Ghana vaccine technical brief summary

Purpose Health Survey) have shown endemicity ranging from intermittent transmission in the Greater Accra Region to In January 2016, Ghana responded to the World Health intense seasonal transmission in the Upper West Region Organization (WHO) call for national ministries of health and seasonal transmission in the rest of the country. to express interest in collaborating in the RTS,S/AS01 pilot implementation programme, Parasite prevalence in children 6 to 59 months of which was reaffirmed in March 2016. Furthermore, the age according to microscopy in 2011 and 2014* WHO is planning a delegation with partners from PATH MICS, 2011 DHS, 2014 and GlaxoSmithKline (GSK) to speak with high level 2011 2011 officials, Ministry of Health and Ghana Health Services (GHS) officials to discuss Ghana’s potential participation in the RTS,S/AS01 malaria vaccine pilot implementation programme.

This document is a summary of the RTS,S/AS01 vaccine background, data, and information to support policy and decision-makers make an evidence-based decision on the use of a malaria vaccine in Ghana. This brief was drafted by the Ghana Malaria Vaccine Technical Working Group (TWG), a sub-committee of the National Malaria Control Program (NMCP), composed of representatives from the GHS, WHO, members of academia and multilaterals, and compiled with support from PATH, an international nongovernmental organisation (NGO). *Both surveys were implemented during the peak transmission season: mid-September – mid-December Source: 2011 Multiple Indicator Cluster Survey (MICS) and 2014 Background and rationale Ghana Demographic and Health Survey (DHS)

Malaria kills nearly 600,000 people a year globally and causes illness in many more, about 90% of which are in Ghana has made notable progress in malaria prevention sub-Saharan Africa and 83% are children under the age and control with existing interventions, significantly of five.1 In Ghana, malaria causes about 2,000 deaths contributing to a reduction in malaria-related deaths. annually, approximately 48% of which afflict children However, the country continues to have a significant under the age of five, and is a major cause of hospital disease burden and could benefit from the deployment attendance, contributing to an estimated 30% of of additional tools in the fight against malaria. A well- admissions.2 falciparum is the tolerated and effective vaccine with an acceptable predominant malaria parasite in Ghana, causing safety profile could be a potentially important tool for approximately 80 to 90% of severe morbidity and malaria control. mortality, particularly in children under five years of age WHO position and pregnant women. Malaria is generally stable in Ghana and recent studies in 2011 (Multiple Indicator In January 2016, WHO issued a position paper calling for large-scale pilot implementations of RTS,S/AS01 in Cluster Survey) and 2014 (Ghana Demographic and

1 World Malaria Report, 2015 2 Ghana DHIMS2, 2015

children 5 to 9 months of age, alongside other malaria prior to the initiation of vaccination in the pilot control interventions in settings of moderate-to-high implementation programme and Phase IV studies. parasite transmission in Africa. Specifically, “WHO recommends that the pilot implementations use the 4- Vaccine efficacy dose schedule of the RTS,S/AS01 vaccine in 3 to 5 Following the Phase III clinical trial which studied two distinct epidemiological settings in sub-Saharan Africa, age groups, infants aged 6-12 weeks and young children at subnational level, covering moderate-to-high 5-17 months of age at first vaccination; however, the transmission settings,” with three doses administered WHO has recommended use of the vaccine among to children between 5 and 9 months of age, followed by young children (5-17 months) due to higher efficacy and a fourth dose 15–18 months later.3 The pilot projected impact3. implementation programme will compile evidence on the feasibility, impact, and safety of the vaccine Phase III clinical trial efficacy data was analyzed at 12 delivered in country immunization programmes and 18 months following 3-doses of vaccination and at alongside other currently recommended malaria 48 months following 4-doses of vaccination post-dose 1 control measures. among both age groups. Highest efficacy was shown shortly after vaccination, which waned over time (Appendix Table 1). More specifically among children 5- RTS,S/AS01 malaria vaccine 17 months of age: The RTS,S/AS01 malaria vaccine, also known as Mosquirix™, is currently the only candidate malaria  Three doses of RTS,S/AS01 reduced clinical malaria vaccine to have received a positive regulatory by approximately half at one year of follow-up, by assessment, which was issued by the European 46% at 18 months of follow-up, and by 26% at 48 Medicines Agency (EMA) Committee for Medicinal months of follow-up, compared to children 6,7 Products for Human Use (CHMP).4 The vaccine immunized with a comparator vaccine. development spanned a 30 year process, initiated in  A fourth dose of RTS,S/AS01, administered at 18 1987 by scientists working at GlaxoSmithKline’s (GSK) months after the primary series was shown to laboratories. At present, no regulatory authority in the enhance protection and reduce the number of African region has licensed RTS,S/AS01 for use as a 5 clinical malaria cases by 39% at 48 months of malaria vaccine. follow-up.7

The Phase III efficacy and safety trial of RTS,S/AS01 Efficacy results were achieved on top of existing malaria began in May 2009 and was completed in early 2014 at interventions, such as insecticide-treated bed nets, 11 sites in seven African countries (Burkina Faso, Gabon, which were used by almost 80% of the trial participants. Ghana, Kenya, Malawi, Mozambique, and Tanzania) The RTS,S/AS01 Phase III clinical trial showed that the with 15,459 infants and young children participating— vaccine could provide meaningful benefit making this the largest malaria vaccine trial in Africa to by reducing the burden of malaria when used alongside date. currently available interventions such as bed nets and 7 Ghana participated in the Phase III clinical trial, with two insecticides. research centers in Agogo and Kintampo. Currently, Ghana is participating in an RTS,S/AS01 baseline study Vaccine safety through the Kintampo and Navrongo Health Research RTS,S/AS01 displayed an acceptable safety and Centres to evaluate adverse events of specific interest tolerability profile throughout the entire Phase III and making the centers eligible for participation in the clinical trial. Adverse events following immunization RTS,S/AS01 Phase IV studies. These would commence (AEFI) included local reactions (such as pain or swelling), following successful application to national regulatory which were observed more frequently after RTS,S/AS01 authorities by GSK, as RTS,S will need to be licensed administration, compared to children immunized with a comparator vaccine.8

3 World Health Organization. Weekly Epidemiological Record. 2016; 5 WHO Questions and Answers on Malaria Vaccines: 91(4): 33–52. http://www.who.int/immunization/research/development/malaria_ 4 The RTS,S/AS01 vaccine has received a positive Scientific Opinion vaccine_qa/en/ by EMA in accordance with Article 58 of Regulation (EC) No 726/2004 6 The RTS,S Clinical Trials Partnership, PloS Medicine. 2014;11(7): which allows the Agency’s Committee for Medicinal Products for e1001685. Human Use (CHMP) to give opinions, in co-operation with WHO, on 7 RTS,S Clinical Trials Partnership, The Lancet. 2015; 386 (9988): 31– medicinal products for human use that are intended exclusively for 45. markets outside of the European Union (EU). For more information: 8 Alonso P, Aponte J, Aide P, et al. The Lancet. 2007; 370 (9598): http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/d 1543–1551. ocument_ listing/document_listing_000157.jsp, accessed January 2016. 2

The incidence of fever one week after vaccination was Following publication of the Phase III clinical trial results higher in children who received the RTS,S/AS01 vaccine and conclusion of the Article 58 regulatory procedure, than in those receiving the comparator vaccine. In RTS,S/AS01 became the only candidate malaria vaccine some, this resulted in febrile reactions that were to have received a positive regulatory assessment, accompanied by generalized convulsive seizures, but all which was issued by the European Medicines Agency affected fully recovered within seven days. (EMA) Committee for Medicinal Products for Human Use (CHMP).9 The Article 58 process—initiated in July The rates of other serious adverse events seen in the 2014—allowed EMA, in cooperation with WHO, to trial (mainly medical events requiring hospitalization, assess the quality, safety, and efficacy of the RTS,S/AS01 regardless of whether they were considered to be malaria vaccine and its benefit-risk balance. According caused by the study vaccine) were comparable between to the EMA, the CHMP concluded that “…despite its the RTS,S/AS01 and control recipients, except for cases limited efficacy, the benefits of Mosquirix™ outweigh of meningitis and cerebral malaria (which were reported the risks in both age groups studied,” and “the benefits in low numbers) more often in the RTS,S/AS01 group. of vaccination may be particularly important among According to the European Medicines Agency (EMA), children in high-transmission areas in which mortality is the imbalance of meningitis cases is most likely to be a very high.”10 chance finding, as some of these cases occurred years after vaccination without any obvious relationship to vaccination. The increased occurrence of meningitis and risk for severe malaria (including cerebral malaria), will Estimated public health impact and be followed closely in Phase IV studies and the pilot 11 implementations. cost effectiveness of RTS,S/AS01 RTS,S/AS01 vaccine public health impact and cost Malaria case fatality rates for children under effectiveness modelled estimates projected the five years of age from 2010 to 2015 vaccine’s potential to have a substantial public health impact when used alongside other malaria control measures. Modelling groups predict a positive public health impact over a 15-year time horizon with the introduction of RTS,S/AS01 in parasite prevalence (PfPR2-10) settings between 10% and 65%. Depending on malaria transmission settings, it is estimated that 6 to 29% of deaths in children under five years of age could be averted with the addition of RTS,S/AS01 to existing long lasting insecticide-treated nets (LLIN) coverage (68%12,13) and with access to malaria treatment. For areas where PfPR2-10 is greater than 10%, RTS,S/AS01 is predicted to be cost-effective compared to standard norms and thresholds.21 In the context of Ghana, the entire country has PfPR2-10 greater than 10% and 7 out of 10 regions are above 20%, suggesting that given its high disease burden, Ghana could potentially see a substantial public health impact with the introduction of RTS,S/AS01 (Appendix, Table 2).14

The estimated absolute impact of RTS,S/AS01 for clinical cases and malaria deaths in vaccinated children was shown to be greater in areas of higher malaria

9 The RTS,S/AS01 vaccine has received a positive Scientific Opinion 11 For a full description of the modelling methods used to generate by EMA in accordance with Article 58 of Regulation (EC) No 726/2004 the RTS,S vaccine public health impact estimates, please see the which allows the Agency’s Committee for Medicinal Products for article published by: WHO Harmonization and Comparison Project, Human Use (CHMP) to give opinions, in co-operation with WHO, on Penny et al, The Lancet 2015 medicinal products for human use that are intended exclusively for 12 Efficacy and safety of RTS,S/AS01 malaria vaccine with or without markets outside of the European Union (EU). For more information: a booster dose in infants and children in Africa: final results of a http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/d phase 3, individually randomised, controlled trial. RTSS Clinical Trials ocument_ listing/document_listing_000157.jsp, accessed January Partnership. 9988, 2015, Lancet, Vol. 386, pp. 31-45. 2016. 13 World Health Organization, the United Nations Children's Fund. 10 First malaria vaccine receives positive scientific opinion from EMA, Achieving the malaria MDG target: reversing the incidence of malaria European Medicines Agency. 24 July 2015. 2000-2015. Geneva : World Health Organization, 2015. 14 Ghana Demographic and Health Survey, 2014

3 transmission settings. The vaccine is estimated to avert rubella vaccine (MR1); therefore introducing two new 116,500 (30,900-160,000) cases of clinical malaria and visits at 7 and approximately 24 months. To achieve 484 (195-838) deaths per 100,000 vaccinated children optimal coverage for new visits, RTS,S/AS01 under a four-dose schedule for PfPR2-10 between 10% implementation could build off the well-established and 65%. This translates to approximately one malaria CHPS strategy for integrated service delivery structure death prevented for every 200 children fully vaccinated, during immunization days, alongside other vaccinations, and using a vaccine price proxy of USD $5 per dose long-lasting insecticide-treated nets (LLINs), growth equates to $87 ($42-244) per DALY averted (Appendix, monitoring, vitamin A supplementation, and health Table 3).21 promotion. Additionally, civil society organizations (CSOs) and the Christian Health Association of Ghana RTS,S/AS01 and the Ghana context (CHAG) are two effective mediums that could be The Ghana National Immunization Programme (EPI) is leveraged based on the considerable role they play in high-performing and a leader in sub-Saharan Africa for delivering vaccines and health services to hard-to-reach effectively introducing new vaccines into the EPI. The populations, including routine immunization, EPI currently delivers vaccines against 12 vaccine campaigns, and other services. preventable diseases (VPDs). Historically, Ghana has been able to absorb new vaccines into its programme Communication and social mobilization with limited disruption to its health system. DISTRIBUTION OF CAUSES OF DEATH RTS,S/AS01 has been recommended for use alongside AMONG CHILDREN AGED UNDER 5 other malaria control interventions, so with the YEARS IN GHANA, 2008 introduction of the vaccine, focus in the areas outlined in the 2014-2020 National Malaria Strategic Plan should Other be continued. The key malaria intervention areas are: 18% Malaria integrated vector management; malaria case Measles 26% management (including malaria in Pregnancy and 2% HIV/AIDS synchronized with Community Health Planning Services 3% [CHPS] activities), seasonal malaria chemoprevention, Neonatal and the Private sector Co-payment Mechanism to sepsis expand access to quality-assured affordable ACTs, 9% Prematurity Monitoring and Evaluation, and surveillance. Diarrhoea Birth 12% Health system strengthening 9% Pneumonia asphyxia 10% 11% With the introduction of a new vaccine, certain system elements require strengthening. For example, cold Source: Ghana country statistics, WHO/AFRO, 2008, http://www.aho.afro.who.int/profiles_information/index.php/File:Dis chain at national and some sub-national areas in Ghana tribution_of_causes_of_death_among_children_aged_under_5_years have reached maximum capacity and would require _percent_in_Ghana,_2008.JPG#file expansion to accommodate new vaccines, including

RTS,S/AS01. However, preparation for meningococcal Communication and social mobilization will be critical to group A (MenA) and Inactivated Polio Virus (IPV) vaccine ensure timely vaccination, and optimal coverage of all introductions could anticipate introduction of four RTS,S/AS01 doses, in addition to sensitizing RTS,S/AS01 in the cold chain expansion plan. populations on continued use of other malaria control Vaccination schedule and delivery interventions. A socio-cultural research study on community perceptions of a malaria vaccine conducted RTS,S/AS01 is a four-dose regimen with a proposed in Ghana found potential for high acceptance of a vaccination schedule at 6, 7, 9, and 24 months of age (or malaria vaccine and a shared understanding that 15-18 months after the third dose). The 6-month visit malaria prevention requires a comprehensive would align with the vitamin A supplementation, an approach.16 Data from this research has informed a already established visit with 70% coverage,15 and the 9- draft malaria vaccine communication plan for Ghana, month visit would align with the first dose of measles-

15 WHO/UNICEF 2015 estimates, 16 Meῆaca A, Tagbor H, Adjei R, Bart-Plange C, Collymore Y, et al. http://apps.who.int/immunization_monitoring/globalsummary/coun (2014) Factors Likely to Affect Community Acceptance of a Malaria tries?countrycriteria%5Bcountry%5D%5B%5D=GHA&commit=OK, Vaccine in Two Districts of Ghana: A qualitative Study. PLoS ONE accessed 25 July 2016 9(10): e109707. 4 developed under the leadership of the National Malaria compiling and reviewing the various drafts and for their Communications Committee, as a collaborative effort efforts in the development of this technical brief. We across the NMCP, EPI, health promotion, and other are also grateful to all partners, particularly PATH and expertise. the WHO for their support and useful comments that have enriched this work. We thank all the members of Financing the Technical Working Group for their inputs and Ghana currently purchases all of its traditional routine editorial comments: vaccines. For recently introduced vaccines (e.g., PCV, rotavirus, MR), Ghana pays a pre-determined co- Dr. Samuel O. Sackey (TWG Chair), Prof. Isabella Quakyi financing percentage of the cost, and Gavi, the Vaccine (Former TWG Chair), Prof. Edwin Afari, Dr. Felicia Alliance (Gavi) provides support for the balance. Gavi Owusu-Antwi, Dr. Constance Bart-Plange, Mr. James also provides financial support for health system Frimpong, Ms. Vivian N.A. Aubyn, Mr. Fred Osei- strengthening needs related to immunization. However, Sarpong, Mr. John Frederick Dadzie, Dr. George Bonsu, Ghana has recently become a middle-income country, Dr. K.O. Antwi-Agyei, Dr. Kwaku Poku Asante, Dr. Seth exceeding the current gross national income (GNI) Owusu-Agyei, Prof. Tsiri Agbenyega, Prof. Daniel eligibility for Gavi support and has therefore entered Ansong, Mrs. Delese Darko, Ms. Patience Dapaah, Mr. into a preparatory transition out of Gavi support. As a John Bawa, Mr. Kofi Aburam, Mrs. Kelli Cappelier. result, Ghana’s vaccine co-payment to Gavi is gradually increasing and eligibility for support will cease by 2022. The government will pay 20% of all co-financed vaccines in 2016 to 2018. This will rise to 40% in 2019, 60% in 2020, 80% in 2021 and by 2022 will begin to make the full payment (100%).17 Evidence-based decision-making In the absence of a National Immunization Technical Advisory Group (NITAG) in Ghana, the National Malaria Control Program, through the joint efforts of the malaria and immunization programs, endorsed the Ghana malaria vaccine TWG sub-committee in 2009. Since then, the TWG has filled the role of compiling and synthesizing data and information in a technical brief to support evidence-based decision-making for use of a malaria vaccine in Ghana. The TWG has representation from the Ghana Health Service (GHS), members of academia, WHO, multilaterals, with support from PATH.

Acknowledgements The task team of the Malaria Vaccine TWG NMCP sub- committee compiled the requisite technical data and wrote this technical brief summary document. We are particularly grateful to members of the task team for

17 Gavi Joint Appraisal Report, Ghana, 2015.

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Appendix: Summary of Phase III clinical trial efficacy data and public health impact estimates

Table 1: RTS,S/AS01 Vaccine efficacy in children aged 5-17 months at first dose7

Vaccine efficacy against Vaccine efficacy against Vaccine efficacy against clinical malaria severe malaria hospitalisation caused (95% CI) (95% CI) by malaria (95% CI) Over 12 months follow-up 51% 45% 48% from dose 3 (47; 55) (22; 60) (35; 59) (ATP* cohort, N=6880) Over 18 months follow-up 46% 36% 42% from dose 3 (42; 49) (15; 51) (29; 52) (ATP* cohort, N=6880) 3 doses only (ATP* cohort, N=6918) Over 30 months follow-up 34% 2% 18% from dose 3 (29; 39) (-28; 25) (1; 32) Over 46 months follow-up** 26% -6% 12% from dose 3 (21; 31) (-35; 17) (-5; 26) 3 doses + 4th dose; (ATP* cohort, N=6918) Over 30 months follow-up 46% 32% 40% from dose 3 (42; 50) (10; 50) (26; 52) Over 46 months follow-up** 39% 29% 37% from dose 3 (34; 43) (6; 46) (24; 49) *According-to-protocol (ATP) cohort: all infants immunised according to schedule, N= total number in all 3 study groups ** The follow-up period from dose 3 to study end was not the same for all subjects because the study ended on a fixed date. The median length for this follow-up period is 36 months.

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Table 2: Estimated median deaths averted per 100,000 children vaccinated with RTS,S/AS01, based on subnational parasite prevalence settings in Ghana

Estimated median deaths Annual modelled Parasite prevalence Surviving infants averted per 100,000 range Region 14 18 malaria deaths for PfPR2-10 (2014) (2017) 19 (min to max) based on children <5 yrs old 21 PfPR2-10 Northern 40% 76,500 4,200 523 (486-831)

Western 39% 73,000 4,200 523 (486-831)

Upper West 38% 21,100 1,300 523 (486-831)

Central 38% 66,700 3,700 523 (486-831)

Eastern 30% 82,500 4,300 459 (406-715)

Brong-Ahafo 27% 71,200 4,000 459 (406-715)

Volta 25% 67,100 2,800 420 (372-650)

Ashanti 17% 154,500 6,900 400 (336-616)

Upper East 12% 31,700 1,800 229 (189-344)

Greater Accra 11% 129,800 3,500 229 (189 -344) 36,700 (malaria) Total 774,100 54,000 (all-cause)20 Estimated global malaria-related deaths averted per 100,000 children vaccinated with 3 doses of RTS,S/AS01, 21 by PfPR2-10 Median deaths 229 353 400 420 459 519 523 546 averted range (189-344) (250-511) (336-616) (372-650) (406-715) (465-831) (486-831) (507-854) (min to max)

PfPR2-10 10 15 20 25 30 35 40 45

Table 3: Estimated malaria cases and deaths averted in children receiving 4 doses of RTS,S/AS01 in malaria transmission 21 settings with PfPR2-10 between 10 to 65 percent

Percentage of events averted in PfPR2-10 Impact per 100,000 vaccinated children settings of 10 to 65% (entire population) (children under 5 years of age) Malaria clinical cases 21% (8-31%) 116,500 (31,500 to 160,500)

Malaria deaths 18% (6-29%) 484 (190 to 860)

18 United Nations, 2017 projection for children <1 year of age, sourced from Gavi, the Vaccine Alliance 19 SwissTPH, Estimated annual malaria-related deaths among children under 5 in 2016 (modeled estimates based on Malaria Atlas Project parasite prevalence) 20 WHO Global Health Observatory , Estimated number of all-cause deaths for children under 5 in 2015; accessed 4 Dec 2015 21 WHO Harmonization and Comparison Project, Penny et al, The Lancet 2015 7