Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in children in Sierra Leone: a randomised, double-blind, controlled trial.

BACKGROUND: Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone. METHODS: This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1-17 years were enrolled in three age cohorts (12-17 years, 4-11 years, and 1-3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 1010 viral particles; first dose) followed by MVA-BN-Filo (1 × 108 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494. FINDINGS: From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1-3 years after placebo injection to 21% (30 of 144) of children aged 4-11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12-17 years and 4-11 years age cohorts after the first and second dose, and pyrexia in the 1-3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12-17 years (9929 ELISA units [EU]/mL [95% CI 8172-12 064]), in 119 (99%) of 120 aged 4-11 years (10 212 EU/mL [8419-12 388]), and in 118 (98%) of 121 aged 1-3 years (22 568 EU/mL [18 426-27 642]). INTERPRETATION: The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1-17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

Safety and long-term immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in adults in Sierra Leone: a combined open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2 trial.

BACKGROUND: The Ebola epidemics in west Africa and the Democratic Republic of the Congo highlight an urgent need for safe and effective vaccines to prevent Ebola virus disease. We aimed to assess the safety and long-term immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in Sierra Leone, a country previously affected by Ebola. METHODS: The trial comprised two stages: an open-label, non-randomised stage 1, and a randomised, double-blind, controlled stage 2. The study was done at three clinics in Kambia district, Sierra Leone. In stage 1, healthy adults (aged ≥18 years) residing in or near Kambia district, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) on day 1 (first dose) followed by an intramuscular injection of MVA-BN-Filo (1 × 108 infectious units) on day 57 (second dose). An Ad26.ZEBOV booster vaccination was offered at 2 years after the first dose to stage 1 participants. The eligibility criteria for adult participants in stage 2 were consistent with stage 1 eligibility criteria. Stage 2 participants were randomly assigned (3:1), by computer-generated block randomisation (block size of eight) via an interactive web-response system, to receive either the Ebola vaccine regimen (Ad26.ZEBOV followed by MVA-BN-Filo) or an intramuscular injection of a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo on day 57 (second dose; control group). Study team personnel, except those with primary responsibility for study vaccine preparation, and participants were masked to study vaccine allocation. The primary outcome was the safety of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen, which was assessed in all participants who had received at least one dose of study vaccine. Safety was assessed as solicited local and systemic adverse events occurring in the first 7 days after each vaccination, unsolicited adverse events occurring in the first 28 days after each vaccination, and serious adverse events or immediate reportable events occurring up to each participant's last study visit. Secondary outcomes were to assess Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second vaccine in a per-protocol set of participants (ie, those who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response) and to assess the safety and tolerability of the Ad26.ZEBOV booster vaccination in stage 1 participants who had received the booster dose. This study is registered at ClinicalTrials.gov, NCT02509494. FINDINGS: Between Sept 30, 2015, and Oct 19, 2016, 443 participants (43 in stage 1 and 400 in stage 2) were enrolled; 341 participants assigned to receive the Ad26.ZEBOV and MVA-BN-Filo regimen and 102 participants assigned to receive the MenACWY and placebo regimen received at least one dose of study vaccine. Both regimens were well tolerated with no safety concerns. In stage 1, solicited local adverse events (mostly mild or moderate injection-site pain) were reported in 12 (28%) of 43 participants after Ad26.ZEBOV vaccination and in six (14%) participants after MVA-BN-Filo vaccination. In stage 2, solicited local adverse events were reported in 51 (17%) of 298 participants after Ad26.ZEBOV vaccination, in 58 (24%) of 246 after MVA-BN-Filo vaccination, in 17 (17%) of 102 after MenACWY vaccination, and in eight (9%) of 86 after placebo injection. In stage 1, solicited systemic adverse events were reported in 18 (42%) of 43 participants after Ad26.ZEBOV vaccination and in 17 (40%) after MVA-BN-Filo vaccination. In stage 2, solicited systemic adverse events were reported in 161 (54%) of 298 participants after Ad26.ZEBOV vaccination, in 107 (43%) of 246 after MVA-BN-Filo vaccination, in 51 (50%) of 102 after MenACWY vaccination, and in 39 (45%) of 86 after placebo injection. Solicited systemic adverse events in both stage 1 and 2 participants included mostly mild or moderate headache, myalgia, fatigue, and arthralgia. The most frequent unsolicited adverse event after the first dose was headache in stage 1 and malaria in stage 2. Malaria was the most frequent unsolicited adverse event after the second dose in both stage 1 and 2. No serious adverse event was considered related to the study vaccine, and no immediate reportable events were observed. In stage 1, the safety profile after the booster vaccination was not notably different to that observed after the first dose. Vaccine-induced humoral immune responses were observed in 41 (98%) of 42 stage 1 participants (geometric mean binding antibody concentration 4784 ELISA units [EU]/mL [95% CI 3736-6125]) and in 176 (98%) of 179 stage 2 participants (3810 EU/mL [3312-4383]) at 21 days after the second vaccination. INTERPRETATION: The Ad26.ZEBOV and MVA-BN-Filo vaccine regimen was well tolerated and immunogenic, with persistent humoral immune responses. These data support the use of this vaccine regimen for Ebola virus disease prophylaxis in adults. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV.

The impact of a human papillomavirus (HPV) vaccination campaign on routine primary health service provision and health workers in Tanzania: a controlled before and after study.

BACKGROUND: The burden of cervical cancer and shortage of screening services in Tanzania confers an urgent need for human papillomavirus (HPV) vaccination. However, the sustainability and impact of another new vaccine campaign in an under-resourced health system requires consideration. We aimed to determine the impact of the government's school-based HPV vaccine campaign in Kilimanjaro region on the provision of routine primary health services and staff workload. METHODS: Data on daily numbers of consultations were collected from health facility register books in 63 dispensaries and health centres in North-West Tanzania for 20 weeks in 2014. Changes in outpatient, antenatal care (ANC), family planning (FP) and immunisation service activity levels before, during and after the two HPV vaccination campaigns in 2014 in 30 facilities within Kilimanjaro region ('intervention facilities') were compared with changes in activity levels in 33 facilities in Arusha region ('controls'). Qualitative interviews were conducted with health workers in Kilimanjaro region who delivered HPV vaccination and those who remained at the facility during in-school HPV vaccine delivery to explore perceptions of workload and capacity. RESULTS: Health facility activity levels were low and very variable in both regions. Controlling for district, facility type, catchment population, clinical staff per 1000 catchment population and the timing of other campaigns, no evidence of a decrease in consultations at the health facility during HPV vaccination week was found across outpatient, ANC, routine immunisation and FP services. However, compared to the average week before and after the campaign, health workers reported longer working hours and patient waiting times, feeling over-stretched and performing duties outside their normal roles whilst colleagues were absent from the facility conducting the HPV vaccine campaign. CONCLUSION: Qualitative interviews with health workers revealed that staff absence from the health facility is common for a number of reasons, including vaccination campaigns. Health workers perceived that the absence of their colleagues increased the workload at the health facility. The numbers of consultations for each service on 'normal days' were low and highly variable and there was no clear detrimental effect of the HPV vaccination campaign on routine health service activity.

Uptake contexts and perceived impacts of HIV testing and counselling among adults in East and Southern Africa: A meta-ethnographic review.

INTRODUCTION: HIV testing and counselling (HTC) interventions are key to controlling the HIV epidemic in East and Southern Africa where HTC is primarily delivered through voluntary counselling and testing (VCT), provider initiated testing and counselling (PITC), and home-based counselling and testing (HBVCT). Decision making processes around uptake of HTC models must be taken into account when designing new interventions. Counselling in HTC aims to reduce post-test risk taking behaviour and to link individuals to care but its efficacy is unclear. This meta-ethnography aims to understand the contexts of HTC uptake in East and Southern Africa and to analyse the perceived impacts of counselling-based interventions in relation to sexual behaviour and linkage to care. METHODS: We conducted a systematic literature review of studies investigating HTC in East and Southern Africa from 2003 -April 2014. The search and additional snowballing identified 20 studies that fit our selection criteria. These studies were synthesised through a thematic framework analysis. RESULTS: Twenty qualitative and mixed-methods studies examining impacts of HTC models in East and Southern Africa were meta-synthesised. VCT decisions were made individually while HBVCT decisions were located in family and community units. PITC was associated with coercion from healthcare providers. Low quality counselling components and multiple-intersecting barriers faced by individuals mean that counselling in HTC was not perceived to be effective in reducing post-test risk behaviour and had limited perceived effect in facilitating linkage to care. CONCLUSION: HBVCT is associated with minimal stigma and should be considered as an area of priority. Counselling components in HTC interventions were effective in transmitting information about HIV and sexual risk, but were perceived as ineffective in addressing the broader personal circumstances preventing sexual behaviour change and modulating access to care.

Feasibility and acceptability of delivering adolescent health interventions alongside HPV vaccination in Tanzania.

BACKGROUND: Human papillomavirus (HPV) vaccination offers an opportunity to strengthen provision of adolescent health interventions (AHI). We explored the feasibility of integrating other AHI with HPV vaccination in Tanzania. METHODS: A desk review of 39 policy documents was preceded by a stakeholder meeting with 38 policy makers and partners. Eighteen key informant interviews (KIIs) with health and education policy makers and district officials were conducted to further explore perceptions of current programs, priorities and AHI that might be suitable for integration with HPV vaccination. RESULTS: Fourteen school health interventions (SHI) or AHI are currently being implemented by the Government of Tanzania. Most are delivered as vertical programmes. Coverage of current programs is not universal, and is limited by financial, human resource and logistic constraints. Limited community engagement, rumours, and lack of strategic advocacy has affected uptake of some interventions, e.g. tetanus toxoid (TT) immunization. Stakeholder and KI perceptions and opinions were limited by a lack of experience with integrated delivery and AHI that were outside an individual's area of expertise and experience. Deworming and educational sessions including reproductive health education were the most frequently mentioned interventions that respondents considered suitable for integrated delivery with HPV vaccine. CONCLUSIONS: Given programme constraints, limited experience with integrated delivery and concern about real or perceived side-effects being attributed to the vaccine, it will be very important to pilot-test integration of AHI/SHI with HPV vaccination. Selected interventions will need to be simple and quick to deliver since health workers are likely to face significant logistic and time constraints during vaccination visits.

Access and Attitudes to HPV Vaccination amongst Hard-To-Reach Populations in Kenya.

BACKGROUND: Sub-Saharan Africa bears the greatest burden of cervical cancer. Human papillomavirus (HPV) vaccination programmes to prevent the disease will need to reach vulnerable girls who may not be able access health and screening services in the future. We conducted formative research on facilitators and barriers to HPV vaccination and potential acceptability of a future HPV vaccination programme amongst girls living in hard-to-reach populations in Kenya. METHODS: Stakeholder interviews with Ministry of Health staff explored barriers to and support for the uptake of HPV vaccination. A situation assessment was conducted to assess community services in Maasai nomadic pastoralist communities in Kajiado County and in Korogocho informal settlement in Nairobi city, followed by focus group discussions (n=14) and semi-structured interviews (n=28) with health workers, parents, youth, and community and religious leaders. These covered marriage, knowledge of cervical cancer and HPV, factors that might inhibit or support HPV vaccine uptake and intention to accept HPV vaccine if a programme was in place. RESULTS: Reported challenges to an HPV vaccination programme included school absenteeism and drop-out, early age of sex and marriage, lack of parental support, population mobility and distance from services. Despite little prior knowledge of cervical cancer and HPV, communities were interested in receiving HPV vaccination. Adequate social mobilisation and school-based vaccination, supplemented by out-reach activities, were considered important facilitating factors to achieve high coverage. There was some support for a campaign approach to vaccine delivery. CONCLUSIONS: Given the high level of support for a vaccine against cervical cancer and the experience of reaching pastoralist and slum-dwellers for other immunizations, implementing an HPV vaccine programme should be feasible in such hard-to-reach communities. This may require additional delivery strategies in addition to the standard school-based delivery, with vaccine offered at multiple venues, potentially through a campaign approach.