In recent years, the topic of "HPV vaccine" has maintained a high level of attention, with netizens complaining about the difficulty of obtaining a vaccine.

Cervical cancer ranks fourth among the global incidence rates of malignant tumors among women, and human papillomavirus (HPV) infection accounts for 90% of cervical cancer cases. Preventive HPV vaccination has become an effective means of preventing cervical cancer.

HPV is a non-enveloped circular double-stranded deoxyribonucleic acid (DNA) virus. The core of the virus is the viral genome, which consists of an upstream regulatory region (NCR region), an early transcription region (E region), and a late transcription region (L region). The E region is divided into E1 to E7 open reading frames, mainly encoding proteins related to viral replication, transcription, regulation, and cell transformation. The L region is divided into L1 and L2, encoding the major capsid protein and minor capsid protein, respectively. The L region is where the virus-type-specific neutralizing antibody-dependent epitopes are located. The expressed L1 protein can assemble into virus-like particles (VLPs), which can induce high-titer neutralizing antibodies in humans. Therefore, it can be used as a target antigen for preventive HPV vaccines and is also the main component of preventive HPV vaccines. Currently, 206 types of HPV have been identified, which are divided into high-risk and low-risk types based on their pathogenic characteristics. Subtypes that are clearly related to malignant tumors are high-risk types, including HPV16/18/31/33/35/39/45/51/52/56/58/59/68. Cervical cancer caused by high-risk HPV infections accounts for 90%, with 16 and 18 subtypes accounting for 70%. Among them, HPV16 is most closely related to cervical squamous cell carcinoma, while HPV18 is most likely to cause cervical adenocarcinoma. Subtypes that cause benign lesions are low-risk types, including 6/11/40/41/42/43/44/54/61/72/81. Low-risk HPV can cause genital warts, and HPV6/11 account for over 90% of the attributable risk of condyloma acuminata.

HPV Carcinogenic Mechanism

Integration of high-risk HPV DNA with host genes is a critical factor in the development of cervical cancer. HPV DNA integration can be detected in 90% of cervical cancer tissues, with a higher integration rate observed in HPV16/18/45 among high-risk HPV types. The integration sites are randomly distributed in the host cell genome, often occurring in fragile sites prone to mutation on host cell chromosomes. After integration, the E6, E7 genes, and their upstream transcriptional regulatory sequences are often retained, while the E1 and E2 regions are often deleted. In the absence of E2 protein to inhibit the promoters of E6 and E7 genes, this leads to the continuous high expression of E6 and E7 proteins in epithelial cells, promoting carcinogenesis through multiple mechanisms. ① E6 protein can directly bind to PDZ proteins or degrade them through the ubiquitin enzyme pathway, disrupting intercellular signaling; ② It can increase telomerase activity by binding to telomerase reverse transcriptase (hTERT) protein, affecting chromosomal stability in cells; ③ It can affect various cellular processes by regulating microRNAs (miRNAs). E7 protein can directly affect cell cycle regulation by binding to pRb protein and the transcription factor AP-1 family. Persistent HPV infection can cause loss of MHC I expression in tumor cells, reducing the antigen-presenting ability of antigen-presenting cells and inhibiting the production and expression of interferons and cytokines, leading to immune escape and further promoting carcinogenesis.

HPV Preventive Vaccine's Mechanism of Action

HPV vaccines are divided into preventive HPV vaccines and therapeutic HPV vaccines. The principle of preventive vaccines is to utilize L1 and L2 proteins to induce the production of virus-like particles (VLPs) that target specific antibodies. These VLPs are assembled on different vector systems such as yeast, baculovirus, and E. coli, inducing the production of specific antibodies and memory B cells in the body, thus protecting the body from HPV infection. Preventive vaccines express type-specific VLPs through recombinant DNA technology, activating the human immune system to produce virus-neutralizing antibodies and memory effects, thereby preventing HPV infection.VLPs are envelope-free DNA virus particles with three key characteristics that make them highly immunogenic: they have neutralizing antigenic determinants on their surface, they may prevent the activation of immature dendritic cells in the body, and they can be quickly recognized by immune cells. VLPs can induce the production of high-titer anti-L1 antibodies IgG, IgA, and specific cytotoxic T lymphocyte (CTL) responses, providing protective effects to the body. Additionally, HPV VLPs can induce an antibody memory response in the body. After vaccination, the antibody response reaches its peak as expected, and the antibody concentration decreases after 12 to 18 months, then remains at an effective stable level.

Currently, HPV subtype vaccines composed of L1 proteins with adjuvants have received marketing approval. 2-valent, 4-valent, and 9-valent vaccines are all capable of inducing high-titer neutralizing antibodies, which are highly effective in preventing persistent HPV-related infections and cervical lesions. However, they are limited by the number of vaccine subtypes. The complexity of producing multivalent L1-VLP vaccines restricts the number of VLP types and the breadth of vaccine protection. Additionally, the high variability of L1 peptides limits their ability to induce cross-immunity, as L1-VLPs can only effectively inhibit some high-risk HPV types and cannot prevent infections from other HPV subtypes.

In contrast, the smaller capsid protein L2 contains common antigenic epitopes and can induce lower-titer but broader cross-neutralizing antibodies against HPV subtypes in animal models, providing cross-protection. Enhancing the immunogenicity of L2 peptides and developing broad-spectrum HPV L2 peptide vaccines are new approaches in the research of HPV preventive vaccines.

Approval and Launch of HPV Preventive Vaccines in China

In September 2006, Europe's first licensed HPV vaccine was Gardasil, a quadrivalent vaccine targeting HPV types 6, 11, 16, and 18. This was followed by the approval of Cervarix, a bivalent HPV vaccine targeting HPV types 16 and 18, in September 2007. The Gardasil 9, a nonavalent HPV vaccine, received approval in June 2014, providing additional protection against five more HPV types (31, 33, 45, 52, 58) compared to its predecessor.

The China Food and Drug Administration (CFDA) approved the bivalent Cervarix vaccine in July 2016, the quadrivalent Gardasil vaccine in May 2017, and the nonavalent vaccine in April 2018 for formal or conditional launch in China. The first domestically produced bivalent HPV vaccine, from Wantai Biological, was approved in late December 2019 and officially launched for sale in May 2020. In March 2022, the second domestically produced HPV vaccine, a bivalent HPV vaccine from Walvax Biotechnology, was officially approved, becoming the second domestic bivalent HPV vaccine. Since then, the number of approved HPV vaccines in China has increased to five. Details are provided in the table below.

Vaccine Safety Research

Since VLPs (Virus-Like Particles) do not contain an infectious genome and cannot infect or cause HPV-related diseases, the commonly available HPV vaccines on the market have demonstrated strong safety and effectiveness. Research has confirmed that adverse reactions after HPV vaccination are generally not severe and short-lived, with local mild reactions at the injection site being the most common, such as pain, swelling, erythema, and itching. Over 90% of local adverse reactions are mild to moderate. The most common systemic adverse reactions (occurring in 2% of cases) are headache, fever, nausea, dizziness, and fatigue. The nonavalent HPV vaccine is more likely to cause local adverse reactions, including severe ones, compared to the quadrivalent HPV vaccine. However, the incidence of systemic adverse reactions is similar in both vaccine groups, at 55.8% and 54.9% respectively. Young women in China have shown good tolerability to the quadrivalent HPV vaccine, with 61.8% of the quadrivalent HPV group and 57.1% of the placebo group reporting local adverse reactions, and the occurrence of systemic adverse reactions was not related to vaccine injection.

HPV vaccines can be used for individuals with impaired immune function and/or HIV-infected individuals. However, data on the safety of HPV vaccination during pregnancy is limited, and thus pregnant women should avoid receiving the HPV vaccine. If a young woman becomes pregnant after starting the vaccination series, the remaining doses should be postponed until after the pregnancy is completed. If the vaccine is accidentally administered during pregnancy, there is no need to terminate the pregnancy.

Severe autoimmune adverse reactions such as gastroenteritis, rheumatoid arthritis, thrombocytopenia, systemic lupus erythematosus, vasculitis, alopecia, central nervous system demyelination, ovarian damage, or irritable bowel syndrome have been associated with the vaccine, and these often occur within 3 to 37 days after injection. However, some research has shown that there is no evidence to support a link between the administration of the quadrivalent HPV vaccine and autoimmune, neurological, or venous thromboembolic adverse events. While an association between three autoimmune events was initially observed, further evaluation found these associations to be weak and unrelated to the duration of vaccine exposure. This issue still requires further study.

The research and development technology for preventive HPV vaccines has become increasingly mature, and the effectiveness and safety of the three preventive HPV vaccines currently available on the market have been proven. Increasing vaccine coverage can further enhance the efficacy of the vaccines, and the resulting herd effect will further reduce the incidence of HPV-related diseases, significantly reducing the burden of disease in various countries. With the launch of China's first HPV vaccine, universal vaccination against HPV will gradually be achieved, significantly reducing the occurrence of HPV-related diseases in China. Currently, universal vaccination is still a challenge in many developing countries. It is hoped that future research can utilize more economical manufacturing systems to lower vaccine costs, develop vaccines that combine prevention and treatment, make vaccination more convenient, and achieve universal vaccination, benefiting more people and greatly reducing the incidence of diseases.

References

[1] Zhao Yang, Huang Xiaojie, Liu Cuie. Clinical research progress of prophylactic HPV vaccine [J]. Chinese Journal of AIDS & STD, 2020, 26(08): 911-915. DOI: 10.13419/j.cnki.aids.2020.08.33.

[2] Jin Bixia, Kong Weimin. Progress in clinical application of prophylactic human papillomavirus vaccine [J]. Chinese Journal for Clinicians, 2019, 47(02): 148-151.

[3] Zhang Xinrui, Li Xiaodong. Application and progress of HPV prophylactic vaccine [J]. Dermatology Bulletin, 2020, 37(04): 364-368+4.

[4] Ding Lianchun, Luo Min, Hu Qian, Chen Junling. Research progress on the safety of HPV vaccine [J]. Kangyi, 2022, (Issue 20).

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.