Recently, a new Cochrane Systematic Review on prophylactic vaccination against Human Papillomaviruses (HPV) to prevent cervical cancer and its precursors has been published. In view of the long post, I am not offering my own comments here.
Human papillomaviruses (HPV) are sexually transmitted and are common in young people. Usually they are cleared by the immune system. However, when high-risk (hr) types persist, they can cause the development of abnormal cervical cells, which are referred to as cervical precancer if at least two thirds of the surface layer of the cervix is affected.
Precancer can develop into cervical cancer after several years. Not everyone who has cervical precancer goes on to develop cervical cancer, but predicting who will is difficult.
There are a number of different hrHPV types which can cause cervical precancer and cancer. HPV16 and 18 are the most important high-risk types, since they cause about 70% of cervical cancers worldwide.
Preventive vaccination, by injection of HPV virus-like particles in the muscle, triggers the production of antibodies which protect against future HPV infections.
The objectives of this review were:
- To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.
The investigators searched for Randomised Controlled Trials (RCTs) comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine).
They used Cochrane methodology and GRADE to rate the certainty of evidence for protection against
- cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+],
- CIN grade 3 and above [CIN3+], and
- adenocarcinoma-in-situ [AIS]),
and for harms.
They distinguished between the effects of vaccines by participants’ baseline HPV DNA status.
The outcomes were
- precancer associated with vaccine HPV types and
- precancer irrespective of HPV type.
Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets.
- 10 trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS.
- 23 studies evaluated vaccine safety over a period of 6 months to 7 years.
Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes.
All but one of the trials was funded by the vaccine manufacturers.
Most included trials were judged to be at low risk of bias.
Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7).
Most women were under 26 years of age. Three trials recruited women aged 25 and over.
The review summarizes the effects of vaccines in participants who had at least one immunisation.
In adolescent girls and women aged 15 to 26:
A. Efficacy endpoints by initial HPV DNA status
- High-risk HPV (hrHPV) negative
HPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo.
There is high-certainty evidence that vaccines lower
- CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and
- CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10).
There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).
- reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and
- probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty).
The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines
- bivalent: RR 0.08 (0.03 to 0.23), high certainty;
- quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty.
Data in older women were not available for this comparison
2. HPV16/18 negative
In those aged 15 to 26 years, HPV vaccines reduce
- CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10).
*In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty).
- CIN3+ associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty)
- AIS associated with HPV16/18 in younger women (RR 0.09 (0.01 to 0.72), moderate certainty).
No trials in older women have measured these outcomes.
Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.
3. Regardless of HPV DNA status
In younger women HPV vaccines reduce
- CIN2+ risk associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty).
- CIN3+ risk associated with HPV16/18 (high certainty).
- AIS prevalence associated with HPV16/18 from 14 to 5/10,000 with HPV vaccines (high certainty).
HPV vaccines reduce
- any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and
- any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty).
The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).
In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.
B. Adverse effects
The risk of serious adverse events is similar between control and HPV vaccines in women of all ages.
Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty).
The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.
C. Pregnancy outcomes
Among those who became pregnant during the studies, an increased risk of
- miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or
- termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty)
was not detected.
The effects on congenital abnormalities and stillbirths are uncertain.
Cochrane Plain Language Summary
There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and women who are vaccinated between 15 and 26 years of age.
The protection is lower when a part of the population is already infected with HPV. Longer-term follow-up is needed to assess the impact on cervical cancer.
The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination. There are limited data from trials on the effect of vaccines on deaths, stillbirth and babies born with malformations.
Link to the Cochrane Systematic Review:
Link to Expert Reaction to the Review:
Link to CDC Fact sheet on HPV and Men (English) [PDF]: