| Protocol No: | ECCT/19/06/03 | Date of Protocol: | 11-03-2019 |
| Study Title: | An evaluation of the cluster-randomised pilot implementation of the RTS,S/AS01 malaria vaccine through routine health systems in western Kenya
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| An evaluation of the cluster-randomised pilot implementation of the RTS,S/AS01 malaria vaccine through routine health systems in western Kenya: a post-authorization observational study | |
| Study Objectives: | Research questions and objectives Key questions on impact, safety, and feasibility The following key questions will be evaluated in groups of children, aged 5-39 months, who have or have not received one or more doses of RTS,S/AS01.
Impact:
Safety:
Feasibility:
The overall impact of RTS,S/AS01 will be evaluated in the malaria vaccine program evaluation. As with other vaccines, any risks identified need to be weighed against the benefits to understand the overall impact of the vaccine. The overall assessment will consider both feasibility and impact outcomes. The evaluation of risks and benefits will be made by the Data Safety Monitoring Board and presented to WHO’s Global Advisory Committee on Vaccine Safety (GACVS), SAGE, and MPAC to develop the WHO policy recommendation on the large-scale deployment of the RTS,S/AS01 vaccine.
Objectives related to impact and community-based surveillance
Objectives related to safety and surveillance in sentinel hospitals
Objectives related to feasibility
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| 2 | 7. Research questions and objectives 7.1. Key questions on impact, safety, and feasibility The following key questions will be evaluated in groups of children eligible to receive RTS,S/AS01 vaccine, residing in the RTS,S/AS01 implementation and comparison clusters. Impact: • Is there any reduction in all-cause mortality following the introduction of routine delivery of RTS,S/AS01 ? • By how much does the routine delivery of RTS,S/AS01 vaccine reduce the incidence of hospital admission with severe malaria? Safety: • Does the routine introduction of RTS,S/AS01 result in an increased rate of meningitis and/ or cerebral malaria in communities where the vaccine is introduced? • Does the frequency and profile of meningitis and cerebral malaria among children admitted to sentinel hospitals, differ by vaccination group (implementing versus comparison areas) or status (RTS,S/AS01 vaccinated versus unvaccinated)? • Does the introduction of RTS,S/AS01 have a different effect on all-cause mortality for boys and girls?. Does RTS,S/AS01 increase mortality in girlsWhat is the frequency and profile of RTS,S/AS01 reported AEFI? Feasibility: • What coverage is achieved with RTS,S/AS01 (including the fourth dose in the second or third year of life ) and how timely are the doses? • What is the coverage and timeliness of recommended EPI vaccines (including MCV2) and does it change with RTS,S/AS01 introduction? • What is the coverage and utilization of other recommended malaria prevention and control measures, including ITN and IRS, and does it change with RTS,S/AS01 introduction? • Do treatment seeking behaviors for febrile children, use of malaria prevention measures, and EPI vaccination coverage change with the introduction of RTS,S/AS01? If so, why? • Does the introduction of RTS,S/AS01 alter the coverage of other key childhood interventions, including anti-helminth administration (deworming) and Vitamin A supplementation? • What is the acceptability of the RTS,S/AS01 vaccine, and what are the barriers and facilitators of RTS,S/AS01 vaccination? The overall impact of RTS,S/AS01 will be evaluated in the malaria vaccine program evaluation. As with other vaccines, any risks identified need to be weighed against the benefits to understand the overall impact of the vaccine. The overall assessment will consider both feasibility and impact outcomes. The evaluation of risks and benefits will be made by the Data Safety Monitoring Board and presented to WHO’s Global Advisory Committee on Vaccine Safety (GACVS), SAGE, and MPAC to develop the WHO policy recommendation on the large-scale deployment of the RTS,S/AS01 vaccine. 7.2. Objectives related to impact and community-based surveillance 7.2.1. Primary impact objective • To estimate the effect of routine vaccine delivery on all-cause mortality (excluding accidents/trauma) in children , comparing by vaccination group (implementing versus comparison areas) or status (RTS,S/AS01 vaccinated versus non-vaccinated ). • To estimate the effect of routine delivery of RTS,S/AS01 on the incidence of hospital admission with severe malaria (severe malaria anaemia or cerebral malaria). 7.2.2. Secondary impact objectives • To estimate the effect of routine RTS,S/AS01 vaccine delivery on o All-cause mortality excluding non-malaria causes of death (such as trauma, poisoning, drowning, and other agreed upon causes ). o Gender-specific all-cause mortality o Age-specific all-cause mortality o Cause-specific mortality (from verbal autopsy or hospital diagnosis) 7.3. Objectives related to safety and surveillance in sentinel hospitals 7.3.1. Primary safety objectives • To estimate the effect of RTS,S introduction on the incidence of hospital admissions with a) probable or confirmed meningitis and b) cerebral malaria in children admitted to sentinel hospitals, and compare by vaccination group (implementing versus comparison areas) or status (RTS,S/AS01 vaccinated versus non-vaccinated) among children aged 1-59 months admitted to sentinel hospitals 7.3.2. Secondary safety objectives • To estimate the incidence of meningitis, cerebral malaria, severe malaria anaemia, severe malaria, all-cause hospital admissions, malaria-associated hospital admissions, non-malaria hospital admissions (overall and by cause), malaria-associated hospital mortality, cerebral malaria-associated hospital mortality, requirement for or provision of blood transfusions, serious adverse events, and anemia, based on vaccination group (implementing versus comparison areas) or status (RTS,S/AS01 vaccinated versus non-vaccinated), among children admitted to sentinel hospitals. These will be agreed upon with the NVIP and with the Data Safety and Monitoring Board (Annex 4). 7.4. Analysis populations • For each death and each hospital patient, cluster of membership will be determined from the location of normal residence. Within each implementation and comparator cluster, the following groups will be defined: children who are age-eligible for the vaccine and children who are not age-eligible for the vaccine, based on date of birth and age at the time of the RTS,S/AS01 introduction. • All primary outcome measures will also be analysed, in an exploratory secondary analysis, in children who received DTP3. 7.5. Objectives related to feasibility 7.5.1. Primary feasibility objectives • To estimate the proportion of children aged 12–23 months who had received three doses of RTS,S/ASO1 by 12 months of age (midline survey), and the proportion of children aged 27-38 months who had received their fourth dose of RTS,S/AS01 by 27 months of age (endline survey) 7.5.2. Secondary feasibility objectives • To estimate the coverage of recommended EPI vaccines (as fully vaccinated and for each individual dose), coverage and utilization of recommended malaria prevention and control measures (including ITN/LLIN and IRS), characterize health seeking behaviors for febrile children, including hospital admissions, dropout rates and the proportion of fully vaccinated children, and coverage of other key childhood interventions (including anthelmintic administration and vitamin A supplementation) based on vaccination group (implementing versus comparison areas) or status (RTS,S/AS01 vaccinated versus non-vaccinated) among children in the target population; and to quantitatively assess the acceptability of the RTS,S/AS01 vaccine, in addition to barriers and facilitators of the RTS,S/AS01 vaccination. • Additional secondary objectives include; the assessment of the relationship between the malaria vaccine status by caregiver recall (from the home-based record) and from immunization registers, in order to understand the validity of RTS,S/AS01 status from different sources and assement of changes in malnutrition as measured by MUAC score. |
| Laymans Summary: | Despite significant gains in malaria control in sub-Saharan Africa, malaria continues to be a major cause of disease and death, particularly in children <5 years of age. Control methods currently used by the National Malaria Control Programs have been very successful in reducing the burden, but there is concern that the effectiveness of many of the tools and the first-line antimalarials, including ITNs and ACTs are being threatened by resistance and may no longer be as effective in the near future. A large Phase 3 trial of the RTS,S/AS01 malaria vaccine in >15,000 infants and children was conducted between 2009–2014, and the results of this were promising in that children aged 5–17 months of age who received 4 doses of the vaccine had a 39% reduction in the number of cases and 31.5% reduction in the severe cases of malaria as compared to the children in the study who did not receive the vaccine. However, while these results were promising, there were concerns that there were more cases of febrile seizures, meningitis, and cerebral malaria in children who received the vaccine than in those who did not, and though rare, there were more deaths in girls in the vaccinated groups than in the unvaccinated groups. While the findings of increased febrile seizures are explained by an association of an increased risk of fevers with the vaccine, the scientific opinion was that the increase in meningitis and cerebral malaria were due to chance and the design of the study, and not to the vaccine itself. In 2015, after reviewing the available data on the vaccine, the European Medicines Agency (EMA) gave a positive scientific opinion of the benefit/risk balance of the vaccine in children aged 5-17 months, and accepted a proposed risk management plan to evaluate the safety signals of meningitis and cerebral malaria in larger Phase 4 studies of the vaccine. Following the EMA’s positive scientific opinion, the WHO’s vaccine experts and malaria advisory committees recommended phased roll-outs of the vaccine by the Ministries of Health in 120,000 children aged 5-17 months in 3 countries (later identified as Ghana, Malawi, and Kenya). The primary objectives of these phased roll-outs is to evaluate, 1) the feasibility of achieving high coverage of 4 doses of the vaccine in the target population, understanding that this may mean up to 3-4 new contacts per child, 2) the impact of rolling out the vaccine on all-cause mortality, and 3) the safety of the vaccine in the context of a programmatic roll-out with specific attention to the signals of cerebral malaria and meningitis. In 2019, the Ministries of Health in Ghana, Malawi, and Kenya will roll-out this vaccine, and partners within each country will evaluate the aforementioned three objectives. The WHO has prepared a master protocol (Appendix 1) to guide the evaluation partners in each of the countries so that their data may be compared and analyzed together. This protocol describes the specific design, methods, and procedures for evaluating the phased roll-out by the consortium in Kenya. |
| Abstract of Study: |
It was recently estimated that in sub-Saharan Africa (SSA) malaria incidence was halved and parasite infection prevalence decreased by 40% from the years 2000–2015. This decrease has largely been attributed to the roll-out of insecticide treated nets (ITNs), and to a lesser degree to indoor residual spraying of insecticide (IRS) and improved case management with rapid diagnostic testing and artemisinin-based combination therapies (ACTs). Despite these gains, in 2016 it was estimated that there were 216 million cases of malaria globally, and 445,000 deaths attributed to malaria, >90% and >80% occurring in children in SSA, respectively. Furthermore, the effectiveness of interventions that have been so successful in reducing the malaria burden in SSA are threatened by insecticide and drug resistance. Therefore, new tools are needed to combat malaria, particularly those targeting vulnerable populations like children.
The RTS,S/AS01 malaria vaccine has been developed to prevent clinical disease caused by the malaria parasite Plasmodium falciparum, the most deadly of the malaria parasites that infect humans. A Phase 3 clinical trial was conducted in 15,459 infants and children in 11 different sites in 7 countries in SSA from 2009 to 2014. Results of this trial confirmed moderate, but significant protection against clinical malaria — in the 12 months following vaccination, clinical malaria was reduced by 51% (95% Confidence Interval [CI] 47–55%), and the incidence of severe malaria was reduced by 44.5% (95% CI 24–60%) in children aged 5–17 months at the time of first vaccination. However, vaccine efficacy (VE) waned over time. In successive 6 month periods after the third dose, VE waned from 68% to 39% to 28%, for an overall VE of 46% against clinical malaria and 38% against severe malaria 18 months after the third dose. A booster dose given 18 months after the third dose, and evaluated over the entire 4-year study increased VE from 26% to 39% against clinical malaria and from -2% to 31.5% against severe malaria. Vaccine efficacy in the cohort of infants vaccinated (6-12 weeks at time of first vaccination) was substantially lower.
While no fatal adverse events were assessed to be causally related to RTS,S/AS01 vaccination, and while the overall incidence of SAEs was lower in children receiving the vaccine than in those who did not, febrile convulsions were found to be a risk in the 7-day period after vaccination. Additionally, more cases of meningitis were identified in the children vaccinated with RTS,S/AS01 than in the comparison group (relative risk [RR] 8.0 (95% CI 1.1–60.3)), and unplanned exploratory analyses revealed increased cases of cerebral malaria (CM) in the RTS,S/AS01 group and more deaths from all causes combined in vaccinated girls compared to the control group. While the increase in febrile seizures is explained by the association between vaccination and increased risk of fever, the potential safety signals of meningitis, CM, and increased deaths in girls have not been demonstrated to be causally related, and were considered likely chance findings.
The European Medicines Agency (EMA) reviewed available data in mid-2015 and provided a positive scientific opinion on the benefit/risk balance of RTS,S/AS01 in children aged 5 to 17 months of age, accepting a proposed risk management plan which included a Phase 4 study to investigate the observed safety signals. The World Health Organization’s (WHO) expert advisors on vaccination and malaria advisory committees reviewed the data and the EMA opinion in late 2015, and recommended phased pilot implementation of the vaccine in moderate to high malaria transmission settings to assess: 1) the programmatic feasibility of achieving high coverage with three to four new contacts, including the fourth dose of vaccine, 2) the vaccine’s impact on all-cause mortality, and 3) the vaccine’s safety in the setting of a routine immunization program with special interest into the safety signals of meningitis and CM.
The Malaria Vaccine Implementation Programme (MVIP), which is comprised of the phased roll-out of the RTS,S/AS01 vaccine in 120,000 children in each of Ghana, Malawi, and Kenya by the Ministries of Health of each country, Phase 4 studies sponsored by GlaxoSmithKline, and a WHO-led Malaria Vaccine Pilot Evaluation (MVPE), will begin in 2019. A Master Protocol (Annex 2) has been developed by WHO to guide the consortia of partners from the various countries who will be evaluating the vaccine so that data can be compared and analysed between countries. This protocol describes the specific design, methodologies, and procedures that the MVPE consortium will use to evaluate the feasibility, impact, and safety of the vaccine roll-out in Kenya.
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It was recently estimated that in sub-Saharan Africa (SSA) malaria incidence was halved and parasite infection prevalence decreased by 40% from the years 2000–2015. This decrease has largely been attributed to the roll-out of insecticide treated nets (ITNs), and to a lesser degree to indoor residual spraying of insecticide (IRS) and improved case management with rapid diagnostic testing and artemisinin-based combination therapies (ACTs). Despite these gains, in 2016 it was estimated that there were 216 million cases of malaria globally, and 445,000 deaths attributed to malaria, >90% and >80% occurring in children in SSA, respectively. Furthermore, the effectiveness of interventions that have been so successful in reducing the malaria burden in SSA are threatened by insecticide and drug resistance. Therefore, new tools are needed to combat malaria, particularly those targeting vulnerable populations like children.
The RTS,S/AS01 malaria vaccine has been developed to prevent clinical disease caused by the malaria parasite Plasmodium falciparum, the most deadly of the malaria parasites that infect humans. A Phase 3 clinical trial was conducted in 15,459 infants and children in 11 different sites in 7 countries in SSA from 2009 to 2014. Results of this trial confirmed moderate, but significant protection against clinical malaria — showed that in the 12 months following vaccination, clinical malaria was reduced by 51% (95% confidence Interval [CI] 47–55
%), and the incidence of severe malaria was reduced by 44.5% (95% CI 24–60%) in children aged 5–17 months at the time of first vaccination. However, vaccine efficacy (VE) waned over time. In successive 6 month periods after the third dose, VE waned from 68% to 39% to 28%, for an overall VE of 46% against clinical malaria and 38% against severe malaria 18 months after the third dose. A booster dose given 18 months after the third dose, and evaluated over the entire 4-year study increased VE from 26% to 39% against clinical malaria and from -2% to 31.5% against severe malaria. Vaccine efficacy in the cohort of infants vaccinated (6-12 weeks at time of first vaccination) was substantially lower.
While no fatal adverse events were assessed to be causally related to RTS,S/AS01 vaccination, and while the overall incidence of SAEs was lower in children receiving the vaccine than in those who did not, febrile convulsions were found to be a risk in the 7-day period after vaccination. Additionally, more cases of meningitis were identified in the children vaccinated with RTS,S/AS01 than in the comparison group (relative risk [RR] 8.0 (95% CI 1.1–60.3)), and unplanned exploratory analyses revealed increased cases of cerebral malaria (CM) in the RTS,S/AS01 group and more deaths from all causes combined in vaccinated girls compared to the control group. While the increase in febrile seizures is explained by the association between vaccination and increased risk of fever, the potential safety signals of meningitis, CM, and increased deaths in girls have not been demonstrated to be causally related, and were considered likely chance findings.
The European Medicines Agency (EMA) reviewed available data in mid-2015 and provided a positive scientific opinion on the benefit/risk balance of RTS,S/AS01 in children aged 5 to 17 months of age, accepting a proposed risk management plan which included a Phase 4 study to investigate the observed safety signals. The World Health Organization’s (WHO) expert advisors on vaccination and malaria advisory committees reviewed the data and the EMA opinion in late 2015, and recommended phased pilot implementation of the vaccine in moderate to high malaria transmission settings to assess: 1) the programmatic feasibility of achieving high coverage with three to four new contacts, including the fourth dose of vaccine, 2) the vaccine’s impact on all-cause mortality, and 3) the vaccine’s safety in the setting of a routine immunization program with special interest into the safety signals of meningitis and CM.
The Malaria Vaccine Implementation Programme (MVIP), which is comprised of the phased roll-out of the RTS,S/AS01 vaccine in 120,000 children in each of Ghana, Malawi, and Kenya by the Ministries of Health of each country, Phase 4 studies sponsored by GlaxoSmithKline, and a WHO-led Malaria Vaccine Pilot Evaluation (MVPE), will begin in 2019. A Master Protocol (Annex 2) has been developed by WHO to guide the consortia of partners from the various countries who will be evaluating the vaccine so that data can be compared and analysed between countries. This protocol describes the specific design, methodologies, and procedures that the MVPE consortium will use to evaluate the feasibility, impact, and safety of the vaccine roll-out in Kenya
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