A Report On Human Papillomavirus Biology Essay

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I chose to research Human Papillomavirus, more commonly referred to as HPV, for my paper topic. My interest in HPV is threefold. First and foremost, my chosen career path and associated course requirements continue to foster my fascination with science, medicine, and related health issues. Second, I have more than one female member of my extended family who has fallen victim to this seemingly ubiquitous STD, and was interested in further exploring the virus and its effects, and the now controversial subject of treatment. And finally, I have two daughters of my own that I know will grow up sooner than I wish and would like to be well informed on the safety of the HPV vaccine and its recommendation for being added to the pediatric immunization schedule, especially considering the latest reports of adverse reactions.

Background of Subject:

According to the Centers for Disease Control and Prevention (CDC), (genital) human papillomavirus is the most common sexually transmitted infection. Over 100 types of HPV have been identified, but only 40 are transmitted sexually, causing infections in the genital areas in both males and females. These same 40 strains have more recently been implicated with causing infections in the mouth and throat. HPV is a highly contagious virus that is spread by skin-to-skin contact. Mode of transmission includes casual genital contact, and vaginal, anal, and oral sex. Infection types and further complications such as genital warts and certain cancers are strain dependent. HPV related problems include genital warts and HPV related cancers, including, cervical, vulvar, vaginal, penile, anal, and more recently, head and neck cancers. Those that are immunocompromised, such as individuals who have HIV or AIDS, are at a higher risk for HPV contraction.

Genital Warts and Cancer:

Most people who contract HPV remain symptom free. Moreover, the CDC claims that in over 90% of cases, the body's immune system clears HPV naturally within two years. Those that do develop symptoms primarily notice the augmentation of genital warts within a timespan of 6 weeks to 3 months after exposure with an infected partner. Genital warts, or papillomas, appear as a small bump or groups of bumps in the perianal area that have been likened to cauliflower. The warts can appear on female and male genitalia affecting the vulva, vagina, and cervix in females, and penis and scrotum in men. They can also be found on the groin and upper thigh. Interestingly, the strains that cause genital warts are not cancer causing agents.

Pathophysiology of Human Papillomavirus

HPV can cause normal skin cells to turn abnormal. More often than not, an infected person is unable to detect any cellular changes, leaving them oblivious to their infectious state and at high risk for transmitting the virus to another uninfected partner, furthering the chain of transmission. HPV infection can be categorized into "high-risk" and "low-risk" classifications. Genital HPV types are classified accordingly, then, with their epidemiological association with cervical cancer incidence. HPV types 6 and 11, "can cause benign or low-grade changes in cells of the cervix, genital warts, and recurrent respiratory papillomatosis" (Dunne, et al, 2007). These strains are considered to be low-risk types. High-risk HPV strains have been implicated with being the causal factors for cervical, anal, and other genital cancers. According to Dunne, et al, "high-risk HPV types are detected in 99% of cervical cancers, and worldwide approximately 70% of cervical cancers are due to HPV types 16 and 18" (Dunne, et al, 2007).

Disease Incidence and Prevention

Current CDC statistics report that "approximately 20 million Americans are currently infected with HPV, (and that) another 6 million people will become newly infected each year. HPV is so common that at least 50% of sexually active men and women get it at some point in their lives" http://www.cdc.gov/vaccinesafety/Vaccines/HPV/gardasil.html.

Currently, there are two HPV vaccines available to protect against types of HPV that cause most cervical cancers: Gardasil and Cervarix. Gardasil is more commonly used in the United States and Canada, whereas the use of Cervarix dominates in Europe. The Gardasil vaccine contains "purified, inactive proteins that come from the 4 most common types of HPV: HPV types 6 and 11 (which cause 90% of genital warts) and HPV types 16 and 18 (which cause 70% of cervical cancer). The vaccine does not protect against other types of HPV and does not contain any antibiotics or preservatives such as thimerosal (van Zyl, 2007).

Additional research confirms that HPV and cervical cancer incidence is problematic worldwide. India has launched new screening options including a VIA test, or visual inspection after acetic acid application, and a single visit approach to screening and vaccine administration in an attempt to reduce the incidence of HPV transmission and number of death associated with cervical cancer. A current study from Basu and Chowdhury claims that cervical cancer is the number one cause of death in middle aged women in India accounting for 20% of all cancer related deaths (Basu, 2009). Indian medical professionals and scientists recognize the important link between early vaccination and prevention, but certain barriers prevent the availability of the vaccine to young female adolescents, the target population. Health care providers are reluctant to recommend the vaccine due to the personal and cultural beliefs of the general population in India that "girls from reputable families do not require such protection" (Basu, 2009). In addition, Indian parents share the same concern as many other parent opponents of the vaccine do as well, insofar that giving the vaccine conveys the wrong message about pre-marital sex. Cost and inadequate access to quality healthcare, however, remain the leading obstacles in providing the vaccine.

Mendez, et al, who conducted their study in Bogota, Columbia, argue "that the elimination of certain HPV types by vaccination might lead to changes in the distribution of other types by enhancing or decreasing the risk of infection" (Mendez, 2005). This suggestion implies a mutation of the virus possibly decreasing the efficacious effects of the vaccination.


Gardasil, which is a quadrivalent human papillomavirus recombinant vaccine (qHPV), is marketed by Merck & Co., Inc, and was first approved for use by the FDA on June 8, 2006. The drug was recommended for females aged 9 to 26 years old to aid in the prevention of infection with HPV types 6, 11, 16, and 18, those strains being identified as cancer causing agents. The Advisory Committee on Immunization Practices, or ACIP, recommended routine prophylactic vaccinations for girls 11 to 12 years of age and "catch-up" doses for girls between the ages of 13 to 26 (Slade, et al, 2009). Doses are administered intramuscularly, and the preventative and prophylactic effects are based on mounting data stating HPV-16 and -18 cause cervical and anogenital cancers, and HPV-6 and -11 are the most common causes of genital warts (Slade, et, al, 2009). Prior to its market debut and during clinical trials, Merck conducted studies on over 21,000 women. Based on clinical trial data, the Gardasil vaccine was "90% to 100% effective in preventing precancerous cervical, vaginal, and vulvar lesions and genital warts caused by infection with the relevant HPV types (6, 11, 16, or 18) in women aged 15 to 26 years who were uninfected prior to vaccination" (Slade, et al, 2009).

There is much controversy surrounding the Gardasil vaccine, its safety, and its efficacy in the role of cervical cancer and HPV prevention. In 2007, the Wall Street Journal published an article titled "FDA Data on Gardasil May Fuel Controversy," which uncovered new findings of adverse effects post vaccination. At that time, only "1,637 reports of adverse reactions" (had occurred), " not an unusually high number given that two million to three million women (had received) the vaccine" (Carreyou, 2007). A spokesperson for the FDA claimed the agency was closely monitoring any adverse effects associated with the Gardasil vaccine up to that point in time. Gardasil became the subject of much controversy after Merck, Gardasil's parent company, lobbied states to add Gardasil to the mandatory vaccination schedule for pre-teen girls, making it a school requirement similar to other required vaccines. Opposition to a mandatory vaccination was founded by religious conservative groups who claimed the "vaccine (conflicted) with their abstinence message," and parents who worried about the novelty of the vaccine and its effects over time that were yet to be uncovered. Scientists also implied that the billions of dollars spent on drug research and formulation could be better spent on Pap-screening and education of high risk-groups, mainly those from low socioeconomic groups (Carreyou, 2007).

Discussion of Primary Research Experiment


In their published article, "Prevalence of HPV Infection Among Females in the United States," Drs. Dunne, Unger, Markowitz, and accompanying researchers Sternberg, McQuillan, Swan, and Patel set out to do just as the article title implies: assess how prevalent HPV infection was, at the time of their research, in the female population of the United States. Their research was based on the context that "Human Papillomavirus (HPV) infection is estimated to be the most common sexually transmitted infection, (and the belief that) baseline population prevalence data for HPV infection in the United States before widespread availability of a prophylactic HPV vaccine would (have been) useful" (Dunne, et al, 2007). The researchers acknowledged the advent of a prophylactic vaccine and supporting efficacy of the vaccine in preventing infection and disease.

Experimental Tests/Protocols

Experimental tests included a sample population study with interview, specimen collection, DNA isolation, HPV Genotyping test, and a statistical analysis. This study was encompassed as part of a larger survey, the National Health and Nutrition Examination Survey 2003 - 2004, or NHANES, that is routinely conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention. Researchers used a representative sample of noninstitutionalized civilian population. This sample was obtained by using " a complex, stratified, multistage probability sample design with unequal probabilities of selection to obtain a nationally representative sample" (Dunne, et al, 2007). Certain minorities were oversampled, including non-Hispanic blacks, Mexican-Americans, and girls of adolescence. Participants ranged in age from 14 - 59. There were 2482 initial candidates eligible for participation. These initial candidates were interviewed in their homes, but only 2387 were eventually examined at the mobile examination center, the locus of specimen collection for the study.

A final total of 2026 candidates submitted cervicovaginal swab specimens for study. The discrepant 466 females were dubbed nonresponders because they "either submitted an inadequate swab specimen or did not submit a swab specimen (at all) (Dunne, et al, 2007).

Mode of collection included a self-swab of a cervicovaginal sample in the mobile examination center. Each candidate was given a collection device that included a foam swab inside an individual reclosable plastic sleeve. Participants received instructions to wash their hands before opening the swab, how to correctly hold the swab and insert it into the vagina to maximize sample validity, and how to replace the swab into the plastic sleeve in order to avoid contact and cross contamination with external genitalia. All participants collected the samples in private and independently. Upon completion, the swabs were given to NHANES personnel and mailed to the CDC lab for processing (Dunne, et al, 2007).

DNA was extracted from the samples within 1 month of collection using slight modifications of the QIAmp Mini Kit Protocol. The swabs were incubated at 56 degrees Celsius for a minimum of 12 hours in proteinase K lysis solution. Eluates were collected, washed, and concentrated in Microcon 100 concentrators. Samples were either tested immediately or stored at -20 degrees Celsius. HPV genotyping was achieved by using the Roche prototype line blot assay. "This assay uses HPV L1 consensus polymerase chain reaction with biotinylated PGMY09/11 primer sets and B-globin as an internal control for sample amplification" (Dunne, et al, 2007). Gel electrophoresis methods, stained with ethidium bromide, were also used.

Statistical analysis was conducted using a SAS version 9.1 method. Variations in demographic estimates were computed using a Taylor series linearization that coalesced the complex sample design previously outlined. All estimates were weighted using 2003-2004 medical examination weights provided by the National Center for Health Statistics. The Wald x2 statistic was used to test association between HPV and demographic and behavioral characteristics. Age was categorized into 4-year intervals to examine the association between age and overall HPV prevalence. These intervals were plotted against log odds of HPV (Dunne, et al, 2007).

Experimental Controls and Variables Used

Controls identified in the overall experiment constitute parts in the DNA isolation methodology, HPV Genotyping, and specimen collection. For every 40 samples from which DNA was being extracted, "a water blank was processed through all steps of extraction to serve as a contamination (and inherent) control" (Dunne, et al, 2007). Likewise, during the HPV detection and typing step, the Roche prototype line blot assay served as an internal control mechanism, as previously mentioned. Variables identified include demographic and lifestyle variances, namely age, race, and sexual activity levels. Another variable was the establishment of responders vs. nonresponders, which affected the final numerical outcome of candidates.

Results: HPV Prevalence Overall and by Age

In total, 2026 female vaginal specimens were collected for the 2003-2004 NHANES experiment. Only 1921 specimens were actually adequate, and of this cluster, 26.8% tested positive for HPV DNA. In correspondence to 2000 Census data, this percentage roughly corresponded to 24.9 million females in the age range of 14 to 59 with prevalent HPV infection. Infection was highest among females aged 20-24, and there was a "statistically significant trend for increasing HPV prevalence with each year of age from 14 to 24 years" (Dunne, et al, 2007). The researchers also restricted the analysis to sexually active females; data still supported the highest prevalence of HPV among participants between the ages of 20-24 years. (Refer to Table 1 in Appendix 1).

Experimental Conclusions/Findings

Data indicated that, at the time of this study, the overall prevalence of HPV infection in the United States was higher than previously estimated. Data also supported the overall finding that prevalence of HPV-16, a high-risk strain, was low and that other HPV types prevailed in participants, mainly HPV-84 and HPV-62. This is in stark contrast to most other studies. The authors attributed these differences to population based studies outside of the United States rather than clinical setting studies. The authors state several limitations to their study. Those named include nonresponders and demographic variables, method of sample collection, and limited number of years of data (only 2). Nonresponders were characterized by significant demographic differences than responders, mainly race, age, country of origin and honest reflection of sexual activity. These demographic differences possibly provide bias. Self-collected cervicovaginal samples, as were obtained in this study, may not have detected the same HPV types as swabs obtained by health care professionals, questioning the credibility of the sample pool (Dunne, et al, 2007).

Questions Not Answered by This Study

My primary research article discussion was based on a JAMA journal article published in 2007, enlisting data from an NHANES 2003-2004 experiment and population information based on the U.S. Census2000. While the date remains well within our paper requirements, i.e. primary journal articles published between 2007-2010, the research and data findings from the experiment are already dated in terms of science, health news, and medicine. Also, the focus of the article was HPV prevalence and really did not address any valuable data or news surrounding prevention of infection and HPV related diseases. Additional review of literature and data allowed me to further explore the topic of the vaccine, its efficacy, and safety.

The HPV Vaccine and Implications for Human Use

All literature and data reviewed for the purposes of this paper indicate two consistent findings. Certain strains of HPV have been implicated in causing cervical and other anogenital cancers (types 16 and 18); types 6 and 11 are known as "non-oncogenic strains (that) are associated with the development of external genital disease, namely genital warts" (Rambout, et al, 2007). Another finding is that for females with no previous infection, the Gardasil vaccine has proven 90% - 100% effective in prevention of disease. Why, then, is there opposition in promoting and administering this vaccine prophylactically if the vaccine has proven effective and can be used to decrease morbidity and mortality?

Recently, reports of adverse affects post-Gardasil-vaccination have surfaced, raising questions of its safety. As recently as August 19, 2009, the JAMA published reports of serious and less serious adverse reactions including: local injections site reactions; syncope, dizziness, and nausea; headaches; hypersensitivity reactions; reports of Guillain-Barre Syndrome; transverse myelitis; motor neuron disease; venous thromboembolic events; pancreatitis; autoimmune disorders; complications with pregnancy; and reports of death (Dunne, et al, 2007).

The FDA and CDC have addressed these reports of adverse effects. As of January, 2010, 28 million doses of Gardasil have been distributed in the United States. CDC Adverse events have been reported in association with Gardasil only, and not Cervarix. This may be attributed to the fact that Cervarix is newer on the market. Actions taken by the CDC and FDA include reminders sent to immunization providers about the recommendation for use and administration; follow up on the two neurological deaths reported (tissue sample analysis at the CDC laboratory); and closer surveillance of adverse reactions, especially blood clots, pulmonary emboli,and syncope http://www.cdc.gov/vaccinesafety/Vaccines/HPV/gardasil.html.

Opposition of the vaccine and the vaccination of adolescent girls really lies in the hands of American society, and how societies and cultures worldwide view sexuality and promiscuity. Many US conservatives have dubbed it "'the promiscuity vaccine,'" while (other) anti-vaccinationists targeted mandatory vaccine legislation and safety and efficacy" (Casper, 2008). Parents in the United States and worldwide, as outlined in the study from India, worry that administering the HPV vaccine will encourage adolescents to engage in sexual activity at an earlier age. This fearful belief has even shaped pediatricians' views on whether or not to vaccinate in their own practice. Hollander conducted a 2007 study of 294 physicians and their beliefs of parental standpoints of the HPV vaccine. Physicians reported being more comfortable vaccinating 13-15 year-olds vs. 10-12 year old females, predicting that parents would be more open to discussion about the vaccine and sexuality with the older age group. Overall, the physicians reported "(they) did not think that being inoculated against HPV infection would encourage youngsters to engage in risky sexual behavior; (rather) only 11% expressed this belief." (Hollander, 2007).


The research reviewed for the purposes of this assignment overwhelmingly stress the importance of early vaccination, should the vaccination be chosen as a preventative measure. Although there are effective vaccines available to prevent cervical cancers, not all populations have access to quality healthcare and thus prophylactic measures. These high- risk groups include those of low socio-economic status and minority groups in the United States, and uneducated persons and those who live in poverty internationally. The unknown and long-term efficacy of the Gardasil and Cervarix vaccines remains to be seen, and this in itself might be comforting for parents of young children, especially girls, who will be able to monitor the evolution of the drug and disease over time. Finally, there is a considerable movement in the nursing community, and the health community in general, to promote health and wellness, and positive health measures and beliefs. "In order to promote gynecological health and increase cervical cancer prevention, women need a better understanding of HPV as a potential precursor... and healthcare providers need to focus on women's health beliefs" (Montgomery, 2010). This supports the idea that all women, and men, for that matter, need to take ownership of their own health and wellness and play an active role in their health promotion and maintenance.


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