The cost of human papillomavirus vaccination delivery at the administrative and health facility levels in the Philippines.

Background: The World Health Organization has recommended the inclusion of human papillomavirus (HPV) vaccines in national immunization programs to address the global problem of cervical cancer. In the Philippines, HPV vaccination was introduced in a phased approach in 2015. This study seeks to estimate the cost of delivery of the HPV vaccination program and its operational context in the Philippines. Methods: This was a retrospective, cross-sectional micro-costing study focused on ongoing HPV vaccination delivery and its operational context across all levels of the health system. Using structured questionnaires and data collection from secondary sources, the weighted mean financial and economic costs and costs per dose at the national, subnational, and health facility levels were estimated. Results: The weighted mean financial and economic costs per dose of the HPV vaccination program aggregated across all levels of the health system were $US3.72and $29.74, respectively. Activities contributing most significantly to costs were service delivery and vaccine collection or distribution and storage at the health facility and administrative levels, respectively. The opportunity costs for health worker and non-health worker time accounted for 77% of the economic cost per dose. Conclusion: The total weighted mean financial and economic costs of HPV delivery are within range of those reported in other countries. Costing studies can help identify cost drivers with local operational context to help inform policymakers and program managers in budgeting and planning interventions to improve program implementation.

Healthcare provider perspectives on delivering next generation rotavirus vaccines in five low-to-middle-income countries.

BACKGROUND: Live oral rotavirus vaccines (LORVs) have significantly reduced rotavirus hospitalizations and deaths worldwide. However, LORVs are less effective in low- and middle-income countries (LMICs). Next-generation rotavirus vaccines (NGRVs) may be more effective but require administration by injection or a neonatal oral dose, adding operational complexity. Healthcare providers (HPs) were interviewed to assess rotavirus vaccine preferences and identify delivery issues as part of an NGRV value proposition. OBJECTIVE: Determine HP vaccine preferences about delivering LORVs compared to injectable (iNGRV) and neonatal oral (oNGRV) NGRVs. METHODS: 64 HPs from Ghana, Kenya, Malawi, Peru, and Senegal were interviewed following a mixed-method guide centered on three vaccine comparisons: LORV vs. iNGRV; LORV vs. oNGRV; oNGRV vs. iNGRV. HPs reviewed attributes for each vaccine in the comparisons, then indicated and explained their preference. Additional questions elicited views about co-administering iNGRV+LORV for greater public health impact, a possible iNGRV-DTP-containing combination vaccine, and delivering neonatal doses. RESULTS: Almost all HPs preferred oral vaccine options over iNGRV, with many emphasizing an aversion to additional injections. Despite this strong preference, HPs described challenges delivering oral doses. Preferences for LORV vs. oNGRV were split, marked by disparate views on rotavirus disease epidemiology and the safety, need, and feasibility of delivering neonatal vaccines. Although overwhelmingly enthusiastic about an iNGRV-DTP-containing combination option, several HPs had concerns. HP views were divided on the feasibility of co-administering iNGRV+LORV, citing challenges around logistics and caregiver sensitization. CONCLUSION: Our findings provide valuable insights on delivering NGRVs in routine immunization. Despite opposition to injectables, openness to co-administering LORV+iNGRV to improve efficacy suggests future HP support of iNGRV if adequately informed of its advantages. Rationales for LORV vs. oNGRV underscore needs for training on rotavirus epidemiology and stronger service integration. Expressed challenges delivering existing LORVs merit further examination and indicate need for improved delivery.

The cost-effectiveness of human papillomavirus vaccination in the Philippines.

Cervical cancer is the second most common cancer among women in the Philippines. Human papillomavirus (HPV) vaccination provides protection from the most common cancer-causing HPV types. This analysis used a proportionate outcomes model to estimate the potential cost-effectiveness of four different HPV vaccine products-Cervarix™, Cecolin®, GARDASIL®, and GARDASIL®9-for routine HPV vaccination of 10 cohorts of 9-year-old girls from the government and societal perspectives. Model parameters included cervical cancer burden, healthcare and program costs, vaccine efficacy with and without potential cross-protection, and vaccination coverage. Univariate and probabilistic sensitivity analyses evaluated the impact of uncertainty on model results. Compared to no vaccination, HPV programs with Cecolin®, Cervarix™, and GARDASIL® are projected to be cost-effective at US$1,210, US$1,300, and US$2,043 per DALY averted, respectively, from the government perspective, and at US$173, US$263, and US$1,006 per DALY averted, respectively, from the societal perspective when cross-protection was considered. When direct comparisons were made across vaccines, GARDASIL® was dominated by Cervarix™ and Cecolin®. In a scenario where cross-protection was not considered, results were similar except that Cervarix™ and GARDASIL® were both dominated by Cecolin®. GARDASIL®9 was not cost-effective under any of the modeled scenarios.

Antibody persistence and immune memory response following primary vaccination and boosting with live attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) in Bangladesh: A phase 4 open-label clinical trial.

INTRODUCTION: Japanese encephalitis (JE) virus is one of the leading causes of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. WHO currently recommends a single CD-JEV dose for infants in endemic settings. However, in the absence of long-term immunogenicity data, WHO has indicated a need for long-term immunogenicity studies to inform optimal dosing schedules and determine the need for booster doses. METHODS: This Phase 4, open-label clinical study measured neutralizing antibody (NAb) titers in Bangladeshi children three and four years after primary CD-JEV vaccination and 7 and 28 days after a booster CD-JEV vaccination given four years after primary vaccination. The study also assessed the tolerability and safety of the booster dose. A NAb titer of ≥1:10 was considered seroprotective. RESULTS: Of 560 children vaccinated between 10 and 12 months of age with CD-JEV three years earlier and enrolled in this study from 30 July 2015 through 03 January 2016, 52 (9.3%; 95% CI: 7.2-12.0) had a seroprotective titer at enrollment. One year later, of 533 children, 66 (12.4%; 95% CI: 9.9-15.5) had a seroprotective titer before receiving a booster dose. Of 524 children who received a booster CD-JEV dose, 479 (91.4%; 95% CI: 88.7-93.5) and 514 (98.1%; 95% CI: 96.5-99.0) were seroprotected 7 and 28 days later, respectively. The geometric mean titer (GMT) was 6 (95% CI: 6-6) at baseline, 105 (95% CI: 93-119) 7 days post-booster, and 167 (95% CI: 152-183) 28 days post-booster. No vaccine-associated neurologic adverse events or other serious adverse events were noted following the booster dose. CONCLUSIONS: Although most children did not have measurable antibody titers three and four years after a single primary CD-JEV dose, more than 90% of seronegative children had a strong anamnestic response within one week of a booster dose. This suggests that these children were immune despite the absence of measurable NAb prior to their booster.ClinicalTrials.gov Identifier: NCT02514746.

Does Anybody Want an Injectable Rotavirus Vaccine, and Why? Understanding the Public Health Value Proposition of Next-Generation Rotavirus Vaccines.

Routine infant immunization with live, oral rotavirus vaccines (LORVs) has had a major impact on severe gastroenteritis disease. Nevertheless, in high morbidity and mortality settings rotavirus remains an important cause of disease, partly attributable to the sub-optimal clinical efficacy of LORVs in those settings. Regardless of the precise immunological mechanism(s) underlying the diminished efficacy, the introduction of injectable next-generation rotavirus vaccines (iNGRV), currently in clinical development, could offer a potent remedy. In addition to the potential for greater clinical efficacy, precisely how iNGRVs are delivered (multiple doses to young infants; alongside LORVs or as a booster; co-formulated with Diphtheria-Tetanus-Pertussis (DTP)-containing vaccines), their pricing, and their storage and cold chain characteristics could each have major implications on the resultant health outcomes, on cost-effectiveness as well as on product preferences by national stakeholders and healthcare providers. To better understand these implications, we critically assessed whether there is a compelling public health value proposition for iNGRVs based on potential (but still hypothetical) vaccine profiles. Our results suggest that the answer is highly dependent on the specific use cases and potential attributes of such novel vaccines. Notably, co-formulation of iNGRVs with similar or greater efficacy than LORVs with a DTP-containing vaccine, such as DTP-Hib-HepB, scored especially high on potential impact, cost-effectiveness, and strength of preference by national stakeholders and health care providers in lower and middle income countries.

HPV vaccination coverage in three districts in Zimbabwe following national introduction of 0,12 month schedule among 10 to 14 year old girls.

BACKGROUND: Zimbabwe has one of the highest incidence rates of cervical cancer in the world - 61.7 per 100,000 women. The government of Zimbabwe introduced bivalent HPV vaccine with a 0,12 month schedule to all 10-14 year old girls using a pulsed-campaign approach in May 2018 (dose 1) and May 2019 (dose 2). METHODS: In August 2019, we conducted a population-based, two-stage cluster survey of households with girls who were eligible for the national HPV vaccination program to determine two-dose HPV vaccination coverage in three districts of Zimbabwe. All households with girls currently aged 11 to 15 years were line-listed through a census conducted in the pre-selected clusters from each district prior to survey administration. A simple random sample of eligible households was selected from these lists to estimate HPV vaccine coverage at sufficient power with a margin of error of +/- 5%. Criteria for district selection included estimated vaccine uptake (low, medium, high), rural/urban/peri-urban, geographic area, estimated number of girls not in school, and recent natural disasters or disease outbreaks. We oversampled households with girls aged 13 or 14 years at the time of dose 1. RESULTS: On-time dose 1 uptake ranged from 88 to 94% and two-dose HPV vaccine coverage ranged from 75 to 86% across the three districts. Nearly all vaccinations occurred in schools, and less than 2% of girls did not attend school. There were challenges assessing ages of girls at schools prior to vaccination - 9% of girls vaccinated were less than 10 years old at time of dose 1. DISCUSSION: Zimbabwe has demonstrated that high uptake and successful completion of 2-dose HPV vaccination can be achieved with an annual dosing schedule. Efforts going forward will need to focus on minimizing dropout between doses and routinizing annual vaccinations in schools for every subsequent new cohort of eligible girls in the country.

Associations between socioeconomic deprivation and pharmaceutical prescribing in primary care in England.

BACKGROUND: Socioeconomic deprivation is associated with health inequality. Previous studies have described associations between primary care prescribing rates and deprivation for individual drugs or drug classes. We explore the correlation between socioeconomic deprivation and the rate of prescribing of individual pharmaceutical drugs, and drug classes, in primary care in England, to identify prescribing inequalities that would require further investigation. METHODS: In this cross-sectional study, national primary care prescribing data, by primary care practice, were retrieved for the calendar year 2019 in England. Socioeconomic deprivation was quantified using the Index of Multiple Deprivation (IMD) score. Correlations were calculated using Spearman's rank correlation coefficient (ρ), adjusting for practice list size and demographics, with a Bonferroni-corrected p value threshold of 5×10-5. RESULTS: We included 1.05 billion prescription items dispensed from 6896 England practices. 142/206 (69%) drug classes and 505/774 (65%) drugs were significantly correlated with IMD score (p<5×10-5). Of the 774 included drugs, 31 (4%) were moderately positively associated with IMD score (ρ>0.4). Only one was moderately negatively correlated with IMD score (ρ<-0.4), suggesting higher prescribing rates in more affluent areas. The drug classes most strongly associated with IMD score included opioid and non-opioid analgesics, antipsychotics and reflux medications. Drug classes most strongly associated with affluence included epinephrine, combined oral contraceptives and hormone replacement therapy. CONCLUSION: We identify novel associations of prescribing with deprivation. Further work is required to identify the underlying reasons for these associations so that appropriate interventions can be formulated to address drivers of inequality.

National stakeholder preferences for next-generation rotavirus vaccines: Results from a six-country study.

BACKGROUND: Currently available live, oral rotavirus vaccines (LORVs) have significantly reduced severe rotavirus hospitalizations and deaths worldwide. However, LORVs are not as effective in low- and middle-income countries (LMIC) where rotavirus disease burden is highest. Next-generation rotavirus vaccine (NGRV) candidates in development may have a greater public health impact where they are needed most. The feasibility and acceptability of possible new rotavirus vaccines were explored as part of a larger public health value proposition for injectable NGRVs in LMICs. OBJECTIVE: To assess national stakeholder preferences for currently available LORVs and hypothetical NGRVs and understand rationales and drivers for stated preferences. METHODS: Interviews were conducted with 71 national stakeholders who influence vaccine policy and national programming. Stakeholders from Ghana, Kenya, Malawi, Peru, Senegal, and Sri Lanka were interviewed using a mixed-method guide. Vaccine preferences were elicited on seven vaccine comparisons involving LORVs and hypothetical NGRVs based on information presented comparing the vaccines' attributes. Reasons for vaccine preference were elicited in open-ended questions, and the qualitative data were analyzed on key preference drivers. RESULTS: Nearly half of the national stakeholders interviewed preferred a highly effective standalone, injectable NGRV over current LORVs. When presented as having similar efficacy to the LORV, however, very few stakeholders preferred the injectable NGRV, even at substantially lower cost. Similarly, a highly effective standalone injectable NGRV was generally not favored over an equally effective oral NGRV following a neonatal-infant schedule, despite higher cost of the neonatal option. An NGRV-DTP-containing combination vaccine was strongly preferred over all other options, whether delivered alone with efficacy similar to current LORVs or co-administered alongside an LORV (LORV + NGRV-DTP) to increase efficacy. CONCLUSION: Results from these national stakeholder interviews provide valuable insights to inform ongoing and future NGRV research and development.

Cost-effectiveness of rotavirus vaccination in the Philippines: A modeling study.

INTRODUCTION: Rotavirus gastroenteritis (RVGE) remains a leading cause of hospitalization and death in children under five years of age in the Philippines. Rotavirus (RV) vaccination was introduced into the national immunization program (NIP) in 2012 but has since been limited to one region due to cost considerations and conflicting local cost-effectiveness estimates. Updated estimates of the cost-effectiveness of RV vaccination are required to inform prioritization of national immunization activities. METHODS: We calculated the potential costs and benefits of rotavirus vaccination over a 10-year-period (2021-2031) from a government and societal perspective, comparing four alternative rotavirus vaccines: Rotavac, Rotasiil, Rotarix and Rotateq. For each vaccine, a proportionate outcomes model was used to calculate the expected number of disease events, DALYs, vaccination program costs, and healthcare costs, with and without vaccination. The primary outcome measure was the cost per DALY averted. Assuming each product would generate similar benefits, the dominant (lowest cost) product was identified. We then calculated the cost-effectiveness (US$ per Disability Adjusted Life Year [DALY] averted) of the least costly product and compared it to willingness-to-pay thresholds of 0.5 and 1 times the national GDP per capita ($3,485), and ran deterministic and probabilistic sensitivity analyses. RESULTS: Introducing any of the four rotavirus vaccines would avert around 40% of RVGE visits, hospitalizations, and deaths over the period 2021-2031. Over the same ten-year period, the incremental cost of vaccination from a government perspective was estimated to be around $104, $105, $220, and $277 million for Rotavac, Rotasiil, Rotarix and Rotateq, respectively. The equivalent cost from a societal perspective was $58, $60, $178 and $231 million. The cost-effectiveness of the least costly product (Rotavac) was $1,148 ($830-$1682) from a government perspective and $646 ($233-1277) from a societal perspective. All other products offered similar benefits but at a higher cost. There is a >99% probability that Rotavac would be cost-effective at a willingness-to-pay threshold set at 0.5 times the national GDP per capita. CONCLUSION: Both Rotavac and Rotasiil are likely to be cost-effective options in the Philippines, but it is not possible to say definitively which product should be preferred. Rotarix and Rotateq are expected to offer similar benefits at more cost, so would need to be priced far more competitively to be considered for introduction.

Immunogenicity and safety of concurrent or sequential administration of live, attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) and measles-mumps-rubella vaccine in infants 9-12 months of age in the Philippines: A non-inferiority Phase 4 randomized clinical trial.

INTRODUCTION: Japanese encephalitis (JE) virus is the leading cause of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. When incorporating a new vaccine into a country's Expanded Program on Immunization (EPI), it is important to show that the new vaccine can be administered concurrently with other routine pediatric vaccines without impairing the immune responses or changing the safety profiles of the co-administered vaccines. This Phase 4 open-label study evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine co-administered with CD-JEV. METHODS: The study randomized 628 healthy Filipino children aged between 9 and 10 months to receive MMR and CD-JEV concurrently or separately. MMR immunogenicity was measured 56 days after MMR vaccination using a measles plaque reduction neutralization test (PRNT), anti-mumps immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), and anti-rubella IgG ELISA, respectively. Neutralizing antibody against JE virus was measured 28 days after CD-JEV vaccination using PRNT. Safety was assessed through solicitation of immediate reactions, adverse events (AEs) within 14 days of vaccination, unsolicited AEs occurring within 28 days, and serious adverse events (SAEs) during participation in the study. RESULTS/CONCLUSIONS: During the study, no post-vaccinal encephalitis cases or related SAEs were reported in either group. Concurrent immunization with CD-JEV and MMR vaccines was not associated with any unusual safety signals when compared with sequential immunization. No significant differences between the regimens were seen in seropositivity or serology titer/concentration results for any of the antigens. Co-administration of CD-JEV and MMR was non-inferior to single administration of either vaccine.

Japanese encephalitis vaccination in the Philippines: A cost-effectiveness analysis comparing alternative delivery strategies.

INTRODUCTION: Japanese encephalitis (JE) is a mosquito-borne viral infection of the brain that can cause permanent brain damage and death. In the Philippines, efforts are underway to deliver a live attenuated JE vaccine (CD-JEV) to children under five years of age (YOA), who are disproportionately infected. Multiple vaccination strategies are being considered. METHODS: We conducted a cost-effectiveness analysis comparing three vaccination strategies to the current state of no vaccination from the societal and government perspectives: (1) national routine vaccination only, (2) sub-national campaign followed by national routine, and (3) national campaign followed by national routine. We developed a Markov model to estimate impact of vaccination or no vaccination over the child's lifetime horizon, assuming an annual incidence of 10.6 cases per 100,000. Costs of illness ($859/case), vaccine ($0.50/dose), routine vaccination ($0.95/dose), and campaign vaccination ($0.98/dose) were based on hospital financial records, expert opinion and literature. The societal perspective included transportation and opportunity costs of caregiver time, in addition to costs incurred by the health system. RESULTS: JE vaccination via national campaign followed by national routine delivery was the most cost-effective strategy modeled with a cost per disability adjusted life year (DALY) averted of $233 and $29 from the government and societal perspectives, respectively. Results were similar for other delivery strategies with cost/DALY ranging from $233 to $265 from the government perspective and $29-$57 from the societal perspective. JE vaccination was projected to prevent 27,856-37,277 cases, 5571-7455 deaths, and 173,233-230,704 DALYs among children under five over 20 consecutive birth cohorts. Total incremental costs of vaccination versus no vaccination over 20 birth cohorts were $6.6-$9.8 million from the societal perspective ($230 K-$440 K annually) and $45.9-$53.9 million ($2.2 M-$2.7 M annually) from the governmental perspective. CONCLUSION: Vaccination with CD-JEV in the Philippines is projected to be cost-effective, reducing long-term costs associated with JE illness and improving health outcomes compared to no vaccination.

Exploring barriers and facilitators to participation of male-to-female transgender persons in preventive HIV vaccine clinical trials.

Observed seroincidence and prevalence rates in male-to-female (MTF) transgender individuals highlight the need for effective targeted HIV prevention strategies for this community. In order to develop an effective vaccine that can be used by transgender women, researchers must understand and address existing structural issues that present barriers to this group's participation in HIV vaccine clinical trials. Overcoming barriers to participation is important for ensuring HIV vaccine acceptability and efficacy for the MTF transgender community. To explore barriers and facilitators to MTF transgender participation in preventive HIV vaccine clinical trials, the HIV Vaccine Trials Network conducted focus groups among transgender women in four urban areas (Atlanta, Boston, Philadelphia, and San Francisco). Barriers and facilitators to engagement of transgender women in preventive HIV vaccine clinical trials led to the following recommendations: (a) transgender cultural competency training, (b) creating trans-friendly environments, (c) true partnerships with local trans-friendly organizations and health care providers, (d) protocols that focus on transgender specific issues, and (e) data collection and tracking of transgender individuals. These results have implications for the conduct of HIV vaccine trials, as well as engagement of transgender women in research programs in general.