorporated HPV vaccines into national immunisation programmes (NIPs) as the latest WHO data.7 A landmark step in China was the November 2025 nationwide rollout of a free bivalent vaccination programme for adolescent girls.8 9 The implementation of China’s NIP stems from the high cost-effectiveness of its domestically supplied HPV vaccines, which enables large-scale implementation and further serves as a model for other LMICs facing a high cervical cancer burden.

Given the inability to culture HPV in vitro and the oncogenic nature of its genome, HPV vaccine development employs recombinant protein technology rather than traditional inactivated or attenuated methods. Among licensed HPV vaccines, seven use eukaryotic expression systems (eg, yeast or insect cells), whereas two are based on the prokaryotic Escherichia coli (E. coli) platform, a system valued for its practical and economic advantages. Notably, China’s first bivalent and nonavalent HPV vaccines, Cecolin (2vHPV) and Cecolin9 (9vHPV), respectively, were developed using this system. We summarises E. coli–based HPV vaccines and discuss their potential to advance cervical cancer elimination in LMICs, supporting global vaccine accessibility and public health goals (figure 1).

Figure 1

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Overview of E. coli-expressed HPV vaccines. 2vHPV, bivalent human papillomavirus vaccine; 9vHPV, nonavalent human papillomavirus vaccine; CIN2+, cervical intraepithelial neoplasia grade 2 or higher; HPV, human papillomavirus; NIP, National Immunisation Programme; NMPA, National Medical Products Administration; VLP, virus-like particle.

Escherichia coli expression system

The development of HPV vaccines has long been hindered by two critical challenges: first, HPV cannot be propagated in conventional cell culture owing to its strict dependence on squamous epithelial cell differentiation.10 Second, traditional eukaryotic expression systems involve high costs and complex production, limiting accessibility, exemplified by the prohibitive price of yeast-produced nonavalent vaccines in resource-limited settings.11 These challenges create an urgent need for alternative manufacturing platforms that enable rapid, low-cost production of safe and efficacious HPV antigens.

E. coli has emerged as a promising alternative platform to address these constraints. As a well-characterised prokaryote, it offers rapid growth, low cultivation costs, high protein yield and excellent scalability. This enables drastically shortened production timelines and significantly reduced costs. A prominent success reference is China’s E. coli–produced recombinant hepatitis E vaccine, Hecolin,12 which showed sustained high efficacy for 10 years and remains the world’s only commercially available vaccine against hepatitis E.13

Although historically considered unsuitable for complex antigens, E. coli has been successfully engineered to express HPV L1 capsid proteins that self-assemble into virus-like particles (VLPs),14 the core immunogenic component of HPV vaccines. VLP production in the E. coli system hinges on optimising the L1 gene codon and truncating its N-terminus.15 These modifications are crucial for enhancing soluble expression,16 which helps prevent inclusion body formation and improves protein-folding efficiency. Following induction, the engineered L1 proteins are harvested through cell disruption and clarified by centrifugation. The target protein is then purified through a multi-step chromatographic process designed to remove host-cell proteins and endotoxin contaminants.17 Subsequently, under appropriate buffer conditions and after the removal of reducing agents, the purified L1 proteins spontaneously assemble into VLPs,14 which closely mimic the structural conformation of native HPV virions.

Safety, efficacy and immunogenicity of the Escherichia coli–produced bivalent vaccine

Cecolin (targeting HPV16/18, hereinafter referred to as 2vHPV), the world’s first E. coli–based HPV vaccine, was WHO-prequalified (WHO-PQ) in 2021.18 A series of rigorous and scientific clinical trials and long-term post-vaccination monitoring has demonstrated safety, immunogenicity and efficacy across diverse populations and dosing schedules, supporting its global use (table 1).

Table 1

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Key characteristics of clinical studies on Cecolin

Safety

2vHPV demonstrated consistent and favourable safety across all clinical trial phases, with no vaccine-related serious adverse events (SAEs) reported, and adverse reactions (ARs) were predominantly mild to moderate.

After an early phase I trial19 preliminarily demonstrated its good tolerability, no clinically significant abnormalities were found in 33 monitored haematological and biochemical parameters. A phase II trial18 confirmed that the safety profile was comparable to the hepatitis B vaccine control group, with local AEs dominated by injection-site pain (18.8%–20.9% in vaccine groups vs 15.9% in controls), followed by induration (3.3%–5.0% vs 2.8%), while erythema, pruritus and rash each occurred in <5.0% of participants. Systemic AEs were mainly fever (37.8%–39.0%), followed by headache (6.8%–8.8%) and fatigue (6.5%–9.6%), and the occurrence of AEs was independent of baseline serostatus.

A large-scale phase III trial20 21 with up to 66 months of follow-up showed that the overall incidence of AEs was comparable between the 2vHPV group and the hepatitis E vaccine control group (local AEs (37.8% vs 42.2%) and systemic AEs (45.6% vs 46.2%)). Local reactions were dominated by injection-site pain (34.0% vs 36.1%), followed by induration (7.1%), redness (4.4%), swelling (4.3%) and pruritus (4.4%). The vast majority were mild to moderate in severity, and grade ≥3 events were rare (0.7% vs 1.8%) and typically resolved within 48–72 hours. Systemic reactions were led by fever (≥37.0 °C, 35.1% vs 34.0%), followed by fatigue (7.5%), headache (7.0%) and cough (5.1%), with grade ≥3 events being rare (0.2% vs 0.1%). Long-term safety over the extended follow-up period was further corroborated by comparable pregnancy outcomes (pregnancy rate, 26.5% vs 26.7%; normal infant rate, 99.9% vs 99.8%) and no increased incidence of autoimmune diseases or other major health events.

For adolescents aged 9–17 years, the priority target population, extended follow-up studies22 23 confirmed that for up to 30 months, no vaccine-related SAEs were reported across all groups. Local reactions were dominated by injection-site pain, with an incidence comparable to that observed in adults. Systemic reactions mainly manifested as low-grade fever and fatigue, all of which were mild and self-limiting. An international phase III trial in Bangladesh and Ghana24 also showed that 2vHPV is highly consistent with Gardasil, exhibiting good tolerability. Specifically, the incidences of local reactions (eg, pain) and systemic reactions (eg, headache) were comparable between the two vaccines, most being mild and self-limiting, and no serious vaccine-related adverse reactions were identified. To date, over 80 million doses of 2vHPV have been administered globally, with no serious vaccine-related events reported, supporting its favourable long-term safety.25

Efficacy

Efficacy of 2vHPV against HPV16/18-related infection and disease was directly evaluated in sexually active women. Given the bimodal age distribution of HPV prevalence in China, a phase III trial20 21 with up to 66 months of follow-up demonstrated that in the per-protocol susceptible population, 2vHPV showed high protective efficacy against HPV16/18-related endpoints compared with the control vaccine. Vaccine efficacy was 97.3% (95% CI 89.9 to 99.7) for 6-month and 96.1% (95%CI 85.2 to 99.5) for 12-month persistent infections. Against histological endpoints, efficacy was 100% (79.8–100) for low-grade lesions (CIN1/VIN1/VaIN1+) and 100% (67.2–100) for high-grade lesions (CIN2/VIN2/VaIN2+), with all 13 high-grade cases occurring in the control group. Notably, 2vHPV demonstrates comparable high efficacy in women aged 27–45 years, supported by the absence of high-grade lesions in vaccinated women, compared with 5 of 13 control group cases in that age group. Furthermore, 2vHPV showed cross-protection against related non-vaccine types (HPV31/33/45), with efficacy against 6-month persistent infection ranging from 27.8% to 71.5%. In a 10.2-year extended surveillance study,26 the vaccine demonstrated 87.5% (95% CI 6.4 to 99.7) protection against HPV16/18-related high-grade lesions and 97.0% (95% CI 78.9 to 100.0) against persistent infection. Only one breakthrough CIN2 case was identified in the vaccine group. This case was diagnosed 90 months after enrolment and occurred in a participant with a complex history of multiple HPV infections. Notably, no evidence of persistent HPV 16 infection was observed during follow-up, whereas HPV53 showed persistent infection and was detected in the majority of lesion tissue blocks. Given that persistent infection is considered a prerequisite for lesion progression, the lesion was more likely attributable to HPV53 rather than vaccine-type HPV16. Taken together, this case does not suggest waning protection, and the consistently high efficacy against persistent infection supports sustained long-term effectiveness of 2vHPV.

Immunogenicity

Clinical trial data demonstrate that 2vHPV elicits robust, durable and type-specific immune responses across age groups and schedules.

In a phase II trial,27 among baseline seronegative participants (primary evaluation population), neutralising antibody (nAb) seroconversion rates for HPV16/18 reached nearly 100% across all vaccine groups, with a single non-seroconversion for HPV18 in the 30 µg group. VLP-based ELISA of IgG antibody results were consistent, showing 100% seroconversion. For nAb titres, a dose-dependent trend was observed for HPV16 antibody titres. The geometric mean titre (GMT) in the 30 µg group (7596) was significantly lower than those in the 60 µg (10548) and 90 µg (12505) groups. For HPV18, GMTs were similar across dose groups (6875, 7261 and 8097, respectively). Notably, nAb GMTs in all vaccine groups were 100-fold higher than those from natural infection, indicating strong protective potential.

A phase III trial20 21 showed that 1 month after the third dose (month 7), the seroconversion rates were 100% for HPV16 and 99.9% for HPV18, with geometric mean concentrations (GMCs) of 790.4 and 267.9 IU/mL (quantified using the WHO international standards), respectively, more than 100-fold and 50-fold higher than natural infection levels. At 66 months post-vaccination, seropositive rates remained at 100% for HPV16 and 98.3% for HPV18. Even after 114 months,26 seropositivity rates remained high (98.9% for HPV16 and 97.0% for HPV18), with substantial GMC (61.84 and 18.73 IU/mL, respectively). These antibody levels were not only significantly higher than those from natural infection but also demonstrated remarkable stability over time.

Immunobridging studies23 confirmed that both a two-dose schedule (0 and 6 months) in girls aged 9–14 years and a three-dose schedule (0, 1 and 6 months) in those aged 9–17 years were non-inferior to the three-dose regimen in women aged 18–26 years. Specifically, the seroconversion rates exceeded 99.5% across all groups (100% for HPV16), and the GMCs in the two-dose group (9–14 years) were 2219 IU/mL for HPV16 and 397 IU/mL for HPV18, with GMC ratios of 1.42 and 1.17 relative to the three-dose group (18–26 years), whereas the three-dose group (9–17 years) had higher GMCs of 2749 IU/mL for HPV16 and 656 IU/mL for HPV18, corresponding to ratios of 1.76 and 1.93. The non-inferiority of nAbs was concurrently verified. Extended follow-up22 at 30 months showed maintained seroconversion (100% for HPV16, 99.6% for HPV18 in the two-dose group) and stable antibody decline, with all GMC ratios continuing to meet non-inferiority criteria (1.01 and 0.88, respectively), and those for the three-dose group (9–17 years) were 1.72 and 2.13, all continuously satisfying the non-inferiority criteria. Based on these data, 2vHPV was approved for the two-dose schedule in females aged 9–14 years.

In response to the global shortage of HPV vaccine supply, WHO and Programme for Appropriate Technology in Health (PATH) initiated an evaluation of single-dose regimens in 2018. Given its advantages of low cost, rapid production and high yield, 2vHPV represents a highly promising candidate for such a strategy.28 To directly assess its potential, PATH independently launched a randomised trial in Ghana and Bangladesh. The results demonstrated that a single dose of 2vHPV induced a robust immune response. At 6 months post-vaccination, the GMCs of antibodies against HPV16 and HPV18 in the 2vHPV group were 1.52-fold and 1.62-fold higher, respectively, than those in the Gardasil group, meeting the pre-specified non-inferiority criteria.24 This immunogenicity advantage persisted at the 24-month follow-up, with 2vHPV-induced GMCs remaining approximately 1.10-fold (HPV16) and 1.40-fold (HPV18) higher than those induced by Gardasil.29 In a parallel clinical trial conducted in Fujian Province,30 China, at 1 month post-vaccination, the 2vHPV group demonstrated 1.52-fold and 2.84-fold higher GMTs of antibodies against HPV16 and HPV18, respectively, than the Gardasil group. Both studies strongly support the protective potential of a single-dose 2vHPV regimen. Based on robust clinical evidence, the WHO formally recommended Cecolin for a single-dose schedule in October 2024.31

A retrospective phase III subgroup analysis32 demonstrated that although GMCs of antibodies in the one-dose and two-dose (0/1 -month or 0/6-month schedules) groups were lower than with the three-dose regimen (HPV16, 10.4, 46.0 and 46.9 vs 72.4 IU/mL; HPV18, 5.3, 12.0 and 17.1 vs 35.9 IU/mL), they remained substantially elevated above levels induced by natural infection (HPV16, 2.8 IU/mL; HPV18, 2.3 IU/mL), indicating sustained protective potential for these regimens in adult women.

Safety, efficacy and immunogenicity of the Escherichia coli–produced nonavalent vaccine

As the successor to 2vHPV, Cecolin9 (covering HPV6/11/16/18/31/33/45/52/58, hereinafter referred to as 9vHPV) is China’s first domestically developed nonavalent HPV vaccine, approved by the National Medical Products Administration (NMPA) in May 2025.33 Its safety, immunogenicity and efficacy against additional genotypes were evaluated through phase I–III trials, head-to-head comparisons with 9vHPV (Gardasil9) and adolescent immunobridging studies (table 2). These trials confirmed its optimal dose, consistent safety profile and non-inferiority to existing vaccines, supporting its clinical application.

Table 2

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Key characteristics of clinical studies on Cecolin9

Safety

Despite using the same E. coli expression system as 2vHPV, 9vHPV has still undergone rigorous safety assessments in phase I–III clinical trials, in light of its increased antigen and adjuvant content.

A phase I dose-exploration trial34 showed that both 135 µg and 270 µg (approved dosage) doses were well-tolerated, with local ARs reported in 50.0% and 58.3% of participants, respectively (injection-site pain as the most frequent), and systemic ARs in 33.3% of both groups; no SAEs or clinically significant laboratory abnormalities were observed. A phase II trial35 confirmed that 97.6% of AEs were mild to moderate, and no vaccine-related SAEs were reported. Local reactions were dominated by injection-site pain (59.1% vs 27.7% in the placebo group) and systemic AR incidence comparable between the vaccine and placebo groups (40.9% vs 34.4%); age-stratified analysis showed no significant safety differences across adult subgroups. A large-scale phase III active-controlled trial (vs 2vHPV) reported similar incidences of total AEs (59.6% vs 51.7%) and grade ≥3 events (1.2% vs 1.1%); local injection-site pain was more common in the 9vHPV group (43.0% vs 30.0%) but predominantly mild. Systemic reactions occurred in 22.6% and 20.7% of participants, respectively, with no statistically significant differences, and all SAEs were unrelated to vaccination.

Head-to-head trials36 37 with 9vHPV (Gardasil9) showed comparable overall AE incidence (52.0% vs 54.0%) and AR rates (43.0% vs 47.0%), with mild and self-limiting systemic reactions (mainly fever). SAEs were uncommon (<1.0%) and deemed unrelated to vaccination.

Immunobridging studies in adolescents aged 9–17 years confirmed lower AR incidence (50.2% in the three-dose group, 49.5% in the two-dose group) than in adult women (60.4%), with most reactions being mild and self-limiting.38 No vaccine-related SAEs or pregnancy-associated adverse outcomes were reported, supporting the consistent safety of 9vHPV across age groups.

Efficacy

The protective efficacy against HPV16/18 of 9vHPV is strongly corroborated by non-inferiority analyses from a phase 3 active-controlled clinical trial.39 At month 7 in the immunogenicity per-protocol set, 9vHPV induced comparable HPV16/18 seroconversion rates (100% for HPV16 in both groups, and 99.88% vs 100% for HPV18). Although 9vHPV induced slightly lower GMCs for HPV16 and HPV18 compared with the 2vHPV, GMC ratios were 0.60 for HPV16 (0.56–0.66) and 0.64 for HPV18 (0.58–0.70), both exceeding the pre-specified non-inferiority margin of 0.5. The non-inferior immunogenicity against HPV16/18 serves as a key surrogate marker for the vaccine’s protective efficacy against infections and lesions associated with these core genotypes, supporting the inference that 9vHPV exhibits comparable efficacy to the marketed 2vHPV in preventing HPV16/18-related diseases. Notably, no HPV16/18-related cervical 12-month persistent infections were observed during follow-up for up to 30 months among HPV-DNA- and nAb-negative recipients of either the 9vHPV or 2vHPV, which demonstrates the high efficacy against HPV16/18 of both vaccines and supports their predicted clinical protection.

For other types, in baseline-negative participants followed, 9vHPV also demonstrated high vaccine efficacy against HPV31/33/45/52/58-related 12-month persistent infection (two consecutive positive DNA tests for the same type at least 300 days apart) reached 98.21% (95% CI 89.58 to 99.96). Cervical-specific efficacy against persistent infection reached 100% (84.89% and 100.00%). Although direct protection against CIN2+remains to be confirmed, follow-up for the cervical lesions is ongoing (with the target case number to be reached approximately 78 months post-vaccination), the observed high efficacy against persistent infection with high-risk HPV types in the anogenital sites, particularly at the cervix, is encouraging. Similarly, while clinical genital wart cases are still accumulating, efficacy against 6-month persistent infection of HPV6/11 was 100% (0 vs 15 cases), suggesting promising protection against these persistent infections, though the corresponding clinical wart endpoint is still being accrued.

Immunogenicity

The immune response elicited by the 9vHPV could be influenced by potential antigenic competition and therefore requires evaluation through rigorous clinical trials.

A phase I trial34 identified 270 µg as the optimal dose: at month 7, seroconversion rates for all nine HPV types reached 100% in the 270 µg group (vs incomplete responses in the 135 µg group), with significantly higher antibody titres for key types (HPV16/18/52/58). A phase II trial35 confirmed that nAb seroconversion rates for all nine types were 99.3%–100% in the vaccine group (vs 0.0%–1.1% in placebo), with GMTs ranging from 1553.9 (HPV11) to 18 370.8 (HPV33), all significantly higher than natural infection levels; seroconversion rates exceeded 88.7% after the second dose, supporting potential schedule optimisation. In the phase 3 clinical trial, nAbs for HPV16/18 induced by 9vHPV were non-inferior to those by 2vHPV. Furthermore, consistent with excellent efficacy, 9vHPV also elicited potent humoral immunity against the seven additional types (6/11/31/33/45/52/58), seroconversion rates ranged from 99.66% to 100%, with substantial type-specific GMCs.

Head-to-head trials36 with 9vHPV (Gardasil9) confirmed non-inferiority for all nine types (GMC ratios 0.79–1.65), with five types (6/31/45/52/58) showing higher GMCs in the 9vHPV group; this comparability was sustained for 34 months,37 with seven types (6/16/31/33/45/52/58) maintaining higher antibody levels in 9vHPV recipients. In adolescents aged 9–17 years, both two-dose and three-dose schedules met non-inferiority criteria compared with adult three-dose regimens,38 with seroconversion rates exceeding 98.5% for all types, with key types such as HPV16, 31, 33 and 58 reaching 100%, supporting the NMPA’s approval of the two-dose schedule for females aged 9–17 years.

Application

The widespread adoption of Cecolin serves as a cornerstone for China’s national immunisation programme

Although China approved its first HPV vaccine in 2016, for nearly a decade afterwards, these vaccines remained voluntary, out-of-pocket category II immunisations and were not included in the NIP. The approval and subsequent availability of Cecolin, with its lower cost,40 significantly improved affordability and access, prompting several developed provinces and municipalities in China to launch free regional vaccination programmes for eligible women between 2020 and 2025. Capitalising on the robust immunogenicity of Cecolin’s two-dose schedule in girls aged 9–14 years,22 23 local governments strategically focused vaccination efforts on girls in junior high school (typically ages 13–14 years).41 This approach proved highly effective, achieving coverage rates exceeding 90% in some areas.42 The success of these regional pilots provided critical evidence and a practical model for the subsequent integration of HPV vaccination into NIP.

Furthermore, with WHO-PQ,18 Cecolin is gaining increasing international recognition. Beyond its procurement and use through mechanisms such as Gavi, the VAccine Alliance (GAVI), the vaccine has received regulatory approval in 24 countries and has been incorporated into the NIP of 11 countries, including Thailand and Nepal. As of December 2025, over 80 million doses of Cecolin have been administered worldwide. As the vaccinated cohorts enter the higher-risk age period, the vaccine’s real-world effectiveness in preventing cervical cancer will be progressively validated.

The progressive rollout of Cecolin9 constitutes an important driver for cervical cancer elimination

In China, HPV16/18 account for 70%–75% of cervical cancers, and HPV52/58 constitute two of the three most common genotypes in both squamous cell carcinoma (5.6% and 5.4%, respectively) and adenocarcinoma (7.3% and 4.5%, respectively), which are not covered by bivalent vaccines. Nonavalent vaccines are estimated to offer an incremental 15%–20% reduction in cervical cancer burden over bivalent vaccines. Therefore, the expansion from ‘bivalent to nonavalent’ coverage within China’s NIP represents a strategic evolution, informed by local epidemiological data and enhanced vaccine supply. Cost-effectiveness modelling shows that transitioning to nonavalent vaccines under national centralised procurement (reducing price barriers) is cost-saving, with mixed strategies saving $13.36 billion and gaining 87 000 quality-adjusted life years.43 The approval of Cecolin9 further ensures supply sustainability.

A health economic model projects that vaccinating >95% of girls aged 9–14 years in China with the bivalent HPV vaccine would lead to a rapid decline in cervical cancer incidence within years, potentially enabling elimination (incidence <4 per 100 000) by the 2070s when combined with screening.44 However, upgrading to the nonavalent vaccine starting in 2030 would accelerate this decline, potentially advancing the elimination timeline to 2047.45 This shift would substantially boost global efforts to reduce the cervical cancer burden. With sufficient resources and high nonavalent vaccine coverage among adolescent girls worldwide, the monumental goal of eliminating cervical cancer within this century could be within reach.46

Discussion

Chinese researchers have achieved pivotal breakthroughs by overcoming the core challenges of soluble expression and in vitro self-assembly of HPV L1 protein into VLPs using the E. coli platform.14 This prokaryotic system offers decisive advantages, shorter production cycles, lower costs and superior scalability over traditional eukaryotic systems. Building on this foundation, a next-generation candidate vaccine, based on chimeric VLP technology and targeting over 20 medium-risk to high-risk HPV types, is currently in development.47–49 This progress promises to provide a wider array of effective options for future global immunisation strategies against cervical cancer.

Tailored to epidemiological needs, China’s domestic HPV vaccines, from the WHO-PQ, cost-effective Cecolin to the broader-spectrum Cecolin9, have built a strong evidence foundation. This supports a dual-track national strategy: using bivalent vaccines to achieve wide coverage through the NIP while offering nonavalent vaccines as an enhanced option for expanded protection, thereby optimising both public health impact and individual choice. Globally, China’s E. coli–based HPV vaccines are advancing cervical cancer elimination worldwide, particularly in LMICs. Their low cost and scalable production directly address key access barriers in high-burden regions. China’s successful integration of a domestic bivalent vaccine into its national programme also provides a practical model to support the WHO’s target of 90% HPV vaccination coverage.

Although the burden of HPV-related diseases is far higher in females, the impact on males, including anal cancer, penile cancer and genital warts, remains non-negligible.50 Previous clinical trials have demonstrated that quadrivalent HPV vaccines were safe, immunogenic and efficacious in males, effectively preventing HPV infection and associated lesions in the anal, penile and oropharyngeal regions while conferring herd protection.51–53 For Cecolin9, the NCT03813940 and NCT05056402 studies in males aged 9–45 years have preliminarily demonstrated robust type-specific nAb responses. The vaccine exhibits a safety profile consistent with that observed in female populations.34 38 However, the efficacy of this vaccine in males remains to be established and warrants validation through long-term follow-up studies. To this end, a large-scale, randomised, controlled phase 3 trial was initiated in China in 2025 (NCT06866574). Enhancing public awareness of male vaccination, conducting health economic evaluations and optimising vaccination strategies remain key challenges to be addressed.

Despite significant progress in HPV vaccine development and equitable resource allocation in China, major challenges in implementation persist. Widespread vaccine hesitancy, for instance, continues to severely hinder coverage rates, underscoring the urgent need for enhanced public education and implementing science.54 Furthermore, the safety and efficacy of HPV vaccination in specific populations who may require additional protection or derive increased benefit, such as pregnant women and individuals with immunocompromised status, still require further validation through targeted clinical trials. The eligible populations and indications for HPV vaccines should also be expanded. Emerging evidence from oral disease cohorts suggests that broader-valency HPV vaccines may offer greater potential protection in certain oral HPV-related settings,55 although the current evidence remains exploratory.56

Conclusion

China has established a robust HPV vaccine ecosystem centred on a cost-effective E. coli platform, enabling large-scale production with its domestically developed bivalent and nonavalent vaccines. These vaccines address national prevention needs and offer a replicable model for resource-limited countries. With an advancing pipeline and a focus on equitable access, China is poised to play a leading role in the global effort to eliminate cervical cancer.

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Human papillomavirus vaccines developed by Escherichia coli expression system: progress and perspectives from China

...

Abstract

Introduction

Figure 1

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Escherichia coli expression system

Safety, efficacy and immunogenicity of the Escherichia coli–produced bivalent vaccine

Table 1

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Key characteristics of clinical studies on Cecolin

Safety

Efficacy

Immunogenicity

Clinical trial data demonstrate that 2vHPV elicits robust, durable and type-specific immune responses across age groups and schedules.

Safety, efficacy and immunogenicity of the Escherichia coli–produced nonavalent vaccine

Table 2

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Key characteristics of clinical studies on Cecolin9

Safety

Efficacy

Immunogenicity

The immune response elicited by the 9vHPV could be influenced by potential antigenic competition and therefore requires evaluation through rigorous clinical trials.