Planning, implementation, and sustaining high coverage of human papillomavirus (HPV) vaccination programs: What works in the context of low-resource countries?

Cervical cancer due to human papillomavirus (HPV) infection is a leading cause of mortality among women in low-resource settings. Many Sub-Saharan African countries have introduced HPV vaccination programs at the national level in the last few years. However, countries are struggling to maintain sustainable coverage. This study focuses on the introduction and sustainability challenges, context-specific key lessons learned, and mechanisms of action to achieve high sustainable coverage from low and lower-middle-income countries (LLMICs) that have introduced HPV vaccination programs by collating evidence from a literature review and key informant interviews. Local data availability was a challenge across countries, with the lack or absence of registries, data collection and reporting mechanisms. Multi-sectoral coordination and early involvement of key stakeholders were cited as an integral part of HPV programs and facilitators for sustainable coverage. Key informants identified periodic sensitization and training as critical due to high staff turnover. Health workforce mobilization was fundamental to ensure that the health workforce is aware of the disease etiology, eligibility requirements, and can dispel misinformation. Schools were reported to be an ideal sustainable platform for vaccination. However, this required teachers to be trained, which was often not considered in the programs. District-level staff were often poorly informed and lacked the technical and logistic capacity to support vaccination rounds and data collection. To improve the sustainability of HPV vaccination programs, there is a need for timely microplanning, efficient preparedness assessment, assessing training approaches, periodic training, finding innovative ways to achieve equity and adoption of a bottom-up approach to ensure that processes between districts and central level are well-connected and resources are distributed efficiently.

Integration of other services with human papillomavirus vaccination; lessons from earlier in the life course highlight the need for new policy and implementation evidence.

Integration of vaccination against human papillomavirus (HPV) with other essential health services for adolescents has been proposed in global strategies and tested in demonstration projects in low- and middle-income countries (LMIC). Published experiences, global guidance, and one key example, the implementation of "HPV Plus" in Tanzania, all demonstrate the need for greater operational evidence to guide future implementation and policy. Review of experiences earlier in the life course, integrating post-partum family planning with infant immunization, show lessons from 13 LMICs that can apply to provision of adolescent health information and services alongside HPV vaccination. Three distinct models of integration emerge from this review comprising: 1) multiple tasks and functions by health staff providing vaccination and other care, or 2) secondary tasks added to the main function of vaccination, or 3) co-location of matched services provided by different staff. These models, with strengths and weaknesses demonstrated in family planning and immunization experiences, apply in different ways to the three main platforms used for HPV vaccination: school, facility or community. For HPV vaccination policy and programming, an initial need is to combine the existing evidence on vaccine service delivery - including coverage, efficiency, cost, and cost-effectiveness information - with what is known on how integration works in practice; the operational detail and models employed. This synthesis may enable assessment which models best suit the different service delivery platforms. An additional need is to link this with more tailored local assessments of the adolescent burden of disease and other determinants of their well-being to develop new thinking on what can and cannot be done to integrate other services alongside HPV vaccination. New approaches placing adolescents at the center are needed to design services tailored to their preferences and needs. The potential synergies with cervical cancer screening and treatment for older generations of women, also require further exploration. Coordinated action aligning HPV vaccination with broader adolescent health and wellbeing will generate social, economic and demographic benefits, which in themselves are sufficient justification to devote more attention to integrated approaches.

Integrating HPV vaccination programs with enhanced cervical cancer screening and treatment, a systematic review.

A WHO global strategy launched in November 2020 sets out an ambitious pathway towards the worldwide elimination of cervical cancer as a public health problem within the next 100 years. Achieving this goal will require investment in innovative approaches. This review aims to describe integrated approaches that combine human papillomavirus (HPV) vaccination and cervical cancer screening in low- and middle-income countries (LMIC), and their efficacy in increasing uptake of services. A systematic review was conducted analyzing relevant papers from Embase, Medline, CINAHL and CAB Global Health databases, as well as grey literature. Narrative synthesis was performed on the included studies. Meta-analysis was not appropriate due to the heterogeneity and nature of included studies. From 5,278 titles screened, 11 uncontrolled intervention studies from four countries (from Africa and east Asia) were included, all from the past 12 years. Four distinct typologies of integration emerged that either increased awareness of HPV and/or cervical cancer screening, and/or coupled the delivery of HPV vaccination and cervical cancer screening programs. The synthesis of findings suggests that existing HPV vaccination programs can be a useful pathway for educating mothers and other female caregivers about cervical cancer screening; through in person conversations with care providers (preferred) or take-home communications products. Integrated service delivery through outreach and mobile clinics may overcome geographic and economic barriers to access for both HPV vaccination and cervical cancer screening, however these require significant program and system resources. One study promoted HPV vaccination as part of integrated service delivery, but there were no other examples found that examined use of cervical cancer screening platforms to promote or educate on HPV vaccination. This review has demonstrated gaps in published literature on attempts to integrate HPV vaccination and cervical cancer screening. The most promising practices to date seem to relate to integrated health communications for cervical cancer prevention. Future research should further explore the opportunities for integrated health communications to support the efforts towards the new global cervical cancer elimination agenda, and costs and feasibility of integrated service delivery for underserved populations.

Acting on the call: A framework for action for rapid acceleration of access to the HPV vaccination in low- and lower-middle-income countries.

Cervical cancer, caused by HPV infection, is responsible for more than 311  000 preventable deaths every year. A global call to accelerate efforts to eliminate this disease has generated a new global strategy proposing ambitious, but achievable, targets for HPV vaccination of girls, and screening and treatment of women. The present paper addresses the suboptimal access to HPV vaccination in low-income and lower-middle-income countries (LICs/LMICs), where the burden of disease weighs most heavily, in part through co-infection with HIV. A proposed framework for action was formulated by first reviewing the reasons underlying gaps in HPV vaccine coverage. Good practices from recent introductions of HPV vaccine at scale in LICs/LMICs were then assessed based on targeted literature reviews and the experience and views of the authors. Difficulties in uptake and coverage of the HPV vaccine relate to the costs of the vaccine and service delivery, lack of prioritization, the challenges of vaccinating adolescents, and shortage of vaccines as the supply failed to keep pace with the rapid expansion in global demand, including from LICs/LMICs. The framework for action calls for new strategic thinking to consolidate global learning and invigorate operationalization at a country level.

Experiences of operational costs of HPV vaccine delivery strategies in Gavi-supported demonstration projects.

From 2012 to 2016, Gavi, the Vaccine Alliance, provided support for countries to conduct small-scale demonstration projects for the introduction of the human papillomavirus vaccine, with the aim of determining which human papillomavirus vaccine delivery strategies might be effective and sustainable upon national scale-up. This study reports on the operational costs and cost determinants of different vaccination delivery strategies within these projects across twelve countries using a standardized micro-costing tool. The World Health Organization Cervical Cancer Prevention and Control Costing Tool was used to collect costing data, which were then aggregated and analyzed to assess the costs and cost determinants of vaccination. Across the one-year demonstration projects, the average economic and financial costs per dose amounted to US$19.98 (standard deviation ±12.5) and US$8.74 (standard deviation ±5.8), respectively. The greatest activities representing the greatest share of financial costs were social mobilization at approximately 30% (range, 6-67%) and service delivery at about 25% (range, 3-46%). Districts implemented varying combinations of school-based, facility-based, or outreach delivery strategies and experienced wide variation in vaccine coverage, drop-out rates, and service delivery costs, including transportation costs and per diems. Size of target population, number of students per school, and average length of time to reach an outreach post influenced cost per dose. Although the operational costs from demonstration projects are much higher than those of other routine vaccine immunization programs, findings from our analysis suggest that HPV vaccination operational costs will decrease substantially for national introduction. Vaccination costs may be decreased further by annual vaccination, high initial investment in social mobilization, or introducing/strengthening school health programs. Our analysis shows that drivers of cost are dependent on country and district characteristics. We therefore recommend that countries carry out detailed planning at the national and district levels to define a sustainable strategy for national HPV vaccine roll-out, in order to achieve the optimal balance between coverage and cost.

Molecular epidemiology and surveillance of circulating rotavirus and adenovirus in Congolese children with gastroenteritis.

Infectious Diarrhea caused by rotavirus and adenovirus, is a leading cause of death in children in sub-Sahara Africa but there is limited published data on the diverse rotavirus genotypes and adenovirus serotypes circulating in the Republic of Congo. In this study, we investigated the prevalence of severe diarrhea caused by rotavirus A (RVA) and Adenovirus serotype 40 and 41 in Congolese children hospitalized with severe gastroenteritis. Stool samples were collected from 655 Congolese children less than 60 months of age hospitalized with acute gastroenteritis between June 2012 and June 2013. Rotavirus and adenovirus antigens were tested using commercially available ELISA kits and the RVA G- and P- genotypes were identified by seminested multiplex RT-PCR. Three hundred and four (46.4%) children were tested positive for RVA. Adenovirus infection was found in 5.5% of the 564 tested children. Rotavirus infection was frequently observed in children between 6-12 months (55.9%). The dry season months recorded increased RVA infection while no seasonality of adenovirus infection was demonstrated. The most common RVA genotypes were G1 (57.5%), G2 (6.4%), G1G2 mixture (15.5%), P[8] (58%), P[6] (13.2%), and P[8]P[6] mixture (26%). Additionally, the genotype G12P[6] was significantly associated with increased vomiting. This first study on Congolese children demonstrates a high prevalence and clinical significance of existing rotavirus genotypes. Adenovirus prevalence is similar to that of other Central African countries. This baseline epidemiology and molecular characterization study will contribute significantly to the RVA surveillance after vaccine implementation in the country.

Factors influencing acceptability of voluntary HIV testing among pregnant women in Gamboma, Republic of Congo.

BACKGROUND: This study was carried out to identify factors affecting the acceptability of voluntary HIV testing among pregnant women in a semi-rural city, Gamboma, Republic of Congo. METHODS: A cross-sectional study was conducted between January and September 2012. Pregnant women attending antenatal heath care at an integrated health center were enrolled after informed consent and followed through voluntary HIV testing. RESULTS: Among 136 participants, 98 women (72 %) accepted voluntary HIV testing after pre-test counseling. Women with basic education, those who cited blood transfusion as a mode of transmission and prevention of mother-to-child transmission (MTCT) were more likely to accept testing as well those informed about free HIV testing. Interestingly, pregnant women who had heard about HIV/AIDS from hospital setting were less likely to accept testing. CONCLUSIONS: Our data indicate that increasing general education on HIV transmission/prevention modes is crucial for increasing acceptability of screening. Furthermore, HIV/AIDS knowledge disseminated to patients in hospital settings should be carefully monitored. Lastly, scaling-up MTCT services along with a better and larger community information, may address accessibility barriers observed in the present study.

Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization.

RATIONALE: Matrix vesicles (MVs) are specialized structures that initiate mineral nucleation during physiological skeletogenesis. Similar vesicular structures are deposited at sites of pathological vascular calcification, and studies in vitro have shown that elevated levels of extracellular calcium (Ca) can induce mineralization of vascular smooth muscle cell (VSMC)-derived MVs. OBJECTIVES: To determine the mechanisms that promote mineralization of VSMC-MVs in response to calcium stress. METHODS AND RESULTS: Transmission electron microscopy showed that both nonmineralized and mineralized MVs were abundantly deposited in the extracellular matrix at sites of calcification. Using cultured human VSMCs, we showed that MV mineralization is calcium dependent and can be inhibited by BAPTA-AM. MVs released by VSMCs in response to extracellular calcium lacked the key mineralization inhibitor matrix Gla protein and showed enhanced matrix metalloproteinase-2 activity. Proteomics revealed that VSMC-MVs share similarities with chondrocyte-derived MVs, including enrichment of the calcium-binding proteins annexins (Anx) A2, A5, and A6. Biotin cross-linking and flow cytometry demonstrated that in response to calcium, AnxA6 shuttled to the plasma membrane and was selectively enriched in MVs. AnxA6 was also abundant at sites of vascular calcification in vivo, and small interfering RNA depletion of AnxA6 reduced VSMC mineralization. Flow cytometry showed that in addition to AnxA6, calcium induced phosphatidylserine exposure on the MV surface, thus providing hydroxyapatite nucleation sites. CONCLUSIONS: In contrast to the coordinated signaling response observed in chondrocyte MVs, mineralization of VSMC-MVs is a pathological response to disturbed intracellular calcium homeostasis that leads to inhibitor depletion and the formation of AnxA6/phosphatidylserine nucleation complexes.

Proteomic and metabolomic analysis of smooth muscle cells derived from the arterial media and adventitial progenitors of apolipoprotein E-deficient mice.

We have recently demonstrated that stem cell antigen 1-positive (Sca-1(+)) progenitors exist in the vascular adventitia of apolipoprotein E-deficient (apoE(-/-)) mice and contribute to smooth muscle cell (SMC) accumulation in vein graft atherosclerosis. Using a combined proteomic and metabolomic approach, we now characterize these local progenitors, which participate in the formation of native atherosclerotic lesions in chow-fed apoE(-/-) mice. Unlike Sca-1(+) progenitors from embryonic stem cells, the resident Sca-1(+) stem cell population from the vasculature acquired a mature aortic SMC phenotype after platelet-derived growth factor-BB stimulation. It shared proteomic and metabolomic characteristics of apoE(-/-) SMCs, which were clearly distinct from wild-type SMCs under normoxic and hypoxic conditions. Among the differentially expressed proteins were key enzymes in glucose metabolism, resulting in faster glucose consumption and a compensatory reduction in baseline interleukin-6 secretion. The latter was associated with a marked upregulation of insulin-like growth factor binding proteins (IGFBPs) 3 and 6. Notably, reconstitution of interleukin-6 to levels measured in the conditioned medium of wild-type SMCs attenuated the elevated IGFBP expression in apoE(-/-) SMCs and their vascular progenitors. This coregulation of apoE, interleukin-6, and IGFBPs was replicated in wild-type SMCs from hypercholesterolemic mice and confirmed by silencing apoE expression in SMCs from normocholesterolemic mice. In summary, we provide evidence that Sca-1(+) progenitors contribute to native atherosclerosis in apoE(-/-) mice, that apoE deficiency and hypercholesterolemia alter progenitor cell behavior, and that inflammatory cytokines such as interleukin-6 act as metabolic regulators in SMCs of hyperlipidemic mice.

Integrated membrane protein analysis of mature and embryonic stem cell-derived smooth muscle cells using a novel combination of CyDye/biotin labeling.

Cultivated vascular smooth muscle cells (SMCs) were surface-labeled with CyDyes followed by biotinylation. After enrichment on avidin columns, proteins were separated on large format gradient gels by SDS-PAGE. A comparison between CyDye-tagged and non-tagged gel bands revealed a substantial increase of protein identifications from membrane, membrane-associated, and extracellular matrix proteins with a corresponding reduction in co-purified intracellular proteins. Notably the majority of identified proteins were involved in cellular adhesion processes. To demonstrate the quantitative potential of this platform, we performed a comparison between mature and embryonic stem cell-derived smooth muscle cells (esSMCs) and identified the membrane proteins E-cadherin, integrin alpha6, and CD98 (4F2) to be significantly up-regulated in esSMCs suggesting that SMCs derived from embryonic stem cells maintain characteristics of their embryonic stem cell origin. This was subsequently confirmed by RT-PCR: despite expressing a panel of smooth muscle markers (calponin, Sm22, and aortic smooth muscle actin), esSMCs remained positive for markers of stem cell pluripotency (Oct4, Nanog, and Rex1). In summary, we describe a novel strategy for the profiling of cell membrane proteins. The procedure combines DIGE technology with biotin/avidin labeling to discriminate membrane and membrane-associated proteins from intracellular contaminants by fluorescence tagging and permits semiquantitative differential expression analysis of membrane proteins.