Application Evaluation of HPV Vaccine

Human papillomavirus (HPV) is a double-stranded DNA virus that is non-enveloped, mucosal, and cutaneous epithelium. It belongs to the genus Pseudomonas, and it is associated with condyloma acuminata, vulgaris, flat warts, ticks, and abalone. Benign lesions such as warm papules are closely related to cervical cancer, anal, vulva, vagina, penis and oropharyngeal malignancies. At present, there are about 170 subtypes of HPV identified, which are classified into low-risk types including HPV6, 11,34,40,42,43,44,81 and high-risk HPV16 according to their pathogenic hazards. 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 73, 82, and the like. High-risk HPV16 and 18 can cause cervical cancer, vaginal cancer, vulvar cancer and male penile cancer, while low-risk types such as HPV6 and HPV11 can cause genital warts. Some HPV subtypes also have recurrent respiratory polyps and laryngeal cancer. Have a close relationship. Although HPV has multiple subtypes, its genetic structure is similar. HPV viral DNA consists of three parts: early gene region (E), late gene region (L), and long control region (LCR). The early gene region encodes early proteins such as E1 and E2, as well as E6 and E7 oncogenes, and the late gene region encodes structural components of the late protein (L1 and L2) viral capsids. Among them, E6 and E7 proteins in the gene region have carcinogenic effects, E6 can regulate the activity of P53 and PDZ domain proteins, and E7 protein acts on pRb and retinoblastoma protein family members, which negatively regulates cell cycle. Abnormal cell proliferation and destruction of DNA damage repair mechanisms lead to abnormal aggregation of damaged DNA in infected cells, which gradually causes canceration. In addition, the cell regulation of the cervix can be out of control through many other mechanisms of action, ultimately leading to malignant lesions. Although there are many gene deletion mutations in the late stage of cervical cancer, E6 and E7 have always played a role in the development of cervical cancer, so they are also the best target for HPV vaccine. At present, immunotherapy for HPV infection such as cervical cancer and malignant lesions caused by it is attracting more and more attention. High-efficiency HPV vaccine and specific immunization methods are used to prevent and treat related diseases, and to prevent and treat HPV infection such as cervical cancer. The disease is very important.

1. Types and action mode of HPV vaccine

In recent years, HPV vaccine research can be divided into two categories, namely, preventive vaccine research and therapeutic vaccine research. Among them, there are many types of therapeutic vaccines, including carrier vaccines, peptide vaccines, protein vaccines, DNA vaccines, and cell vaccines. . However, due to its complicated mechanism, it is still in the experimental stage. There are three HPV vaccines that have been successfully developed and approved by the Food and Drug Administration (FDA), all of which are preventive vaccines, namely the first generation of HPV vaccines: four-valent HPVs launched in June 2006. (6/11/16/18) Vaccine (gardasil) with the second-generation (6/18) vaccine (cervarix) in October 2009 and the second-generation nine-price (listed in February 2015) 18/31/33/45/52/58) Vaccines. Bivalent and gardasils have been listed in the world’s more than 100 countries for many years. These two vaccines have good preventive effects on cervical cancer caused by high-risk HPV16,18. Low-risk HPV6,11 caused by anal genital lesions with good preventive protection. The new listing time of the Gardasil 9 is still short, and the clinical data for evaluating its effect is still insufficient. The HPV gene is composed of two structural proteins, the major capsid protein (L1) and the minor capsid protein (L2). L1 contains the main antigenic epitope that induces neutralizing antibodies, and the L protein capsid is self-assembling, which can form the same virsus like particle (VLP) as the natural recombinant virus. The prophylactic vaccine can pass VLP. Combines with different adjuvants to activate the human immune system, activates CD4+ T cell-mediated humoral immune responses, and produces high-potency protective neutralizing antibodies against HPV capsid proteins L1 and L2, once the same virus invades the body, Specific anti-L1 and L2 neutralizing antibodies can encapsulate the virus and prevent the invasion or reinfection of the HPV virus. Since VLPs contain only viral antigens and do not contain viral DNA, they are not infectious or carcinogenic to those who receive vaccination, and thus have become advantageous conditions for the study of preventive vaccines.

2. The population of HPV vaccine

Applicable population vaccination method HPV vaccine has been approved for worldwide application. The applicable population is women aged 9 to 45 years old and men aged 9 to 26 years old. The main target group is pre-adolescent girls before sexual behavior. The US Food and Drug Administration (FDA) and the Centers for Disease Control (CDC) recommend that men and women between the ages of 11 and 12 be routinely vaccinated and vaccinated as early as 9 years of age. If you are still not vaccinated at the age of 12, you can vaccinate at 13 to 26 years of age. HPV vaccine storage should be refrigerated, the inoculation site is intramuscular injection of deltoid muscle, inoculated into three needles, each 0.5mL injection intramuscular injection, of which, gardasil gardasil and Gardasil 9 (gardasil9) inoculation time For the 0th, 2nd and 6th months. The cervarix vaccination time was 0, 1 and 6 months.

3. Clinical effects evaluation of three HPV vaccine

In the evaluation of the efficacy of HPV vaccine, the World Health Organization (WHO) vaccine regulatory agency will have cervical intraepithelial neoplasia (CIN)/III and adenocarcinoma in situ (AIS) for ethical considerations. As an end point of the clinical study of vaccine efficacy trials, invasive cervical cancer was not set as a clinical endpoint. Most HPV infections are transient infections that the body can remove automatically, but if persisted, it may cause related diseases. Therefore, HPV persistent infection can be used as a vaccine efficacy (VE) assessment endpoint and is supported by many studies.

3.1 Gardasil

In the evaluation of the efficacy of HPV vaccine, the World Health Organization (WHO) vaccine regulatory agency will have cervical intraepithelial neoplasia (CIN)/III and adenocarcinoma in situ (AIS) for ethical considerations. As an end point of the clinical study of vaccine efficacy trials, invasive cervical cancer was not set as a clinical endpoint. Most HPV infections are transient infections that the body can remove automatically, but if persisted, it may cause related diseases. Therefore, HPV persistent infection can be used as a vaccine efficacy (VE) assessment endpoint and is supported by many studies.

The gardasil (gardasil) is the first HPV prophylactic vaccine approved for women aged 9 to 45. It is also recommended for men aged 9 to 26, mainly for the prevention of genital warts caused by HPV6,11 infection. And HPV16, type 18 infection caused by cervical cancer, cervix, vulva, vaginal precancerous lesions, atypical lesions.

3.1.1 Study of women who have not had genital warts and no cervical disease

3.1.2 For women who have previously been infected with HPV

In one study, 18 174 patients aged 16 to 26 years old with serologically positive and PCR-negative women were followed up for 3 to 4 years, and the efficacy of the gardasil was analyzed based on serological and HPV DNA (PCR method) conditions. The results showed that women aged 16 to 26 were 100% effective against HPV6/11/16/18-related CIN and genital disease vaccines, but not for current infections, ie serologically negative and PCR-positive women. Found to have a preventive effect. Another study looked at an average of 4 years of follow-up in women with a history of HPV infection between the ages of 24 and 45. The immunization efficacy of at least one dose of Gardasil was 66.9%. Therefore, the gardasil is considered to be present in adult women with previous HPV infection. benefit. FUTUREI/II Study Group introduced 12,000 women aged 15 to 26 years without HPV in a randomized, double-blind, multicenter phase III clinical trial. The follow-up of 42 months showed that the gardasil gardasil was used to prevent persistent HPV infection, cervical The effective rate of lesions CIN2, CIN3 and cervical carcinoma in situ is 100%, and the effectiveness of preventing the anal external genital warts caused by the corresponding virus is 99.0%. It is effective in preventing vulvar intraepithelial neoplasia level 1 (VINI) and vaginal intraepithelial neoplasia. The level 1 (VAINI) and VINII/III or VAINII/III are 100% effective.

3.2 Cervarix

The cervarixis approved worldwide for use in women aged 9 to 45 years to prevent cervical cancer and cervical precancerous lesions caused by HPV16,18 infection. Cervarix has been approved for use in approximately 100 countries around the world. A phase III study enrolled 18,644 women aged 15 to 25 years to evaluate the effects of HPV cervarixs on the prevention of CINII and III caused by HPV genotypes. Women enrolled in the study were not exposed to HPV 16 or 18 at baseline and had at least 1 dose (normal injections were 3 doses: 0, 1, 6 months). The study, after an average of 14.8 months of follow-up, concluded that the efficacy of the cervarix against CINII-III induced by HPV16 or HPV18 was 90% (95% CI: 53-99). In an extended phase II study, 776 women aged 15 to 25 years of follow-up were followed for 6.4 years. For women who received at least 1 dose and were not exposed to the relevant HPV genotype at baseline, the cervarix The protective effect against CINII-III caused by HPV16 and HPV18 was 100% (95% CI: 51-100). In a study of cervarix for up to 8.4 years, the effectiveness of cervarixs in preventing HPV16/18 transient infection was 95.1%, and the effectiveness of preventing HPV16/18-related 6 and 12 months of persistent infection was For 100%, the effectiveness of preventing HPV16/18-related CINII+ is also as high as 100%. In a phase III clinical trial of cervarix, which included data from 135 centers in 14 countries, after four years of follow-up, a cervarix was injected on HPV 16/18 subjects with previous infections and no current infections. The effectiveness of prevention of HPV16/18-related 6-month persistent infection, CINII+ was 72.3% and 68.8%, respectively, whereas in patients with previous infections and no current HPV16/18 infection, vaccine prevention HPV16/18-related The 6-month persistent infection, the effectiveness of CINII+ was 90.3% and 94.6%, respectively; indicating that the vaccine is more potent against previously infected and currently uninfected subjects.

3.3 Gardasil 9

The Gardasil 9 (gardasil 9) is currently available for women aged 9 to 26 and men aged 9 to 15 to prevent cervical cancer and anus caused by high-risk HPV16, 18, 31, 33, 45, 52 and 58 infections. Genital warts caused by cancer and vulvar, vaginal cancer, and low-risk HPV type 6 and type 11 infections. In a randomized clinical trial conducted in Merck, USA, 14215 women aged 16 to 26 years were enrolled in a randomized controlled trial. Women who received the Gardasil 9 gardasil 9 were used as the experimental group, and women who received the tetravalent vaccine gardasil as the control group. Two groups of women were sampled for 54 months. The results of the trial showed that the incidence of cervical cancer, vulva, and vaginal cancer caused by HPV31, 33, 45, 52, and 58 in the experimental group was an average of 0.1 per 1,000 people per year; the control group was 1.6. The disease, the effectiveness of the Gardasil 9 in preventing the above five HPV-type cancers is as high as 96.7% (95% CI: 80.9-99.8). At the same time, the Gardasil 9 has the same effect as the tetravalent vaccine in blocking the four HPV types shared by the two vaccines. A phase III, double-blind, randomized, clinical trial compared the immunogenicity of gardasil 9 and gar-dasil in 603 girls aged 9 to 15 and found that the serum antibody titers produced by the two vaccines were very close: anti-HPV6 Antibody titers were 1679 mMU/mL and 1565 mMU/m L, anti-HPV11 antibody titers were 1315 mMU/mL and 1417 mMU/mL, and serum anti-HPV16 antibody titers were 6739 mMU /mL and 6887 mMU/mL, respectively. Anti-HPV18 antibody titer They were 1956.6 mMU/mL and 1795 mMU/m L, respectively, and the anti-HPV16 and 18 antibody titers of girls aged 9-12 were higher than those of 13-15 years old. Another clinical study on vaccine immunogenicity divided 3,066 men and women into 9 to 15 year old girls, 9 to 15 year old boys and 16 to 26 year old young women in three experimental groups, at 0, 2 and 6 Three experimental groups were vaccinated with a Gardasil 9 and serum anti-HPV antibodies were monitored on days 1 and 7 of the month. The results showed that the serum antibody was measured at 4 weeks after the third injection, and the number of HPV-type antibodies produced in the three experimental groups was >99%, and the anti-HPV response duration was 2.5 years. The adverse reactions after vaccination mainly occurred at the injection site, and the local adverse reactions of girls and boys aged 9-15 years were less than those of 16-26 years old. The adverse reaction rates of the three were 81.9%, 72.8% and 85.4%, respectively. Because the safety, protection rate, and immunogenicity of the three experimental groups were similar, it was considered that the results of the 16- to 26-year-old women could be bridged to the 9- to 15-year-old group.

4. Safety of HPV vaccine

As of 2015, the number of HPV vaccines worldwide has exceeded 57 million. The common adverse reactions reported were dizziness, headache, syncope, nausea, vomiting, fever, rash, pain at the injection site, local edema and muscle tension. The three HPV vaccines had a brief pain during the inoculation process, except for a few allergic conditions, no other serious adverse reactions, and no serious complications caused by the use of the vaccine, which currently showed good safety. Both gardasil and cervarix conducted extensive studies to assess the safety of prophylactic HPV vaccines prior to approval. The experimental results showed that the most common adverse events in the vaccine group were: adverse reactions at the inoculation site, fever, nausea and dizziness. There were no differences between the vaccine and placebo groups in terms of serious adverse events, new autoimmune and chronic disease rates. The cause of death was not found in the analysis of death cases in clinical trials. Compared with the tetravalent vaccine, subjects with a pentavalent vaccine had a higher incidence of adverse events at the injection site, most commonly pain, swelling, erythema and itching; the incidence of systemic adverse events was similar. Clinical trials have shown that HPV vaccines are safe, but it is still unclear whether the vaccine will be effective for life. At present, the large-scale post-marketing safety monitoring of preventive vaccines is still underway. It is considered that there are certain adverse effects on pregnant women and their fetuses, such as spontaneous abortion, fetal malformation, and fetal death. Therefore, it is not recommended to vaccinate pregnant women. The American College of Obstetricians and Gynecologists and the International Federation of Obstetrics and Gynecology do not recommend testing women for pregnancy before vaccination. However, it is recommended to use contraception during vaccination. If pregnancy is found, follow-up vaccination should be stopped until vaccination is completed after delivery. Lactation during the HPV vaccine is safe for both mother and child.

5. Current problems of HPV vaccine

In the past few years, the progress and application of preventive vaccine research are encouraging, but the following problems exist in the three vaccines themselves and in the promotion process: 1 The vaccine immunization program is lengthy and needs to be carried out in relevant medical institutions within 6 months. Needle injection. 2 vaccine production costs are too high, expensive, are more than 100 US dollars / dose, vaccination three needles need about 300 US dollars or more, so it can only be implemented in economically more developed countries, and the high incidence of cervical cancer in developing countries due to its high price Promotion is limited. The 3HPV vaccine cannot target all types of HPV, and the cross-protection rate is low. At the same time, the HPV preventive vaccine has no therapeutic effect on existing infections, intraepithelial neoplasia, cervical cancer, etc., while the HPV therapeutic vaccine lacks a corresponding large scale. The results of clinical trials still face many challenges, and many problems remain to be solved. 4 Parents and adolescents lack awareness of the likelihood of HPV infection, the risk of infection, and the preventability of infection.

6. Conclusion of HPV vaccine

In summary, the safety and efficacy of the prophylactic HPV vaccine as a new development has been clinically recognized, but because of its limited HPV subtype infection, the duration of immune protection has not been clarified, and Applicable people limit the vaccination before women have sex to achieve maximum effectiveness, these problems make the preventive vaccine still have some limitations. On the other hand, the problems faced in the promotion of vaccines should also actively promote the promotion of vaccines in developing countries by improving vaccination programs, reducing production costs, and increasing vaccine protection rates. Compared with HPV preventive vaccines, HPV therapeutic vaccines have broader clinical application prospects, but the mechanism is more complicated and the corresponding large-scale clinical trial results are still lacking. The research and application still face many problems. Although there are many places that are not perfect enough, the author firmly believes that with the continuous improvement of vaccines, HPV vaccine has a good clinical application prospect and exerts positive influence.