Kenneth A. Alexander, MD, PhD,
is an Associate Professor of Pediatrics and Chief of the Section of Pediatric Infectious Diseases in the Department of Pediatrics at the University of Chicago.

Stan L. Block, MD,
is Professor of Clinical Pediatrics at the University of Louisville, and Professor of Clinical Pediatrics at the University of Kentucky. Dr. Block is also president of Kentucky Pediatric Research in Bardstown, Kentucky.

Kevin A. Ault, MD,
is Associate Professor in the Division of Gynecologic Oncology in the Department of Gynecology and Obstetrics at Emory University School of Medicine in Atlanta, Georgia.

Craig S. Derkay, MD,
is Professor and Vice Chairman of Otolaryngology and Head and Neck Surgery. He is director of Pediatric Otolaryngology in the Department of Otolaryngology, Head and Neck Surgery at Eastern Virginia Medical School.

Daron G. Ferris, MD,
is the Director of the Gynecologic Cancer Prevention Center in the Medical College of Georgia in Augusta, Georgia.

Figure 1. Papillomaviruses grouped according to the L1 gene sequence. (Reprinted from Virology. Volume 324. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses, pp 17-24. Copyright 2004, with permission from Elsevier.)

Figure 2. Percentage of cervical cancers attributed to oncogenic HPV serotypes.⁴

Q & A

How closely related do the HPV genotypes have to be for cross protection from vaccine antigens to occur?

Kenneth A. Alexander, MD, PhD: During the vaccine clinical trials, there was hope that the HPV16 and HPV18 antigens would confer protection against more oncogenic HPV types than just HPV16 and HPV18. Indeed, this is what was found. HPV16 antigen can induce protective immunity against closely related HPV types, such as HPV31 and HPV33. Similarly, HPV18 antigen induces protection against HPV45, a genotype with L1 sequence similar to HPV18.

Craig S. Derkay, MD: From a simplistic standpoint, serotyping is based on nucleic acid sequence and the assigned sequential numbers are based on the order of discovery. Serotyping does not have any relationship to phylogeny so that if you have less than 90% sequence identity, you have a new number.

Alexander: Sequence similarity in the L1 protein is the underlying basis of cross protection.

An issue associated with the pneumococcal vaccine is the emergence of more nonvaccine strains. What is the possibility of this occurring with the HPV vaccine?

Stan L. Block, MD: There should be no serotype replacement with these strains. I think HPV is more along the lines of hepatitis B. Once you eliminate hepatitis B infectious armamentarium, it is eliminated for good in the patient. There will not be a replacement phenomenon.

What percentage are mixed infections?

Alexander: Mixed infections occur in approximately 15% to 20% of cases. They are not rare. One of the advantages of looking at persistent infection is that it is readily measured, and the virus causing the persistent infection can be identified. Cytological end points, while clinically relevant, pose the problem that it can be difficult to ascribe cytopathic changes to a specific HPV type, especially when there is a mixed infection.

Do HPV strains compete with one another in the genital tract?

Kevin A. Ault, MD: HPV has a limited genome and does not exchange DNA with other bacteria or virus. Current information indicates that there is no competition between HPV types during cervical infections.

Alexander: Papillomaviruses are double-stranded DNA viruses. DNA viruses are stable and mutate very little over time. Furthermore, papillomaviruses have no mechanism for recombination. As a consequence, papillomavirus sequences are very stable and are not prone to spontaneous mutation. If we see genotype replacement, it is going to be at the speed of evolution, rather than at the speed of mutation.

What is the role of antibodies in HPV infection?

Block: The correlation seems to be quite good. Women get robust antibody responses and almost 100% protection. We know at least at some level, these women are highly protected with the vaccine, and the two seem to be correlated fairly well. The other question is durability of the antibody.

Alexander: The HPV vaccine and the hepatitis B vaccine contain pseudovirion antigens. Decades of experience show that the hepatitis B vaccine is one of the safest vaccines available. Hepatitis B vaccine is immunogenic, and it confers durable immunity, possibly life-long durability. Serum antibody levels to hepatitis B do not correlate well with protection. This is good in one sense because, over the years, vaccine-induced antibody levels drop, but protection against hepatitis B does not appear to wane. This loss of antibody titer does, however, make it difficult to interpret clinical trials, which often use antibody titers as a surrogate marker for vaccine efficacy.

Vaccine-induced antibody titers can be used to measure immune memory, which is a key determinant of the durability of vaccine efficacy. A recent study by Olsson and colleagues (Vaccine. 2007;25:4931-4939) looked at the serological response to a booster dose of HPV vaccine. This study was done to assess whether HPV vaccine induces immune memory. The hallmark of good immune memory is that, following reexposure to the antigen, even years after primary immunization, a brisk humoral response ensues. In the Olsson study, a cohort of patients who were in a clinical trial for HPV vaccine were given a single booster dose 5 years after initial immunization. If the HPV vaccine induced good immune memory, then the anticipated response to the booster dose would be a brisk and rapid rise in anti-HPV antibody titers. The trial result was what was anticipated: Boosting with HPV vaccine led to a rapid antibody response that was higher than that induced by the primary vaccine series.

What percentage of women with natural infection develop antibodies?

Alexander: HPV appears to be able to stay under the radar of the immune system. Approximately 50% to 70% of a cohort of women with proven genital HPV mount a detectable antibody response. In contrast, HPV vaccines lead to virtually 100% seroconversion. This is what makes these vaccines so impressive. By injecting HPV pseudovirions somewhere deeper than the skin, be it in the subcutaneous fat or in the deltoid muscle, the vaccine is being administered where the immune response will be quick and effective. There are no data available describing whether a woman would still be protected after 5 years, but if the experience with the hepatitis B vaccine is extrapolated, even as antibody levels drop, it is likely that these women are going to be protected. Furthermore, normal, healthy sexually active women are constantly being reexposed to antigen, which may boost the immune response.

Derkay: If women are administered a challenge several years after they receive the vaccine, then there may be a difference in the result than if all the challenge happened in that first 5 years.

Alexander: Is the type of immunity that confers protection against HPV infection different than the type of immunity that clears an established infection? It is possible that IgA on surfaces may be important for protection. But clearance of infection is a different issue. An important factor in both the bivalent and quadrivalent vaccines is that, while these vaccines clearly prevented high-grade disease, they reduced, but did not eliminate, incident infection. These vaccines are effective at preventing disease but are not 100% effective for preventing infection. Given what we know about vaccines, this is to be expected.

If antibody levels are dropping, is there likely to be a benefit from a booster?

Block: The Olsson data show an anamnestic response which is rapid and very potent with a booster at 5 years, suggesting an immune memory postvaccination that would offer women long-lasting protection without the necessity for a booster immunization after the three-dose primary series. One question is will there be sufficient protection 10 to 15 years after immunizing a 9- to 11-year-old child with three doses of HPV. If the women in the clinical trials show an anamnestic response with a booster 10 years postvaccination, then it is promising that the children vaccinated at an early age will be protected for many decades postvaccination.

Alexander: The data from Olsson and associates indicate that HPV vaccines induce strong, durable immune memory. While I doubt that a booster dose of vaccine will be needed, the fact that these vaccines induce immune memory means that a booster dose would likely be effective.

At what level do the neutralizing antibody titers have to be to offer protection?

Ault: We do not know the minimum protective level of antibodies for the HPV vaccine. In the 5-year follow-up of the phase 2 trials, antibody levels began to fall but we did not see an increase in cervical disease.

Figure 1. Percentage of children and young adults who have had intercourse according to age group. In an analysis of 1,552 adolescents and young adults, the subset (n = 1,014) featured in this figure reported having engaged in sexual intercourse. These data suggest minimal risk of exposure in 9- to 11- year-olds.^8,9

Figure 2. Antibody titers measured in mMU/mL against each HPV strain in the quadrivalent vaccine. The highest levels are seen against HPV16. Girls and boys show higher titers compared with young women.¹⁵

Q & A

Should HPV vaccines be included in vaccination schedules to combat the neck and throat cancers that are caused by HPV serotypes?

Craig S. Derkay, MD: HPV is responsible for at least 20% of neck and throat cancers and perhaps as many as 90% of oropharyngeal cancers. Subsets of oropharyngeal cancers exist in which the profile of the patient is different than what has been appreciated in the past. It is not the smokers and drinkers, it is the younger patients who have developed the disease in their 30s and 40s. If there was a way to identify these patients ahead of time as being at risk, then vaccinating men would be of some benefit.

If all boys were vaccinated in the early adolescent years, there is good reason to believe that we may prevent this subset of head and neck cancer patients from developing in the next couple of decades. Immunizing a large group of 40-year-old men right now to prevent them from developing squamous cell carcinoma of the oropharynx, however, is probably an unreasonable expectation.

Kenneth A. Alexander, MD, PhD: What structures in the head and neck are most commonly associated with HPV-related cancers?

Derkay: Waldeyer’s ring, the oropharyngeal structures — the tonsil, the base of tongue, the retromolar trigone — are higher in terms of their predilection for being an HPV-related cancer than the larynx or the salivary glands, the hypopharynx, the mobile tongue, and the floor of the mouth. The dominant HPV types are 16 and 18 and a little bit of 33 and 35.

Why is it beneficial to immunize patients when they are young?

Daron G. Ferris, MD: HPV antibody titers are higher for younger girls. Moreover, nearly 10% of 11- to 12-year-old girls have been exposed to HPV. Hence, there are good reasons to begin vaccinating children when they are 9 to 10 years old. The vaccine is 100% effective for vaccine types when given prior to HPV exposure.

Stan L. Block, MD: The number one reason would be to optimize protection. At age 15, 20% of young girls possibly have been exposed to HPV16/18, which are the most oncogenic of the serotypes. It is optimal to give three doses of the vaccine if you catch them at an early age and before they become sexually active. If the second or third dose is skipped, there is still time to get the second or third doses in prior to their becoming sexually active.

Derkay: There is also the convenience factor. Girls are coming into the office at 11 and 12 years old to get the tetanus, diphtheria, pertussis vaccine or the meningitis vaccine which offers the opportunity to vaccinate them with HPV vaccine. The statistics also point out that the number of visits to the pediatrician decreases significantly at age 14 to 16. Also, it is difficult to get them in three times in 6 months at that age.

Alexander: I tell parents, “I am immunizing your 11-year-old daughter not because I think she is going to be sexually active tomorrow; I am immunizing her now because she is here.”

Block: The best way to ensure uniform vaccination is to get school-mandated policies for entry to high school.

Alexander: The importance of reminder-recall with adolescents cannot be underemphasized. Reminder-recall works. Furthermore, in 2008, reminder-recall is not limited to a phone call to parents. Now, text messaging and email are easy and inexpensive ways to communicate directly with teenagers.

What additional studies are needed to demonstrate efficacy and durability, and, in doing so, expand HPV vaccination to different patient populations?

Derkay: The first step, with respect to the respiratory papilloma population, is to establish the anti-HPV6 and the anti-HPV11 antibody levels in a cohort of actively treated patients with recurrent respiratory papilloma to try to determine who might benefit from therapeutic administration of the vaccine. A cohort of children, both girls and boys, currently in remission from the disease, could be vaccinated and followed for several years to see if their period of remission is extended. A surveillance study has already begun to look at new onset recurrent respiratory papilloma disease and compare this over time to the incidence and prevalence in a self-contained medical community.

Merck is currently involved in trying to estimate the incidence and prevalence of recurrent respiratory papilloma worldwide to try to set a baseline of the degree of disease and then reexamine those numbers using large medical databases 5 years and 10 years from now.

Block: Were any obvious warts present in the mouth?

Derkay: Warts in the mouth are lumped in the category of recurrent respiratory papilloma more so than squamous cell carcinoma. Warts in the mouth are not a precursor for the development of squamous cell carcinoma.

What is the role of immunizing men? What information do we have? What information do we need?

Alexander: I suspect that there will be efficacy in immunizing males because these vaccines are immunogenic in males. What remain to be sorted out are the issues of cost-benefit. Until cost-benefit questions about male immunization are answered, our immunization efforts are best spent getting a high proportion of females immunized.

Derkay: Herd immunity is going to be necessary if we are going to make a substantial effect in terms of cervical cancer. HPV causes disease in males. It causes anal disease and penile disease; and so, although not at the same degree that cervical cancer is an issue, HPV is still an issue in the male gender. There is also a higher incidence of HPV-related oral pharyngeal cancers in males than in females. They tend to be in younger patients and in a cohort that is not the typical head and neck squamous cell carcinoma patient. They are the nonsmokers and the nondrinkers.

Alexander: The reason to immunize males may have as much to do with the protection of males themselves rather than for the protection of females.

What are contraindications to HPV immunization other than pregnancy?

Kevin A. Ault, MD: Allergy to a prior dose is the main contraindication to this vaccine.

Block: There have been significant Arthus reactions. One in 200 girls will have an Arthus reaction to the vaccine and become extremely red and swollen in their arm. The question is, if it occurs due to the first dose or the second dose, should they still receive the second or third dose? Should the practitioner try to convince the patient to get their next dose if needed? Most girls who developed a major local reaction received a subsequent dose and did fine.

What are some comments about the recently reported adverse events and deaths associated with the HPV vaccine?

Block: The most common reactions seen in preclinical trials were local, that is, pain, swelling, and redness. The most common systemic adverse events were fever and nausea, but both were the same as placebo. A practitioner can explain to the family that there is a 1 in 2 likelihood that the patient will have mild-to-moderate pain, 1 in 10 will have redness and swelling, and 1 out of 200 will have major swelling more like an Arthus reaction. Four percent had a temperature of higher than 100°, but few higher than 102°.

The Vaccine Adverse Event Reporting System (VAERS) is a voluntary reporting system and anyone can make a VAERS report. While VAERS is set up to be a fairly sensitive reporting system, it is not as specific as it should be. Rarely is there any association with causality. For example, the “Judicial Watch Group” reported that the VAERS data postvaccine showed 11 deaths and 3,461 adverse reactions linked to HPV vaccine. There were 77 pregnancies after vaccination with almost half showing induced spontaneous abortions and/or fetal abnormalities. Paralysis, Bell’s palsy, Guillain-Barré syndrome, and seizures have also been associated with this vaccine.

In reality, data from the clinical trials showed that 40% of women have spontaneous abortions whether receiving vaccination or placebo. Also, an equal number of deaths occurred between the vaccinated and placebo groups.

Four deaths following quadrivalent HPV vaccine have been reported but apparently are not attributable to the HPV vaccine. One patient had myocarditis and cardiac disease prior to vaccination. One patient was a smoker on contraceptives who developed a pulmonary embolism and sudden cardiac death. Another had a blood clot 3 hours postvaccination. The fourth was a 14-year-old who had nasopharyngeal influenza B and methicillin-resistant Staphylococcus aureus and was hospitalized with extracorporeal membrane oxygenation. All of these deaths appear to be out of the realm for being vaccine-related.

Are thrombosis or blood clots related to the vaccine?

Ault: The thrombotic complications originally reported to VAERS were likely due to oral contraceptives. The most up-to-date information can be found on the CDC’s Web site.

Block: Deep venous thrombosis is not uncommon among women and does not mean it is related to the vaccine. The background rate is between 3 and 50 per 100,000. The background rate of venous thromboembolism is 21 to 31 per 100,000 woman years among oral contraceptive users for women aged 14 to 29 years. The rate among oral contraceptive users for all ages is approximately 41 per 100,000 woman years. And among ages 20 to 29 years, without oral contraceptive use or smoking the rate was about 3.3 to 4 per 100,000 woman years.

Alexander: These reported adverse events are a consequence of the population that is being immunized. Many of the women being vaccinated take oral contraceptives and, unfortunately, many of these women also smoke cigarettes. Cigarette smoking and oral contraceptive use are a well-established formula for thrombotic events in young women. Therefore, when a patient is in the office for HPV immunization, the practitioner should use the opportunity to remind her that she should not be smoking, especially if she is on an oral contraceptive. When patients present for immunization, we also have an opportunity to discuss contraception and to discuss sexual hygiene. An HPV immunization visit affords pediatricians an important guidance opportunity that can be used in a way to bring up other important topics.

Does the HPV vaccine cause Guillain-Barré syndrome?

Block: Guillain-Barré occurs naturally in 1 per 100,000 teenagers. Therefore, you have to look at the Guillain-Barré syndrome data carefully. The VAERS postvaccine data reported 13 cases. The expected background rate is in the 30 to 50 range. Thus, for the HPV vaccine, these data look extremely good. Among those cases reported, six had received the meningococcal (groups A, C, Y and W-135) polysaccharide diphtheria toxoid conjugate vaccine at the same time and data suggest that patients aged 15 to 19 may be at a very minimal increased risk for Guillain-Barré after the meningococcal vaccine.

Eight of these cases had insufficient data to confirm that it was actually Guillain-Barré. Of the cases, only five of 13 met the criteria for Guillain-Barré. Five cases in the last year means there is no issue with Guillain-Barré for this vaccine.

Alexander: The rate of Guillain-Barré syndrome in vaccinees is comparable to or below that of the general population.

Ault: Agreed, Gullian-Barré syndrome cases appear to be less than background.

Are there issues with immunizing pregnant women and women who are breastfeeding?

Ault: Currently, the HPV vaccine is contraindicated during pregnancy. It is not necessary to screen women for pregnancy prior to giving the vaccine. Likewise, if the vaccine is accidentally given to a pregnant patient, no special measures are needed. However, as with any new medication, it is not a good idea to give it during pregnancy without more data.

Alexander: Merck maintains a registry that will be used to determine if there are any rare teratogenic effects associated with HPV immunization during pregnancy. The toll-free number for the registry is printed in the package insert.

Derkay: The HPV vaccine may prevent the development of recurrent respiratory papillomatosis in newborns and that may be a reason to vaccinate pregnant women who are HPV-positive. Animal studies in rats in which the animals were given the HPV vaccine showed high levels of HPV6 and HPV11 antibodies in the respiratory tracts of baby rats. If human babies are exposed to the antibodies generated from vaccinating HPV-positive pregnant women, it may prevent the babies from developing disease.

If a vaccine dose is missed, must the schedule be restarted?

Block: All patients should receive three doses as long as they were given after the minimal interval of 1 month apart for first and second and 3 months apart for the second and third. It does not make a difference if the second and third doses are administered later than the minimal interval.

Alexander: There is a great deal of flexibility in the dosing schedule.

Block: There is flexibility for late doses, but there is a rigid schedule for the early dosing. In fact, data suggest that, if the third dose is given later, at 7 or 8 months, the antibody levels are slightly higher.

What are the problems with immunizing women past the age of 26?

Ault: The data supporting the vaccination of women older than 26 have just been reported at the International Papillomavirus Society in Beijing. The vaccine has been reported to be 90% effective up to age 45. It will take several months for a publication and subsequent clinical recommendations from the Advisory Committee on Immunization Practices.

Block: The efficacy of the vaccine and the durability of the antibody protection are the two major limiting factors of immunizing older women.

Alexander: There will be concern that their antibody responses will not be as vigorous. What that will mean in terms of vaccine efficacy has yet to be determined.

As we discussed, the immune response to natural HPV infection is modest. This is probably because HPV infection occurs in the epidermis, much of which is beyond the purview of the immune system. In contrast to HPV infection, which occurs out of reach of the immune system, HPV vaccine goes into the deltoid muscle, right where the immune system can get at it. As a consequence of our administering HPV vaccine where the pseudovirion antigens can be detected by the immune system, the immune response to HPV vaccines is brisk, and exceeds the normal immune response to natural disease.

Block: The natural infection antibody titers are usually between 40 and 80. After vaccination, the levels are in the thousands. Compared with natural infection, in children, postvaccine antibody levels are about 50-fold higher, and in adults it is on the order of about 20- to 30-fold higher.

Should the vaccine be used under any circumstances for the treatment of existing HPV infection?

Derkay: There are studies that suggest that the vaccine is unlikely to be beneficial when administered for therapy in patients who have existing HPV infection. A randomized trial in a cohort of women from Costa Rica showed that there was no evidence of clearance of virus at 6 or 12 months between a group of women given the bivalent vaccine or placebo (Hildesheim A, et al. JAMA. 2007;298:743-53). The conclusion was that vaccination in women should not be used to treat prevalent infections.

Otolaryngologist are looking for a cure for children with recurrent respiratory papilloma disease and the data from the studies suggest it is not therapeutic in the cervix but that may not apply to the larynx, it may not be a fair transposition. There are some data with canine papilloma disease that suggests that there may be some benefit for using L1 VLP to treat dogs that have canine papilloma in their larynx and the hope is to do some clinical trials with this vaccine to see if it could be beneficial from a therapeutic standpoint.

Has there been much off-label use of the HPV vaccine?

Ferris: There has been great interest in the HPV vaccine by women older than 26. Use at this time is considered off-label and the final results from the Mid-Adult Women study will not be available until next year. However, many older women have received the vaccine. Unfortunately, until FDA approval, there is no insurance coverage.

In the real world, what happens with women getting infected with HPV?

Ault: According to a study done at the student health center at the University of Washington, 50% of women get an HPV infection within the first 3 years of becoming sexually active. Other studies have similar numbers.

Block: About 5% of girls at age 13 have already experienced vaginal intercourse and, by age 16, 50% to 60% are sexually active.

Alexander: Transmission of HPV is not limited to direct vaginal intercourse. HPV is a nonenveloped virus and is stable in the environment. Therefore, transmission of genital HPV does not necessarily require direct genital contact.

Derkay: Condoms alone are not sufficient to prevent the transmission of genital HPV.

Alexander: Condoms are not 100% effective because they just do not cover everything. Nonetheless, in a study of women who had genital HPV and associated cervical abnormalities, the rates of resolution of their cervical abnormalities and the loss of their infections were significantly higher if their partners reliably used condoms. Bottom line, even though condoms are not 100% effective at blocking transmission of HPV infection, they still play a vital role in prevention of HPV-associated diseases.

There is a good body of evidence that says that parents grossly underestimate the sexual activity of their adolescents. How would you respond when a parent says “Well, I’m going to wait until my daughter becomes sexually active, and then I’ll immunize her”?

Block: Odds are reduced. The data show that 85% of sexually active women aged 16 to 25 have not been infected with HPV16, even though they have been sexually active with one to six partners. By waiting for years to be vaccinated, the patient has reduced the odds of having 100% protection (versus 85% protection) that they can get with the vaccine against types 16/18. Optimizing protection is one key to preventing cervical cancer.

How do you bring up the dangers of oral contraceptives and smoking with women?

Ault: Oral contraceptives are contraindicated in women over the age of 35 who smoke. Most patient information brochures about birth control pills will inform women of these risks.

Ferris: It is important to tell all women not to smoke and use oral contraceptives, but many do what they want regardless of the professional advice. Smoking is also an important cofactor for cervical carcinogenesis. HPV infection and smoking are a bad combination, hence an important reason for receiving the HPV vaccine.

What is the emotional and psychological burden of CIN1, CIN2, and CIN3 and genital warts?

Ferris: Both CIN and genital warts inflict significant emotional reactions in girls and women. These are similar reactions to women being diagnosed with any STI or cancer. Women worry about being contagious to others, potential adverse reproductive effects, who gave it to them, and how long they have had it.

Block: Removal of genital warts often involves multiple expensive and painful treatments.

Derkay: The vaccine is going to prevent not only cancers, but also the testing, the treatments of the precancers, the abnormal Pap test that gets followed up by laser surgery, by a colposcopy, by biopsy, by the emotional burden of, “Do I have cancer from this?” With an effective vaccine, you eliminate a large number of those precancer treatments as well as preventing the cancer itself.

Does the vaccine get us out of performing Pap tests?

Ferris: At this point, Pap screening should continue at the same current intervals. For girls, screening should begin 3 years following coitarche or age 21. When liquid-based Pap tests are used, screening every other year is indicated for girls/women up to 30 years old. The rate of abnormal Pap tests, colposcopy examinations and surgery is reduced in women who have been vaccinated.

The HPV vaccine is highly efficacious and the adverse events are minimal. Families need to be warned, however, that the vaccine reduces the risk of disease but does not eliminate it. It is a highly effective vaccine against cervical cancer.