A Discussion on Human Papillomavirus Vaccine Efficacy and ControversyObjectives:This report will discuss the efficiency of human papillomavirus (HPV) vaccines and it will touch on some of the social and ethical controversies surrounding vaccination programs for sexually transmitted diseases. HPV’s direct connections to many types of cancers which require different vaccination processes and work. Thus, further understanding of HPV biology is not just recommended, but urgently needed. Specifically, the efficiency of the vaccine on different carcinomas, in different genders and age groups. While also looking at the therapeutic uses of the vaccine and use in secondary prevention. The main question being addressed here is whether the benefits of vaccination compensate for the risks involved and for the ethical issues.Introduction: “HPV infection remains one of the most commonly sexually transmitted infections in both females and males”  (White, 2014). White goes on to say that effective vaccination processes have been available globally for quite a while now, but problems still do arise. Of course, it is quite understandable that ethical and practical concerns will show up when dealing with vaccination for diseases that have been made taboo by societies (due to association with sexual activities) especially when dealing with the younger patients. “There has been an explosion of literature regarding HPV vaccination programs and the relative difficulty in adopting the vaccine series with a completion rate of under 50% of patients in the recommended age ranges for vaccination” (White, 2014). Certainly, there are current efforts being made to increase that percentage of completion and hopefully have globally wide immunization programs that offer both vaccination and the corresponding needed education and information for the population.Before understanding the realities of the vaccination process and what problems the medical facilities deal with, one must first fully comprehend the biology of the virus. “HPVs are a group of double-stranded DNA viruses famous as the primary cause of cervical cancer, however, evidence has now established their role in non-melanoma skin cancers, head and neck cancer, and the development of other anogenital malignancies” (Mattoscio, et al., 2018). For example, penile cancer is a very aggressive and very rare disease, and “up to 50% of penile carcinomas are HPV-related “ (Schlenker & Schneede, 2018). Thus, a dramatic reduction of several types of cancer can be achieved by using an HPV vaccination program for both sexes from an early age.These double-stranded DNA HPVs just like other viruses have a certain control over autophagy. Autophagy is a natural occurring process in the body (responsible for the degradation of cell organelles and proteins, “recycling”) however when essentially it gets hijacked by viruses during viral infections or cancers, it results in further complications in the body. Current research suggests a link between HPV and autophagy, “leading to the conceivable development of novel anti-viral strategies aimed at restraining HPV infectivity” (Mattoscio, et al., 2018). Although autophagy is understood in a molecular level now, there is still research being made in to the process of intracellular component degradation how it provides a nutrient source to promote survival of cells in metabolic distress. “At its later stages this would lead to apoptosis, but also activates autophagy, which may degrade intracellular components and provide fuel for mitochondrial bioenergetics. The precise metabolic role of autophagy and how it intersects with the apoptotic pathways in growth factor withdrawal, however, has been uncertain” (Altman & Rathmell, 2009).Figure 1: (Mattoscio, et al., 2018)In figure 1 shown above the following process is visualized: “HPV16 binding and internalization inhibits autophagosome formation. HPV virions with HPSGs interact with EGFRs present on the plasma membrane of target cells, resulting in Akt and PTEN phosphorylation, and in phosphorylation and activation of mTOR. Activated mTOR phosphorylates and inactivates ULK1, present on isolation membranes, inhibiting autophagosome nucleation and, therefore, delays L1 digestion and capsid degradation inside autophagosomes” (Mattoscio, et al., 2018)“Mainly HPV is transmitted sexually; therefore, the risk for penile cancer is increased 3–5-fold by multiple sexual partners and early age of first intercourse [15, 16 is considered early] in a population without HPV vaccination. Kid’s gender-neutral HPV vaccination will enable reduction of all HPV-related cancers (not just penile cancer) for the entire population and even in boys who grow up to be homosexuals. Furthermore, circumcision when young might reduce the incidence of some subtypes of penile cancer” (Schlenker & Schneede, 2018).Clinical Trials Discussion:  There are two clinical trials being reviewed in this report, one study assesses the immunogenicity and safety of a double dose schedule of the AS04-HPV-16/18 vaccine compared to the double dose and triple dose of the 4vHPV vaccine in young girls (Ages: 9-14). So, this is looking at primary level prevention and the efficacy of HPV vaccines in increasing antibodies. The second study assess the immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine in HIV-positive Spanish homosexual men. So, this is looking at secondary level intervention (therapeutic, treatment) and thus has placebo groups for comparison. Of course, the results from both studies are addressing different things but both will help draw an image of how the research field currently looks and the most efficient treatment and prevention methods for different ages and gender. The first study (young girls) discusses the results: “The recent licensure of 2D schedules of the HPV vaccines for adolescents is crucial for global public health, because this will most likely facilitate the introduction of vaccination programs in third-world countries. Furthermore, this may help improve the relatively low vaccine coverage and series completion rates observed in a few first-world countries”(Leung, et al., 2018). The second study also showed the safety and availability of the vaccine by highlighting how “there were no serious adverse events attributable to the vaccine, this suggests that patients could benefit from receiving qHPV vaccine. Older age was the main protective factor against HR-HPV infection, and non-suppressed HIV viremia was a risk factor” (Hidalgo-Tenorio, et al., 2017).Figure 2: (Leung, et al., 2018)Figure 2 above relays the statistical data gathered by the first study and shows the serostatus of the sample group under each vaccination program. For the antibody responses, it also shows ATP after 36 months for each of the three programs. Further antibody responses: “In each group, all initially seronegative subjects from the ATP cohort had seroconverted for HPV-16/-18 antibodies at M7 when measured by ELISA and PBNA. At M36, all initially seronegative subjects (100%) from the 2D AS04-HPV-16/18 group and nearly all subjects from the 2D (99.3%) and 3D (99.7%) 4vHPV groups had seroconverted for anti-HPV-16 antibodies when measured by ELISA. For HPV-18 antibodies, all subjects (100%) from the 2D AS04-HPV-16/18 group were still seroconverted at M36. In the 4vHPV 2D and 3D groups, a proportion of subjects became seronegative during the study, i.e. 13.9% with 2D 4vHPV and 7.2% with 3D 4vHPV” (Leung, et al., 2018).Although, the first and second studies discussed above are talking about different types of HPV vaccines, we can get a general idea about the attention that is being given to the field and the amount of research being conducted in this area. This brings us to the second aspect of this discussion which relates less to the efficacy and dosage but to the actual practical and ethical issues associated with the vaccine and HPV generally.Controversy Discussion: Now that we fully understand what the current results on HPV vaccination efficiency have to say, we are free to discuss the socio-economic aspects of vaccination and the ethical issues related to sexually transmitted diseases. The main issue starts with age; “public health institutes currently recommend an HPV vaccination of kids of both sexes at the age of 9–14 yrs. (catch up vaccination to age of 17 yrs.) to prevent HPV-related diseases” (Schlenker & Schneede, 2018). Now this puts pressure on the kids’ parents to explain the sexual nature of the disease and here is where uncomfortableness may arise. With different vaccination methods and research out there, it is difficult for medical officials to fully educate the parents on the topic and the risks involved. It is even more difficult then, for these parents, to relay that information to the kids. This however, does not mean that vaccination (HPV particularly) has no side effects. There are complications that may arise with several reports showing symptoms such as fainting, local reactions at the site of immunization, dizziness, nausea, and headache and even a few reports showing deaths (White, 2014). However, “upon further screening of the reported deaths, there were no common patterns to the deaths that would suggest that they were caused by the vaccine. Some of the deaths were attributable to diabetes, viral illness, illicit drug use, and heart failure” (White, 2014). Clearly, the side affects are rare and not very serious. So, the real controversy is more focused on ethical rather than practical issues. “Several ethical issues are highlighted in analysis; including whether to vaccinate people who have opted to abstain from sex and whether obtaining the vaccine increases the early onset of sexual relations” (White, 2014). With the latter being a reoccurring topic for several debates whenever HPV vaccination is being promoted in a new region. At the very end parents make this decision for their kids and probably this accounts for the vaccination programs not being completed. “Physicians cite financial concerns and parental attitudes, while most parents require more information about the vaccine before they will consent to administration. Just like other interventions, the parents look to the clinician for the ultimate recommendation to vaccinate.” Thus, it is crucial that medical facilities educate parents and not rely alone on schools for immunization programs. Schools can hold conferences and lectures, with medical professionals, to explain the benefits and risks of HPV vaccination to parents and students. This will promote vaccination course completion and reduce risks of HPV related carcinomas. Conclusion:“Despite the ethical concerns raised, the benefits of vaccination with regard to cancer prevention outweigh the risks and potential side effects related to the quadrivalent vaccine administration” (White, 2014). More recent research suggests the increasing efficiency of new HPV vaccinations. Different types of HPV vaccinations and dosage courses are continuously being tested clinically. Such was the research shown assessing the immunogenicity and safety of a double dose schedule of the AS04-HPV-16/18 vaccine in young girls. “Furthermore, there is no defined correlate of protection for HPV, however, the higher immune response observed following vaccination with AS04-HPV-16/18 can suggest a longer period of protection or prevention” (Leung, et al., 2018). Thus, showing that research is still being updated and new observations are being made even at this very moment. So, we can have an optimistic outlook towards the future of HPV vaccination and the corresponding reduction in HPV related carcinomas. The same outlook can be also shared with therapeutic HPV vaccination for secondary prevention at the clinical stage of penile cancer (specifically), and other carcinomas (generally), where the mode of intervention is just not health promotion but actual treatment (Schlenker & Schneede, 2018). So not only have HPV vaccines proven useful across different genders, sexual orientations, and age groups; but they also help in treatment at the therapeutic level for several carcinomas.ReferencesAltman, B. & Rathmell, J., 2009. Autophagy: not good OR bad, but good AND bad. Autophagy, 5(4).Hidalgo-Tenorio, C. et al., 2017. Safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccine in HIV-positive Spanish men who have sex with men (MSM). AIDS Research and Therapy, 14(34).Leung, T. et al., 2018. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9-14?years: Results to month 36 from a randomized trial.. Vaccine, 36(1), pp. 98-106.Mattoscio, D., Medda, A. & Chiocca, S., 2018. Human Papilloma Virus and Autophagy.. International Journal of Molecular Sciences, 19(6).Schlenker, B. & Schneede, P., 2018. The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents.. European Urology Focus, Issue 18, pp. 2405-4569.White, M. D., 2014. Pros, cons, and ethics of HPV vaccine in teens—Why such controversy?. Translational Andrology and Urology, 3(4), pp. 429-434.