Human papillomavirus (HPV) is family of almost 200 viruses’ types; most of them cause highly common viral infection of the female reproductive tract. It’s mainly transmitted through sexual contact and most people are infected with HPV shortly after the onset of sexual activity [1]. Many types of HPV don’t cause health complications. However, infections with the high-risk HPV types can persist and progress to cervical cancer; among these high-risk types, HPV16 and HPV18, are responsible for 70% of cervical cancers and precancerous cervical lesions. In 2018, 570,000 women developed cervical cancer and 311,000 died from it. Nowadays, it’s the second most common cancer in women living in developing regions [1]. Approximately 84% of all cervical cancers and 88% of all deaths caused by this cancer occurred in lower-resource countries [2].

It’s, therefore, a serious health problem, which reflects the need to adopt stringent preventive and control measures. The main procedures involve primary prevention (HPV vaccine), secondary prevention (cytological or molecular HPV testing screening) and tertiary prevention (diagnosis and treatment of invasive cervical cancer) [1]. Most of these public health attitudes allowed developed countries to decrease the incidence and mortality rates from HPV. However, this isn’t the scenario for developing countries as these sites have limited medical contact and poor infrastructures to adequate prevention and control measures, which leads to cervical cancers being diagnosed at very advanced stages, without the possibility of effective treatment¹. Protection against HPV infection and cervical cancer is such pertinent public health assertiveness that, since 2009, WHO recommends the introduction of HPV vaccine in national immunization programs [3]. In fact, vaccinating girls between 9 and 14 years old is assumed as the most cost-effective public health intervention against cervical cancer [1]. Currently, there are 3 prophylactic vaccines that protect against infections caused by HPV 16 and 18, other oncogenic HPVs and two non-oncogenic HPV (Table 1). Clinical trials and post-marketing surveillance showed significant evidence that these vaccines are safe and effective. Despite the fact that they protect against others additional HPV types besides 16 and 18, WHO considers that all 3 equally prevent cervical cancer [4] [5]. From 2009 to 2018, over 80 countries have implemented these vaccines in their immunization programs, but the majority was applied in developed countries. Developing countries, which have the highest burden of cervical cancer and the most need for vaccination, are still the ones with more barriers in the introduction of the vaccine [6]. Financial

supports from several institutions based on demonstration projects were implemented by like Gavi (Vaccine Alliance), which nowadays funds the majority of these projects to increase access to HPV vaccine worldwide [5] [6]. Thus, it’s important to assess the application and coverage of the HPV vaccine after the efforts made by organizations and to identify the main challenges that developing countries are facing. Herein we aimed to investigated, using a systematic review model, the difficulties and inequalities related to the HPV vaccine introduction, and discuss potential actions to optimize aid and maximize the access to HPV vaccines, improving the prevention of HPV-induced cervical cancer. We also sought to evaluate the percentage of application of HPV vaccination in girls between 9 and 14 years old in developing countries; and identify the main challenges in the implementation of HPV vaccine in developing countries.

In order to enable a good data collection and, consequently, its analysis, this systematic review was based on a set of defined objectives, as well as a set of inclusion and exclusion criteria.

Until 16 March 2020, we searched in two electronic databases, PubMed and Scopus, for relevant articles, since 10 years ago. Through the combination of keywords (HPV OR “Human Papillomavirus”) AND (Vaccine or Vaccination) AND (“Developing countries” OR “Low and middle-income countries”) appearing in titles and abstracts, these databases presented a list of possible studies. Then, we selected the articles according to the type of study, title, abstract and full text in a sequential way.

The results herein reported in this systematic review were primarily focused on the interest to evaluate the implementation of the HPV vaccine in developing countries, mostly through demonstration of different programs, in order to comprehend the existing barriers of HPV vaccine employment and recognize the

^aMost of the girls in this article were between 9 and 14 years old, however there is a group of 102 girls who were included in this analysis but who were over 14 years old. The article does not refer to the maximum age found in girls in this age group (>14 years old) so, as our systematic review includes an age range between 9 and 18 years old, this group will be included in our study in order to use the coverage data in this article.

^aIn a school-based delivery model, the vaccination sites used are schools attended by the target population. ^bIn a health-centre-based delivery model, the vaccination sites used are health facilities attended by the target population. ^cIn a mixed delivery model, the vaccination sites used are schools as well as health facilities attended by the target population.

distinct lessons learnt from different countries experiences. We would like to believe that the results of this systematic review presented here could contribute to support Public Health Authorities from low and middle-income countries to apply the HPV vaccine at national level in an organized and efficient manner. The findings published in the studies we analyzed clearly demonstrate that only in this way it becomes possible to overpass the barriers and inequalities in the women’s access to the important health interventions. Indeed, until 2017, forty-three developing countries have acquired experience in delivering the HPV vaccine to adolescent girls through pilot programs, demonstration programs and national introductions of vaccination programmes [3]. Although more developing countries have currently adopted the implementation of the vaccination, developed countries still represent the paradigm of HPV vaccine adoption as a means of primary prevention of cervical carcinoma and remain the majority of settings that included HPV vaccine in their national program [6]. Paradoxically, despite of having limited access, many of the lower-resources countries reached higher coverage rates than some of the richer countries, including France, USA, Japan or Denmark that have struggled to achieve even 50% coverage [6]. Our study found that the mean coverage rate of Ladner et al. [11], that assessed 21 programs of 14 developing different countries, was 88.7%; in Ladner and colleagues [13], which evaluated 8 programs in 7 countries, the rate was similar, reaching to 87.8%. Regarding Manhiça, a county from Mozambique [10], a rate of 73.3% of coverage was achieved; finally, Fregnani et al. [12] showed that in Barretos county, Brazil, the coverage rate was 85% after the implementation of a vaccination program. These results combined are in accordance with findings from Gallagher and co-workers [6], in which the majority of small-scale pilots and demonstration projects achieved 70% - 90% coverage with the 2 or 3 dose schedule, and four national programs in low and middle-income countries had 80% - 90% of the adolescents targeted receiving at least one dose of the vaccine. Likewise, in Gallagher et al. [5], 33 developing countries reached more than 50% final dose coverage and almost half (42%) reported 90% or higher coverage. Conversely, such high coverage rates weren’t found in the two studies from Uganda or in the other two African regions of the study of Mozambique, which the results were below 50%. These discrepancies in vaccination coverage rates between different developing countries are yet to be better explained. Nevertheless, the good news is that coverage of 100% is not needed to have a significant impact on HPV incidence and mortality, since this can be achieved with coverage even lower than 40% [6]. The success of vaccination implementation on a national level, measured by high coverage rate, rely fundamentally on the capacity of developing countries to apply the knowledge and experience gathered by others that have already implemented with positive results [3]. To do that, it’s necessary to recognize the barriers and challenges that compromise the vaccination. The main difficulties identified by all the studies we analyzed were lack of knowledge of the population, insufficient financial means and issues concerning delivery models, health professionals and vaccine supplies.

Regarding knowledge, the principal problems were lack of awareness about HPV and vaccine due to lack of properly education and discussion with girls and their parents or guardians. Consequently, from that arise uncertainty, misbeliefs, worries and myths that can undermine the success of the vaccination programs [10] [14]. Beside that it’s important that, when given, the information is clear, with plain and accessible language as anticipated by Wigle and colleagues [15].

Financial problems are also critical in various aspects, namely in the start of the implementations, their success and the capacity to evolve into national immunization programs. The lower socioeconomic development of developing countries and the lack of funds to financing pre-introduction activities, development of new delivery infrastructure and the deployment of human resources or reallocation of existing personnel were the relevant points addressed in the articles included in this review. All these aspects were stated by Gallagher K.E. et al. [6], which highlights the idea that the co-financing resources are insufficient, so these countries have to make decisions based on priorities, ending up to postpone the HPV vaccine introduction. The reality is that total costs and proportion spent in different components of the programs varied widely between countries, so it isn’t possible to assume exactly how much the HPV vaccine implementation will cost, according to LaMontagne et al. [3]. Thus, one of the major concerns of policy makers of the developing countries is the fact that HPV vaccine programs may be expensive and unsustainable [6].

Concerning delivery models, the school-based one appears to have higher effectiveness compared to the health-center-based model, even with the need of integration of the health and education systems. This model optimizes the vaccination coverage rate, because girls with age ranges recommended for the vaccine are likely to attend school, so it’s easier to vaccinate than might occur at health clinics. This finding is in agreement with Gallagher et al. [6] and Gallagher et al. [16], which refer that school-based delivery strategies with some specific mobilization to reach out-of-school girls should be the predominant model chosen to reach high coverage rate. The only aspect that came into conflict was the fact that Ladner et al. [13] found that mixed models were more effective than school-based ones unlike Ladner et al. [11]. As this article contains a larger number of programs and population and concludes the same as other reviews, it is more likely that its results are more reliable.

Lack of sufficient human resources and appropriate training in implementing the interventions are also a challenge. Insufficient vaccine supplies are likewise a serious question because of the current increasing demands. Actually, due to the inability to meet the demands of 2020 and 2021, some Gavi-eligible countries have to postpone multi-age vaccinations so other countries can start the single-age vaccination [17].

Lastly, a challenge that wasn’t addressed in our search but that Wigle et al., [15] refers and that compromises the successful implementation of the intervention is the lack of political will and commitment to new health technologies.

All these findings were based in a collection of articles, mostly classified with a moderate quality. The general problems encountered during the analysis, both from observational and cross-sectional studies specifically, relate to confounders not being addressed or clearly defined and poor description of the statistical methods used to analyze data. Beyond that, other limitations were present in these studies. The first limitation relates to the type of study itself, since a cross-sectional design limits the possibility of making causal inferences about the main outcome and independent variables. The use of census information is an imprecise methodology that can induce errors in determining target population, which can impact the coverage rates calculated. Indeed, percentages greater than 100% encountered in some programs indicate an under-estimation of the target population and/or recruitment of girls from outside of the original target area, suggesting that methodologies used for determining the target population may be suboptimal. In these studies, there may be a loss of representativeness of population and inability to generalize onto a national level in terms of results of the coverage and involved expenses, because the programs were implemented in specific regions of the countries. Finally, the use of questionnaires and open-ended questions give rise to possible poor recall of information and misclassification of the responses achieved by the investigators, respectively. Likewise, this review has some limitations. One of them is the fact that only English language was included, which may have eliminated potentially important studies in other languages. Missing data related to the study population (total number and sociocultural characteristics) and distinct measurement methods between studies can also limited the interpretation and comparison of the results.

The main challenges we found in several publications can be briefly resumed as a permissive combination of lack of information of the population, prejudice regarding the vaccine being linked to a sexually transmitted agent, inflexible cultural and religious values, lack of adequate infrastructure and medical care, lack of financial resources for the introduction and proper maintenance of vaccination, and lack of medical surveillance of periodic monitoring and well-organized preventive care of risk group women.

In conclusion, the introduction of a primary prevention as HPV vaccine has a remarkable impact on the burden of cervical cancer, specifically in developing countries where screening and treatment are non-existent or limited. To achieve a successful implementation of vaccination programs, it’s obviously necessary robust financial resources, strong and responsible political determination and efficient strategy to reach the target population and trace the outcomes. It’s also required tailoring specific interventions to meet the needs, because in public health care, with huge divergent cultural backgrounds, Public Health authorities must face challenges and observe the priorities of each region. In reality, regarding health interventions, one size doesn’t fit all. Actually, the common barrier among developing countries to implement HPV vaccination seems to be related to the underserved medical assistance and economic governmental support, as well as, the substantial lack of information of the population, maybe related to illiteracy or low schooling pattern of the majority of women, mainly those living in remote areas. Therefore, in the future, it will be essential that more developing countries have access and opportunity to implement the vaccine and discuss the possible solutions for these challenges. It would be beneficial as well to conduct studies that analyze the coverage rates of the countries after the elimination of the barriers and the repercussions on the mortality rates, to assess if they are as important as they seem.

The adoption of a vaccination system in poor and developing countries must, first of all, rely on the formal commitment of the health authorities and the categorical commitment of the political agents in each region. Preserving the health of a population is, before a medical act, a political commitment. Any effort that is made without the support of the political agents of a country seems doomed to fail, as they will not resist the advance of time. Disease prevention may have a start day, but it must not have an end date.

The authors declare no conflicts of interest regarding the publication of this paper.

Gonçalves, I.M.B., Fernandes, J.R.M., Ribeiro, F. and Longatto-Filho, A. (2020) HPV Vaccination in Young Girls from Developing Countries: What Are the Barriers for Its Implementation? A Systematic Review. Health, 12, 671-693. https://doi.org/10.4236/health.2020.126050

Strobe checklist

Checklist for observational studies (combined)

1a) Indicate the study’s design with a commonly used term in the title or the abstract? 1b) Provide in the abstract an informative and balanced summary of what was done and what was found? 2) Explain the scientific background and rationale for the investigation being reported? 3) State specific objectives, including any prespecified hypotheses? 4) Present key elements of study design early in the paper? 5) Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection? 6a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants? Describe methods of follow-up?; Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection? Give the rationale for the choice of cases and controls?; Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants? 6b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed?, Case-control study—For matched studies, give matching criteria and the number of controls per case?; 7) Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers? Give diagnostic criteria, if applicable?; 8) For each variable of interest, give sources of data and details of methods of assessment (measurement), describe comparability of assessment methods if there is more than one group?; 9) Describe any efforts to address potential sources of bias?; 10) Explain how the study size was arrived at?; 11) Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why?; 12a) Describe all statistical methods, including those used to control for confounding?; 12b) Describe any methods used to examine subgroups and interactions?; 12c) Explain how missing data were addressed?; 12d) Cohort study—If applicable, explain how loss to follow-up was addressed?, Case-control study—If applicable, explain how matching of cases and controls was addressed?, Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy?; 12e) Describe any sensitivity analyses?; 13a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed?; 13b) Give reasons for non-participation at each stage?; 13c) Consider use of a flow diagram?; 14a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders?; 14b) Indicate number of participants with missing data for each variable of interest?; 14c) Cohort study—Summarize follow-up time (eg, average and total amount)?; 15) Cohort study—Report numbers of outcome events or summary measures over time?, Case-control study—Report numbers in each exposure category, or summary measures of exposure?, Cross-sectional study—Report numbers of outcome events or summary measures?; 16a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval)? Make clear which confounders were adjusted for and why they were included?; 16b) Report category boundaries when continuous variables were categorized?; 16c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period?; 17) Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses?; 18) Summarize key results with reference to study objectives?; 19) Discuss limitations of the study, taking into account sources of potential bias or imprecision? Discuss both direction and magnitude of any potential bias?; 20) Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence?; 21) Discuss the generalizability (external validity) of the study results?; 22) Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based?