Long-Term Effects of Human Papillomavirus Vaccination: Comparison
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Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Masayuki Sekine.

The preventive effect of Human papillomavirus (HPV) vaccines against anogenital and oropharyngeal cancers has been proven in both clinical trials and real-world data. We reviewed the published evidence about the long-term efficacy and effectiveness of the HPV vaccine in available papers of clinical trials and real-world data. As far as we searched, tThe longest period of preventive effect for the bivalent, 4-valent, and 9-valent vaccine were 11 years in the Costa Rica trial, 14 years in the FUTURE II, and 8 years in the LTFU extension study of V503-002 and the Scandinavian study, respectively. The sustained clinical effect during the observation period was longest for the 4-valent vaccine. In real-world data, the longest observation period of the vaccine effectiveness was 12 years in an Australian study for the 4-valent vaccine. For the bivalent vaccine, additional long-term follow-up studies may not have been planned due to the launch of the 4-valent and 9-valent vaccines. In some studies of the 9-valent vaccine, the results have not yet been published because of the short observation period. The additional results are expected in the future. In a national immunization program, most girls and boys are inoculated with HPV vaccine by the time puberty begins; thus, it is important to monitor the vaccine effect at least until the sexually active period in their 20s and 30s.

  • HPV vaccination
  • long-term effect
  • clinical trial
  • real-world data
  • seropositivity

1. Introduction

Human papillomavirus (HPV) is mainly transmitted through sexual activity. In fact, HPV sequences have also been identified in chorionic villi tissues from pregnant females and other districts of the reproductive tract [1,2][1][2]. HPV infection is the most common viral infection of the genital tract and persistent infection with high-risk HPV types (HR-HPV) can cause changes from normal cells to precancerous and cancerous lesions [3] in both men and women. It is estimated that about 80% of men and women become infected during their lifetime, and are usually cured by the host’s immune system [4]. Due to persistent HPV infection, HPV DNA is integrated into the host DNA. As a result, the onco-proteins E6 and E7 are expressed, causing the degradation of p53 and pRb, respectively. This is followed by the alteration of many cellular processes such as DNA repair, angiogenesis, apoptosis, etc., which ultimately lead to carcinogenesis [4].
More than 200 types of HPV have been identified, which are classified into high-risk types (such as types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82) that are carcinogenic, and low-risk types (such as types 6, 11, 42, 43, and 44) that cause anogenital warts and benign tumors, such as condyloma acuminata. High-risk HPV types are thought to be responsible for 7–8% of human malignancies, including 96% of cervical cancers, 93% of anal cancers, 64% of vaginal cancers, 51% of vulvar cancers, 36% of penile cancers, and 63% of oropharyngeal cancers.
HPV is estimated to cause nearly 36,000 cases of cancer in men and women every year in the United States. HPV vaccination can prevent 33,000 of these cancers by preventing the infections that cause them [6][5]. Especially in the prevention of cervical cancer, many reports from clinical trials have shown that the preventive effect of HPV16/18 infection and the development of cervical precancerous lesions are close to 100% [7,8,9,10,11,12,13,14,15,16][6][7][8][9][10][11][12][13][14][15]. The preventive effect against invasive cervical cancer has also been clearly proven worldwide. A significant reduction in invasive cervical cancer was reported in Sweden in 2020, followed by Denmark and England in 2021 in real-world data [17,18,19][16][17][18].
The HPV vaccine has been available since 2006 and targets mainly adolescent girls [20][19]. Currently, a national immunization program with the HPV vaccine is conducted in more than 100 countries [21][20]., and most programs target mainly young adolescent girls [22][21]. However, since the risk of HPV infection persists throughout the period of sexual activity in women, it is important to confirm the long-term preventive effect of the HPV vaccine [23][22].

2. Available Vaccines

Currently, three types of HPV vaccines are used worldwide to prevent the development of cervical cancer. The bivalent vaccine (Cervarix®) against HPV 16/18 (high-risk HPV type: HR-HPV), 4-valent vaccine (Gardasil®) against HPV 6/11 (low-risk HPV type: LR-HPV) and HPV 16/18 (HR-HPV), and 9-valent vaccine (Gardasil 9®) against HPV 6/11 (LR-HPV), and HPV 16/18/31/33/45/52 (HR-HPV) [24][23]. Cervarix® and Gardasil® could prevent 70% of cervical cancer cases, and Gardasil-9® almost 90% [24][23]. Table 1 shows the vaccination schedule, dose, and adjuvant in each vaccine [25,26,27][24][25][26].
Table 1.
Information of available HPV vaccines.
 

Bivalent Vaccine

Cervarix

®
Table 3.
Long-term effect on 4-valent vaccine.

Study

Study

Design

4-Valent Vaccine

Gardasil

®

9-Valent Vaccine

Gardasil9

®

Target HPV types

HPV 16/18 (HR-HPV)

HPV 6/11 (LR-HPV)

HPV 16/18 (HR-HPV)

HPV 6/11 (LR-HPV)

he difference in efficacy depending on the vaccine used and target age was considered (Table 2, Table 3 and Table 4).
Table 2.
Long-term effect on bivalent HPV vaccine.

Study

Study

Design

Study

Study Subjects

Subjects

Efficacy and Effectiveness

Follow-Up Period

Efficacy and Effectiveness

(Seropositivity)

Follow-Up Period

12 years
CIN, cervical intraepithelial neoplasia; AIS, adenocarcinoma in situ; AIN, anal intraepithelial neoplasia; MSM, men who have sex with men; EGL, external genital lesion.
Table 4.
Long-term effect on 9-valent vaccine.

Study

Study

Design

Study Subjects

Efficacy and Effectiveness

Follow-Up Period

(Clinical Effect)

(Seropositivity)

Follow-Up Period

(Seropositivity)

Follow-Up Period

(Clinical Effect)

Follow-Up Period

(Clinical Effect)

HPV 001 [28]

[27]

FUTURE I [39]

[38]

Latin American study [52]

[51]

Clinical trial

Clinical trial

HPV 16/18/31/33/45/52 (HR-HPV)

Clinical trial

Young women

(15–25 years)

Young women

(16–24 years)

Young women (16–26 years)

and girls and boys (9–15 years)

Reduced HPV 16/18 infection and

HPV 16/18-related cytological abnormalities

Reduced HPV-related anogenital disease

Prevented HPV31/33/45/52/58-related high-grade cervical, vulvar and vaginal dysplasia3.6 years

2 years

3.6 years

5 years

3.6 years

Schedule

5 years

HPV 032/063 [29]

[28

HPV P007]

[40]

[39]

Over 10 years

0, 1, and 6 months

Clinical trial

Over 9 years

0, 2, and 6 months

Young women

Over 9 years

0, 2, and 6 months

(20–25 years)

No case of HPV16/18–associated CIN1+

4 years

Clinical trial

4 years

Young women

(16–23 years)

Extension V503-001 [53]

[52]

Clinical trial

Young women

(16–26 years)

Prevented persistent vaccine-targeted HPV infection, cytological abnormalities, high-grade lesions, and cervical procedures

VLP dose

Extension NCT00196937 [30]

[29

L1 dose 20/20 μg

]

L1 dose 20/40/40/20 μg

Clinical trial

Women

(15–55 years)

L1 dose 30/30/60/40/20/20/20/20/20 μg

Sustained anti-HPV-16/18 seropositivity rates

6 years

-

Adjuvant

500 μg aluminum hydroxide,

50 μg 3-O-deacylated-4-monophosphoryl lipid A

225 μg aluminum hydroxyphosphate sulfate

500 μg aluminum hydroxyphosphate sulfate

VLP, virus-like particle; HR-HPV, high-risk HPV type; LR-HPV, low-risk HPV type.

3. Long-Term Efficacy: Clinical Trials

Numerous clinical trials have been conducted to date for each vaccine. We considered tT

5 years

6 years

LTFU extension study of V503-002 [54]

[53]

Clinical trial

Girls and boys

(9–15 years)

HPV 007 [31]

[30]

Clinical trial

Young women

(15–25 years)

No case of persistent infection or CIN2+ associated with HPV-16/18

6.4 years

6.4 years

6 years

VIVIAN study [32]

[31]

Clinical trial

Adult women

Nordic P015 [43]

[42]

Clinical trial

Young women

(16–23 years)

No case of HPV 6/11/16/18-related CIN

9 years

Clinical trial

Women

(15–55 years)

Sustained anti-HPV-16/18 antibody titers

10 years

-

Costa Rica Vaccine Tria [36]

[35]

Clinical trial

Young women

(18–25 years)

Reduced HPV16/18–related CIN2/3

-

11.1 years

No case of HPV 6/11/16/18-related CIN

5 years

5 years

Extension P007 [41]

[40]

Clinical trial

Young women

(16–23 years)

Sustained serum anti-HPV 6/11/16/18 immunoglobulin levels

5 years

–

No case of vaccine-targeted HPV infection, or

high-grade CIN, AIS, VIN, VaIN, PIN, or genital warts

7 years

8 years

Extension P019 [42]

[41]

Clinical trial

Scandinavian study [55]

[54]

Adult women

(24–45 years)

Reduced HPV 6/11/16/18-related CIN

6 years

(> 25 years)

Reduced HPV 16/18 infection,

Cytological abnormalities and CIN1+

-

7 years

8 years

HPV 023 [33]

[32]

Clinical trial

Young women

(15–25 years)

No new infection or CIN2+ associated with HPV 16/18

8.4 years

8.4 years

Clinical trial

Young women

(16–26 years)

Extension HPV023 [34]

[33]

P011–NCT 00309166 [37]

[36]

Clinical trial

Men

(10–18 years)

Higher antibody titers of HPV 16/18

7 months

7 months

Niigata Study

P019-21 [26]

[25]

Clinical trial

Adult women

(24–45 years)

No case of HPV 6/11/16/18-related CIN, AIS and EGL

10 years

10 years

V501-018-11 [44]

[43]

Clinical trial

Young women

(15–25 years)

No case of HPV16/18 infection and HPV16/18–related Histropathological abnormalities

Clinical trial

Girls and Boys

(9–15 years)

No case breakthrough disease in the form of genital warts or cervical and/or genital precancers and cancers

9.4 years

10.5 years

9.4 years

10 years

NCT 00947115 [

FUTURE II (P015-21)35]

[34] [45]

[44]

Clinical trial

Young women

(16–23 years)

No case of HPV16/18 related CIN2+ and cervical cancer

14 years

14 years

P020-AIN substudy [46]

[45]

Clinical trial

Men-MSM

Reduced AIN (grade 2+)

-

3 years

NCT00090285 [47]

[46]

(Extension P020/P020-11)

Clinical trial

Men (including MSM)

(16–26 years)

No case of HPV 6/11/16/18-related EGL

-

9.5 years in early vaccination

4.7 years in catch-up vaccination

[38]

P020-21[37]

[48]

[47]

Real–world data

Clinical trial

Young women

(25–26 years)

Reduced HPV 16/18 and HPV31/45/52 infection

Men

-

(16–26 years)

No case of HPV 6/11-related genital warts, HPV 6/11/16/18-related EGL or AIN

10 years

9 years

CIN, cervical intraepithelial neoplasia.

No case of HPV 16/18/31/33/45/52/58-related

high-grade CIN

-

8 years

10 years (up to 11.5 years)

Australian study (2015) [49]

[48]

Real-world data

Women

(18–24, 25–35 years)

Reduced vaccine-targeted HPV infection

-

9 years

Danich study [50]

[49]

Real-world data

Adult women

(born in 1993, 1983)

Reduced high-grade CIN

-

10 years

Australian study (2020) [51]

[50]

Real-world data

Women

(18–35 years)

Reduced vaccine-targeted HPV infection

-

CIN; cervical intraepithelial neoplasia; AIS, adenocarcinoma in situ; VIN, vulvar intraepithelial neoplasia; VaIN, vaginal intraepithelial neoplasia; PIN, penile intraepithelial neoplasia.

4. Long-Term Effectiveness: Real-World Data

There are several reports on bivalent and 4-valent vaccines (Table 2 and Table 3).

4.1. Young Women

The observation period of long-term effectiveness for the 4-valent vaccine was 9 years in an Australian study (2015) [49][48], 10 years in a Danish study [50][49] and 12 years in another Australian study (2020) [51][50].
The Australian study (2015) [49][48] compared HR-HPV prevalence in women aged 18–24 and 25–35 years between the vaccinated and pre-vaccine introduction generations. The results showed that the prevalence of vaccine-targeted HPV types was significantly reduced in the young women 9 years after vaccination.
Recently, the long-term 9-year effectiveness of the bivalent vaccine against HPV16/18 and 31/45/52 infection was reported in Japanese women aged 25–26 years [38][37]. HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (p = 0.0018), and the vaccine effectiveness was 100%. Cross-protective-type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%: p = 0.013).

4.2. Adult Women

In the Australian study (2015), the 4-valent HPV vaccination program targeting girls aged 12–13 years commenced in 2007, with catch-up vaccination of women aged 14–26 years through 2009. In the study, HPV prevalence in women aged 18–24 and 25–35 years in 2015 was compared with that in 2005–2007 [49][48]. The results showed that the prevalence of the 4-valent HPV vaccine types decreased from 11.8% (2005–2007) to 1.1% (2015) among women aged 25–35 years (p = 0.001), and its effectiveness was confirmed 9 years after vaccination. The authors stated that despite the low vaccination rate of 40.3% among women aged 25–35 years, the significant reduction in HPV prevalence may be due to the effect of strong herd protection.

5. Long-Term Persistence of HPV Vaccine-Induced Seropositivity

5.1. Bivalent Vaccine

The observation period of long-term persistence of HPV vaccine-induced seropositivity for the bivalent vaccine was 4 years in HPV 032/063 [64][55], 6 years in Extension NCT00196937 [56], 9.4 years in HPV001/007/023/Extension HPV023 [34][33], and 10 years in NCT 00,947,115 trial [35][34].
In the HPV-001 [28][27], 007 [34][33], and 023 [33][32] trials for women aged 15–25 years, the geometric mean titer (GMT) for HPV 16/18 peaked 7 months after the first inoculation and was maintained for 9.4 years (113 months). At that time, GMT was more than 10 times the antibody titer due to natural infection in both HPV 16/18 types [25][24], and the antibody positive rate was maintained at 100% [34][33] in the Extension 023 trial.
The P014 trial [29][28] and its follow-up study (NCT00196937) [30][29] evaluated the persistence of antibody titers in women aged 15–55 years who received their first vaccination. The study showed that GMTs for HPV 16/18 at 18 months after the first inoculation were in the same range as the plateau GMTs in the HPV-001 and 007 studies. Furthermore, although the GMTs were slightly lower in the age group of 26–55 years than in the age group of 15–25 years, the antibody titer after 48 months was maintained at a higher level than that after natural infection. The antibody titer was maintained for 6 and 10 years after the first inoculation in Extension NCT00196937 [56] and NCT00947115 [35][34], respectively.
In healthy boys, the P011-NCT00309166 trial examined the efficacy of the bivalent vaccine in healthy boys [37][36]. The antibody titers of HPV 16/18 in boys aged 10–18 and 10–14 years at 7 months after vaccination were higher than those in women aged 15–25 and 10–14 years in previous studies [57].

5.2. 4-Valent Vaccine

The longest period of long-term persistence of HPV vaccine-induced seropositivity for the 4-valent vaccine was 14 years in FUTURE II [45][44] (P015-21) for women, and 10–10.5 years in the P020-21 [48][47] and V501-018-11 [44][43] trials for men.
In the final report of the P015-21 (follow-up study of the P015 FUTURE II) in women aged 16–26 years, the antibody positivity rates of HPV 6/11 (LR-HPV) and HPV 16/18 (HR-HPV) were 90.6%, 91.1%, 98.3%, and 52.4% at 14 years after the first inoculation, respectively [45][44].
In the P020 trial for men aged 16–26 years, the antibody positivity rates for HPV 6/11/16/18 after 3 years were 86.9%, 78.0%, 92.3%, and 60.7%, respectively [59][58]. Furthermore, in the follow-up study (P020-21), the antibody positivity rates for HPV 6/11/16/18 were 79.1%, 79.9%, 94.9%, and 40.2% at 10 years after inoculation, respectively [48][47].
The V501-018-11 [44][43] trial was conducted on boys and girls aged 9–15 years, and the antibody positivity rates for HPV 6/11/16/18 at 10.5 years after the first inoculation were 86.6%, 87.2%, 94.1% and 59.6% in boys, respectively. In contrast, the antibody positivity rates were 91.0%, 90.1%, 97.7%, and 61.4% in girls, respectively. There seems to be no difference in HPV antibody titers between boys and girls.

5.3. 9-Valent Vaccine

The longest period of long-term persistence of HPV vaccine-induced seropositivity for the 9-valent vaccine was 5 years in Extension V503-001 [53][52] and the Latin American study [52][51] for young women, and 7 years in the LTFU extension study of V503-002 [54][53] for girls and boys.
The V503-001 trial confirmed that the antibody response against the 9-valent HPV vaccine type persisted for at least 5 years in women aged 16–26 years, and the antibody positivity rate was ranged from 78% to 100% at 5 years after the third inoculation [53,65][52][59]. In the V503-002 trial in girls and boys aged 9–15 years, it was confirmed that the antibody response lasted for at least 5 years after three doses of the 9-valent vaccine [62[60][61],63], and the antibody positivity rate against HPV 6/11 (LR-HPV) and HPV 16/18/31/33/45/52/58 (HR-HPV) ranged from 90% to 99% at 5 years after inoculation [62][60].
A Latin American study [52][51] confirmed that the antibody titer of the 9-valent vaccine was sustained for 5 years in boys aged 9–15 years.
In the LTFU extension study [54][53], three doses of the 9-valent vaccine induced HPV antibodies that persisted for at least 7 years in girls and boys aged 9–15 years. GMTs reached its peak at 7 months (1 month after three doses), then declined sharply at 12 months, followed by a slower decrease between 24 and 90 months. Most participants remained seropositive for each 9-valent HPV vaccine type at the last immunogenicity assessment. GMTs at 90 months in the participants were equal to or higher than the GMT at 60 months for women who received the 9-valent vaccine in a previous study [53][52].

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