Cervical Pre-invasive – Role of Vaccines

1. What every clinician should know

Are you sure your patient has the disease? What should you expect to find?

Cervical cancer has an estimated incidence of 12,990 new cases and 4,120 deaths in the United States in 2016. Worldwide, over a half of a million women are diagnosed annually with cervical cancer, and more than half of these women die from their cancer. The lowest burden of cervical cancer is in developed regions of the world, where there are organized screening programs, whereas the highest burden is found in developing regions of the world, particularly sub-Saharan Africa and Southeast Asia.

New methods for screening and point of care treatment, especially in regions of the world with limited resources, have resulted in a decreased incidence of and mortality from advanced cervical cancer. Many of the newly-implemented methods include HPV testing at its foundation. In addition to these screening methods, there has been the development of vaccines that can prevent some types of Human Papillomavirus (HPV) which, in turn, can subsequently prevent cervical precancerous lesions and cervical cancer.

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HPV is ubiquitous, with nearly four in five individuals having an active infection at some point in their lives. While infection with HPV is common, disease related to this virus is uncommon. Most who are infected with HPV will never get any clinically-relevant HPV-associated disease. HPV infection is almost always asymptomatic, unlike other viral infections, which usually elicit a prodrome or systemic response.

There is a well-documented natural history from HPV infection to precancerous lesions of the cervix to invasive carcinoma. All of these steps have been proven with high quality prospectively- followed cohorts, including the fact that high grade cervical intraepithelial neoplasia (CIN) is the immediate clinical precursor of invasive cancer. Other factors, however, are implicated in this natural history from infection to malignant transformation of the cervix. When HPV is stopped before infection can occur, hypothetically cervical cancer as well as other HPV associated cancers can be prevented.

2. Diagnosis and differential diagnosis

The majority of risk factors for developing cervical cancer are attributable to infection and persistence of oncogenic HPV types. These risk factors include sexual risk factors, such as early age of coitarche, multiple sexual partners, and a history of sexually transmitted infections. In addition to sexual risk factors, other risk factors include immunosuppression (e.g., human immunodeficiency virus (HIV), chronic steroid use), low socioeconomic status, and smoking.

The risk from smoking is increased in current smokers with increasing number of cigarettes smoked per day and with younger age at initiation of smoking. Oral contraceptive (OC) use has been shown to increase risk of high grade cervical intraepithelial neoplasia (CIN), a precancerous cervical lesion and cervical cancer. While there is no evidence of a genetic link to cervical cancer, there may be some susceptibility genes related to HPV persistence and cervical cancer.

Over 95% of cervical cancer is due to an infection from an oncogenic (‘‘high risk’’) HPV type. These include types that have been associated with malignant transformation to cervical cancers including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. The HPV subtypes that cause the majority of pre-invasive disease and cervical cancer are HPV 16 and 18.

HPV 16 accounts for 20% of HPV infections but is attributable to 40% of high grade cervical dysplasia and the majority of cervical cancers. HPV 16 is the most common HPV type found attributable to squamous cell carcinoma, up to 60%, and is the second most common type found in adenocarcinoma. HPV 18 accounts for 10-20% of all cervical cancer and is in nearly equal proportions to HPV 16 in adenocarcinoma and adenocarcinoma in-situ (AIS).

Epidemiologically, there is a natural history of HPV infection, to precancerous disease, to cervical cancer. In general, the course from infection to cancer is indolent, with cervical cancer developing over a course of over a decade. Most new HPV infections will regress within a year. While most new infections will regress, particularly in young women, those women that have persistent infection can have progression to pre-invasive cervical disease.

In organized screening programs, the goal is to use cytology and other testing to identify precancerous lesions that can be treated before they progress. If not treated, some may progress to invasive cervical cancer, a process which takes an average of 10-15 years. While there are reports of ‘‘rapid onset’’ cervical cancers, this makes up less than 3% of all incident cervical cancers, with the majority taking over a decade to develop, thus allowing them to be amenable to screening.

3. Management

A. What therapies should you initiate immediately?


The long and indolent period of time required to develop invasive cancer from an incident HPV infection allows screening to make a significant impact through early diagnosis and treatment of pre-invasive disease, thus decreasing the incidence of invasive cervical cancer. The routine use of the Pap test as a primary screening method has led to a decrease in the incidence of as well as death from cervical cancer. The overall incidence of invasive cervical cancer has decreased by over 50% in the last 40 years.

The vast majority of women who are diagnosed with cervical cancer either have never been screened or have been inadequately screened. In the U.S., over half of women diagnosed with cervical cancer have not had a Pap test for over five years. The performance of the Pap test can be affected by inadequate sampling, obscuring blood or mucous from the cervix, and human error. While liquid-based cytology improves many of the sampling issues, diagnostic yields of conventional Pap smears compared with liquid based cytology are similar.


Implementation of clinically validated high risk HPV testing improves risk stratification of equivocal pap tests, such as atypical squamous cell of unknown significance (ASCUS). In May 2012, the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) jointly sponsored a consensus conference and released updated guidelines for cervical cancer screening. The recommended screening strategy is contesting with both cytology and HPV testing. Additionally, an alternative strategy is primary HPV screening with FDA approved testing.


Vaccines that prevent HPV 16 and 18 are an additional cervical cancer prevention strategy. With early vaccination and widespread screening, cervical cancer can be a largely preventable cancer. There has been tremendous progress in the research and development of vaccines against HPV in an effort to decrease morbidity and mortality from HPV-associated diseases.

The CDC-preferred HPV vaccine is the newly approved nanovalent vaccine (Gardasil®, Merck & Co, Inc. Whitehouse Station, NJ). In addition to preventing against oncogenic types HPV 16 and 18, which account for over 70% of cervical cancers and 50% of pre-invasive cases of the disease, the vaccine also prevents disease from 5 additional types as well as against HPV 6 and 11, which account for approximately 90% of genital warts.

Clinical trials for the nanovalent vaccine show very high protection in essentially HPV naïïve young women and is especially good at preventing high grade CIN related to HPV 16 and 18. However, with prior exposures, the efficacy is less, as expected. The vaccine was overall well tolerated with few side-effects, with the most common side-effect being injection site pain. Further study of vaccines in men, with a specific cohort of men who have sex with men (MSM), also showed efficacy at prevention of in situ lesions of the anus and other external genital lesions, such as genital warts.

Based on these clinical studies, in addition to other factors, such as the epidemiology of disease, cost-benefit, and risk, the U.S. Federal Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of all girls and boys ages 11 and 12. The vaccine series can be started as young as age 9 and can be administered in a catch-up population up to age 26. The vaccine series schedule is at day zero, one to two months later, and six months after the first dose. The ACIP has now recommended that girls and boys from 9-14 can now get only two doses instead of three.

In addition to prophylactic vaccination, there are ongoing investigations of therapeutic vaccines, topical immunomodulators, and other local therapies for high grade CIN and invasive cervical cancer. These vaccines generally target HPV oncoproteins or stimulate an immune response against HPV-infected cells. These agents have a different mechanism of action than prophylactic HPV vaccines.

Much of what is known about the mechanism of HPV infection and the host immune response, including how prophylactic vaccination works, has been derived from animal and in-vitro models. Although animal models are limited by the species specificity of the viruses (HPV will not infect other animal species), animal models and in-vitro studies have provided important insight into the stages of initial infection, viral replication, viral clearance, and tumorigenesis, including how these stages relate to the expression of viral oncogenes and capsid proteins.

One murine model uses HPV pseudoviruses to allow for analysis of the initial phases of infection in the epithelium. Recent results suggest that papillomaviruses seem to require at least a microabrasion in the cell lining of the cervix or vagina to allow infection of basal cells of the epithelium, which is adjacent to the basement membrane. The model suggests that initial virus binding is predominantly to the basement membrane.

From HPV vaccine clinical studies and pathological assessment, the transformation zone of the cervix seems to be particularly susceptible to carcinogenic progression, although it may not be preferentially susceptible to infection. This is likely to be a consequence of the exposure of thin layers of immature basal cells during the process of squamous metaplasia in this zone in adolescent and young women, and also a result of particular biological properties of these cells that remain undefined.

It is thought that high levels of neutralizing antibodies that are generated systemically exudate through the basement membrane and are also present at high levels at the site of HPV infection. This has been found in the clinical trials for HPV vaccines, which assessed HPV L1 antibodies in the cervicovaginal tract. These local antibodies essentially block HPV infection of the immature basal cells in the epithelial layers.

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

Side effects of vaccination with an HPV vaccine are similar to other vaccines. The most commonly reported side effects are local, including redness/soreness where the shot is administered, headaches, and fever. Occasionally fainting can occur, but it is not uncommon for some preteens and teens to faint for any medical procedure. There is no trend for differences in pregnancy outcomes in women who have received a vaccine around the time of conception, and the vaccines have a pregnancy classification of ‘‘B’’. Voluntary reporting of pregnancies at the time of vaccination is recommended to CDC-supervised registries.

5. Prognosis and outcome

A. "What if" scenarios

What if the patient has had a Pap abnormality or has already been treated for high grade disease?

It is unlikely that a patient has been previously exposed to all types that have been found to be efficacious with vaccination. However, if exposure to one of the vaccine-contained types or one of the types found to be cross-protective with vaccination, it is unlikely the vaccine will be efficacious against that type. So, patients should know that while the vaccines will likely have efficacy for them, but less than if they received the vaccine prior to sexual debut.

What about HPV testing before vaccination?

Current Federal Advisory Committee on Immunization Practice (ACIP) recommendations are age based and have been carefully selected based on the natural history and epidemiology of the disease, clinical trial data, cost, and logistics. HPV testing adds cost and time, which is a barrier to vaccination. Additionally, if the testing were positive or negative, it would not change your management of the patient. A negative test does not tell you if the patient has not been previously exposed to vaccine-contained types and has had a natural regression. A positive test does not necessarily mean that they will not receive protection from the vaccine.

What if the patient is over the age of 26?

Current increases in separation and divorce and other factors have prompted questions about the potential for new HPV exposures in older women. In randomized controlled trials in women aged 27-45, the primary endpoint of efficacy was significantly different between those who were vaccinated and those who were not, yet those who had no prior HPV exposure did have some protection. The recommended cut off age of 26 still holds for the U.S. ‘‘catch-up’’ population. Use of the vaccine over this age group would be considered off labeled, and clinical judgment should be used when administering any medication in this manner. Of note, insurers generally do not reimburse for this off labeled use due to the trials that were negative for their primary endpoints in women 27-45.

Can prophylactic HPV vaccines treat HPV infections, cancers, or warts?

HPV vaccines will not treat or get rid of existing HPV infections. Also, HPV vaccines do not treat or cure CIN, cancer, or warts caused by an HPV infection that occurred prior to vaccination. It is important stress that adult women should still get cervical cancer screening even if they have completed the vaccine series.

Does my patient even need a booster?

No. Current data suggests protection lasts many years. Also, there have been post-vaccination challenge studies in which vaccinated women receive a fourth dose. All of them have nearly a similar level of immune responses after the challenge dose than if they just receives their third dose. This suggests that similar immune memory will occur in the event of exposure to a new type of HPV. Recent ACIP recommendations support even less doses in girls and boys under 15.

If my patient missed a dose or comes in many months after they are due for a dose, do I restart the series?

No. Current data suggests high levels of protection even after one or two doses. Current recommendations are to just resume the series (e.g., if the third dose has not been given yet, then just give that dose, and no further doses are necessary.)