Rural Summer Externship | Experience Reflection
One Rural Externship Grant is given out by the NAFP Foundation each year. Below is an experience reflection submitted by our 2019 extern, Grant Goertzen. To learn more about the externship, click here.
History of Human Papillomavirus Vaccine
Sexually transmitted infections (STIs) have a massive impact on worldwide health. Each day, more than 1 million STIs will be acquired, with over 376 million cases each year.  In the United States, the most common STI is the human papillomavirus (HPV), which will cause 6.2 million new cases each year and currently infects approximately 20 million individuals in the US. [2,3] HPV is a small, double-stranded DNA virus with more than 120 variants, 40 of these being linked with infections of mucosal epithelium, that are differentiated by its outer capsid protein L1 sequence.  The virus targets basal cells of stratified squamous epithelia, causing an infection that is graded as low-risk or high-risk. Low-risk infections are considered non-oncogenic and are associated with genital warts and laryngeal papillomas, such as HPV types 6 and 11. High-risk infections are oncogenic. The virus acts as a carcinogen that can cause anal, cervical, vulvar, or vaginal cancer. There are many types of HPV that are oncogenic, including 16, 18, 31, 33, 45, 52, and 58.  Because of the association of HPV with high morbidity, it was incredibly important for a vaccine to be developed in order to help reduce the incidence of these cancers. For example, over 99% of cervical cancers have been linked to HPV, especially types 16 and 18. Oropharyngeal cancer is also highly linked with HPV, specifically type 16, with approximately 70% of cases potentially caused by the virus. 
The relation between HPV and cervical cancer was first suggested in the 1930s after rabbits developed cancer after having cotton tail papilloma extracts injected. In the early 1970s, HPV was implicated as a potential cause of cervical cancer, but, at the time, the herpes simplex virus was widely considered to be the most likely cause of cervical cancer. This caused researchers to narrow their sights on this virus alone. It was Harald zur Hausen, a German virologist, who began to investigate HPV as the cause. Hausen became the Chair of the Institute of Virology in Freiburg, Germany in 1977 where he and his colleagues experimented with HPV. Their research showed a connection between HPV and genital warts when they were able to isolate HPV types 6 and 11 from genital warts. This prompted research that found the association between HPV and cervical cancer.  In the early 1980s, studies were able to prove the linkage between HPV 16 and 18 and cervical cancer by isolating the virus from cervical cancer biopsies.  Epidemiological and further experimental studies were able to confirm this data in the 1990s. This corroborated evidence prompted further studies and an inquiry into producing a vaccine that could prevent the HPV infection.
Two companies, Merck and GlaxoSmithKline (GSK), developed vaccines using virus-like particle (VLP) technology.  VLPs mimic authentic native viruses by means of a multiprotein structure that impersonates the organization and conformation of the virus without having the viral genome.  Through VPL technology, Merck created Gardasil, while GSK created Cervarix. Gardasil was approved by the FDA in 2006, while Cervarix was approved in 2009. Cervarix is used against HPV types 16 and 18, and the original Gardasil protects against HPV types 6, 11, 16, and 18. The new, Gardasil 9, protects against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Since the introduction of these vaccines, the rates of cervical cancer have fallen drastically. This was evidenced by a study looking at cervical cancer rates among women ages 15-34. It was found that women from 15-24 saw a 29% drop in cervical cancer rates, while women 25-34 saw a decrease of 13%.  As the number of vaccinations continue to increase, cervical cancer rates will continue to fall.
HPV Vaccination Practices
As of 2017, Gardasil 9 is now the only approved HPV vaccine approved in the United States. Gardasil 9 was approved in 2014 by the FDA and protects against 9 types of HPV, as opposed to the 4 types of the initial vaccine.  Gardasil 9 prevents genital warts by blocking HPV types 6 and 11. It also protects against cervical, vaginal, vulvar, and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58. This vaccine has been approved for individuals ages 9 to 45, having been raised from age 27 as of October 2018.  For children ages 9 to 14, the vaccine can be given in 2 doses or 3. For a 2-dose schedule, the second dose should be given 6 to 12 months after the first dose. If the second dose is given less than 5 months after the first, a third dose should be given at least 4 months later. The 3-dose schedule should be given at months 0, 2, and 6. For individuals 15 and older, they should receive a 3-dose schedule also at 0, 2, and 6 months. The duration of immunity has not yet been determined. 
Gardasil 9 has been contraindicated in patients with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of Gardasil 9 or Gardasil (the quadrivalent version). Some may develop syncope with or without tonic-clonic movements or other seizure-like activity. These are transient and vaccinees should be monitored in the clinic for at least 15 minutes following the vaccine. Safety and effectiveness in pregnant women have not been established yet. 
Improving Vaccination Rates at Lincoln Pediatric Group
The HPV vaccination rate in the US is about 49% with approximately 66% of adolescents (ages 13-17) having received the first dose. It is estimated that rural areas are about 11% less. In Nebraska, the HPV vaccination rate is at least 60% of adolescents. While the numbers of individuals receiving the vaccine is rising, it is important to monitor the rates within a physician’s own clinic or patient population. By just knowing a physician’s personal vaccination rates, the physician can recognize low rates and raise these substantially. This was evident when looking at the HPV vaccination rates among Lincoln Pediatric Group (LPG) in Lincoln, Nebraska.
OneHealth ACO is an accountable care organization that works with 19 clinics that includes family practice, obstetrics & gynecology, and pediatrics. LPG is one of these clinics. OneHealth keeps track of how well the clinics they work with perform on quality measures, such as: colon cancer screening, breast cancer screening, and HPV vaccination rates. While the former two do not apply to LPG, the latter does. OneHealth found that the rolling average for LPG’s HPV vaccination rates among Blue Cross Blue Shield (BCBS) members was 16% of 13 years old’s. The BCBC sets a very high bar for vaccination adequacy as it only includes those individuals covered by BCBS that had the complete dose schedule for HPV completed by the age of 13. Even if the patient completed the vaccination schedule one month after the age of 13, they were not included. As such, this does not include the full patient population of LPG and is not a completely accurate representation. This rate, though, was much lower than desired. After discovering this, the rolling average for these rates increased from 16% to 27%. So how did this clinic raise their rates so substantially?
One of the lead physicians saw this data and decided to see how each of the physicians at LPG was doing on their individual HPV vaccination rates. In a vacuum, each physician believed most of their patients were receiving their vaccinations. However, when rates per physician were measured, they varied anywhere from 54% to 97% throughout the clinic. This measured the percent of 13-16-year olds who had been completely vaccinated. Interestingly, once the physicians saw this data, the rates rose. This shows that just having the knowledge of the physician’s personal rates can be enough to increase rates. This was not all, though. The lead physician investigated why the rates varied so widely and found that the way the vaccine was presented to the individual, or rather the parent, would lead to a difference in vaccination rates. Physicians, or whomever presented the vaccine for them, had higher rates when recommending all three vaccines together at the seventh-grade physical (the other two being meningococcal and TDAP). If the parent was presented with the vaccines as being two required and one recommended (since HPV is not required), the parent was less likely to opt having their child receive the HPV vaccine. This shows the importance of wording in terms of vaccines. While the parent does have the option to decline the HPV vaccine, it is important to present it in a way that shows the physician recommends all three at once. It is also highly beneficial to mention how this vaccine can lead to the prevention of certain cancers. The lead physician also found that the physicians with higher rates also presented the vaccine at an earlier point. If the patient comes in for a visit and is at least 9 years old, they are eligible for the vaccine. Thus, offering it earlier may help in increasing the vaccination rate.
This data, while only applying to an individual clinic, offers an idea of a way to improve vaccination rates throughout other clinics and throughout the state. LPG was able to raise rates by 11% in their BCBS patients, which, as mentioned earlier, is the same percent difference between urban and rural areas. Knowing personal vaccination rates and presenting the vaccines earlier as a recommended bundle could be a step to, while not eliminating, narrowing the disparity in HPV vaccinations and raising statewide vaccination rates.
I was lucky to receive the opportunity to spend 6 weeks this summer working with OneHealth ACO, Think Healthcare, and York Medical Clinic. I was able to learn what accountable care organizations (ACOs) are and how they work with physicians and clinics to improve care for their patients, while reducing patient costs. ACOs can collect data from insurance companies about how well the clinics are keeping up on quality measures, like HPV vaccinations, and present that to the physicians. This data can be used to improve clinics and patient care and outcomes, which was evidenced by LPG and their improvement in HPV vaccinations. I am thankful for being able to learn about ACOs like this and getting to see them in action, while also having to opportunity to work with physicians and improve myself along the way.
1. Rowley, J. et al. (2016). Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. [online] Who.int. Available at: https://www.who.int/bulletin/online_first/BLT.18.228486.pdf [Accessed 30 Jun. 2019].
2. Cdc.gov. (2018). Pinkbook | HPV | Epidemiology of Vaccine Preventable Diseases | CDC. [online] Available at: https://www.cdc.gov/vaccines/pubs/pinkbook/hpv.html [Accessed 30 Jun. 2019].
3. Ault K. A. (2006). Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infectious diseases in obstetrics and gynecology, 2006 Suppl, 40470. doi:10.1155/IDOG/2006/40470
4. Merckvaccines.com. (2019). GARDASIL®9 (Human Papillomavirus 9-valent Vaccine, Recombinant) for Health Care Professionals. [online] Available at: https://www.merckvaccines.com/Products/Gardasil9 [Accessed 30 Jun. 2019].
5. Grimes, J. (2006). HPV vaccine development: A case study of prevention and politics. Biochemistry and Molecular Biology Education, 34(2), pp.148-154.
6. Nvic.org. (n.d.). What is the History of HPV Vaccine Use in America?. [online] Available at: https://www.nvic.org/Vaccines-and-Diseases/hpv.aspx [Accessed 30 Jun. 2019].
7. Roldão, A., Mellado, M., Castilho, L., Carrondo, M. and Alves, P. (2010). Virus-like particles in vaccine development. Expert Review of Vaccines, 9(10), pp.1149-1176.
8. Jenco, M. (2018). Cervical cancer declines follow HPV vaccine introduction. [online] aappublications.org. Available at: https://www.aappublications.org/news/2018/08/09/cervicalcancer080918 [Accessed 30 Jun. 2019].
9. Cdc.gov. (2016). HPV Vaccine Information for Clinicians. [online] Available at: https://www.cdc.gov/hpv/hcp/need-to-know.pdf [Accessed 30 Jun. 2019].
10. U.S. Food and Drug Administration. (2018). FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. [online] Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-expanded-use-gardasil-9-include-individuals-27-through-45-years-old [Accessed 30 Jun. 2019].
11. Cdc.gov. (2018). HPV | For Clinicians | HPV Vaccination Coverage | CDC. [online] Available at: https://www.cdc.gov/hpv/hcp/vacc-coverage/index.html [Accessed 30 Jun. 2019]
Submitted by Grant Goertzen, University of Nebraska Medical Center, Class of 2022