HPV Vaccines Protect Against Precancerous Cervical Lesions

Vaccination against the human papillomavirus (HPV) is highly protective against precancerous cervical lesions in adolescents and young women compared with placebo, especially those who are negative for HPV at the time of vaccination, a systematic Cochrane review concludes.

In contrast, the same vaccines are much less effective in older women who are more likely to have been exposed to HPV before receiving the vaccine, the same review suggests.

"Vaccination aims to prime the immune system to produce antibodies that can block subsequent natural HPV infection," Jo Morrison, MD, consultant, gynaecological oncology, Musgrove Park Hospital, Somerset, United Kingdom, said in a statement.

"These data show that immunizing against HPV infection protects against cervical precancer and it is very likely that this will reduce cervical cancer rates in the future," she added.

It is very likely that this will reduce cervical cancer rates in the future. Dr Jo Morrison

However, she added: "Cervical cancer can take many years to develop following HPV infection and development of precancer lesions. Therefore, long-term follow-up studies are needed to find out the effects of HPV vaccination on cervical cancer rates."

Morrison also emphasized that because none of the HPV vaccines prevent all cervical cancer, "it is still important to have regular screening, even if you have been vaccinated."

The review was published online May 9 in the Cochrane Library.

Review of Literature

Researchers reviewed results from 26 studies in 73,428 women conducted across all continents over the last 8 years.

Most participants were younger than age 26 years, although three trials were carried out in women age 25 to 45 years.

Women received the bivalent HPV vaccine that targets HPV types 16 and 18 (Cervarix, GlaxoSmithKline) or the quadrivalent vaccine that targets HPV types 6 and 11 as well as 16 and 18 (Gardasil, Merck & Co).

The newer vaccine that targets nine different HPV types (Gardasil 9, Merck & Co) was not included in the review because it has not been compared against placebo in a randomized trial.

Stratifying efficacy by baseline HPV status, researchers found that HPV vaccination dramatically reduces cervical intraepithelial neoplasia grade 2 and above (CIN2+) and grade 3 and above (CIN3+), as well as adenocarcinoma in situ (AIS) in recipients age 15 to 26 years who were free of high-risk HPV infection at the time of vaccination.

In this group of recipients, CIN2+ rates associated with HPV 16 or 18 dropped from 164 per 10,000 among placebo controls to 2 of 10,000 among vaccine recipients.

The same vaccines reduced the incidence of CIN3+ associated with HPV 16/18 from 70 in 10,000 for placebo patients to 0 of 10,000 among vaccine recipients.

The risk for AIS from HPV 16/18 again dropped to 0 of 10,000 in females who had been vaccinated vs 9 of 10,000 among those who received placebo.

HPV 16/18–Negative at Baseline

The vaccines worked extremely well against CIN2+ and CIN3+ in adolescent girls and women who tested negative for HPV 16 and 18 at baseline, the authors note..

Table 1. Effect of HPV Vaccination on Cervical Lesions in Girls and Women Age 15 to 26 Years Negative for HPV 16/18 on Vaccine Receipt

Lesion	Placebo	HPV Vaccine Recipients
CIN2+	113 per 10,000	6 per 10,000
CIN3+	57 per 10,000	3 per 10,000
AIS	12 per 10,000	0 per 10,000

Vaccine efficacy did wane among adolescent girls and young women regardless of their HPV status on vaccine receipt, but vaccination was still associated with some level of protection.

Table 2. Effect of HPV Vaccination on Cervical Lesions in Girls and Women Age 15 to 26 Years Regardless of Baseline HPV Status

Lesion	Placebo	Vaccine Recipients
CIN2+ associated with HPV 16/18	341 per 10,000	157 per 10,000
CIN3+ associated with HPV 16/18	165 per 10,000	91 per 10,000
AIS associated with HPV 16/18	14 per 10,000	5 per 10,000
CIN2+ (irrespective of HPV type)	559 per 10,000	391 per 10,000
CIN3+ (irrespective of HPV type)	266 per 10,000	178 per 10,000
AIS (irrespective of HPV type)	Not assessed

Lead author, Marc Arbyn, MD, Unit Cancer Epidemiology, Scientific Institute of Public Health, Brussels, Belgium, also noted that women who did not receive all three doses of the vaccine, as is recommended for both the bivalent and the quadrivalent vaccine, also had high levels of protection if they were 15 to 26 years old and had not been exposed to HPV at the time of vaccination.

Effects in Older Women

The effects of vaccination in older women were small.

In women age 24 to 45 years, the incidence of CIN2+ associated with HPV 16 and 18 was marginally lower among vaccine recipients, at 107 per 10,000 compared with 145 per 10,000 for placebo controls.

However, the risk for precancerous lesions regardless of HPV status at baseline was similar between those who received the vaccine and those who did not. No data were reported for CIN3+ lesions or AIS in this age group.

No Safety Signal

The risk for serious adverse events was similar between HPV and control vaccines (placebo or vaccine against an infection other than HPV), the authors concluded.

The rate of death was similar overall (11/10,000 in control group, 14/10,000 in HPV vaccine group) (low certainty). The number of deaths overall was low, although more deaths occurred in older women, the authors note. No pattern in the cause or timing of death has been established.

"Among those who became pregnant during the studies, we did not find an increased risk of miscarriage…or termination," the study authors note, although the vaccines' effect on congenital abnormalities and stillbirths remains uncertain.

Commenting further on safety in a statement, Cochrane lead author Arbyn said, "The findings of this review should be viewed within the context of multiple global surveillance studies, which have been conducted by the Global Advisory Committee on Vaccine Safety from the WHO [World Health Organization] since the vaccinations were licensed. That Committee concluded that the risk-benefit profile of prophylactic HPV vaccines remains favourable and expressed its concerns about unjustified claims of harm that lack biological and epidemiological evidence, and which may affect the confidence of the public. At the same time, the Committee encouraged health authorities to continue surveillance and examination for potential adverse events."

"This intensive and rigorous Cochrane analysis…provides reassuring and solid evidence of the safety of these vaccines in young women," Margaret Stanley, OBE, emeritus professor of pathology, Cambridge University, United Kingdom, said in a statement.

"It reinforces the evidence that preventing infection by vaccination in young women…reduces cervical precancers dramatically," she added.

The two vaccines reviewed are manufactured by GlaxoSmithKline (bivalent vaccine, Cervarix) and Merck (quadrivalent vaccine, Gardasil).

Cochrane Library. Published online May 9, 2018. Abstract

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