Knowledge and Awareness of HPV Vaccine and Acceptability to Vaccinate in Sub-Saharan Africa: A Systematic Review

Objectives We assessed the knowledge and awareness of cervical cancer, HPV and HPV vaccine, and willingness and acceptability to vaccinate in sub-Saharan African (SSA) countries. We further identified countries that fulfill the two GAVI Alliance eligibility criteria to support nationwide HPV vaccination. Methods We conducted a systematic review of peer-reviewed studies on the knowledge and awareness of cervical cancer, HPV and HPV vaccine, and willingness and acceptability to vaccinate. Trends in Diphtheria-tetanus-pertussis (DTP3) vaccine coverage in SSA countries from 1990–2011 were extracted from the World Health Organization database. Findings The review revealed high levels of willingness and acceptability of HPV vaccine but low levels of knowledge and awareness of cervical cancer, HPV or HPV vaccine. We identified only six countries to have met the two GAVI Alliance requirements for supporting introduction of HPV vaccine: 1) the ability to deliver multi-dose vaccines for no less than 50% of the target vaccination cohort in an average size district, and 2) achieving over 70% coverage of DTP3 vaccine nationally. From 2008 through 2011 all SSA countries, with the exception of Mauritania and Nigeria, have reached or maintained DTP3 coverage at 70% or above. Conclusion There is an urgent need for more education to inform the public about HPV, HPV vaccine, and cervical cancer, particularly to key demographics, (adolescents, parents and healthcare professionals), to leverage high levels of willingness and acceptability of HPV vaccine towards successful implementation of HPV vaccination programs. There is unpreparedness in most SSA countries to roll out national HPV vaccination as per the GAVI Alliance eligibility criteria for supporting introduction of the vaccine. In countries that have met 70% DTP3 coverage, pilot programs need to be rolled out to identify the best practice and strategies for delivering HPV vaccines to adolescents and also to qualify for GAVI Alliance support.


Introduction
The introduction of vaccines has been one of the most effective public health interventions for combating infectious diseases [1,2]. The establishment of the Expanded Programme on Immunization (EPI) in 1974 by the World Health Organization (WHO) led to the global eradication of smallpox and has greatly reduced the burden of several infectious diseases, including poliomyelitis, measles, tuberculosis, tetanus and diphtheria in many parts of the world [2]. Despite slow progress in increasing vaccine access and immunization coverage, the EPI has reported 83% coverage of infants worldwide of the three doses of Diphtheria-tetanuspertussis (DTP3) vaccine in 2011, similar to coverage in 2009 (82%) and 2010 (85%) [1,3]. Expansion and delivery of life-saving vaccines in the 2010-2020 ''decade of vaccines'' is expected to save 6.4 million lives, valued at hundreds of billions of dollars in low and middle-income countries [4]. Currently, DTP3 coverage by age 12 months is a key indicator of immunization program performance of a country and is associated with the level of capacity to effectively manage and deliver a new vaccine to a target cohort [5,6].
Worldwide, 15% of all cancer cases and nearly 26% of cancer cases in developing countries are attributable to infectious agents, particularly viruses [7]. Cervical cancer, which is caused by the human papillomavirus (HPV), is the leading cause of cancer mortality among women in sub-Saharan Africa (SSA) [8,9]. The approval and recommendation of two vaccines -Gardasil and Cervarix -provide a huge opportunity to curb the burden of cervical cancer [10]. As one of the key strategies in preventing cervical cancer in developed countries, providing HPV vaccines in low and middle income countries is a critical pillar for meeting the global action plan for closing the cancer divide [5]. However, outstanding barriers to achieving this goal in low-income countries remain. These include high cost of vaccine and vaccine delivery [11], low cervical cancer screening levels [12], poor health system capabilities [11,13], inaccessibility to medical care [14], low awareness and knowledge of HPV and cervical cancer [14][15][16][17][18], and failure of cervical cancer to be recognized as a major health concern [19].
Several recent developments have emphasized HPV vaccine as an important prevention strategy. The 2009 WHO position paper on HPV vaccines recommended they be included in routine national immunization programs as a public health priority [20]. Furthermore, one of the goals of the 2006 Global Immunization Vision and Strategy (GIVS) is to introduce new vaccines to all eligible populations within five years of introduction in national programs [3]. Additionally, major milestones during 2007-2011 have brought access to HPV vaccines within reach for many adolescents in low-income countries. In May 2013, for the first time ever, a public offer was made by GAVI Alliance for a price of $4.50 per dose for both Gardasil and Cervarix to low-income countries [21], a drastic reduction from $360 for the required three doses [22,23].
Currently, the GAVI Alliance uses two criteria to determine eligibility for vaccination support, including HPV vaccine: 1) a DTP3 threshold of 70% national coverage (WHO/UNICEF estimates) and 2) a pilot demonstration of the ability to deliver a complete multi-dose series of vaccines to at least 50% of the target vaccination cohort in an average sized district in a country [24]. Recently, Rwanda was the first country to take advantage of the low pricing through a partnership with pharmaceutical manufacturer Merck, achieving 93% coverage of HPV vaccination of all grade six adolescent girls in 2011 [25][26][27], which is, to the best of our knowledge, the highest in the world. Through other sources of subsidized HPV vaccines, 88.9% of girls were fully vaccinated in Uganda using a school-based pilot program supported by PATH International in 2009 [28]. A similar HPV vaccination pilot initiative was recently undertaken in Cameroon [15], Tanzania [29], Lesotho [30] and South Africa [31]. More recently, Kenya became the first SSA country to receive GAVI Alliance support to roll out a HPV vaccine pilot project (see: http://www.gavialliance. org/support/nvs/human-papillomavirus-vaccine-support). GAVI Alliance also announced that in 2014 it will support the first nationwide introduction of HPV vaccine in Rwanda for girls of all eligible ages, as well as other HPV demonstration projects in Mozambique, Zimbabwe, Ghana, Madagascar, Malawi, Niger, Sierra Leone, and Tanzania (see: http://www.gavialliance.org/ support/nvs/human-papillomavirus-vaccine-support).
These developments, coupled with SSA's recent success in reaching 70% coverage for other routine vaccines, namely measles, hepatitis B, Influenza, tuberculosis and polio since 1990 [3], provide strong evidence of how introducing HPV vaccine can be achieved in other countries meeting the GAVI Alliance eligibility criteria. The success of pilot demonstrations in Rwanda, South Africa, Cameroon, Lesotho, Tanzania and Uganda also provide lessons on how to design and implement national HPV vaccination programs tailored for a specific group of individuals in resource-limited regions.
Nevertheless, introducing HPV vaccine in SSA offers unique challenges, especially due to limited awareness of cervical cancer, its relationship to HPV, concerns about safety and future fertility, and political factors [32], as seen in recent cases in Rwanda [26,27] and Cameroon [33]. These unsubstantiated rumors about side effects or adverse outcomes that may not be casually related to the vaccine may negatively impact public trust and adversely impact HPV immunization programming leading to suspension of the program altogether as recently experienced in Japan [34] and India [35].
In this study, we assessed the knowledge and awareness of cervical cancer, HPV and HPV vaccine, willingness and acceptability to vaccinate through a systematic review of peerreviewed literature. We further identified the fulfillment of GAVI Alliance eligibility criteria among countries in SSA. To the best of our knowledge this is the first systematic review of the potential readiness for introduction of HPV vaccine in the sub-continent, which reveals further insight into some of the unique challenges that need to be addressed.

Identification of Studies
Studies examining awareness, knowledge of cervical cancer, HPV and acceptability of HPV vaccines in SSA were identified by searching PubMed/MEDLINE (NCBI), Embase (Elsevier), African Index Medicus (AIM), and POPLINE (K4Health) from their earliest dates through July 11, 2013. Bibliographies of relevant reviews and eligible studies were examined for additional sources. The search was performed by a librarian (PAB) using terms for papillomavirus vaccines and vaccination, acceptability or awareness, and the names of all SSA countries (Appendix S1). The search was conducted without language restriction. Titles and abstracts of identified articles were reviewed by two authors (SP and JGO) and categorized as relevant using the criteria outlined below.
The review was conducted using methodology reported in the National Health Service Centre for Reviews and Dissemination report, supplemented by Harden's recommendations for systematic reviews of qualitative studies [36]. We also adhered to guidance on methods for conducting and reporting systematic reviews in the PRISMA statement where it could be applied to mixed method reviews [37]. Two authors (JGO and RGW) appraised the quality of the studies using a checklist developed by the National Institute for Health and Clinical Excellence [38], and surveys using a checklist adapted from Pettigrew and Roberts [39] provided in supplementary Table 1 and Table 2, respectively.

Inclusion Criteria
Studies included in the review needed to meet the following criteria: 1) it occurred in a SSA country; 2) it was published in 2006 or later, after HPV vaccination was introduced; 3) it focused on one or more of the three key demographics (adolescents, parents/guardians, healthcare workers); and 4) it examined at least one or more of the following key themes: a) level of awareness of HPV and/or cervical cancer; b) level of knowledge of cervical cancer and/or awareness; c) willingness to vaccinate; d) and acceptability of HPV vaccine. Studies that conducted a pilot HPV vaccination program were automatically included in the review. Animal studies were excluded from the review.

Article Review
A systematic review of the identified studies was then performed summarizing key results. The authors' findings were treated as primary data and studies were synthesized using a framework approach. Data were extracted and organized by key information such as demographic, method and sample size, and key findings of the study about levels of knowledge, awareness, willingness and acceptability. Any strategies for vaccination or increasing awareness (whether recommended or implemented strategies) were also

Analysis
Levels of awareness, knowledge, acceptability and willingness were broken down into these categories: 1) awareness of cervical cancer, HPV and/or HPV vaccine; 2) knowledge of cervical cancer, HPV and/or HPV vaccine; 3) acceptability of HPV vaccine (and in one case, acceptability of cervical cancer screening); and 4) willingness to vaccinate or get vaccinated. Willingness was broken down further into categories based on how each individual article defined it as seen in Table 1. Levels of awareness, knowledge, acceptability and willingness to vaccinate were summarized based on how each individual study categorized the levels (high, low or moderate). The articles were then tallied for each relevant category. Some articles had multiple levels of awareness and knowledge, resulting in one article being counted more than once (i.e. one article may have high awareness of cervical cancer but low awareness of HPV). Strategies for vaccination/increasing awareness and factors influencing acceptability provided qualitative insight and allowed us to identify important themes for awareness, implementation and acceptability of HPV vaccination.

Overview of Studies Examined
The literature search returned 142 unique records as summarized in the flow chart (Fig. S1). Review of selected article bibliographies uncovered 10 other articles. A total of 124 relevant articles were selected and reviewed and 29 articles based on 27 studies in 13 different SSA countries met the inclusion criteria. Ten studies focused on women, with ages ranging from 12 to 84, eight studies focused on medical professionals, five focused on parents and six focused on girls in primary schools. Six countries implemented HPV vaccination pilot programs (Cameroon, Lesotho, Rwanda, South Africa, Tanzania and Uganda). Table 1 shows a detailed summary of identified studies and Table 2 summarizes the key findings from each study.

Study Quality
Two qualitative studies were considered to be of good standard while one was considered moderate and one was considered poor. Nearly all of the surveys were well conducted and 17 of these had a sample size greater than 200 respondents. Sixteen of those had a response rate greater than 70%. The remaining studies varied in quality from moderately good to poor [30].

Awareness and Knowledge of Cervical Cancer and HPV
Fifteen studies examined awareness of cervical cancer, HPV and/or HPV vaccine among specific demographic groups. Levels of awareness were mixed with 11 studies demonstrating high awareness, nine studies demonstrating low awareness and two studies demonstrating moderate awareness. Levels of knowledge of cervical cancer and HPV were consistently low. Of the 16 studies examining knowledge of cervical cancer, HPV and HPV vaccine, all noted low levels of knowledge, three reported no knowledge, and two reported moderate knowledge. Only one study specified a moderately high level of knowledge of HPV vaccine.

Willingness and Acceptability of HPV Vaccine and Cervical Cancer Screening
Categories of willingness varied across studies: willingness to recommend HPV vaccine (five studies); willingness to get vaccinated (four); willingness to get daughter vaccinated (four); willingness to participate in vaccine trials (one); ''interest'' in the vaccine for daughters (one); and ''interest in learning more about the vaccine'' (one). All studies reported high rates of willingness in their respective categories. Twelve studies examined acceptability levels of HPV vaccine and one study examined acceptability of    cervical cancer screening (Table 1). All 12 studies reported high levels of acceptability of HPV vaccine. However, multiple levels of acceptability were found within the studies because some assessed and compared different vaccine delivery strategies within and in different countries.

Strategies and Factors for Increasing Awareness and Acceptability of HPV Vaccine
Of the 27 studies, 26 discussed strategies for vaccination and increasing awareness. Studies in the six countries in the review where HPV vaccination pilot programs were conducted discussed the implementation strategies used for vaccination while the remaining countries in this review discussed recommended strategies for implementation. Rwanda, South Africa Tanzania and Uganda used school-based strategies achieving 93.2%, 97.8%, 71.6% and 88.9% vaccine uptake, respectively [25,28]. Lesotho used a mixed vaccination strategy (clinic and school-based) [30]. Cameroon used three distinct approaches to deliver vaccines namely school-based, health facilities and community outreach programs in churches and mother-to-daughter [15,17,18]. In addition, all studies, with the exception of Lesotho specifically mentioned that sensitization campaigns were used in their vaccination strategies [30]. Rwanda conducted a nationwide campaign while South Africa, Tanzania, Cameroon and Uganda conducted focused educational campaigns to targeted groups [15,25,28,29,31]. Two studies in both Botswana [40] and Ghana [41] recommended schools as the ideal venue for HPV vaccine delivery.
Education for increasing awareness was a strong theme throughout the majority of studies. Recommended strategies to implement sensitization programs included community health education programs, continuing medical education for nurses, midwives, doctors and other healthcare workers, and health promotion and policy programs including awareness through social and mass media (i.e. public radio, television and folk media).
Factors influencing acceptability also varied. Twelve studies addressed reasons for acceptability of HPV vaccine. Two studies in Nigeria [42,43] discussed reasons for rejection among nurses and university students while one study in Tanzania [29] noted that head teachers at three private schools would not permit vaccination, fearing negative parental feedback. In Nigeria [43], nurses' reasons included: insufficient knowledge about HPV vaccine; girls were too young and not sexually active; girls are not yet at risk to HPV infections; and it encourages promiscuity. In addition, university students who rejected the HPV vaccine based their decisions on fear of side effects, fear of the unknown, and controversies surrounding the vaccine [42]. Themes surrounding acceptability included access to the vaccine, side effects and effectiveness, protection against and prevention of cervical cancer, provider and teacher recommendations, support from the National Immunization Program and cost [42,43].

GAVI Alliance Eligibility Based on DTP3 Levels and Pilot Demonstration Projects on HPV Vaccine Delivery
Of the 13 countries included in this review, 12 have achieved 70% coverage or higher of the DTP3 vaccine since 2003, one of GAVI Alliance's criteria for vaccine support; the exception is Nigeria ( Table 3). Six of those countries had an HPV vaccination pilot program (Cameroon, Lesotho, Rwanda, South Africa, Tanzania and Uganda). There were 31 sub-Saharan African countries not included in the review because there were no studies based in these countries that met the inclusion criteria. The majority of these countries did not start consistently reaching  (Table 4).

Discussion
This review identified low levels of knowledge and mixed levels of awareness on cervical cancer, HPV and HPV vaccine, and high levels of acceptability of HPV vaccine among all key demographics. In particular, high acceptability of HPV vaccine despite the lack of knowledge about cervical cancer and HPV represents an opportunity for increased education and awareness strategies about cervical cancer, HPV and HPV vaccine. This is important to help key demographics understand the transmission of HPV, its characteristics and associated risks [17,44], and the benefits of HPV vaccine.
Engaging all key demographics through improved and increased education will elevate public trust, which is a critical component of successful implementation of widespread vaccine coverage. Incidences such as those seen in Japan, India and Rwanda [26,27,34,35,45] have challenged public trust in HPV vaccines. Additionally, the qualitative insight provided by this review shows that factors influencing acceptability are often tied to issues of public trust, such as concerns over side effects and safety. This is not only a concern in low-and mid-income countries. For instance, Japan's Ministry of Health recently withdrew its recommendation for administering HPV vaccine because of reports of side effects, although it still pays for the vaccine for parents consenting to immunize their daughters [34].
Anti-vaccination groups frequently post inaccurate information about vaccine side effects on the web, which is publicized by both local and national media [46,47]. These examples indicate the need to constantly engage and educate the public to avoid the risk of health programs failing [48,49]. While it may not be advisable or possible to respond to all such misinformation, it is essential to counteract it by providing scientifically correct information in a proactive manner so people will seek appropriate medical advice for clarification [50].
Tailored community-based interventions and sensitization programs are a viable means to achieve this for multiple reasons.
They have the potential to curb concerns about safety and effectiveness of the vaccine while dispelling negative myths or controversies [45]. Specific training for healthcare workers, the first contact point for patients, will provide them with the accurate knowledge and information necessary to discuss cervical cancer, HPV and HPV vaccine with their patients as well as the ability to properly detect, screen and test for HPV and cervical cancer [18,43].
In addition to understanding levels of knowledge, awareness and acceptability, this review uncovered encouraging trends concerning SSA countries' eligibility for GAVI Alliance support. Only six countries have currently met the two criteria required by the GAVI Alliance to support introduction of the HPV vaccine at a lower cost of US$4.50 per dose [21]. Of the six, Rwanda has already achieved 93.2% vaccine coverage among girls in grade six and is taking the lead to enroll all eligible girls for HPV vaccination through GAVI alliance support in 2014.
Further, our analysis of national vaccine coverage for DTP3 in SSA shows rapid expansion from just one country reaching 80% in 1980 to 35 countries in 2010 [6]. Of the 31 countries that did not meet the review inclusion criteria, only Mauritania did not consistently achieve GAVI Alliance's eligibility criteria requiring DTP3 coverage levels greater than or equal to 70% (Table 4). Of the countries included in this review, only Nigeria failed to meet this threshold. The challenges in Nigeria are perhaps unique especially in the context of the recent polio vaccine boycott and killings [51]. This calls for interrogating vaccine acceptance determinants using, for instance, the health-belief model [45] and addressing these through a re-emphasis on contextualized public communication and education to mitigate resistance and to build trust [6].
Such consistently high DTP3 coverage levels among the majority of SSA countries indicates structural health system capabilities to deliver simple vaccines to the population [1,3]. This further demonstrates the feasibility for these countries to deliver multi-dose vaccines, such as HPV, for 50% of a target vaccination cohort in an average size district, which would qualify them for GAVI Alliance support. Support from GAVI Alliance is a critical and essential gateway to preventing cervical cancer through vaccination in SSA and bridging the global cancer divide [5].  1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 As this review shows, engaging all stakeholders at multiple levels in countries that meet these requirements is necessary for successful HPV vaccine implementation. Governments should leverage the high levels of acceptability and willingness to vaccinate by increasing education for healthcare workers, women/girls and parents/guardians. Governments should also determine appropriate strategies for disseminating information and vaccine delivery by building upon current infrastructures, such as existing EPIs and school-based programs. This has been shown to be an effective approach because it relies on the involvement of multiple critical stakeholders from the government down to the community level, as seen in Rwanda, South Africa, Uganda and Tanzania [2,6,25,26,28,31]. Tailored community-based sensitization campaigns aimed at a targeted population, as used in Cameroon, also proved effective [15,17,18]. Thus, using hybrid delivery system models may be more beneficial as per country experiences in the EPI and can help inform and determine best practices when developing HPV vaccine pilot programs [4,6].

Conclusions
The objective of this study was to provide a systematic review of knowledge and awareness of HPV vaccine, willingness to vaccinate, and acceptability of the vaccine, as well as fulfillment of GAVI Alliance's eligibility criteria for vaccine assistance in SSA. To the best of our knowledge, this is the first systematic review of the potential readiness for introduction of HPV vaccine in the subcontinent. Examining the region collectively offers insight into its readiness and ability to implement HPV vaccination on a broader scale while shedding light on the successes, challenges, and lessons of implementation.

Limitations
There were some limitations in this review. The studies reviewed lacked consistency in regards to psychometric characteristics used. Not all of the studies used a theoretical framework, consistent labeling of themes examined, or rigorous testing and validation of the measures as previously outlined [52]. While some assessed levels of knowledge and awareness of cervical cancer and HPV, others did not. Still others discussed levels of willingness to vaccinate and acceptability of HPV vaccine while others did not.
Some studies discussed all themes. This indicates a need for more standardized methods on awareness and knowledge of HPV and HPV vaccine, and acceptability and willingness to vaccinate to provide better insight to guide health care practitioners in developing successful community and clinical interventions and scaling up HPV vaccination. Every effort was made to include all studies but it is possible some were missed.  Checklist S1 PRISMA Checklist (DOC) Appendix S1 Search strategies for bibliographic databases.