Vaccine strategies
Fifteen years of vaccination against the human papilloma virus in Spain. An update
Quince años de vacunación frente al virus del papiloma humano en España. Actualización
F. Moraga-Llop
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Societat Catalana de Pediatria, Asociación Española de Vacunología, Barcelona, Spain
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An update</span>" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "394" "paginaFinal" => "399" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "F. Moraga-Llop" "autores" => array:1 [ 0 => array:4 [ "nombre" => "F." "apellidos" => "Moraga-Llop" "email" => array:1 [ 0 => "fernandomoragallop@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cr0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Societat Catalana de Pediatria, Asociación Española de Vacunología, Barcelona, Spain" "identificador" => "af0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Autor para correspondencia." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Quince años de vacunación frente al virus del papiloma humano en España. Actualización" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Prophylactic vaccination against human papillomavirus (HPV) is the cornerstone of the World Health Organisation's (WHO) global strategy to accelerate the elimination of cervical cancer as a public health problem. It is estimated that implementation of this strategy could prevent 60 million cases of cervical cancer and 45 million deaths over the next 100 years.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a></p><p id="p0010" class="elsevierStylePara elsevierViewall">Half a century ago, in the 1970s, Orth<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a> demonstrated the oncogenic potential of HPV in epidermodysplasia verruciformis and in the 1980s Zur Hausen<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> identified HPV DNA in most cervical cancers. He was awarded the Nobel Prize in Physiology and Medicine for demonstrating the role of infection in the pathogenesis of cervical cancer 15 years ago in 2008, together with Barré-Sinoussi and Montaigner for their discovery of the human immunodeficiency virus.</p><p id="p0015" class="elsevierStylePara elsevierViewall">In the 1990s, work by Xavier Bosch et al., Walboomers et al., and Nubia Muñoz confirmed that there was an association with HPV in almost all cases (99.7%) in a series of cervical cancer biopsies from 22 countries.<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> The virus is a necessary, but not sufficient, cause for cervical cancer to develop, as there are other co-factors determining neoplastic progression following HPV infection. Cervical cancer results from persistent infection with one of the 12–15 oncogenic or high-risk genotypes of the more than 200 cutaneous and mucosal types of this virus, which is the most frequent agent of sexually transmitted infections in the world.</p><p id="p0020" class="elsevierStylePara elsevierViewall">The risk of progression from low-grade lesions to high-grade lesions (dysplasia and neoplasia) is higher in people with persistent infection with one of the oncogenic genotypes. However, the vast majority of infections are inapparent and transient, and resolve spontaneously within 2 years of infection.</p><p id="p0025" class="elsevierStylePara elsevierViewall">Five percent of all human cancers worldwide are HPV-related.<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a> The breakthrough has been that the most common HPV-related infections and neoplasms can be prevented by immunisation, and may in the future be treated with therapeutic vaccines that are under investigation. The end of 2022 marked the 15th anniversary of the marketing in Spain of the first two HPV vaccines, first the tetravalent vaccine in October 2007, and then the bivalent vaccine in January 2008; the third vaccine, nonavalent, was authorised in 2015.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0030" class="elsevierStylePara elsevierViewall">On 10 October 2007, the Interterritorial Council of the National Health System recommended, and included in the calendar of that same year, the systematic vaccination of girls in a cohort aged 11 from to 14 years to be chosen by each autonomous community according to their needs, priorities, and the logistics of the vaccination programmes, with a deadline for implementation set at 2010; 3 communities started vaccination at the end of 2007 and the rest did so during 2008.<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a> It is therefore 15 years since vaccination began, included in the routine immunisation regimen for girls. This recommendation has been extended to boys, to coincide exactly with this anniversary. Vaccination, therefore, irrespective of gender, achieves immunisation equity.</p><p id="p0035" class="elsevierStylePara elsevierViewall">In early 2007, Australia became the first country to introduce a publicly funded national HPV vaccination programme in schools, administering 3 doses of tetravalent vaccine to girls aged 12–13 years. From 2007 to 2009, the programme targeted females aged 12–26 years through a school and community-based programme, and has since continued in schools for adolescent girls aged 12–13 years. From 2013 it was extended to boys, with a 2-year catch-up for 14–15-year-olds, making it the first country to introduce vaccination irrespective of sex. In 2018, the schedule changed to 2 doses (6 months apart) in line with WHO recommendations and moved to a nonavalent vaccine for girls and boys, with catch-up up to 19 years of age. By the end of 2021, all Australian women up to the age of 32 years and men up to the age of 23 years were part of the candidate cohorts for vaccination through the school-based programme.<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p><p id="p0040" class="elsevierStylePara elsevierViewall">On the 10th anniversary of HPV vaccination in Spain, we wrote an article reviewing the historical origins of the virus and the beginnings of this immunisation, the second (after hepatitis B) for cancer prevention, and the achievements and progress made, which we are now updating 5 years on.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p></span><span id="s9010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st9030">HPV vaccination 15 years on. Decalogue</span><p id="p9045" class="elsevierStylePara elsevierViewall">In the 15 years of HPV vaccination, there have been major advances in immunisation strategies, indications, and recommendations, and we now have data on the effectiveness of the vaccine in preventing cervical cancer. We should highlight the following aspects:<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="li0005"><span class="elsevierStyleLabel">•</span><p id="p0055" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Initiation of vaccination</span></p></li></ul></p><p id="p0060" class="elsevierStylePara elsevierViewall">The age of vaccination has been brought forward from 14 to 11–12 years, with the possibility of vaccination from the age of 9, as per the technical data sheet, as already implemented in some countries. Early vaccination is important for children who have been sexually assaulted, at the age of 9. For maximum preventive potential, vaccination should occur before the onset of sexual intercourse to ensure that uninfected persons are vaccinated. The protective effect of vaccination decreases with age, as the effectiveness is lower when the first dose is administered at 16 years of age. Therefore, it is necessary to vaccinate “in time” before the onset of sexual activity.<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="li0010"><span class="elsevierStyleLabel">•</span><p id="p0065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Vaccination regimen</span></p></li></ul></p><p id="p0070" class="elsevierStylePara elsevierViewall">Two-dose vaccination regimens have been approved for the two vaccines that are currently marketed (bivalent and nonavalent; tetravalent not available from 2022) in the population aged 9–14 years, which facilitate vaccination compliance, acceptability, and efficiency.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Some countries (Australia, Ireland, UK) have started to recommend and implement the one-dose regimen before the age of 14 years. The WHO, in a position paper (December 2022), envisages the possibility of choosing between a one- or two-dose strategy for girls and boys from 9 to 20 years of age. This will make the programme more efficient from a public health perspective (fewer doses, fewer resources needed, and easier implementation of vaccination).<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">The UK Joint Committee on Vaccination and Immunisation has concluded that a single-dose regimen will free up funds and resources that can be devoted to enhancing adolescent immunisation programmes, and will simplify the immunisation regimen and reduce the needle-stick burden on adolescents, and will be better accepted by the population. However, moving to a single dose and a single visit in schools may reduce the opportunity, compared to the current regimen, for those who missed their first dose to catch up, which has the potential to increase inequity. This should be mitigated by greater capacity to follow up those who miss vaccination when it is first offered. Some of the resources available due to reduced vaccination sessions should be redirected to interventions that strengthen programme delivery, increase coverage rates, and reduce inequity.<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">The scientific rationale for recommending a dose in these settings is based on clinical trials of immunogenicity and efficacy, but there are several limitations to these studies: they are mostly conducted in girls, focus on prevention of persistent infection, and have short follow-up time.</p><p id="p0090" class="elsevierStylePara elsevierViewall">Data from immunogenicity trials, follow-up analyses of efficacy trials and post-marketing observational studies in women have shown that a single dose of vaccine is sufficient to elicit an immune response that provides protection analogous to that of a multi-dose regimen against initial and persistent HPV infections. Seropositivity in persons receiving a single dose is not lower than that observed after 2 or more doses, antibody titres are lower among those receiving one dose than among those receiving 2 or 3 doses, but antibody avidity does not differ in relation to the number of doses received, and seroprotection is maintained for at least 10 years after vaccination with one dose.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bb0060"><span class="elsevierStyleSup">12–16</span></a></p><p id="p0095" class="elsevierStylePara elsevierViewall">Data from efficacy studies, with methodological limitations, conducted in India, Costa Rica, the United States, and Kenya show high efficacy in preventing persistent infection and decreasing the prevalence of infection (in the United States).<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bb0085"><span class="elsevierStyleSup">17–19</span></a> There are data on effectiveness from Denmark, the United States, and Valencia,<a class="elsevierStyleCrossRefs" href="#bb0100"><span class="elsevierStyleSup">20–22</span></a> which indicate significant protection with both one and two doses of the vaccine.</p><p id="p0100" class="elsevierStylePara elsevierViewall">Therefore, more studies, of longer duration, are needed to demonstrate the efficacy of the one-dose regimen against preneoplastic lesions. For the moment it is prudent to continue with the 2-dose regimen as indicated on the package insert until more complete information with more scientific evidence is available.<ul class="elsevierStyleList" id="l0015"><li class="elsevierStyleListItem" id="li0015"><span class="elsevierStyleLabel">•</span><p id="p0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Vaccination in at-risk populations</span></p></li></ul></p><p id="p0110" class="elsevierStylePara elsevierViewall">Spanish research groups have published the first vaccination recommendations for populations at high risk of HPV infection (acquisition and persistence of infection, and progression to premalignant and malignant lesions): persons infected with human immunodeficiency virus, men who have sex with men, women over 25 years of age with HPV infection or premalignant cervical lesions, and patients with inflammatory bowel disease, congenital medullary insufficiency syndrome, primary immunodeficiencies, survivors of childhood neoplasms, solid organ or haemopoietic progenitor transplantation, on immunosuppressive or biological therapy, or with recurrent respiratory papillomatosis. These recommendations are based on the available scientific evidence.<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a> The GRADE (Grading of Recommendations Assessment, Development and Evaluation working group) system<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a> has been used to classify levels of evidence and the degree and strength of the recommendations.<ul class="elsevierStyleList" id="l0020"><li class="elsevierStyleListItem" id="li0020"><span class="elsevierStyleLabel">•</span><p id="p0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Vaccination of healthy women beyond adolescence</span></p></li></ul></p><p id="p0120" class="elsevierStylePara elsevierViewall">Vaccination of healthy women beyond adolescence is a new perspective in the primary prevention of cervical cancer and HPV-associated disease. It should be noted that the risk of acquiring new HPV infections in sexually active women remains significantly high throughout life, and viral persistence increases with age and the onset of immunosenescence. In women over 25 years of age, clinical trials have shown the vaccines to be safe, immunogenic, and effective. However, the benefit of vaccination is variable because this population is very heterogeneous in terms of HPV immune status, and therefore efficacy decreases with age. This is why recommendations made from a public health perspective do not include women over 25 years of age, and vaccination depends on a consensual decision between the woman and the doctor (“shared clinical decision-making”).<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRefs" href="#bb0125"><span class="elsevierStyleSup">25–27</span></a><ul class="elsevierStyleList" id="l0025"><li class="elsevierStyleListItem" id="li0025"><span class="elsevierStyleLabel">•</span><p id="p0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Vaccination of adolescent boys</span></p></li></ul></p><p id="p0130" class="elsevierStylePara elsevierViewall">The systematic vaccination of boys, at 12 years of age, has been incorporated into the <span class="elsevierStyleItalic">common lifelong vaccination schedule</span> of the Interterritorial Council of Spain's National Health System of 2023 (to be implemented before the end of 2024).<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a> A few months earlier, in April 2022, Catalonia agreed to its incorporation and it was included in the September 2022 schedule, at 11–12 years of age, in the sixth year of Primary Education,<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a> and subsequently Galicia, the Valencian Community and the Region of Murcia also did so. Similarly, in 1988, rubella vaccination of girls, for the future prevention of congenital rubella, was replaced by immunisation of boys and girls, a more logical and effective way of limiting as much as possible the transmission of rubella virus infection in the population. Vaccination irrespective of sex also ensures vaccine equity.<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0135" class="elsevierStylePara elsevierViewall">Vaccination against HPV in males has a dual benefit: a direct benefit for the vaccinated and an indirect or population-based benefit. Immunisation prevents anogenital warts, respiratory papilloma, and HPV-related cancers in males in several locations: anus, penis, scrotum, and head and neck (oropharynx, oral cavity, and larynx), there has been a notably increased incidence of the latter in recent years. Moreover, as these tumours are not easily and effectively screened for in men, unlike in women with cervical cancer, diagnosis is more difficult and delayed.<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a></p><p id="p0140" class="elsevierStylePara elsevierViewall">Another justification and benefit of universal vaccination is the prevention of sexual transmission of the virus, as both men and women are part of the epidemiological chain of infection. Both can be asymptomatic carriers, transmitters, and can be infected or ill. Vaccination irrespective of sex will decrease the rate of transmission of the virus, which will protect unvaccinated women and unvaccinated men who have sex with men. This is a major population and public health benefit.</p><p id="p0145" class="elsevierStylePara elsevierViewall">On 18 September 2009, shortly after the vaccination programmes began, Nobel laureate Zur Haussen stated in the century-old Barcelona newspaper <span class="elsevierStyleItalic">La Vanguardia</span> that in order to reduce the prevalence of HPV, men must be vaccinated, as they are transmitters of the infection, and encouraged them to get vaccinated.<ul class="elsevierStyleList" id="l0030"><li class="elsevierStyleListItem" id="li0030"><span class="elsevierStyleLabel">•</span><p id="p0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Impact and effectiveness of routine vaccination</span></p></li></ul></p><p id="p0155" class="elsevierStylePara elsevierViewall">Registered clinical trials on HPV vaccines demonstrated high efficacy in preventing precancerous lesions of the cervix, vulva, vagina, and anus associated with the vaccine genotypes. In addition, tetravalent and nonavalent vaccines prevent anogenital warts linked to genotypes 6 and 11.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a> Subsequently, a reduction in oral infection and probably HPV-related head and neck carcinomas has been demonstrated.<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a> The package inserts states that Gardasil® 9 is indicated for “the prevention of other head and neck cancers caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45, 52, and 58”.<a class="elsevierStyleCrossRef" href="#bb0170"><span class="elsevierStyleSup">34</span></a></p><p id="p0160" class="elsevierStylePara elsevierViewall">Data on impact and effectiveness are now available. HPV vaccination was already known to have reduced the incidence of genital infections and warts,<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a> but now data have been added on significant reductions in premalignant lesions and cancers of the cervix and other anogenital sites. In addition, an important community effect is being demonstrated, as vaccinated individuals prevent transmission of infection.<a class="elsevierStyleCrossRef" href="#bb0175"><span class="elsevierStyleSup">35</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0180"><span class="elsevierStyleSup">36</span></a></p><p id="p0165" class="elsevierStylePara elsevierViewall">A meta-analysis of studies with data from more than 60 million individuals and a follow-up of up to 8 years compared the incidence rates of HPV infection, anogenital warts, and cervical intraepithelial neoplasia grade 2<span class="elsevierStyleHsp" style=""></span>+, before and after the introduction of the vaccination programme, and found a clear decrease.<a class="elsevierStyleCrossRef" href="#bb0185"><span class="elsevierStyleSup">37</span></a></p><p id="p0170" class="elsevierStylePara elsevierViewall">The effect of vaccination on cervical cancer prevention has been demonstrated. In two studies, conducted in Sweden and Denmark, women aged 10–30 years vaccinated before the age of 17 years showed an 88% and 86% lower risk of cancer than unvaccinated women, respectively, with effectiveness decreasing with increasing age at vaccination.<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a></p><p id="p0175" class="elsevierStylePara elsevierViewall">Studies have also been published that have shown the population impact of a vaccination programme on cervical cancer. In England, a substantial reduction in cervical cancer cases and CIN3 incidence in young women was observed after the introduction of the HPV immunisation programme, compared to unvaccinated baseline cohorts. The reduction was 87% (95% confidence interval [95% CI]: 72–94) in those offered the vaccine aged 12–13 years, and fell to 62% (95% CI 95%: 52–71) in those immunised aged 14–16 years. The HPV immunisation programme has nearly eliminated cervical cancer in women born since 1 September 1995.<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">40</span></a><ul class="elsevierStyleList" id="l0035"><li class="elsevierStyleListItem" id="li0035"><span class="elsevierStyleLabel">•</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">New data on the nonavalent package insert</span></p></li></ul></p><p id="p0185" class="elsevierStylePara elsevierViewall">New data on the prevention, through vaccination of girls and women of childbearing age, of juvenile-onset recurrent respiratory papillomatosis, a rare paediatric condition that is difficult to treat and has a recurrent course, have recently been included in the Spanish Agency of Medicines and Health Products' nonavalent vaccine package insert.<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a> It is caused by HPV infection of the upper respiratory tract, mainly HPV types 6 and 11, which is acquired through vertical transmission during childbirth. Observational studies in the United States and Australia have shown that the introduction of the tetravalent HPV vaccine since 2006 has led to a decrease in its incidence in the population.<ul class="elsevierStyleList" id="l0040"><li class="elsevierStyleListItem" id="li0040"><span class="elsevierStyleLabel">•</span><p id="p0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Vaccine safety</span></p></li></ul></p><p id="p0195" class="elsevierStylePara elsevierViewall">Safety, which has been well researched and studied in registered clinical trials on the three vaccines, has been one of the key aspects of post-marketing surveillance. In the first years of vaccination, false reports of adverse effects attributed to the 2 available vaccines from anti-vaccination groups had to be refuted, leading to a temporary and localised decline in vaccination coverage in some areas.<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">The WHO Global Advisory Committee on Vaccine Safety has regularly reviewed safety. Since 2007, this committee has published 8 safety reports: 6 in the first 10 years (2007–2009, 2013–2015)<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a> and 2 in the last 5 years (2017 and 2019).<a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bb0210"><span class="elsevierStyleSup">42</span></a> No serious safety concerns have been identified in these frequent reviews. In the first 11 years (data from the 2017 report), 2 adverse reactions related to vaccination were reported: anaphylaxis and syncope. The incidence of anaphylaxis is estimated at 1.7 cases per million doses administered. Syncope, which is related to anxiety and stress after vaccination, is the most frequent adverse effect. No other significant effects have been reported so far.</p><p id="p0205" class="elsevierStylePara elsevierViewall">In a recent retrospective cohort study (2015–2017) involving more than 200,000 people on the safety of the nonavalent vaccine, most of the findings had been previously described, preceded vaccination, or had other causes. There were no deaths that could be considered to be related to vaccination. The paper concludes that no new safety issues were identified, and its findings were consistent with those previously reported in surveillance studies of the other two vaccines.<a class="elsevierStyleCrossRef" href="#bb0215"><span class="elsevierStyleSup">43</span></a></p><p id="p0210" class="elsevierStylePara elsevierViewall">In summary, after more than 500 million doses of the vaccine have been distributed since its licensure in 2006, and numerous studies and reviews on vaccine safety have been conducted, we can state that no serious safety issues have been detected, except for rare cases of anaphylaxis, as with all vaccines.<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a><ul class="elsevierStyleList" id="l0045"><li class="elsevierStyleListItem" id="li0045"><span class="elsevierStyleLabel">•</span><p id="p0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Global HPV vaccination. WHO (2021–2030): strategy to accelerate the elimination of cervical cancer</span></p></li></ul></p><p id="p0220" class="elsevierStylePara elsevierViewall">In August 2020, the 73rd World Health Assembly adopted the Global Strategy 90–70-90 to accelerate the elimination of cervical cancer as a public health problem, based on 3 pillars. The first concerns the HPV vaccine being introduced in all countries with the goal of achieving 90% coverage of girls by the age of 15 years. Given that HPV vaccine introduction rates in member states are currently 55% and average HPV vaccination coverage is only 54%, the next 10 years will require significant investment to introduce the vaccine in low- and middle-income countries, as well as programme improvements to reach 90% coverage in both low- and high-income settings, as envisaged in the 2030 targets.</p><p id="p0225" class="elsevierStylePara elsevierViewall">The second pillar of this strategy is for 70% of women to be screened before the age of 35, and then before the age of 45, with an HPV test. And as a third pillar, 90% of women with high-risk lesions or cancer should be diagnosed and treated.<a class="elsevierStyleCrossRef" href="#bb0220"><span class="elsevierStyleSup">44</span></a><ul class="elsevierStyleList" id="l0050"><li class="elsevierStyleListItem" id="li0050"><span class="elsevierStyleLabel">•</span><p id="p0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Future prospects for HPV vaccination</span></p></li></ul></p><p id="p0235" class="elsevierStylePara elsevierViewall">The near future for vaccination is to include boys, to achieve high vaccination coverage, and to determine whether the strategy of a single dose in early adolescence is sufficient. A very important aspect is the vaccination of all risk groups (always with 3 doses) and to consider the real and effective possibility of vaccination at ages beyond that recommended in the routine vaccination regimen, in females and in males. Finally, and very importantly, we need to strive towards immunisation worldwide, a difficult and longer-term goal to achieve, but one that is fundamental to the elimination of cervical cancer. To date, 125 countries (64%) have introduced the vaccine into their national immunisation programme for girls, and only 47 countries (24%) have also done so for boys.<a class="elsevierStyleCrossRef" href="#bb0225"><span class="elsevierStyleSup">45</span></a> There remains, therefore, a major, arduous task ahead to achieve maximum vaccine equity.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:3 [ "identificador" => "xres2078657" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1773371" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2078658" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1773372" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "s9010" "titulo" => "HPV vaccination 15 years on. Decalogue" ] 6 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-05-08" "fechaAceptado" => "2023-05-08" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1773371" "palabras" => array:4 [ 0 => "HPV" 1 => "Human papillomavirus" 2 => "Implementation" 3 => "Vaccine" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1773372" "palabras" => array:4 [ 0 => "VPH" 1 => "Virus del papiloma humano" 2 => "Implementación" 3 => "Vacuna" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Prophylactic vaccination against human papillomavirus (HPV) is the cornerstone of the World Health Organisation global strategy to accelerate the elimination of cervical cancer as a public health problem. At the end of 2007, the first two HPV vaccines were marketed in Spain. Therefore, 15 years have passed since the start of vaccination, included in the schedule of systematic immunizations for girls. Coinciding with this anniversary, this recommendation has been extended to boys. A vaccination that therefore achieves immunisation equity, regardless of sex. The purpose of this work is to offer an update on vaccination against HPV in Spain after 5 years of the initial work previously published on the historical origins of the virus and the beginnings of this immunisation, the second (after hepatitis B) for the prevention of cancer, and of the achievements and advances obtained.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">La vacunación profiláctica contra el virus del papiloma humano (VPH) es el pilar fundamental de la estrategia mundial de la Organización Mundial de la Salud para acelerar la eliminación del cáncer de cuello uterino como problema de salud pública. A finales de 2007 se comercializaron en España las dos primeras vacunas frente al VPH. Se cumplen por tanto 15 años del inicio de la vacunación, incluida en el calendario de inmunizaciones sistemáticas de las niñas, y precisamente, coincidiendo con este aniversario, se ha extendido esta recomendación a los varones. Una vacunación, pues, con independencia de sexo, que logra la equidad vacunal. El propósito de este trabajo es ofrecer una actualización de la vacunación frente al VPH en España tras el trabajo inicial publicado anteriormente sobre los orígenes históricos del virus y de los inicios de esta inmunización, la segunda (tras la de la hepatitis B) para la prevención del cáncer, y de los logros y avances obtenidos, que ahora, 5 años después, actualizamos.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="np4005">Please cite this article as: Moraga-Llop F. Quince años de vacunación frente al virus del papiloma humano en España. Actualización. Vacunas. 2023. <span class="elsevierStyleInterRef" id="ir9005" href="https://doi.org/10.1016/j.vacun.2023.05.001">https://doi.org/10.1016/j.vacun.2023.05.001</span></p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:45 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human papillomavirus vaccines: WHO position paper, 2022" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "WHO" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Wkly Epidemiol Rec" "fecha" => "2022" "volumen" => "97" "paginaInicial" => "654" "paginaFinal" => "672" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bb0010" "etiqueta" => "2." 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