Introducing human papillomavirus vaccines—questions remain

Abstract

Genital human papillomavirus (HPV) infection and HPV‐associated cervical and other anogenital cancers are significant public health problems. HPV 16 and HPV 18 are responsible for approximately 70% of all invasive cervical cancers worldwide. The first prophylactic HPV virus‐like particle (VLP) vaccine against HPV types 6/11/16/18 was licensed in 2006 for girls and women aged 9–26 years. The second prophylactic HPV vaccine against HPV types 16 and 18 has been licensed this year. These vaccines are almost 100% effective in preventing infection and high‐grade precancer associated with the HPV types included in the vaccine.

The vaccines are well tolerated, safe, and highly immunogenic when given in three doses within 6 months. Efficacy of the vaccine against external vulvar and HPV‐related vaginal lesions is also high.

Even though the vaccine is highly effective against high‐grade cervical, vaginal, or vulvar precancers, this only applies to women unexposed to these HPV types and only to high‐grade intraepithelial lesions caused by these HPV types. Therefore, it is important to understand that the population impact of the vaccines will be much lower than vaccinating naive populations. Implementing HPV vaccine is a great opportunity but also a great challenge. However, mandatory HPV vaccination may raise many questions, and more answers are needed.

• Cervical cancer
• CIN
• HPV
• HPV vaccine
• VaIN
• VIN

Genital human papillomavirus (HPV) infection and HPV‐associated cervical and other anogenital cancers are significant public health problems globally. An estimated 493,000 cervical cancer cases occur each year with 274,000 deaths. More than 80% of cervical cancer deaths worldwide occur in developing countries. Cervical cancer is the second most common cancer in women.

It was almost 40 years ago when Harald zur Hausen first suggested that HPV might cause cervical cancer and other anogenital cancers 1. HPV is the most common sexually transmitted viral infection. The lifetime risk for HPV infection is in the order of 80%. A large proportion of adolescents are exposed to HPV soon after sexual debut. Approximately 90% of women with new HPV infections clear the infection within 2 years 2.

Although well organized mass screening programs have led to a significant decline in the incidence and mortality from cervical cancer in developed countries, such programs are costly and are difficult or impossible to implement in developing countries.

HPV 16 and HPV 18 are responsible for approximately 70% of all invasive cervical cancers worldwide. All cervical cancers are caused by oncogenic HPV types, but the attributable proportion for other high‐risk HPV types is relatively small, with HPV 45 and 31 being the next most common causal types. In addition to cervical cancer, HPV also causes a proportion other anogenital cancers, including vulvar cancer, vaginal cancer, and anal cancer. These cancers are less common than cervical cancer. Vulvar and vaginal cancer account for approximately 6% of all gynecological cancers (for review, see 3). No screening programs exist for vaginal and vulvar cancers. Treatment for vulvar or vaginal intraepithelial neoplasia (VIN, VaIN) is challenging, can be disfiguring, and requires long‐term follow‐up, since disease recurrence is common. Risk for other anogenital cancers is increased in women with cervical intraepithelial neoplasia (CIN) due to the multifocal nature of HPV disease. Studies based on cancer registries from Finland and Sweden have shown that women treated for CIN have a high risk of other anogenital cancers up to 10–20 years after the initial diagnosis of CIN 4, 5.

Molecular and epidemiologic evidence suggest an important role for HPV in the etiology of squamous cell carcinoma of the head and neck 6. High‐risk type HPV has been detected in approximately 26% of all squamous cell carcinomas of the head and neck worldwide. A recent case‐controlled study demonstrated HPV 16 DNA in 72% of oropharyngeal cancer cases 6. Exposure to HPV increased the risk for oropharyngeal cancer regardless of tobacco and alcohol use. Number of lifetime sex partners and oral sex increased the risk for oropharyngeal cancer suggesting that oral HPV infection is sexually transmitted. Thus, there is a link between oropharyngeal cancer, risk‐taking sexual behavior, HPV exposure, and oral HPV infection.

The first prophylactic HPV virus‐like particle (VLP) vaccine against HPV types 6/11/16/18 was licensed in 2006 for girls and women aged 9–26 years. The second prophylactic HPV vaccine against HPV types 16 and 18 has been licensed this year. Key findings of studies of vaccine efficacy in preventing cervical and vulvar or vaginal disease are summarized in Table I. Clinical phase III trials show that these vaccines are almost 100% effective in preventing infection and high‐grade precancer associated with the HPV types included in the vaccine 7–9. Studies also show that the vaccines are well tolerated, safe, and highly immunogenic when given in three doses within 6 months. Many countries have already given recommendations of HPV vaccination of young girls and women. The ethics of compulsory vaccination has raised much debate, particularly in the US.

Table I. Randomized trials of HPV 16/18 or HPV 6/11/16/18 vaccines for prevention of anogenital and cervical disease (genital warts, CIN, AIS, VIN, VaIN).

Study (ref)	Vaccine	Number of participants		Age range (years)	Mean follow‐up	End points	Vaccine efficacy (percent, 95% CI)
		Vaccine group	Control group ^a				Per protocol (efficacy for vaccine‐type HPV) ^b	Modified intention‐to‐treat (efficacy for vaccine‐type HPV) ^c	Modified intention‐to‐treat (efficacy for vaccine‐type HPV) ^d	Intention‐to‐treat (efficacy for any HPV type) ^d
TFIISG, 2007 7	HPV 6/11/16/18	6,087	6,080	15–26	3 years	CIN 2/3, AIS,	98 (86–100)	NR	44 (26–58)	17 (1–31)
TFIISG, 2007 8 ^e	HPV 6/11/16/18	10,291	10,292	16–26	2.5–3.5 years	CIN 2/3, AIS	99 (93–100)	NR	44 (31–55)	18 (7–29)
Garland, 2007 10^f	HPV 6/11/16/18	2,241	2,258	16–24	3 years	CIN 2/3, AIS	100 (94–100)	NR	55 (40–66)	20 (8–31)
		2,261	2,279	16–24	3 years	GW, VIN 1–3, VaIN 1–3	100 (94–100)	NR	73 (58–83)	34 (15–49)
Joura, 2007 11 ^g	HPV 6/11/16/18	7,811	7,785	16–26	3 years	VIN 2/3, VaIN 2/3	100 (72–100)	NR	71 (37–88)	49 (18–69)
Harper, 2006 12	HPV 16/18	481	470	15–25	4.5 years	CIN 1‐3	NR	100 (42–100)	NR	NR
		481	470			CIN 2/3	NR	100 (−8–100)	NR	NR
Paavonen, 2007 9	HPV 16/18	7,788	7,838	15–25	15 months	CIN 1‐3	NR	89 (59–99) ^h	NR	NR
		7,788	7,838			CIN 2/3	NR	90 (53–99) ^h	NR	NR

^a In HPV 6/11/16/18 vaccine trials, control group received placebo; in HPV 16/18 vaccine trials, control group received a hepatitis A vaccine.

^b Efficacy in participants who received all three doses of vaccine or placebo, had no major protocol violations, were seronegative and HPV DNA‐negative for vaccine‐type HPV up to 1 month after third dose, and may have been infected with non‐vaccine‐type HPV or have an abnormal Pap test at baseline.

^c Efficacy in participants who received at least one vaccine dose, who were seronegative and HPV DNA‐negative for vaccine‐type HPV at month 0, and who may have been infected with non‐vaccine‐type HPV or have had a low‐grade abnormal Pap test at baseline.

^d Efficacy in participants who received at least one vaccine dose and had at least one follow‐up visit after first dose, and who may have had infection or disease associated with either non‐vaccine‐type or vaccine‐type HPV before vaccination.

^e TFIISG, 2007 8 = pooled analysis of four clinical trials.

^f Separate analyses of efficacy for prevention of cervical disease and anogenital disease.

^g Pooled analysis of three clinical trials.

^h 97.9% CI.

HPV = human papillomavirus; CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in‐situ; GW = genital warts; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia; NR = not reported; TFIISG = The Future II Study Group.

A randomized, double‐blind phase III trial of the quadrivalent HPV vaccine among 12,167 women followed for an average of 3 years after receiving the first dose of vaccine or placebo showed that the vaccine efficacy in women who had not been previously infected with HPV 16 or HPV 18 was 98% 7. The vaccine efficacy was 44% in an intention‐to‐treat population of all women including those with or without previous infection. The vaccine efficacy against all high‐grade cervical lesions (CIN 2/3) regardless of causal HPV type was 17%. This study was performed in 13 countries and 90 study sites. The results were confirmed in a combined analysis of four randomized clinical trials with a mean follow‐up of 3 years after first dose 8. The corresponding vaccine efficacies were 99%, 44%, and 18%. This combined analysis included 20,583 women aged 16–26 years.

The efficacy of the quadrivalent prophylactic HPV vaccine against vulvar and vaginal lesions was also high 10, 11. Combined analyses of three randomized clinical trials of 18,174 women, 16–26 years old, showed that the vaccine was 100% effective against VIN 2–3 or VaIN 2–3 associated HPV 16 or HPV 18 11. In the intention‐to‐treat population the vaccine efficacy was 71%. The vaccine was 49% effective against these high‐grade vulvar or vaginal lesions irrespective of whether or not HPV DNA was detected.

A very recent interim analysis of another large international phase III study of an adjuvant HPV 16/18 VLP prophylactic vaccine among 18,644 women aged 15–25 years showed vaccine efficacy of 90.4% against CIN 2/3 after a mean of 15 months since the first dose 9. The study population included women who had prevalent oncogenic HPV infections often with several HPV types as well as low‐grade cytological abnormalities at study entry. A large proportion of end point cases with high‐grade CIN had several oncogenic HPV types. Additional exploratory analyses were performed to address the causality of specific HPV types in the lesions taking into account preceding HPV infection and HPV gene expression. This vaccine also demonstrated cross‐protection against incident infection with HPV 45, HPV 31 and HPV 52, which is in line with the results of previous phase II trials 12. This phase III trial is still ongoing.

Even though the vaccine is highly effective against high‐grade cervical, vaginal, or vulvar precancers, this only applies to women unexposed to these HPV types (negative by PCR and serology) and only to high‐grade intraepithelial lesions caused by these HPV types 13. Therefore, it is important to understand that the population impact of the vaccines will be much lower for those already sexually active and exposed to HPV. The vaccine efficacy in the intention‐to‐treat analyses of all end point cases regardless of the HPV type has only been 17%–44%, which is not surprising since the vaccines are not therapeutic. It has been estimated that 129 women would need to be vaccinated in order to prevent one case of high‐grade CIN during an average of 3 years 13. The reason why vaccine efficacy is modest at most in the entire vaccinated cohort is the apparent lack of efficacy among subjects with previous exposure to HPV types included in the vaccine. So far it is difficult to infer both the effectiveness of vaccination and the role of non‐vaccine HPV types in the overall rates of precancerous lesions.

High‐grade intraepithelial neoplasias used as surrogate end points have variable likelihood of regression and variable potential to progress to cancer. Although CIN 2/3 is considered an acceptable surrogate marker for cervical cancer, grade 2 CIN regresses spontaneously in up to 40% suggesting that CIN 2 is not a very strong or consistent surrogate end point. With CIN 3, spontaneous regression is less likely and progression more likely. However, it is important to understand that both CIN 2 and CIN 3 trigger treatment in clinical practice.

As with CIN 2/3, high‐grade VIN and VaIN are surrogate markers for potential development of vulvar and vaginal cancer. The treatment of choice for VIN 2/3 is surgery. Since the disease can be multifocal, surgery can be mutilating and disfiguring to these patients, and adequate margins are sometimes difficult to achieve. The recurrence rates for vulvar and vaginal lesions are high, and these women have substantial risk of developing invasive cancer even after treatment.

Vaccine efficacy trials also raise many other questions 14. The availability of HPV cancer vaccine has elicited enormous enthusiasm in the medical community. Although the HPV vaccine development has been a remarkable and rapid achievement, the efficacy of the vaccine is limited by several factors. Firstly, not all cervical, vaginal, or vulvar cancers are caused by HPV 16 or HPV 18. Secondly, for full benefit it appears necessary to vaccinate young women before they are infected with these two HPV types. Thus, preadolescents before their sexual debut make up the primary target population. Cost‐effectiveness studies are needed of secondary target populations, i.e. catch‐up vaccination of older women up to 26 years. For vaccination of older age groups resources should not be diverted from the primary target group.

Also, whether the efficacy against high‐grade precancer can be extended to prevention of true cancers and prevention of cancer‐related deaths remains unanswered. It is also possible although not very likely that when selective immunologic pressure is applied with vaccination, non‐vaccine‐related HPV types emerge as important oncogenic high‐risk HPV types. Even more important, the current vaccines seem to provide cross‐protection against persist infection or CIN caused by oncogenic HPV types other than 16/18 9, 15.

Should young men also be vaccinated? Vaccination and eradication of rubella infection is an example that both women and men had to be vaccinated before rubella was eradicated, although the transmission is different. Development of herd immunity in the population requires that both girls and boys, or women and men, should be vaccinated 16. Introduction of a gender‐specific vaccine against a sexually transmitted infection (STI) may not be a good idea, and the ethics of a gender‐specific vaccination policy is a difficult concept. Studies on vaccination of males are emerging.

What is the durability of immune protection? Studies so far suggest that the neutralizing antibody levels persist for at least 5 years 12. Follow‐up studies are still under way to determine the true duration of protection.

Of the European countries, at least 13 have given recommendations of the use of HPV vaccination, included HPV vaccination in the national vaccination programs, or reimbursed the costs of the vaccination, including three of the Nordic countries (Denmark, Norway, Sweden). Thus, surprisingly many countries with different health care settings have already taken steps to implement the vaccination. At least 20 US states are currently considering laws to make HPV vaccination mandatory for preteen girls 17. The rush to make HPV vaccination mandatory in school‐aged girls presents ethical concerns 18, 19. The push to mandate HPV vaccine has triggered considerable heat, particularly in the US. Since HPV infection is not a communicable disease that one can catch in a classroom setting or airborne, many feel that schools should not tell parents that they must have their children vaccinated. This has raised debate across religious and political lines.

Also, adverse effects may still emerge over time, although the vaccines have been studied in 33 countries and one is already licensed in more than 80 countries. Therefore, postmarketing surveillance of safety and effectiveness of HPV vaccines will be of paramount importance.

Vaccination and screening should be complementary and synergistic cancer control strategies. Emerging evidence supports HPV DNA testing in primary screening followed by Pap cytology triage. Thus, it is likely that screening programs will be modified.

In summary, primary prevention of HPV infection, the most common sexually transmitted infection, has elicited enormous enthusiasm but also fears across religious and political fields. The efficacy of the two prophylactic HPV vaccines against high‐grade cervical, vaginal, and vulvar HPV 16/18‐related precancers approaches 100%, although this only applies for women not exposed to the vaccine HPV types before vaccination, and precancers associated with vaccine HPV types only. Results suggest that both vaccines demonstrate almost similar efficacy. These data so far provide sufficient evidence to support policy recommendations for the introduction of the HPV vaccines. Implementing HPV vaccine is a great opportunity but also a great challenge. However, mandatory HPV vaccination raises many questions and more answers are needed.

Key messages

• Human papillomavirus (HPV) vaccines are safe, well tolerated, and highly immunogenic.

• HPV vaccines are almost 100% effective against high‐grade cervical, vaginal, and vulvar precancers caused by the vaccine HPV types in unexposed women.

• The real‐life population impact of the vaccines will be much lower.

• Implementation of HPV vaccination is a great opportunity but also raises many questions.

• Vaccination and screening should be complementary and synergistic cancer control strategies.