A Review of Ethical and Legal Aspects of Gender-Neutral Human Papillomavirus Vaccination

Human papillomavirus (HPV), the world's most common sexually transmitted infection (1), can cause malignant and benign diseases in males and females. The number of new HPV-related cancer cases worldwide in 2018 was estimated to be 69,400 in males and 625,100 in females (2). HPV causes almost all cases of cervical cancer (3) which, in 2018, was the fourth most common cancer in women, responsible for approximately 570,000 incident cases and 311,000 deaths (4). HPV is also causally associated with oropharyngeal, anal, penile, vaginal, and vulvar cancers (referred to hereafter as HPV-related noncervical cancers; ref. 5).

Prevention of HPV-related diseases by vaccinating girls and boys against HPV, known as gender-neutral HPV vaccination (GNV), would be an effective public health strategy. However, given that HPV vaccines were originally indicated for females to protect against cervical cancer, GNV has not been adopted worldwide. As of 2019, only 30% of countries offered HPV vaccination to both females and males (6).

The World Health Organization (WHO) has set a global goal to eliminate cervical cancer through a combination of primary, secondary, and tertiary prevention targets to be implemented by 2030 (7). This three-pronged approach aims to have 90% of 15-year-old girls fully vaccinated against HPV, 70% of women screened for cervical cancer by age 35 to 45, and 90% of women with precancerous cervical lesions and 90% with invasive disease treated (7). The WHO acknowledged that the HPV vaccine demand is expected to increase in the next 10 years, manufacturers of the HPV vaccines cannot meet the growing demand, and countries that have not yet implemented a vaccination program might have to wait until supply can meet demand (8). Many of the latter are low- and middle-income countries (LMIC) that bear a high cervical cancer burden and should be prioritized (4). In 2012, more than 65% of cervical cancer cases occurred in developing countries, with the highest rates occurring in South-Eastern Asia, Latin America, and Sub-Saharan Africa (5).

To mitigate the vaccine shortage, the WHO recommended in 2019 that countries stop gender-neutral, older age group (>15), and multicohort (multiple age group) HPV vaccination until supply meets demand (9). However, as of 2020, several countries such as Australia, Canada, New Zealand, the United Kingdom, and the United States have continued with GNV (10).

In light of the controversy surrounding such high-level policies, we conducted a narrative review of the ethical and legal aspects related to GNV from an international perspective, but with a focus on North America. We also provided an overview of available HPV vaccines and the evolution of HPV vaccine recommendations, including male vaccination.

To identify currently licensed HPV vaccines, we searched the PubMed database and Google. For North American guidelines on HPV vaccinations, we searched the United States Centers for Disease Control and Prevention (CDC) and Canadian government websites. For simplicity, many vaccine recommendations, and in consequence this review, use female and male (sex) and girls and boys (gender) interchangeably, without distinguishing between them. To create a timeline of country-level implementation of GNV, we searched the WHO Immunization Profile (last updated October 15, 2020) to pinpoint the countries that had begun vaccinating males (10). We then searched the literature and government websites (Google) to identify country-specific dates for implementing HPV vaccination.

To identify ethical and legal aspects of GNV, we searched OVID Medline using a combination of MeSH headings and keywords related to HPV, ethics, jurisprudence, public policy, and male, from inception to February 19, 2021, without applying a language restriction. The search strategy (Supplementary Table S1) was validated by an experienced librarian. Records were managed in Endnote Version X9. Titles and abstracts (primary screening) and full text articles (secondary screening) were reviewed for relevance in Rayyan (a free webtool for systematic reviews). To be eligible, articles had to discuss ethical and/or legal implications of GNV. The term “ethical” in this context encompassed equity, social justice, morality, and/or equality, whereas “legal” related to laws, legislation, and/or public policy. We extracted (using Excel) information on author, year, country, study type, and relevant direct quotes. We performed a thematic analysis based on these quotes and deduced seven overarching constructs of ethical and/or legal themes. M. Logel and C. Laurie reviewed the records during primary and secondary screening, and performed the thematic analysis.

Figure 1 shows the overall methodology and main results. Information on currently licensed vaccines was obtained from 13 sources consisting of governmental websites, research articles, and news reports (Supplementary Table S2). North American HPV vaccine recommendations in the United States (Supplementary Table S3) and Canada (Supplementary Table S4) by year were obtained from two government websites (Supplementary Tables S3 and S4). The male HPV vaccine milestones: country-specific male vaccination dates (n = 35), the FDA vaccination approval, and the WHO call to halt GNV (n = 5) were acquired through a Google literature scan (Supplementary Tables S5 and S6). Regarding ethical and legal aspects of GNV (Supplementary Fig. S1), 148 of 652 records identified in OVID Medline were considered potentially eligible at primary screening. A total of 89 records were excluded after full text screening (including one article written in Hungarian as we were not able to read or translate it), and 59 were included. These articles were published between 2007 and 2021, and most were from North America and Europe.

As shown in Table 1, two bivalent [Cervarix (11) and Cecolin (12)], one quadrivalent [Gardasil (13)], and one nonavalent [Gardasil 9 (14)] prophylactic vaccines are currently licensed for use (15–20). Cecolin was licensed by China's National Medical Products Administration in December 2019 (21). The other three vaccines have obtained prequalification from the WHO (8), which ensures the “quality, safety, and efficacy” of vaccines (22). Dosage follows manufacturers’ recommendations (23). Studies of Cecolin were performed using three doses in women ages 18 to 45 (12), and a two- and three-dose regimen in girls ages 9 to 14 (24). However, the vaccine has been approved as a two-dose regimen only for girls ages 9 to 14 (21). With the introduction of Gardasil 9, neither Cervarix nor Gardasil continued to be sold in the United States as of 2016. Gardasil 9 is currently used in North America, except in the Canadian province of Quebec which uses a mixed dosed schedule of Cervarix and Gardasil 9. Gardasil was discontinued in Canada as of 2016 (Merck, personal communication, March 19, 2021).

A 2020 UNICEF report, which included data from the Global Vaccine Market Model, indicated that at least 27 HPV vaccine candidates are being developed, comprising vaccines from five companies in China (Beijing Health Guard, GNBG Shanghai, Shanghai Bolvax, Walvax, and Xiamen Innovax), two in South Korea (Bioleaders Corp and Eyegene) and one in each of India, Iran, Sweden, and the United States (Serum Institute of India, Iran University of Medical Sciences, 2A Pharma, and Janssen, respectively; ref. 25). Of these vaccines, 60% are in the preclinical/discovery phase and 40% are in phases I–II clinical trials. Xiamen Innovax's HPV vaccine has now been licensed (21). The availability of additional safe and effective HPV vaccines will increase vaccine demand and facilitate worldwide GNV rollout.

Table 2 shows changes to HPV vaccine recommendations over the years. The FDA approved Gardasil, Cervarix, and Gardasil 9 in 2006 (16), 2009 (18), and 2014 (19), respectively. Health Canada correspondingly approved these in 2006 (26), 2010 (27), and 2015 (28). Vaccine recommendations followed from the United States' Advisory Committee on Immunization Practices (ACIP) and Canada's National Advisory Committee on Immunization (NACI). In the United States, Gardasil was recommended for females in 2006 (16) and for males in 2009 (permissive, not routine recommendation; ref. 17), while in Canada, vaccination with Gardasil was recommended for females in 2007 (29) and for males in 2012 (30). Vaccination with Gardasil 9 was recommended for both females and males in 2015 (19) in the United States and a year later in Canada (31). Initially, HPV vaccination recommendations included ages 9–26, comprising routine recommendations, catchup, and/or permissive use. In 2012, NACI recommended the vaccine for females over age 26 to age 45 (26). ACIP recommended the vaccine for some adults ages 27 to 45 (at the clinician's discretion) in 2019 (20). A two-dose schedule option began in Canada in 2015, when NACI recommended a two- or three-dose schedule for girls and boys ages 9 to 14 (32). This Canadian recommendation was followed by a two-dose schedule recommendation by ACIP for younger individuals in 2016 (33).

On the basis of data from 2019, approximately 30% (33/107) of HPV vaccination programs worldwide were gender neutral (6). As illustrated in Fig. 2, after FDA approval of Gardasil for use in males ages 9 to 26 in 2009 (17), Puerto Rico (34) and the United States (33) began vaccinating males. Multiple countries followed suit between 2013 and 2014 including Australia (35), Austria (36), some Canadian provinces (Alberta and Prince Edward Island; ref. 37), Liechtenstein (36), and Trinidad and Tobago (34). In 2014, the FDA approved Gardasil 9 for use in males ages 9 to 15 (19). The Bahamas (38), province of Nova Scotia (Canada) (37), and Israel (39) began vaccinating males in 2015. At the end of 2015, the FDA approved Gardasil 9 for use in an older age cohort: males ages 16 to 26 (40). Between 2016 and 2018, Antigua (34), Argentina (34), Barbados (34), Bermuda (34), Brazil (34), other Canadian provinces and territories (British Colombia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nunavut, Ontario, Saskatchewan, Quebec, Yukon; ref. 37), Croatia (36), Italy (36), New Zealand (41), Panama (34), Serbia (42), and Switzerland (43) began vaccinating males. In 2018, the FDA approved Gardasil 9 in a third cohort: males ages 27 to 45 (44). Germany (36) and Norway (45) followed suit with GNV in 2018. In 2019, Belgium (10), Denmark (36), Dominica (6), Chile (46), the Czech Republic (36), Guyana (6), Ireland (36), Luxembourg (36), Niue (6), Saint Kitts and Nevis (10), Saint Lucia (10), and the United Kingdom (47) began vaccinating males.

Although at the end of 2019, the WHO called for countries to halt GNV until there is equitable access to vaccines for countries with high cervical cancer rates (9), France recommended male vaccination to begin in 2020 (48). The HPV vaccine is also available for males in certain situations in Armenia (opportunistic), Bahrain (private), and Greece (males at high-risk; ref. 10), but we could not ascertain approval dates for these countries.

Our thematic analysis of 59 records distinguished six ethical constructs: lower awareness by males of HPV and HPV vaccination, challenges with allocation of resources, shared social responsibility among both sexes to reduce HPV transmission, lack of protection of men who have sex with men (MSM) and unvaccinated women through a female-only vaccination strategy, lack of screening for HPV-associated noncervical cancers, and the importance of considering principles of equity, social justice, discrimination, and equality when prioritizing HPV vaccination for one or both sexes. Only one legal construct was identified relating to the implementation of female-only versus GNV immunization program mandates. Table 3 lists the identified articles by construct, documenting their characteristics. Most were editorials (n = 16) and reviews (n = 19). Specific findings for each construct are summarized below.

When the HPV vaccine was first introduced in the United States, accompanying guidelines were developed by ACIP for a cervical cancer prevention indication in females, which might have led to the notion that the vaccine was not suitable for both sexes (49). At the time, no data were available to demonstrate safety and efficacy of the vaccine for men. A 2011 content analysis of United States news coverage found that articles tended to focus on HPV causing cervical cancers but not other cancer types (50). While all articles mentioned cervical cancer, only 25% mentioned genital warts and 19% mentioned anal and penile cancers (50), HPV-related diseases that affect males.

A 2012 survey administered in two states in the United States found that on average 21.5% of 361 respondents thought only women were affected by HPV and 73% were unaware that the vaccine was available for both sexes (51). In the same year, a review article stated the need for improvement in education and access to vaccination because men are also infected by HPV (52). Nationally representative survey data (n = 6862) from 2013 to 2014 in the United States found that men typically had less HPV knowledge and awareness; fewer men (57.1%) had heard of HPV than women (74.5%) and fewer had heard of the HPV vaccine (55.2% of men vs. 76.4% of women; ref. 53).

Prior to South Korea's implementation of a funded HPV vaccination program for girls in 2016 (54), a cross-sectional study administered in 2014 to Korean students ages 15 to 27 (n = 495) found 2.4% reported having received the HPV vaccine, with 98.0% stating that they had not received education about HPV vaccination (55). A 2015 United States study consisting of two small focus groups (n = 24) found none of the participants (African American MSM) knew the HPV vaccine was approved for male use (56). An online survey (2015–2016) on barriers to HPV vaccination, completed by 86 participants (mean age of 45 years) in eight western states in the United States, found that one third had a child eligible for HPV vaccination (57). However, nearly 40% of participants did not know boys could also be vaccinated.

In 2016, the “Cervical Cancer Prevention Act” was approved in South Carolina (58). This bill aimed to improve education about the vaccine (by providing a brochure to parents of children in sixth grade) and HPV vaccine coverage (by offering a “cervical cancer vaccination series” to seventh grade children). While the bill was for both sexes, state leaders (n = 34) from South Carolina interviewed prior to the bill's approval stated that marketing of the vaccine to prevent cervical cancer could mislead the public into thinking that both sexes do not need the vaccine (59). A survey (2016–2017) of United Kingdom parents (n = 168) of teenage males found that parents of sons only had less awareness of HPV and the vaccine than those having sons and daughters; however, once educated about HPV, most parents (85.5%) believed it was important for their son to be offered the vaccine (60).

Collectively, the five cycles (2008–2018) of the U.S. Health Information National Trends survey which included 25,487 participants showed that HPV vaccination awareness peaked in 2013 but has since decreased in some groups, including males (61). In 2019, a cross-sectional survey of 574 male college students in the United States found one-third each had either received, not received, or did not know whether they had received the HPV vaccine, highlighting the need for promotion of HPV vaccination in males via social-marketing campaigns (62). A recent review of United States HPV vaccine policy changes underlined the importance of monitoring vaccination rates in males and the need for programs to educate the public about vaccine recommendations to reduce differences in vaccination coverage of males and young adults (49). GNV in countries that have so far offered female-only HPV vaccination might reduce confusion among health care professionals and the public (63), and consequently improve vaccine uptake.

The decision to implement GNV cannot be guided solely by ethics; cost is also a main consideration (64). With limited health care dollars and lower disease burden in males, the need to vaccinate men was questioned (65). There have been arguments that efforts to increase vaccination coverage in females should be a higher priority than vaccinating males (66), while some were unsure where to allocate resources (i.e., whether efforts to increase female vaccination would be preferable to including boys in vaccination programs; refs. 67, 68). However, choosing to focus on increasing HPV vaccination coverage in females implies the expectation that female vaccination rates are to increase (66), an outcome that might not occur.

Initial approval of the vaccine for females only led to HPV infection and prevention being mistaken for an exclusively female problem and responsibility (69). The State of Virginia has school-entry HPV immunization laws specific to females (70). Women should not bear this responsibility alone (71–75) but rather should share it with men for reducing HPV, cervical cancer (76), and HPV-related noncervical cancers.

Vaccinating boys will achieve “social fairness” (77). Midwives at youth clinics expressed ethical concerns about exclusion of males from HPV vaccination programs and the responsibility for HPV prevention resting on women (78). A study on HPV vaccination views from online discussion forums suggested that vaccinating females only was an individualistic perspective, but vaccinating males could help create a collectivist view (79).

Sharing the responsibility of HPV vaccination between sexes (63, 80, 81) could reduce the misplaced belief that girls are primarily responsible for HPV prevention and transmission (82) and might decrease stigmatization associated with female-only vaccination (63). Both men and women could transmit an HPV infection and therefore should help prevent it (81). Female-only vaccination might lead to a higher psychologic burden and gender inequalities (83). It would also support the following false beliefs: only women are affected by HPV and HPV-related diseases, women are more promiscuous, and women alone are responsible for HPV transmission (84). In a 2018 review of HPV vaccine herd effects, Malagon and colleagues asked whether it is ethical to depend on one's sexual partner for protection from HPV (85). Overall, both sexes contribute to HPV transmission, and from an equity standpoint, both sexes should be vaccinated (86) and expected to participate in prevention (87).

The “direct effects” of HPV vaccination refer to protecting the vaccinated individual. In contrast, “herd effects” describe the indirect protection vaccinated individuals provide to those who are unvaccinated (88). A systematic review of mathematical models of herd and population effects of HPV vaccination reported that, even at coverage rates as low as 20%, HPV vaccination will produce herd effects in both sexes and that with moderate to high coverage of girls, the benefit to males is small (89). These models did not include the MSM population, which would not be expected to impact the estimates of herd effects; however, they overlooked the HPV burden in this population. Perez and colleagues (68) reiterated that some cost-benefit models do not include MSM, who receive no protection against HPV from exclusive female vaccination (90). The argument is that if we were to vaccinate only females, then neither MSM (69, 91) nor unvaccinated females are protected (92, 93). Moreover, men do not receive the anticipated herd protection due to low female vaccination rates (69, 94). An editorial highlighted that it is unethical and discriminatory not to consider vaccinating men because MSM and men acquiring HPV from unvaccinated women remain unprotected (95). From a lens of gender equality, men, especially MSM, should be considered for vaccination (96–98). Prior to the implementation of GNV in the United Kingdom in 2019 (47), doctors stated that if we wait to vaccinate boys, then each year many males will acquire an HPV infection and remain unprotected (99).

From a public health perspective, preventing HPV is a better strategy than screening (100). Notably, screening for cervical cancer is a well-established health care process in most countries but there is no equivalent benefit for HPV-related noncervical cancers (83, 84, 100). The natural history of HPV-related noncervical cancers is also not as well understood. Randomized controlled trials to evaluate vaccine efficacy against oropharyngeal cancer might never be conducted because there is no recognized precursor lesion for these cancers to serve as trial endpoints (101). While there is a similar burden of HPV-related disease between sexes, no routine screening is yet available for HPV-related noncervical cancers, such as oropharyngeal and anal cancers (102), which affect both sexes. GNV would provide more protection for women in countries that lack the critical infrastructure and resources needed to introduce HPV vaccination. It would also reduce dependence on cervical cancer screening programs. However, in China where cervical cancer screening programs need to be improved (103), adolescent girls should be the first to receive the HPV vaccine (104).

Equity of HPV vaccination has been repeatedly emphasized (71, 105–108). Because HPV-related diseases affect both sexes, questions arise on whether female-only vaccination is health equitable (109). Because the vaccine is expected to save lives, equity must be considered during vaccine distribution (110) and the interests of people who are homosexual (111). Excluding males from HPV vaccination programs undermines health equity and unethically overlooks the male HPV-related disease burden (108). Supporters of GNV believe that vaccine prioritization should be based on specific ethics principles, not on economic modeling (76). As Schwartz and colleagues noted, economics can appear to be ethically neutral but “economic modeling can reflect the values and priorities of communities in improving public health” (76). Ultimately, decisions must be based on ethical principles, not only cost-effectiveness (84).

GNV supports equality between all sexes and identities (75). Equal access to health care should be considered, as vaccinating both sexes provides equal rights to protection (83). It is “unethical and discriminatory” to withhold HPV vaccination from males, because the vaccine would protect them from HPV-related diseases (93). Abramowitz and colleagues state that GNV provides equal protection against HPV to everyone and, ethically, withholding male vaccination in areas with low HPV vaccination coverage is debatable (81). Ethical and social aspects of HPV vaccination must be considered (112), because vaccinating both sexes is more ethical (113) and the most socially just action (97). Vaccinating everyone might help to eliminate “sociocultural barriers” and perhaps allow “defavorized groups” access to protection (81). Notwithstanding the above arguments, scientific advisory committees, such as the United Kingdom Joint Committee on Vaccination and Immunization (JCVI) are “not tasked to consider ethics and equality issues” (75).

A school entry immunization mandate (defined as an order to act) requires vaccination prior to school entry. In 2008, Purdue (114) reported that during the time when the HPV vaccine was approved only for females, mandating vaccination for girls only was considered discriminatory and potentially would violate Title IX of the Education Amendments of 1972 (115), which “prohibits discrimination on the basis of sex in any federally funded education program or activity”. (116) In 2010, Homan considered requiring male vaccination to be unconstitutional, and argued against placing a burden on men related to potential costs and doctors’ visits (117). Conversely, the way to correct the “feminization of HPV”, according to Daley and colleagues is through mandatory school immunization programs, which would “normalize the HPV vaccine” and lead to recognition of both male and female health (69). In 2019, Bayefsky and colleagues further argued that HPV vaccination should be required for school entry in the United States; at that time the vaccine was approved for both sexes and could no longer be considered discriminatory based on sex (100). However, currently in the United States, vaccination is not required for school entry in most states (118). A policy-related intervention suggested by Koskan and colleagues (62) is to make vaccination a requirement for college admissions to increase vaccination rates (119).

The WHO's calls to stop GNV temporarily (9) and prioritize cervical cancer elimination (7) have ethical and legal implications. To the best of our knowledge, this is the first review to address, in conjunction or separately, the identified constructs of GNV. These have important public health repercussions for policy-level interventions in terms of HPV vaccination recommendations.

While most HPV vaccination programs are female-only and cervical cancer burden is high in LMICs (4), the HPV-related disease burden is similar in both sexes in some geographic areas, such as the United States (120) and Canada (121). GNV might help to eliminate HPV-related diseases justly in all individuals regardless of sex. Admittedly, we do recognize that ours is a view from a high-income country in North America with well-established HPV vaccination programs. However, in Canada, there remain groups, such as Indigenous peoples, with high HPV prevalence, low screening uptake, and potentially lower HPV vaccination rates (122). Other high-income countries such as Australia, New Zealand, and the United States have comparable vaccine coverage between the overall population and Indigenous peoples (123). GNV could improve vaccine coverage in Indigenous populations (89).

In 2019, Canada's NACI expanded its mandate to include consideration of ethics and equity in its recommendations (124). The United Kingdom's scientific advisory committee, JCVI, does not consider these issues (75). The 2017 “JCVI Interim Statement on Extending HPV Vaccination to Adolescent Boys” asserted that the JCVI was not equipped to fully consider equality issues in detail (125). However, based on the stakeholders advocating for equality of access, the JCVI referred the issue of GNV to the Department of Health and Social Care (DHSC). The DHSC's equality analysis of 2018 concluded that both continuing a girls-only program or including boys could be justified on the basis of equality, due to uncertainties surrounding the cost-effectiveness of vaccinating boys (126). In terms of legal issues, the DHSC did not consider a girls-only vaccination program unlawful, as this does not contradict the Equality Act 2010 (a United Kingdom statute protecting against discrimination) if HPV vaccination is considered a “single-sex service.”

Both Canada and the United States recommend a two-dose schedule for females and males 9 to 14 years old (32, 33). Recent studies reported that one dose of Cervarix may have comparable vaccine efficacy to two or three doses (127, 128). A future reduction in recommended doses might improve availability and costs associated with HPV vaccination, thereby making the “vaccine supply” argument against GNV moot.

Not all United States school-based mandates are gender-neutral. Of the four states [Rhode Island, Virginia (129), Hawaii (130), and Puerto Rico] (131) and the United States capital (District of Columbia; ref. 129) that mandate HPV vaccination, Virginia is female specific (70), while the other four are gender-neutral. Jurisdictions that choose to mandate HPV vaccinations should perhaps do so for both sexes to make obvious that everyone shares the responsibility to prevent HPV.

The 14th Amendment to the United States Constitution consists of an equal protection clause which protects an individual from government discrimination based on gender or race (132): “No State shall… deny to any person within its jurisdiction the equal protection of the laws” (133). Similarly, section 15(1) of the Canadian Charter of Rights and Freedoms states: “every individual is equal before and under the law and has the right to the equal protection and equal benefit of the law without discrimination and, in particular, without discrimination based on race, national or ethnic origin, color, religion, sex, age or mental or physical disability” (134). Although not vaccinating males could be considered discriminatory based on sex, the government could argue that, in light of the HPV vaccine shortage, vaccinating only girls is the necessary choice. Even if HPV vaccine manufacturers were to increase supply to meet global demand, one might think the ethical and legal aspects of GNV need not be considered because everyone would theoretically have access to the vaccine. However, there are several other barriers to vaccination, including cost and willingness to vaccinate (135).

When the COVID-19 vaccination campaign began in Canada, vaccines [Pfizer-BioNTech, AstraZeneca/COVISHIELD, Moderna, Janssen (Johnson & Johnson)], were first available for at risk, priority groups recognized by NACI (136). These included older adults, health care workers, adults in Indigenous, racialized and marginalized communities, residents and staff of shared living spaces, and first responders (136). Similarly, in light of the current global HPV vaccination shortage, the WHO strategy to prioritize individuals at highest risk of HPV and HPV-related cancers might be the most just action from an ethical perspective.

The cost-effectiveness of HPV vaccination depends on vaccine uptake by females (137). Because vaccinating females leads to indirect protection for males (herd effects), the addition of boys in vaccine programs makes vaccination less cost-effective (85). Universal female-only vaccination is considered cost-effective assuming a high vaccination coverage, which would provide herd immunity and cross-protection for unvaccinated males against benign and malignant HPV-related diseases (137). At low vaccine coverage (40%), the incremental relative reduction in prevalence of the oncogenic HPV16 type from vaccinating boys in addition to girls is 19% for females and 35% for males; however, at high vaccine coverage (80%), corresponding values are lower (7% and 16%; ref. 89). GNV is not considered cost-effective if there is moderate to high vaccine coverage of the female population (89); it is cost-effective only in areas where high female vaccination coverage is difficult or too expensive to achieve (111).

Our review did not consider all the complexities of GNV. The definition of ethics might have led to a personal bias in our results due to the subjective nature of the term. We expected to find articles discussing other ethical constructs, such as vaccine acceptance and hesitancy in the context of GNV. We did not consider the gray literature and we ignored, in particular, the abundant information on the Internet that encourages an antivaccination stance.

On balance, the evidence yielded from our thematic analysis evenly considered the views of GNV and female-only HPV vaccination. However, the articles that discussed the ethical construct of equity, social justice, discrimination, and equality ostensibly favored GNV, although both GNV and female-only vaccination strategies have meritorious arguments outside of these domains. One may hastily regard health equity and discrimination to be major issues in female-only HPV vaccination, given that HPV-associated cancers affect both sexes. Nevertheless, the underlying complexities of vaccine deployment and its context must be considered. Indeed, suspending GNV may seem reasonable in the context of vaccine shortages and low affordability in LMICs where cervical cancer burden is high and a remarkably smaller proportion of the female population is vaccinated compared with high-income countries (4, 6). In such settings, it could be argued that female-only vaccination is the most equitable and just from societal and even individual perspectives. Such considerations should be weighed in with the guiding principle of avoiding health inequity and gender disparities in health outcomes. Therefore, the merits of GNV and female-only vaccination should be considered in its multiple dimensions of ethics, social justice, public health context, and cost-effectiveness.

To conclude, it is imperative for policy makers to consider, in addition to scientific evidence, the many ethical and legal issues when issuing HPV vaccine recommendations and identifying target priority groups.

M. El-Zein reports a patent for DNA methylation markers for early detection of cervical cancer, pending. E.L. Franco reports grants from Canadian Institutes of Health Research and Cancer Research Society during the conduct of the study; grants from Merck and Roche outside the submitted work; in addition, E.L. Franco has a patent for Methylation markers, pending to self. No disclosures were reported by the other authors.

We would like to thank Andrea Quaiattini (McGill Librarian, Schulich Library of Physical Sciences, Life Sciences, and Engineering) for assisting with the search strategy. We also acknowledge Dr. Talía Malagón for pertinent comments on a previous version of the article and Parker Tope for assistance with the development of and research for Fig. 2. This work was supported by the Canadian Institutes of Health Research (Foundation Grant FDN-143347 awarded to E.L. Franco) and Cancer Research Society (Operating Support to the McGill Division of Cancer Epidemiology).

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