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The clinical impact of HPV vaccination and guidelines for its use.
Human papillomavirus (HPV) infection is associated with virtually all cervical cancers, as well as with more than 90% of anal cancers, 65% of vulvar and vaginal cancers, 35% of penile cancers, and 70% of head and neck cancers. It is also the causative agent of benign genital warts.1-6 HPV is the most common sexually transmitted infection, with a worldwide point prevalence of 11.7%,7 and an estimated lifetime prevalence of 80%–90% in both women and men by age 45.8 Approximately 14.1 million incident HPV infections occur in the United States each year.9
In the past decade, the prevention of HPV-related disease became a public health priority. In 2006, a quadrivalent vaccine (Gardasil) became the first commercially available HPV vaccine, targeting high-risk HPV serotypes 16 and 18, which alone account for 70% of cervical cancers,10 as well as low-risk serotypes 6 and 11, which are predominantly responsible for genital warts. A bivalent vaccine (Cervarix) was released in 2007 in Europe and in 2009 in the United States, and targets high-risk types 16 and 18. More recently, Gardasil 9 was licensed for use by the Food and Drug Administration (FDA) in December 2014. This newest vaccine targets the 7 most common cancer-causing subtypes (16, 18, 31, 33, 45, 52, and 58), which account for more than 90% of HPV-related cancers,11 as well as subtypes 6 and 11. It is hoped that widespread use of these vaccines will significantly reduce the number of women and men who develop HPV-related disease.
More than 40 of the 100+ distinct types of HPV are known to infect the genital and oral mucosa. Infections with low-risk types like 6 and 11 can cause low-grade cervical cell changes, genital warts, and recurrent respiratory papillomatosis. Fifteen known high-risk HPV types-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82-are classified as carcinogens implicated in development of many cancers.12
HPV has a high infectivity rate, with an estimated 40%–60% probability of transmission per coital act.13 The virus is introduced into the body through microabrasions on mucosal surfaces and infects the basal layer of the epithelium. After infection, epithelial cells that are normally non-dividing remain in an active cell cycle. This can result in a thickened, sometimes exophytic, epithelial lesion. The virus is released as cells exfoliate from the epithelium. In precancerous lesions, the viral DNA is integrated into the human genome. Because of integration, the E6 and E7 genes are constitutively expressed in HPV-positive cervical cancer; these oncogenes can manipulate cell cycle regulators, induce chromosomal abnormalities, and block apoptosis.14
Most HPV infections, whether with low- or high-risk subtypes, are cleared by the body's immune system. For cervical HPV, the median duration of infection is 8 months;15 70% of infections are cleared by 1 year and up to 90% are cleared in 2 years. Continuing infection progresses slowly through dysplastic phases over the course of several years, with up to 15% of high-grade squamous intraepithelial lesions progressing to invasive cervical cancer in 5 to 10 years (range 1–20 years). 16
The immunogenic particle of the current prophylactic HPV vaccines is a DNA-free virus-like particle (VLP). The HPV VLP does not contain viral DNA and is thus noninfectious.
The L1 VLP has been shown to be highly immunogenic.17 However, because the L1 protein is type-specific, effective vaccines must be polyvalent, combining multiple VLPs from different HPV types.18 VLPs have now been developed for types 6, 11, 16, 18, 31, 33, 45, 52, and 58, thus accounting for the nonavalent vaccine (Figure).11
Quadrivalent vaccine (Gardasil, Silgard)
Four randomized, double-blind, placebo-controlled trials evaluated the efficacy of the quadrivalent HPV vaccine in young women aged 16 to 26. A combined analysis of these trials, which included more 20,000 women, formed the basis for FDA approval of the quadrivalent vaccine. Women were followed for a mean of 3 years after vaccination. In a per-protocol analysis of women negative for HPV16 or HPV18 infection during the vaccination who received all 3 doses (n=17,129), vaccine efficacy was 99% (95% CI, 93–100) for the primary composite endpoint of CIN2+ lesions.19
Moreover, efficacy against high-grade vulvar and vaginal intraepithelial neoplasia related to HPV 16 and 18 was 100% in the per-protocol population, and 71% in the intent-to-treat population in pooled analyses of these trials.20 In the per-protocol populations, the vaccine was 99% effective against HPV 6- and 11-related genital warts, whereas in the intent-to-treat analysis, the efficacy against all-type warts was 82%.21
Long-term follow up of a subset of women in these trials is ongoing in Scandinavia. Available data thus far suggest that the majority of subjects (94% for HPV6, 95.5% for HPV11, 99.1% for HPV16, and 60% for HPV18) remain seropositive 9 years post-vaccination. Antibody titers remain at 70%–93% of their month 48 value 9 years out.22
Bivalent vaccine (Cervarix)
A second, bivalent vaccine was developed with the primary focus of mounting robust immune responses toward the 2 viruses most commonly implicated in cervical cancer, HPV16 and 18. This bivalent vaccine uses a novel aluminum salt (AS04) adjuvant, which is responsible for eliciting a strong immunologic response. In a direct comparison of the bivalent and quadrivalent vaccines, higher immunoglobulin levels were demonstrated after vaccination with the bivalent vaccine, although whether that correlates with clinical endpoints is unknown.23
The bivalent HPV vaccine has demonstrated a per-protocol efficacy against CIN 2+ lesions related to HPV 16/18 of 92.9% in a large randomized controlled trial (RCT) of women followed for up to 3 years post-vaccination.24 In a long-term follow-up study of a subset of enrolled women, vaccine efficacy persisted up to 9.4 years after the first dose, with no persistent infections or cervical lesions recorded (n=437).25
Nonavalent vaccine (Gardasil 9)
In Phase II trials comparing the nonavalent HPV VLP vaccine to the quadrivalent vaccine, the nonavalent vaccine demonstrated non-inferior immunogenicity to the 4 shared VLPs.26 Following these trials, a large efficacy trial evaluating the nonavalent vaccine, which compared the new vaccine with the standard of care (the quadrivalent vaccine), was begun in 2009 and reached fruition in 2013. More than 14,000 women aged 16–26 were included in the study and followed for 4 years. The nonavalent vaccine reduced persistent infection as well as high-grade cervical, vulvar, and vaginal disease related to the 5 additional VLP types (31, 33, 45, 53, and 58) by 97% in the per-protocol group.27
Bridging studies-that is, smaller supplemental studies designed to extrapolate the results of RCTs to different populations-were then performed on 9- to 15-year-old boys and girls (n=3066). One month after receiving the third dose, >99% of participants seroconverted for each vaccine HPV type. Immune responses in girls and boys were non-inferior to those in young women. Persistence of anti-HPV responses was demonstrated through 2.5 years after completion of the vaccination series.28
Other efficacy considerations
Although most large efficacy trials have focused on cervical and vulvovaginal disease as the primary endpoints, data are accumulating on vaccine efficacy in prevention of other genital and oropharyngeal diseases as well. For example, in a subgroup analysis of more than 4000 women who received the bivalent HPV vaccine or placebo in Costa Rica, efficacy against anal infection with HPV16/18 was 83.6%.29 In another subgroup analysis of 5840 women in this same vaccine trial, there was only 1 case of oropharyngeal HPV infection in vaccinated women compared to 15 in women receiving placebo 4 years after randomization, for an estimated vaccine efficacy of 93.3%.30 Studies have also been conducted in men. In an international Phase III trial of the quadrivalent HPV vaccine, the vaccine was 90% efficacious in preventing HPV 6/11/16/18-related external genital lesions in men aged 16–26 years in the per-protocol analysis.31
Nine years after the first prophylactic HPV vaccine entered the market, data from vaccination programs worldwide have consistently documented significant reductions in the burden of HPV-related disease. Australia was one of the first nations to introduce a nationwide vaccination program, with more than 70% of girls aged 12–13 receiving all 3 vaccine doses.32 After 6 years of follow-up, the prevalence of infection with vaccine-targeted HPV genotypes was significantly lower in a post-vaccine-implementation sample of more than 1000 women compared to matched controls (7% vs 29%).33,34 Concomitantly, the prevalence of genital warts has decreased (by 73%–93%)35 as have both low- and high-grade cervical cytological abnormalities (HR 0.72–0.76)36,37 in vaccinated women. Reductions in rates of genital warts were observed in boys and men as well.35 Similar results have been observed in England,38 Sweden,39 and Denmark.40 In the United States, among girls aged 14-19, vaccine-type HPV prevalence decreased from 11.5% in 2003–2006 to 5.1% in 2007–2010, a decline of 56%, despite 3-dose vaccine coverage of only 32% in this age group, suggesting high effectiveness.41
In a systematic review and meta-analysis of 20 epidemiologic studies undertaken in 9 high-income countries, representing 140 million person-years of follow-up, HPV16 and HPV18 infection rates decreased by 68% (RR 0.32, 95% CI 0.19–0.52) and anogenital warts decreased by 61% (RR 0.39, 95% CI 0.22–0.71) in girls aged 13-19 in countries with female vaccination coverage of a least 50%. Reductions were also recorded in rates of infection with HPV31, 33, and 45 in this age group, suggesting cross-protection (RR 0.72, 95% CI 0.54–0.96). Moreover, incidence of anogenital warts in boys younger than 20 (RR 0.66, 95% CI 0.4–0.91) and in women aged 20–39 (RR 0.68, 95% CI 0.51-0.89) significantly decreased after introduction of HPV vaccination of adolescent girls. This suggests development of herd immunity, or the protection of non-vaccinated individuals as a result of decreased transmission of a pathogen within a population based on the acquired immunity to it by a high proportion of members. In countries with vaccination rates lower than 50%, significant reductions in prevalence of HPV16 and HPV18 (RR 0.5, 95% CI 0.34–0.74) and anogenital warts (RR 0.86, 95% CI 0.79–0.94) were still evident in the vaccinated group, but there was no cross protection against other HPV types and no evidence of herd immunity.42
All RCTs of the bivalent, quadrivalent, and nonavalent vaccines have reported a favorable safety profile.43 In addition, post-marketing surveillance and longitudinal studies have consistently confirmed the safety of the HPV vaccines.44-47
The vaccine is well tolerated, and the most common adverse events (AEs) are injection site-related pain, swelling, and erythema that are mild to moderate in intensity and self-limited. Compared to the quadrivalent vaccine, those receiving the nonavalent vaccine experienced more injection-site AEs (40% vs 29% for swelling, and 34% vs 26% for erythema).27 Systemic symptoms such as fever, fatigue, dizziness, nausea, vomiting, diarrhea, myalgia, and arthralgia were reported in both the vaccine and placebo arms of clinical trials, with modestly elevated odds ratios (range 1.17 to 1.97).43
Severe AEs, such as persistent headache, hypertension, gastroenteritis, and bronchospasm, were described in no more than 0.5%.43 No increased risk of autoimmune, venous thromboembolic, or neurologic disease has been shown among HPV-vaccinated subjects in long-term observation studies.48,49
The following recommendations are based on the Advisory Committee on Immunization Practices of the Centers for Disease Control.50
· Choice of Vaccine – Any of the 3 commercially available HPV vaccines can be administered to women, including the bivalent vaccine, the quadrivalent vaccine, and the nonavalent vaccine. The quadrivalent and nonavalent vaccines can also be administered to men. No statements have been made favoring any one vaccine over the others and choice of vaccine is left to the discretion of providers and patients.
· Age of Vaccination – Routine vaccination is recommended for girls aged 11–12. The vaccination series can be started as young as age 9 years, and women aged 13–26 should receive catch-up vaccination. Ideally, vaccine should be administered before potential exposure to HPV through sexual contact; however, girls and women who might have already been exposed to HPV should still be vaccinated.
· Vaccination of Males – Routine vaccination is also recommended for boys aged 11–12.The vaccination series can be started as young as age 9 years, and continued through age 21 in men at average risk. Men who have sex with men and immunocompromised men can receive vaccination until age 26.
· Route of Administration: All vaccines are administered intramuscularly, preferably in the deltoid muscle.
· Vaccination Schedule: All 3 HPV vaccines are currently administered in a 3-dose schedule. The second and third doses should be administered 1–2 and 6 months after the first dose. Studies are ongoing assessing the effectiveness of a 2-dose schedule.
· Minimum Dosing Intervals: the minimum interval between the first and second doses of vaccine is 4 weeks. The minimum recommended interval between the second and third doses of vaccine is 12 weeks.
· Management of Individuals Who Were Incorrectly Vaccinated: Inadequate doses or doses received after a shorter-than-recommended dosing interval should be readministered.
· Interrupted Vaccine Schedules: If the HPV vaccine schedule is interrupted, the vaccine series does not need to be restarted. If the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least 12 weeks. If only the third dose is delayed, it should be administered as soon as possible. Any available HPV vaccine product can be used to continue or complete the series, even if different from the original vaccine received.
· Simultaneous Administration with Other Vaccines: All 3 HPV vaccines can be administered at the same visit as other age-appropriate vaccines, such as the Tdap and quadrivalent meningococcal conjugate vaccines. Each vaccine should be administered using a separate syringe at a different anatomic site.
· Vaccination in those with Equivocal or Abnormal Pap Test or Known HPV Infection: Women should be advised that results from clinical trials do not indicate that the vaccine will have any therapeutic effect on existing HPV infection or cervical lesions. However, the vaccine should still be administered as it may protect against reinfection after appropriate treatment and infection against HPV types other than those of existing infection. Pap testing and screening for HPV DNA or HPV antibody are not needed before vaccination at any age.
· Vaccination of Lactating Women: Lactating women can receive HPV vaccine.
· Vaccination During Pregnancy: HPV vaccination is not recommended for use in pregnancy. The vaccines have not been causally associated with adverse outcomes of pregnancy or AEs in the developing fetus. However, data on vaccination during pregnancy are limited. Until additional information is available, initiation of the vaccine series should be delayed until after completion of pregnancy. If a woman is found to be pregnant after initiating the vaccination series, the remainder of the 3-dose regimen should be delayed until after completion of pregnancy. If a vaccine dose has been unknowingly administered during pregnancy, no intervention is needed.
· Vaccination of Immunocompromised Individuals: Because the HPV vaccines are non-infectious, they may be administered to individuals who are immunosuppressed as a result of disease or medications. However, the immune response and vaccine efficacy may be less than that in individuals who are immunocompetent.
· Nonavalent HPV vaccination of individuals who previously completed HPV vaccination with a different vaccine: No recommendations are made for routine additional nonavalent HPV vaccination of individuals who previously completed a quadrivalent or bivalent vaccination series.51 However, if an individual wants protection against the additional types prevented by the nonavalent HPV vaccine, available data show no serious safety concerns in receiving a second course of HPV vaccination. Decisions should be made on an individual basis.
· Cervical Cancer Screening Among Vaccinated Women: Cervical cancer screening guidelines have not changed for women who receive HPV vaccination.
· Precautions and Contraindications
o Acute Illnesses. HPV vaccination can be administered to individuals with minor acute illnesses (eg, diarrhea or mild upper respiratory tract infections with or without fever). Vaccination of individuals with moderate or severe acute illnesses should be deferred until after the patients improve.
o Hypersensitivity or Allergy to Vaccine Components. Vaccination with either the quadrivalent or nonavalent vaccines is contraindicated for individuals with a history of immediate hypersensitivity to yeast. Vaccination with the bivalent vaccine is contraindicated in those with a history of anaphylaxis to latex.
Despite the benefits of HPV vaccination, pubic health studies have demonstrated low uptake, with 60% of adolescent girls and 40% of adolescent boys receiving one or more doses, and only 40% of girls and 20% of boys completing the series.52 Multiple factors may account for this trend, including financial and insurance coverage issues, irregular preventive care, lack of information, parental attitudes and concerns about the vaccine’s safety or effect on sexual behavior, low perceived risk of HPV infection, and perceived lack of direct benefit, especially to boys.53
Clinicians should encourage HPV vaccination, as patients and parents consistently cited the recommendations of healthcare professionals as one of the most important factors in their decision to pursue vaccination.53-55 Clinicians must also be prepared to respond to common patient and parental concerns and misconceptions. In responding to behavioral and ethical concerns about vaccinating prepubertal children against an STI, clinicians may find it useful to frame the conversation in the context of cancer prevention, while still providing complete and accurate information about the nature of HPV infections. Biologically based arguments may be helpful in addressing vaccine timing: It should be emphasized that childhood vaccination may increase vaccine immunogenicity28,56,57 and that administration prior to coitarche provides maximum pre-exposure protection. Citing the high lifetime prevalence of HPV8 can help normalize the clinical scenario, reduce bias, and refute the perceived low risk of infection. Regarding vaccination of boys, direct benefit can indeed be cited given the growing incidence of HPV related anal, penile, and head and neck cancers.3,5,6 Finally, clinicians can improve compliance with the 3-dose vaccination series by using a patient reminder system (via phone, email or text).58
In what is perhaps one of the greatest success stories in modern medicine, the prevention and treatment of cervical cancer has been revolutionized over the past century, beginning with the development of the Pap smear, through the discovery of HPV as the causal agent in virtually all cervical cancers and a plethora of other malignant and benign diseases, and culminating with the recent development of prophylactic HPV vaccines.
The challenge ahead will be ensuring widespread vaccination coverage at a population level. School-based programs targeting prepubescent boys and girls may be employed to increase vaccination rates.59 In the future, compliance may also be boosted and cost reduced by 2-dose and even 1-dose regimens; the efficacy of such regimens remains under investigation.60 Future public health research in these areas is paramount.
In addition, access to HPV vaccination in the developing world is hindered by cost and need for refrigeration. Efforts to develop alternative prophylactic vaccines are under way, which may provide increased type-coverage and decreased manufacturing and production costs. Finally, development of a therapeutic vaccine aimed at those afflicted with invasive HPV-related cancers continues to be a worthy goal.
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58. Kharbanda EO, Stockwell MS, Fox HW, Andres R, Lara M, Rickert VI. Text message reminders to promote human papillomavirus vaccination. Vaccine. 2011;29(14):2537-2541.
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60. Romanowski B, Schwarz TF, Ferguson LM, et al. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7(12):1374-1386.