A Review of Human Papillomavirus Vaccination and Associated Ethical Concerns

Abstract

Since its Fast-Track approval by the Federal Drug Administration, the human papillomavirus (HPV) vaccine has been marked by controversies. Unconfirmed reports of adverse events in both Japan and Denmark led to suspensions of national vaccination programs, which setback the fight against cervical cancer and associated mortality and morbidity. Despite follow-up studies of vaccine adverse reports, additional randomized control trials, and review reports from both the World Health Organization and the European Commission, there is still a great deal of hesitancy around the vaccine. While all three version of the HPV vaccine have been shown to be efficacious and safe, additional ethical dilemmas deserve to be considered as well.

Introduction

The human papillomavirus (HPV) is a sexually transmitted disease that has been associated with the development of cervical cancer, anal cancer and oropharyngeal cancer, as well as genital warts. While there are greater than 150 HPV genotypes, thirteen of them have been shown to cause cervical cancer, with HPV genotypes 16 and 18 accounting for 66% of total cervical cancer cases and 50-60% of cases of cervical intraepithelial neoplasia 2+ (CIN 2+) [1]. HPV genotypes 31, 33, 45, 52, and 58 cause an additional 15% of the cervical cancer cases in the United States (US) and 25% of the cases of CIN 2+ [1]. Cervical cancer itself is the fourth most prevalent cancer worldwide, and fourth in mortality. Globally, there have been 570,000 new cases and 311,000 deaths in 2018 [2]. In the US, 12,000 women are diagnosed with cervical cancer yearly, 4,000 of whom die from it [3]. Furthermore, 90% of cases of genital warts are caused by HPV genotypes 6 and 11, and, in males, HPV 16 or HPV 18 are associated with 65% of anogenital or oropharyngeal cancers [1].

The HPV vaccines aim to prevent the development of the diseases listed above by preventing people from acquiring different HPV genotypes. There are three types of HPV vaccine which are noninfectious, virus-like particle (VLP) vaccines: a bivalent vaccine (2vHPV) which is protective against HPV genotypes 16 and 18; a quadrivalent vaccine (4vHPV) containing 6, 11, 16, and 18 VLPs; and a 9-valent vaccine (9vHPV) which contains 6, 11, 16, 18, 31, 33, 45, 52, and 58 VLPs [4]. The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for females aged 13–26 with 2vHVP, 4vHVP or 9vHVP, while recommending males aged 13–21 be vaccinated with either 4vHVP or 9vHVP [4]. The 9vHVP vaccine proved efficacious in prevention in CIN 2+ caused by HPV 31, 33, 45, 52 or 58 at 96.3%, while remaining noninferior to 4vHVP for HPV 6, 11, 16, and 18 [4].

While HPV vaccines have been shown to prevent the acquisition of HPV, there are some questions about the costs and benefits of the vaccine. This review attempts to assess the total benefits of HPV vaccine while considering the controversies associated with it. First, the controversies and hesitancy surrounding the vaccines will be briefly explored. Second, the unconfirmed adverse events will be addressed along with the vaccines’ side effects. Third, the vaccines’ benefits and efficacy will be examined. Finally, we offer current opinion and policy on many of the ethical concerns surrounding the HPV vaccination programs (Table 1).

Table 1. Summary of main pros and cons of the HPV vaccine.

Section	Key points
HPV’s impact	- HPV is linked to cervical, anal, oropharyngeal cancers, and genital warts
	- 13 HPV genotypes cause cervical cancer, with types 16 and 18 causing 66% of cases
	- Cervical cancer: 4th most prevalent and deadly cancer globally
	- 90% of genital warts cases are caused by HPV types 6 and 11
	- Three HPV vaccines: bivalent (2vHPV), quadrivalent (4vHPV), and 9-valent (9vHPV)
	- ACIP recommends vaccination for females (13–26) and males (13–21)
Controversies of HPV vaccines	- FDA fast-tracked Gardasil approval despite concerns over evidence sufficiency
	- Japan suspended its HPV vaccination program in 2013 due to adverse event reports and media influence
	- Suspension led to increased cervical cancer mortality and preventable deaths
	- Denmark recovered vaccination rates through national campaigns
Adverse events and side effects	- Injection site reactions: pain, erythema, swelling
	- Systemic effects: headache, fever, syncope
	- Inconclusive links to CRPS, CFS, POTS, Guillain-Barre syndrome
	- Phase III trials and reviews found no new safety concerns and low rates of serious adverse events
	- WHO and European Commission reviews found no causal links to serious conditions and recommended continued vaccination
Efficacy	- HPV vaccines effectively reduce infections, genital warts, and cervical precancer lesions
	- 2vHPV, 4vHPV, and 9vHPV vaccines produce lasting antibody responses
	- 9vHPV covers more HPV types and is non-inferior to 4vHPV
	- Modeling studies show HPV vaccination is cost-effective
Ethical concern	- Parental consent: Barriers exist in adolescent vaccination without parental consent; adolescent autonomy is supported by medical associations
	- Abstinence: Vaccination before sexual activity is more effective and cost-effective
	- Male vaccination: Protects against HPB-V-associated cancers and contributes to herd immunity
	- Parental re-education: Importance of vaccinating before sexual maturity for highest efficacy

HPV, human papillomavirus; ACIP, Advisory Committee on Immunization Practices; FDA, Federal Drug Administration; CRPS, complex regional pain syndrome; CFS, chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome; WHO, World Health Organization.

Controversies

1. Federal Drug Administration (FDA)

Since the creation of the HPV vaccine and its subsequent approval by the US FDA in 2006, its implementation around the world has been marked by controversies. Gardasil, the 4vHPV, was heavily marketed and lobbied by its producing company, Merck, and received Fast Track approval from the FDA [5]. However, authors such as Tomlijenovic and Shaw question how swiftly the approval was given based on what they believed to be insufficient evidence for its safety and efficacy.

2. Japan

In Japan, the national HPV vaccination program began in December 2010; however, it was suspended in June 2013 after reports of adverse events. After committee review, no evidence of causal association between the HPV vaccine and the reported events was found. Nevertheless, the vaccine was not reinstated. Sensational and increasingly negative media reports led to increasing distrust of the vaccine [6]. Furthermore, the Japanese media and anti-vaccination movement encouraged vaccine recipients who experienced adverse events to place blame on the HPV vaccine without proper consideration [7]. This led to a drastic decline in HPV vaccination rates.

Japan lost an opportunity to face cervical cancer and its associated mortalities and morbidities effectively the way countries such as Australia and the United Kingdom had been able to [7]. Mortality from cervical cancer increased in the past ten years [6]. Additionally, based on modeling, it was estimated that by discontinuing the vaccine program from 2013 to 2019 (the year when the modeling was conducted), 5,000 preventable deaths from cervical cancer will result [9]. From 2013 to 2015, HPV vaccination in Denmark received a similar period of negative press. Subsequent national information campaigns restored vaccination levels to pre-2013 levels, offering hope for a similar recovery in Japan [10].

Adverse events and side effects

1. Injection site side effects

Due to the controversies around the HPV vaccine, its adverse events and injection side effects warrant an extended review. Klein et al found that side effects are mostly limited to be local skin infections that present within two weeks of vaccination [11]. In other cases, patients would have same day episodes of syncope, yet these instances tend to be rare and are a common psychological reaction to most vaccinations [11,12].

Evaluation of seven phase III trials, including both male and female subjects between ages 9 and 26, has found the 9vHPV to be responsible for common injection site side effects such as pain, erythema, and swelling, as well as vaccine-related systemic effects such as headache and fever [12]. More concerning though are the safety concerns raised by some after wide-spread vaccination implementation.

2. Inconclusive safety concerns

Some potential adverse events identified through case reports include complex regional pain syndrome (CRPS), chronic fatigue syndrome, postural orthostatic tachycardia syndrome (POTS), and Guillain-Barre syndrome [13]. Additionally, headache, dizziness, fatigue, and syncope as identified in VigiBase, the World Health Organization (WHO) global database of drug adverse event reports for medicines and vaccines, were more commonly reported when compared to non-HPV vaccinations. However, the finding does not imply a causal relationship with the HPV vaccine [13].

An analysis based on a Nagoya City survey found a possible association between memory impairment, involuntary movements, and HPV vaccination. However, again, the analysis could not demonstrate causal relationships [14]. Furthermore surveys are susceptible to reporting biases.

3. Low adverse events

While many studies found concerning associations, more found a lack of new safety concerns. A study with patients who received the 9vHPV analyzed over 28 million administrations of the vaccine with two reported deaths; neither of which were found to be associated with the vaccination [15]. For the 4vHPV, Arana et al. did not find new safety concerns after studying the US’s Vaccine Adverse Event Reporting System [8]. A low number, 19 cases per million doses distributed, of serious adverse events were reported, and there were also no patterns to the deaths reported. Furthermore, a review of 109 studies including over 2.5 million vaccinations found no evidence of CRPS or POTS for 2vHPV, 4vHPV, and 9vHPV [16].

4. Results from randomized control trials

In addition to reviews of adverse event reports, multiple randomized control trials were conducted following the rise in HPV vaccine hesitancy. In a phase III randomized control trial of 1,124 Japanese men, the 4vHPV was found to be safe with side effects of injection site pain and swelling [17]. In a phase III randomized control trial of 4407 women, the bivalent AS04-adjuvanted HPV vaccine was found to be safe and effective against cervical lesions and infections [18]. 0.2% serious adverse events were reported in the experimental group versus 0.3% in the control group [18]. In a randomized control trial of 418 young girls given the 2vHPV, after a 10-year follow-up no serious adverse effects were found and antibody were sustained [19]. Combining 7 phase III trials with over 15,000 subjects, Moreira et al. found that serious adverse events were rare (<0.1%) for the 9vHPV.

5. WHO and European Commission

Due to public concern, after the unconfirmed reports of adverse events associated with the HPV vaccines, both the European Commission and the WHO decided to review the vaccine’s safety and efficacy.

The European Commission requested the European Medicines Agency to review the available evidence and form an opinion on the continued implementation of the HPV vaccine. Following a comprehensive review of the available HPV vaccines, their efficacy, and possible risks, the European Medicine Agency recommended the continuation of vaccination based on risk-benefit analysis. The Agency found no causal relationship between the HPV vaccines and CRPS and POTS [20].

In 2017 WHO published its own review. At the time of the review, over 270 million doses had been administered. The rate of anaphylaxis was established at 1.7 cases per million and syncope was found as stress-induced. Addressing recent concerns, the report found that Guillain-Barre syndrome was not associated with the vaccine, that there were no pregnancy concerns, and that there was no causal evidence for CRPS and POTS. In terms of the vaccine’s intended effect, countries that have made the vaccine part of their immunization program have seen 50% decreases in cervix lesions. The report recommends the continuation of HPV vaccine implementation [21].

Efficacy

HPV infections can cause genital warts or precancerous lesions that develop into cervical cancer [22]. Globally, there were 570,000 new cases and 311,000 deaths in 2018 [2]. Unlike other types of cancers, in which we are unaware if a direct cause exists, HPV has been found to be a primary factor in causing cervical cancer [2].

Multiple phase III randomized control trials have demonstrated the efficacy of all three types of HPV vaccines (2vHPV, 4vHPV, 9vHPV) against HPV infections and its resulting mortality and morbidity. Across a 10-year span, various US studies found a decrease in genital warts, and cervical precancer lesions among young US women who received 4vHPV vaccine [23]. In the previously mentioned phase III study involving 1,124 Japanese men, the 4vHPV vaccine was found to be effective against HPV type 6/11/16/18 [17].The phase III study of 4,407 women found the 2vHPV (type 16/18) to be effective against cervical lesions and infections [16]. In a randomized control trial involving over 18,000 young women, the same vaccine was again shown to be effective against cervical neoplasia [24]. A Cochrane review found that non-valent, 2vHPV, and 4vHPV also produced lasting antibody responses [25].

The more recently approved 9vHPV protects against HPV type 6/11/16/18 and also HPV type 31/33/45/52 [26]. In a randomized control trial founded by Merck, the 9vHPV group experienced fewer infections, cervical lesions, and cervical procedures [26]. Immunogenicity was found to be non-inferior to the 4vHPV as well [4]. Overall, modeling studies have demonstrated the cost effectiveness of HPV vaccines; they are a cost-effective use of public resources to reduce both mortality and morbidity associated with HPV diseases [23].

Ethical Concerns

1. Should children be vaccinated without parental consent?

Despite receipt of the HPV vaccine being highly encouraged, the healthcare industry has repeatedly noticed the rates of HPV vaccines falling short of the indicated public health goals due to medical-decision making authority remaining in the hands of the legal guardian [27]. Between the lack of voice from the younger generation, misinformation received by their elders, and the persistent denouncement of the vaccine, guardians are taking matters into their own hands and preventing vaccination. What the majority of adolescents are unaware of, though, is that US state laws grant adolescents the ability to self-consent to sexually transmitted infection (STI) diagnosis and treatment [27].

This barrier has been very poorly explored on an ethical basis and to prevent any sort of malpractice, physicians try to avoid vaccinating children without direct parental consent. However, it has recently come to light that there are certain issues that prove it is in the best interest of the patient, and physician, to consult adolescents without parental consent. These include sensitive issues such as STI diagnosis, substance abuse, and suicide prevention [27]. A large and growing number of prominent medical associations, including the American Medical Association, the American Academy of Paediatrics, the Society of Adolescent Medicine, the American Academy of Family Practice and the American College of Obstetrics and Gynaecology all have shown their support for classified adolescent care and with the proper resources, adolescents will grow into responsible, autonomous young adults [27].

2. Should people who abstain from sex be vaccinated?

With the given information, global adoption of HPV vaccination would allow for widespread prevention in cervical cancer. However, there are some ethical considerations that arise in proposing a universal vaccination, such as to vaccinate someone who will refrain from sexual relationships. To start, the recommended age range that children be immunized is between the ages 9 and 12 [28]. If an adolescent decides to maintain absolute abstinence, then they would avoid high-risk exposures to HPV infection. However, the choice to maintain absolute abstinence is not an easy one to make, especially at the recommended age of vaccination. If an individual changes their mind, can they be vaccinated later in their life and still reap the benefits? The short answer is yes, but efficacy of the vaccination drops with age due to changes in antibody activation [29].

While potential potency of the vaccine declines with age, chance of sexual interactions increases, providing opportunity for an even greater decrease in efficacy upon potential HPV infection [29]. Not only does vaccinating at a young age provide increased efficacy, but it is also the most cost-effective period for HPV vaccination. One study examined the cost-effectiveness in HPV vaccinations in the preadolescent years, as well as a catch-up program for females into adulthood assuming lifelong immunity [30]. This paper found the cost of vaccination of pre-adolescent girls was half that of the cost of catch-up vaccination of girls at 18 years of age [30]. Rather than arguing complete abstinence as a reason to not vaccinate at a young age, parents should be educated on delaying sexual relations and the consequences of unprotected sex or HPV infection.

3. Should young males be vaccinated?

Although males cannot develop cervical cancer, HPV vaccination can prevent other forms of cancer such as penile and anal cancers [22]. Additionally, universally vaccinating young boys will provide herd immunity and the inability to transmit infection to others in a heterosexual relationship, thus reducing the rates of cervical cancer as well. In fact, the Centers for Disease Control and Prevention (CDC) found that including young males in the group to be vaccinated, originally directly at young females, would be cost-effective [31]. Unfortunately, there is a discrepancy in the amount of adolescent females (60%) and adolescent boys (42%) being immunized. This is possibly due to the continuing stigmatization toward the HPV vaccine, and how its primary function is believed to be the prevention of cervical cancer in females. This is simply not true as stated previously that HPV vaccines can protect males from other types of cancers and also can help achieve herd immunity by preventing transmission in a heterosexual relationship. Therefore, it is important to educate parents and adolescents on the significance of HPV immunization for both males and females.

4. Should parents be re-educated on the purpose of HPV vaccination?

With the undeniable connection between HPV infection and a primary cause of cervical cancer as well as other types of malignancies, one would assume that HPV vaccination would have a high coverage. But according to the CDC, only 51% of teenagers from 13–17 were up to date on their HPV vaccinations [32]. Although the number of adolescents immunized with the HPV vaccine has increased over the years, it still is significantly low compared to other recommended vaccinations [33].

A possible reason there is such a discrepancy could be attitude towards a vaccine that is a preventive measure against a sexually transmitted virus. Due to the virus being sexually transmitted and the fact that recommended time to vaccinate is in the preadolescent years, parents may have the belief that only sexually active people need this vaccination thus delaying their children from obtaining it. But the reason the vaccination is given at a young age is because antibody response will be highest and giving it after HPV infection reduces its efficacy so giving it before sexual maturity is preferred [30].

If this belief is true, then it is imperative to educate parents on allowing their children to be vaccinated regardless if they are high-risk or not of contracting the virus. In fact, one study found that there is a strong association that parents will give their children HPV vaccination if it is recommended by their primary care provider, but an obstacle is that physicians are more likely to recommend it to parents if their adolescent child is considered at risk [33]. Therefore, it is instrumental to educate not only parents and caregivers but also primary care providers to prevent HPV infection.

Conclusion

HPV’s potential to cause serious harm, combined with Merck’s aggressive marketing of their Gardasil vaccine, allowed Gardasil to receive Fast Track approval from the FDA. There has been controversy surrounding whether Gardasil should have been eligible for fast-track approval, as this is reserved for drugs that fill an unmet medical need and Papanicolaou screening was already effective in reducing cervical cancer deaths.

There is clear incentive to administer a vaccine for a disease that has the potential to cause cervical, penile, and anal cancers [1]. A consideration of the side effects in multiple studies point to local skin infections and syncope as the main adverse effects associated with the HPV vaccine [11]. Although this may seem to be at odds with the claims from Tomljenovic and Shaw’s 2012 review of Guardasil’s serious adverse effects, they state that their findings only “point to a potentially causal relationship” and future studies will go to show that these adverse effects are not related [5]. It should be noted, however, that the 9vHPV was found to be responsible for these same adverse effects in greater than 5% of subjects when compared to common vaccines [12]. The importance of vaccination is further emphasized when considering that condoms are not an effective way of preventing HPV infection [34] and while the Papanicolaou test is beneficial, it has a low specificity and thus the highest efficacy in HPV prevention is achieved when combining both HPV vaccination and cervical screening [2].

Despite these benefits, it is important to consider the potential barriers of accessing the Gardasil vaccine, as well as the considerable misinformation disseminated among adults that causes them to act counter to vaccination efforts. Although it is the right of minors to have access to STI treatment or diagnosis, many minors are not aware of this right [27]. It is then the ethical responsibility of healthcare providers to offer Gardasil and other vaccines to minors without parental consent, however, many providers are reluctant to do so to avoid potential malpractice. To encourage physicians to discuss these issues with their adolescent patients, HPV vaccination should be viewed in the same purview as substance abuse, suicide prevention, and other sensitive issues that adolescents might be reluctant to confide in their parents [27]. This stigmatization toward the HPV vaccine can be seen in the lack of equity of uptake of the vaccine. Girls who are born into families of elevated socioeconomic status have a greater chance at superior uptake, signaling the relationship between education and benefit associated with preventive treatment [35]. Finally, there is new evidence to support the necessity of a larger-scale study on the serious adverse effects of Gardasil [14]. Tomljenovic and Shaw’s 2012 review of Guardasil’s serious adverse side effects mostly condemned the lack of proper trials held before its approval, and some countries are waiting for additional trials before approving the vaccine.

After weighing the problems to benefits of the HPV vaccine, we believe that Gardasil’s proven benefits outweigh the potential side-effects, although we would like to see more large-scale clinical trials done on the potential serious adverse effects. We discussed various concerns individuals may have before getting vaccinated. We believe that those who abstain from sexual intercourse should still receive the HPV vaccine as adolescent behavior can change rapidly. Furthermore, we believe that males should also be vaccinated, both for their own benefit but also to protect females in their community through herd immunity. Although parents may be tempted to delay their kids from receiving Gardasil before puberty, the vaccine’s ability to develop strong antibodies will be highest and thus lead to the best efficacy prior to puberty [30].