|Year : 2023 | Volume
| Issue : 2 | Page : 62-68
Human papillomavirus vaccine: An update on recent developments and review of real world data on efficacy
Shalini Rajaram, Ipshita Sahoo, Ayush Heda, Lakhwinder Singh
Department of Obstetrics and Gynecology, AIIMS, Rishikesh, Uttarakhand, India
|Date of Submission||30-Jan-2023|
|Date of Acceptance||08-Feb-2023|
|Date of Web Publication||28-Apr-2023|
Prof. Shalini Rajaram
Department of Obstetrics and Gynecology, AIIMS, Virbhadra Road, Shivaji Nagar, Near Barrage, Rishikesh - 249 203, Uttarakhand
Source of Support: None, Conflict of Interest: None
Cervical cancer is the fourth most common cancer in women worldwide and is a significant public health problem. Currently, there are three bivalent human papillomavirus (HPV) vaccines targeting high-risk HPV types (16, 18), two quadrivalent vaccines targeting two high risk HPV types (16,18) and two low risk types (6,11) and one nonavalent vaccine against HPV 16,18, 31, 33, 45, 52, 58, 6 and 11. All are WHO approved vaccines and show excellent seropositivity (>95%) even at 5–10 years' post-vaccination irrespective of dosing schedule. These vaccines are relatively safe with minor local side effects. The WHO recommends two dosage vaccination schedule for girls aged 9–14 years with an off-label recommendation for a single-dose schedule. HPV vaccination has shown efficacy against the reduction of cervical intraepithelial neoplasia, invasive cervical cancer, anogenital warts and vulvovaginal intraepithelial neoplasia in numerous population/registry-based cohort studies worldwide. Countries such as Australia and Sweden where vaccination began as early as 2006–2008 have seen a major reduction in the incidence of cervical cancer in the vaccinated cohorts. Model based projection studies have also indicated significant vaccine efficacy with two doses and single dose in catch-up programmes. In this article, we provide an update on the vaccine recommendations, immunogenicity and efficacy data derived from registry-based cohort studies and trials published mostly in the last 5 years.
Keywords: Immunogenicity, papillomavirus vaccines, vaccine efficacy
|How to cite this article:|
Rajaram S, Sahoo I, Heda A, Singh L. Human papillomavirus vaccine: An update on recent developments and review of real world data on efficacy. Curr Med Res Pract 2023;13:62-8
|How to cite this URL:|
Rajaram S, Sahoo I, Heda A, Singh L. Human papillomavirus vaccine: An update on recent developments and review of real world data on efficacy. Curr Med Res Pract [serial online] 2023 [cited 2023 May 30];13:62-8. Available from: http://www.cmrpjournal.org/text.asp?2023/13/2/62/375231
| Introduction|| |
With approximately 604,000 new cases and 342,000 deaths worldwide in 2020, cervical cancer is the fourth most common cancer in women worldwide and an important public health problem in low- and middle-income countries. Persistent infection by certain oncogenic human papillomavirus (HPV) types has been identified as the essential cause of cancer of the cervix as well as neoplastic lesions of vulva, vagina, anus, penis and oropharynx. The global HPV prevalence (all types) in cervical samples amongst adult women with normal cervical cytology findings is estimated to be 11.7%. HPV types 16 and 18 are the most frequent worldwide, with HPV16 being the most common one in all regions. Other high-risk types, such as 31, 33, 39, 45, 51, 52, 56, 58 and 59 are the next most common high-risk HPV types. Women initially infected with one HPV type may be re-infected with the same type or co-infected or subsequently infected with other types.
HPV infections are initially restricted to the mucosal epithelial lining and do not induce a strong immune response. The median time from infection to seroconversion has been found to be approximately 8–12 months, although it varies by person, HPV type and duration of infection. About 70%–80% of women undergo seroconversion after natural infection; their antibody responses are of low titre and avidity. Whether immunity to natural infection induces protection against reinfection is equivocal. Failure to develop immune response results in the persistence of infection and, in high-risk HPV infection causes an increased probability of progression to cervical intraepithelial neoplasia (CIN) and cancer.
In 2006, the first vaccine for the prevention of HPV-related diseases was licensed. Currently, six prophylactic HPV vaccines are licensed for use. The administration is recommended before the onset of sexual activity i.e., before exposure to HPV. These vaccines are prepared from purified L1 capsid protein as building blocks for HPV-type specific empty shells, called virus-like particles using recombinant DNA and cell-culture technology. HPV vaccines do not contain live biologic products or viral DNA and are non-infectious. HPV vaccines use different expression systems, contain adjuvants and do not contain antibiotics or preservative agents. All HPV vaccines protect against high-risk HPV types 16 and 18; quadrivalent vaccine also protects against HPV types 6 and 11 (causative agents of genital warts); and the nonavalent vaccine also protects against high-risk HPV types 31, 33, 45, 52 and 58, in addition. All HPV vaccines are recommended for use in females aged 9 years or older and licensed for use up to 26 or 45 years of age in different countries. HPV vaccines are available as a prefilled syringe or in single or 2-dose vials. However, it must be remembered that the HPV vaccine is an adolescent vaccine targeted at girls between 9 and 14 years of age in whom immunogenicity is most robust.
The 2020 WHO global strategy to accelerate the elimination of cervical cancer as a public health problem recommends that HPV vaccines should be included in all national immunisation programmes and should reach 90% of all girls by the age of 15 years by 2030. Till the writing of this paper, 125 countries (64%) have introduced the HPV vaccine in their national immunisation programme for girls and 47 countries (24%) vaccinate boys also.
| Primary and Secondary Target Groups|| |
The primary target population for HPV vaccination is girls aged 9–14 years before initiation of sexual activity for the prevention of cervical cancer. Vaccination of secondary target populations, for example, females aged ≥15 years, boys, older males, or men who have sex with men, is recommended only after adequate coverage is ensured for the primary target group.
| Efficacy of Vaccines|| |
Currently, seropositivity, geometric mean titre (GMT) and antibody stability are used to assess immunogenicity. It is crucial to note that the correlation between the HPV vaccine's immunogenicity and its effectiveness is not well defined. There is no minimum established antibody titre threshold for any HPV vaccine to be effective.
In studies comparing 1-, 2- and 3-dose schedules, geometric mean avidity indices in the group given one or two doses were non-inferior to those in the 3-dose group; however, antibody concentration in the single-dose group was inferior.
The efficacy and immunogenicity of 2-, 4- and 9-valent HPV vaccines against high-risk HPV infection have been studied extensively through clinical trials. Surrogate endpoints in HPV vaccine efficacy studies replaced prevention of invasive cancer. These endpoints were anogenital warts, cervical adenocarcinoma in situ (AIS), CIN grade 2 or higher (CIN 2+) and persistent vaccine type-specific HPV infection at 6 months.
Seropositivity at 66 months' post vaccination was 100% (95% confidence interval [CI] 97–100) for HPV16 and 98% (95% CI 94–100) for HPV18 in a trial with a 3-dose schedule of the bivalent (Cecolin) vaccine amongst women aged 18–45 years. At 14 years after vaccination, seropositivity rates for the quadrivalent (Gardasil) vaccine were 98% for HPV6, 98% for HPV11, 100% for HPV16 and 94% for HPV18. Between 5 and 12 years after girls were vaccinated at age 16 or 17, neutralising antibodies against HPV16 and HPV18 were 6- and 12-fold greater, respectively, for the bivalent vaccine than for the quadrivalent. Between 2–4 years and 5–7 years, there was a 45% drop in the median neutralising antibody titres to HPV16 and a 29% decline in the antibody titres to HPV18 in quadrivalent (Gardasil) vaccine recipients while neutralising antibodies against HPV16 and HPV18 were stable in recipients of the bivalent (Cervarix) vaccine for up to 12 years.
The non-inferiority of immune response in comparison to women with established 3-dose efficacy served as the basis for approval of the 2-dose schedule (immunobridging). In studies comparing immunogenicity outcomes, two doses in girls aged 9–14 years were equally effective or resulted in higher GMTs than three-dose schedule in women aged 15–26 years for all nine HPV types measured except HPV45 (non-inferiority inconclusive). There was no significant difference between groups in seroconversion rates at 7 months for all nine HPV types measured. A Cochrane review of trials confirmed that females who had received fewer than three doses were shielded from HPV16/18-related cervical pre-cancer.
Higher efficacy across all HPV vaccine types was found in the HPV-naïve group., A meta-analysis demonstrated that three doses of the bivalent (Cervarix) and quadrivalent (Gardasil) vaccines offered significant protection against HPV16 and HPV18-associated cervical adenocarcinoma in situ among young women (aged 15–26 years); 88% (95%CI 30–98%).
The other oncogenic HPV serotypes are biologically similar to HPV 16 and 18, and it has been proven that both bi- and quadrivalent vaccinations provide cross-protection against other HPV serotypes. It has been demonstrated that the bivalent vaccine, through cross-protection, offers more efficacy against HPV-31, -33 and -45 than the quadrivalent vaccine. In addition, the 9-valent vaccine offers protection against more oncogenic HPV serotypes. Some cross-protective efficacy against infection with types 31, 33 and 45 has been observed amongst recipients of the Cecolin vaccine but was not statistically significant. The nonavalent vaccine showed the efficacy of 97% and 81% against high-grade disease in HPV-naïve women and the general population, respectively, and 95% efficacy for preventing persistent infection with the five additional high-risk HPV serotypes., In a systematic review of randomised controlled trials (RCTs) involving 13,753 females in the age group 16–26 years, there was little to no difference in efficacy against outcomes caused by the types contained in the respective vaccines between quadrivalent (Gardasil) and nonavalent (Gardasil-9) HPV vaccines (odds ratio 1.00, 95% CI 0.85–1.16).
High efficacy against high-grade cervical, vulvar and vaginal lesions was demonstrated in studies involving HPV naive vaccine recipients: 98% (95% CI 93–100) for CIN2+ and 100% (95% CI 83–100) for vulvar and vaginal intraepithelial neoplasia grade 2+ caused by the HPV types in the quadrivalent vaccine. A recent review confirmed an efficacy of over 90% against vulvar and vaginal lesions.
Data from immunogenicity trials, post hoc analyses of efficacy trials, and post-licensure observational studies in females have shown that a single dose of HPV vaccine is adequate to elicit an immune response that offers comparable protection against initial and persistent HPV infection to a multi-dose regimen. These findings include the outcomes of a high-quality RCT in which 2250 sexually active girls between the ages of 15 and 20 were randomly assigned to receive either the bivalent (Cervarix) or nonavalent (Gardasil-9) vaccination or to a control group. At 18 months after vaccination, the nonavalent vaccine and the bivalent vaccine both had single-dose effectiveness against incident persistent high-risk (HPV16/18) infection of 97.5% (95% CI 82–100). Nine hundred and thirty girls between the ages of 9 and 14 years were randomly assigned to receive 1, 2 or 3 doses of the bivalent (Cervarix) or nonavalent (Gardasil-9) vaccination in a randomised open-label trial (dose reduction immunobridging and safety). Over 97.5% of subjects in all dosage groups for both vaccines were seropositive 24 months after immunisation. Immunobridging showed that a single dose of HPV16/18 produced non inferior antibody responses to those in studies where single-dose efficacy was observed. Systematic reviews have shown seropositivity amongst subjects who received one dose to be non-inferior to that after two or more doses.
In a systematic review and meta-analysis of HPV vaccine outcomes amongst people living with HIV, a high proportion seroconverted for the HPV vaccine types; the proportions seropositive 28 weeks after receiving three doses of bivalent (Cervarix), quadrivalent (Gardasil) or nonavalent (Gardasil-9) vaccine were 99% (95% CI 95–100), 99% (98–100) and 100% (99–100) for HPV16 and 99% (96–100), 94% (91–96) and 100% (99–100) for HPV18, respectively. Despite some reductions in antibody titres and decreased seropositivity after 2 to 4 years, seropositivity remained high in individuals with three doses.
| Types of Vaccines and Administration|| |
The vaccines should be administered intramuscularly preferably in the deltoid region of the upper arm. The standard dose is 0.5 ml. The vaccination schedule, as stipulated by the manufacturers, mostly depends on the age of the recipient. Listed below is information based on the product labels:
- Cervarix is licensed for girls and boys aged 9–14 years on as 2-dose schedule (5–13 months apart). From age 15, three doses should be given (at 0, 1–2.5 months and 5–12 months)
- Cecolin is licensed for girls aged 9–14 years as 2-dose schedule (6 months apart). From age 15, three-dose schedule is indicated (at 0, 1–2 months and 5–8 months)
- Walrinvax is licensed for girls aged 9–14 years as 2-dose schedule (6 months apart, with a minimum interval of 5 months). From age 15, three-dose schedule is indicated (at 0, 2–3 and 6–7 months).
Quadrivalent HPV vaccines
- Gardasil is licensed for girls and boys aged 9–13 years as 2-dose schedule (6 months apart). From age 14, three-dose schedule should be given (at 0, 1–2 and 4–6 months)
- Cervavax is licensed for girls and boys aged 9–14 years, as 2-dose schedule (6 months apart). From age 15, three-dose schedule should be given (at 0, 2 and 6 months).
Nonavalent HPV vaccine
- Gardasil 9 is licensed for girls and boys aged 9–14 years as a 2-dose schedule (5–13 months apart). From the age of 15 years, three-dose schedule should be followed (at 0, 1–2 and 4–6 months).
| Vaccine Safety and Adverse Effects|| |
HPV vaccines are considered highly safe. Overall, 39%–87% of recipients of the bivalent or quadrivalent HPV vaccine reported local side effects. Injection site reactions in males and females of all ages receiving the HPV vaccine included pain (35%–88%), redness (5%–40%) and swelling (4%–35%). About 6% of vaccination recipients reported experiencing severe pain. Compared to quadrivalent (Gardasil), the bivalent (Cervarix) vaccine may cause higher adverse reactions at the injection site (risk ratio [RR] 1.26, 95% CI 1.19–1.33). In comparison to the quadrivalent (Gardasil) vaccine, subjects who received the nonavalent (Gardasil-9) vaccine were marginally more likely to experience pain and swelling (RR 1.06–1.39).
Mild systemic adverse reactions such as headache, myalgia, dizziness, arthralgia and gastrointestinal symptoms (nausea, vomiting and abdominal pain) are sometimes seen post-vaccination. Bivalent (Cervarix, Cecolin) and quadrivalent (Gardasil) vaccine users had systemic reactions at rates of 69%, 49% and 55%, respectively. There is minimal to no difference between nonavalent (Gardasil-9) and quadrivalent (Gardasil) vaccines in terms of overall systemic adverse effects. Systemic reactions observed during post-marketing surveillance were typically described as minor and self-limiting.
Since 2007, new safety data on HPV vaccines has been reviewed periodically by Global Advisory Committee on Vaccine Safety (GACVS, established by the World Health Organization). No significantly increased risk of autoimmune conditions, Guillain–Barre syndrome or thromboembolic adverse events (AEs) was found by GACVS. In addition, no causative association was found between the HPV vaccine and AEs like complex regional pain syndrome and postural orthostatic tachycardia syndrome. A systematic review of studies on the safety of HPV vaccines found little to no difference amongst recipients of bivalent (Cervarix and Cecolin), quadrivalent (Gardasil) and nonavalent (Gardasil-9) vaccines concerning serious AEs or new-onset chronic disease, including new-onset autoimmune disease.
Dizziness and syncope are a rare AE, however, after any vaccination, syncope is commonly reported in adolescents; observation for 15 min after administration is recommended. Severe anaphylaxis is extremely rare (0.3–3 per million). However, the vaccine is absolutely contraindicated in individuals with anaphylaxis to a known vaccine ingredient. Hence, nonavalent HPV (expressed in Saccharomyces cerevisiae) is contraindicated in individuals with known hypersensitivity reactions to yeast. Hypersensitivity to nonavalent or quadrivalent vaccine is a contraindication for further doses.
HPV vaccination is not recommended in pregnancy and a routine pregnancy testing is not a pre-requisite. Spontaneous abortions or adverse birth outcomes are not associated with inadvertent exposure to the HPV vaccine during pregnancy. Non-immunised breastfeeding women can get vaccinated and the vaccine is found to be safe. No association has been found between vaccination and primary ovarian insufficiency or increased infertility.
HPV vaccines in a 3-dose schedule in HIV-infected females and children (aged 7–12 years) are found to be safe, with few serious AEs.
Additional efforts are still needed to modify the components like adjuvants, to mitigate the AEs, without affecting the efficacy of the vaccine.
2020 WHO Global Strategy to 'Accelerate the Elimination of Cervical Cancer' as a Public Health Problem recommends that HPV vaccines should be included in all national immunisation programmes and should reach 90% of all girls by age 15 by 2030. The WHO recommends that girls aged 9–14 years are the primary target population for HPV vaccination. Secondary target populations include females ≥15 years of age, boys and older males, their vaccination is recommended only if this is feasible and affordable. Immunocompromised women and men, including those living with HIV, and children and adolescents who have faced sexual abuse should constitute the priority group in the public health programme.
The choice of HPV vaccine is based on an assessment of locally relevant data and the magnitude of the HPV-associated public health problem.
The WHO recommends 2-dose schedule to be used in the primary target group from 9 years of age and for all older age groups. The minimum interval between the first and second dose should be 6 months. There is no maximum recommended interval between doses. A single-dose schedule can be used in girls and boys aged 9–20 years (WHO off-label option). In immunocompromised or HIV-infected individuals (regardless of age or antiretroviral therapy status), at least two HPV vaccine doses (minimum 6 months interval) and three, where possible is indicated. If the type of vaccine used previously is unknown, any HPV vaccine can be used to complete the recommended schedule.
| Real-World Data on Long-Term Impact of Human Papillomavirus Vaccination|| |
Initial trials before licensure of HPV vaccines were RCTs mostly in women between 15 and 26 years of age, evaluating the reduction in rates of CIN in the vaccinated population and the immunogenicity of the vaccine. These trials had a short follow-up of <5 years and consequently analysis of long-term outcomes was studied in detail in the last decade. Due to the long natural history of the disease, investigating invasive cervical cancer incidence as an outcome is a major challenge in both RCT and real-world settings.
A meta-analysis was conducted by Drolet et al., included 65 studies on the impact of HPV vaccination in 14 high-income countries. Following 5–8 years of vaccination, amongst girls aged 13–19 years, there was a significant decrease in the prevalence of HPV16/18 (83%), other HPV types 31, 33, 45 (54%), anogenital warts (67%) and CIN 2+ (51%).
Three dose quadrivalent (4 vHPV) vaccine has been incorporated in the Australian national immunisation programme since 2007; implemented in girls initially, it was extended to the young male population in 2013 and the programme was upgraded to include two-dose Gardasil 9 (9 vHPV) in 2018. This led to a massive decrease in the prevalence of four HPV vaccine types from 28% to 2.3% in women aged 18–24 and from 18% to 7% in men by the end of 2015. Also the incidence of high-grade cervical abnormalities in women aged <26 years decreased, with the greatest effect being on women younger than 20 years i.e., 5 per 1000 women by 2014 which was less than half the rate in 2007. Furthermore, there was a substantial decrease in the rates of genital warts and there was a noticeable herd effect of the female vaccination programme in young unvaccinated heterosexual males.
Denmark has implemented HPV vaccination in their national schedule since 2009 and has recently included Gardasil. In a large study of women aged 17–30 years in Denmark, 867,689 women were followed for 12 years and the incidence rates of cervical cancer were noted amongst vaccinated and unvaccinated women.
The crude incidence was 11.3 per 100,000 women in the unvaccinated and 6.7 per 100,000 in the vaccinated cohort. The greatest benefit in incidence rate was observed for the cohort vaccinated at <16 years and the cervical cancer incidence rate ratio remained as low as 0.01% in this population. In the cohort vaccinated between 20 and 30 years, the incidence rose sharply after 23 years and the rates were similar to the unvaccinated cohort. HPV vaccination reduced the incidence of cervical cancer by 86% and 68% amongst girls vaccinated at ages <16 years or 17–19 years, respectively.
In another study, the effectiveness of quadrivalent HPV vaccine against high-grade cervical lesions was evaluated in the Danish female population. The incidence of CIN2+ lesions decreased by 66% (1 dose), 51% (2 dose) and 57% (3 doses) respectively. The decrease was 62% for CIN3+ lesions across all age groups irrespective of 1 or 2 doses although for cohort vaccinated <23 years, the protective effect was more pronounced. In addition to this, recent Danish studies have shown evidence of the significant real-world effectiveness of HPV vaccine against vulvovaginal high-grade lesions and genital warts.,
In Sweden, HPV vaccination received approval in 2006 and since then, the quadrivalent HPV vaccine has been used almost exclusively. In a recent Swedish registry study evaluating the impact of HPV vaccination on the incidence rate of cervical cancer, 1,672,983 females who were within 10–30 years of age from 2006 to 2017 were evaluated. The incidence rate of cervical cancer decreased by 88% in women vaccinated at <17 years of age and by 53% in those vaccinated between 17 and 30 years of age; the cumulative incidence rate was 4/100,000 women by age 28 years, in the cohort vaccinated before 17 years. Due to the relatively small number of cases of cervical cancer seen within the vaccinated cohort (47 per 100,000 women), the authors were not able to accurately comment on the association between vaccination and the risk of cervical cancer on the basis of the number of doses of vaccine.
In India, which is one of the main LMICs contributing to the global cervical cancer burden, cervical cancer is the second most common cancer in women after breast, with 123,907 incident cases and 77,348 cases of mortality in the year 2020. HPV vaccine is yet to be incorporated into the national health programme in India. Serum Institute of India has recently developed and tested an indigenous quadrivalent vaccine Cervavac, which will be affordable and likely to be included as a two-dose schedule in the national immunisation programme in the coming years. At present, cost issues have played a major role in limiting the outreach of the available vaccines. In an evidence-based impact projection study, HPV transmission model (EpiMetHeos) was adapted to current Indian data on sexual behaviour, HPV prevalence and cervical cancer incidence. Assuming a 90% vaccination coverage in girls aged 10 years, HPV vaccination could effectively reduce the prevalence of HPV16/18 infection by 97% in 50 years with the age-standardised incidence rate falling below the threshold for the elimination of 4 per 100,000 women years. This study also concluded that in girls aged 11–20 years, single-dose vaccination along with catch-up was more protective than two-dose vaccination without any catch-up, resulting in a decrease of 39%–65% versus 38% in lifetime risk of cervical cancer.
| Future Perspectives|| |
In 2020, the WHO adopted an action call for the elimination of cervical cancer as a public health problem by 2030. The aim is to achieve is ≤4 cases per 100 000 women-years. Three goals have been set for the same: 90% vaccine coverage in target population, 70% women undergoing twice lifetime cervical cancer screening and 90 % women detected with CIN/ cervical cancer undergoing treatment.
To achieve this, the implementation of HPV vaccines to reach all economic strata, especially in LMICs is of utmost importance. Furthermore, questions regarding reduced dosage schedules, addressing coverage issues, effectiveness in immunocompromised/HIV population and role of vaccination for the prevention of disease recurrence need addressed. It boils down to a matter of meeting the demands with adequate supply and effective immunisation and screening programmes to ensure a vaccinated and cancer cervix free cohort in the near future.
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Conflicts of interest
There are no conflicts of interest.
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