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TECHBRIEF HORIZON SCANNING REPORT

Malaria Report No: 003/2017

MaHTAS Medical Development Division Ministry of Health, Malaysia 2017 Prepared by:

Dr. Syaharatul Patimah Kamarudin Medical Officer Principal Assistant Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Reviewed by:

Dr. Izzuna Mudla Mohamed Ghazali Physician Senior Principal Assistant Director Health Technology Assessment Section (MaHTAS) Ministry of Health Malaysia

Dr. Junainah Sabirin Public Health Physician Deputy Director Health Technology Assessment Section (MaHTAS) Medical Development Division Ministry of Health Malaysia

Disclosure: The author of this report has no competing interest in this subject and the preparation of this report is totally funded by the Ministry of Health, Malaysia.

Disclaimer: TechBrief report is prepared based on information available at the time of research and a limited literature. It is not a definitive statement on the safety, effectiveness or cost-effectiveness of the health technology covered. Additionally, other relevant scientific findings may have been reported since completion of this report.

Horizon Scanning, Communication & Information Unit, MaHTAS, Medical Development Division, Ministry of Health, Malaysia, Email: [email protected] Web: http://www.moh.gov.my

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TechBrief VACCINE

SUMMARY people (new cases) and caused an estimated 429 000 deaths. The disease RTS,S/AS01 and PfSPZ are two malaria is a major burden in an African region vaccine candidates which target pre- that contributes to more than 90% of erythrocytic stage of parasite. They only cases and death.1 protect against falciparum , but different strains of malaria Although Malaysia is in the pre- are of high importance in Malaysia. elimination phase, the number of indigenous cases increased from 2921 Less than half of the children may be in 2013 to 3147 in 2014, and the protected against clinical malaria with number of people living in active foci RTS,S/AS01, but the efficacy became remains high (1.3 million). Malaria much lower in infants. The occurrence transmission occurs primarily in the of serious adverse events of meningitis districts of Sabah and Sarawak and in during trial warrants further study to some remote areas in Selangor, investigate the causality. PfSPZ gave Pahang, Kelantan and Perak.1,2 modest protection by time to first infection in adults. Only minimal local In 2012, 61.6% of reported cases were and systemic adverse events were human malaria infection and significant reported. proportions (38.4%) were zoonotic (). Among human There could be potential for the malaria infection, to give false sense of security accounted for 50.2%, followed by to the population and lead to reduction (30.7%), in the use of other preventive measures (16.7%) and such as insecticide treated bed net. mixed infection (2.2%).2 Whereas the vaccines are intended only as an addition to the existing measures. Children below the age of five accounted for small proportion (2.5%) of Keywords: RTS,S/AS01, PfSPZ, all cases. About 61.9% of the cases , horizon were between the ages of 20 to 49 scanning,Plasmodium falciparum years.2 INTRODUCTION Plasmodium knowlesi infection has increasingly becoming public health Malaria is a mosquito borne disease importance in Malaysia owing to its caused by Plasmodium genus parasites rapid and severe clinical course which transmitted by mosquitoes. contributes to high fatality.3 Globally, malaria infected 212 million

1 | P a g e Various approaches has been effective, the vaccine must be safe, well implemented to control and if possible to tolerated, offer the expected protection eliminate malaria. However, the disease against various types of malaria and is still prevalent. is seen as feasible for mass vaccination one of the possible approach in addition programme.7 to the existing measures. Despite vast number of researches done (Table 1), Hence, the objective of this early there is still no single licensed malaria assessment is to evaluate the efficacy, vaccine for use to date.4,5,6 tolerability and safety profile of these two malaria vaccine candidates against Table 1: The main malaria vaccines that are currently undergoing clinical trials phase 2b malaria. and phase 3 THE TECHNOLOGY Vaccines Trial Funder Pre-erythrocytic Projects RTS,S/AS01 (MOSQUIRIX) MALARIA RTS,S/ Phase PATH - Malaria Vaccine VACCINE4 AS01E 3 Initiative (MVI)

National Institute of Until now, RTS,S/AS01 (Mosquirix) is Phase Allergy and Infectious PfSPZ the only malaria vaccine candidate 2b Diseases (NIAID (US NIH)) which reaches phase 3 trials. This

European and vaccine candidate has been developed ChAd63/MV Phase Developing Countries over three decades through a A ME-TRAP 2b Clinical Trials Partnership (EDCTP) partnership between GlaxoSmithKline Biologicals (GSK) and the PATH Malaria Blood-stage Projects Vaccine Initiative (MVI) with funding European and Developing Countries support from the Bill & Melinda Gates Clinical Trials Foundation. Phase Partnership (EDCTP), GMZ2 field 2b African Malaria Network Trust (AMANET), It is a recombinant vaccine in which European Vaccine regions of Plasmodium falciparum Initiative (EVI) are fused to African Malaria Network surface and Trust (AMANET), MSP3 [181- Phase European and adjuvanted with AS01 to enhance 276] field 2b Developing Countries immune response (Figure 1). The Clinical Trials Partnership (EDCTP) preparation available is as a 25 µg powder and solvent for suspension for The RTS,S/AS01 is the most advance injection in vials. malaria vaccine candidate in This vaccine targets the pre-erythrocytic development which already reached stage of the malaria parasite by phase 3 . Another vaccine production of anti-circumsporozoite candidate PfSPZ gains much attention that attack the parasite after showing a breakthrough results in before it can invade human . its recent phase 2 trial. In general, to be

2 | P a g e PfSPZ MALARIA VACCINE

PfSPZ malaria vaccine candidate is developed by Inc., a biotechnology company located in Rockville, Maryland. The vaccine is made up of non-replicating irradiated whole sporozoites (aseptic, purified, Figure 1: RTS,S recombinant protein virus- radiation- attenuated, cryopreserved like particle (Source: European Medical Agency) Plasmodium falciparum sporozoites).11,12

The sporozoites were collected by In addition, it also provokes a strong manually dissecting the mosquitos’ CD4 T-cell response, which can kill the salivary glands, and then irradiate and parasite in the liver before it can break freeze the sporozoites for vaccination. out into the blood stream subsequently to invade red blood cells. PfSPZ is still in the early stage of RTS,S/AS01 is only effective against development but already showed malaria caused by Plasmodium positive result from its early clinical falciparum parasite. Hence, it offers no trials. Based on this, PfSPZ has protection against other types of malaria received U.S. Food and Drug including Plasmodium vivax which Administration Fast Track designation in predominates in Malaysia. September 2016 to help expedite the development process of the vaccine to The European Medical Agency gave reach market.13 positive scientific opinion based on the favourable quality and risk/benefit profile of this vaccine from a regulatory perspective on the 23 July 2015.4,8,9 In October 2015, WHO recommends conducting a pilot implementation studies in three to five sub-Saharan countries with moderate to high levels of malaria transmission to generate more Figure 2: Direct venous of PfSPZ. concrete evidence on protection level, (Source: B. Mordmueller) safety profile and feasibility of vaccination.10 The most effective route of administration is via intravenous In addition, GSK is in the process of injection.12,14 planning phase 4 study to further characterize the safety and effectiveness of RTS,S/AS01 vaccine.

3 | P a g e PATIENT GROUP AND EFFICACY AND SAFETY

INDICATION RTS,S/AS01 (MOSQUIRIX) MALARIA VACCINE Active immunisation against malaria infection (Plasmodium falciparum), in A phase 3 randomised clinical trials has children aged six weeks to 17 months been conducted in seven sub-Saharan for RTS,S/AS01 malaria vaccine African countries to assess the efficacy candidate.15 and safety aspects of the vaccine.

Immunisation against Plasmodium From 2009 until 2011, the study enrolled falciparum malaria infection for PfSPZ 8922 children (age five to 17 months) vaccine. and 6537 young infants (age six to 12 weeks) in which each age group was CURRENT PRACTICE randomly assigned into three groups, namely R3R group (receive three doses Various approaches are use of vaccine at months 0,1 and 2 and a simultaneously in order to control and booster dose at month 20), R3C group eliminate malaria. Preventive measures (three doses of vaccine and a dose of and medical treatment of the infection comparator vaccine at month 20) and both are important. C3C group (receive comparator vaccine WHO recommends the use of at months 0,1,2 and 20 [control group]). Combination Therapy (ACT) The children group was followed up for as the standard treatment for malaria. a median of 48 months after dose one The treatment regimen use antimalarial and for 38 months for young infants drugs such as riamet, , group. The occurrences of clinical and , , and quinine. severe malaria over 12 months after the third dose were picked up via passive Besides that, preventive measures case detection.16 consist of a combination of mosquito avoidance measures and In another study, which was conducted chemoprophylaxis. The mosquito as part of a phase 2 trial, Olutu A et al. avoidance measures include insect evaluated the long term efficacy of repellant, wearing long sleeves, long RTS,S/AS01 by following up the pants, sleeping in a mosquito-free children aged five to 17 months at the setting or using an insecticide-treated time of the first vaccination for seven bed net. The use of diethyltoluamide years. Four hundred and fourty seven (DEET) in lotions, spray, roll-on (447) children were recruited in Kifili, formulation is safe and effective when and Korogwe, Tanzania and applied to the skin of adults and were followed up from March 2007 until children. November 2014 after they received three doses of RTS,S/AS01. However, only 312 children completed the follow

4 | P a g e up (164 children in the RTS,S/AS01 p=0.13) was observed in the fifth year. group and 148 in the control group).17 Then, the efficacy dropped to 3.6% (95% CI: -29.5, 28.2, p=0.81) in the ∑ EFFICACY seventh year which was not statistically 17 This study showed that RTS,S/AS01 significant. gave low protection against malaria (see In children, RTS,S/AS01 with booster Appendix, Table 2 and 3). The best dose had averted more clinical malaria, protection was seen in the older children severe malaria cases and malaria who received four doses of vaccine with hospital admission when compared with a of 36.35% (95% CI: no booster (1774 versus 1363 cases, 19 31.8, 40.5), p value <0.0001 against versus 8 cases and 40 versus 26 cases clinical malaria and significant protection per 1000 children, respectively) (see 32.2% (95% CI: 13.7, 46.9), p value Appendix, Table 5). While in infants, this 16 0.0009 against severe malaria. vaccine averted 983 clinical malaria The efficacy dropped to 25.9% (95% CI: cases in those who received booster 19.9, 31.5), p value <0.0001 in infants compared with those without booster group who received four doses of dose only 558 cases averted per 1000 16 vaccine. Infants and young children who infants. did not receive the booster dose had an In the seven year follow up study, they even lower vaccine efficacy against reported not statistically significant (317 clinical malaria, 18.3%, and 28.3% cases [95% CI -357; 973]) cases of respectively. In infants, no significant clinical malaria averted per 1000 efficacy was noted against severe children who received RTS,S/AS01.17 malaria, with or without a fourth dose.16 SAFETY From the study, the efficacy of the primary vaccination reduced over time. Meningitis cases were reported to be However, administration of booster dose higher in children who received the gave longer protection against clinical RTS,S/AS01 when compared with malaria in both age groups although the control group (11 in R3R group, ten in protection was lower in infants group R3C group and one in C3C group). compared with older children (see However, there was no significant Appendix, Table 4).16 different in meningitis cases seen in infants groups (five cases in the R3R Olutu A et al. found a similar finding in group, seven in the R3C group, and six children group who received primary in the C3C group). Hence, from this trial vaccination and followed up for seven the researchers were unable to years . In the first year after vaccination, conclude any association of the vaccine RTS,S/AS01 gave low protection of with occurrence of meningitis.16 35.9% vaccine efficacy (95% CI: 8.1, 55.3, p=0.02). However, negative efficacy of -27.6 (95% CI: -74.8, 6.8,

5 | P a g e On the other hand, no cases of in subjects who received higher dose of meningitis were reported in a study by PfSPZ. (at least 5.12 x 104 PfSPZ). The Olutu et al.17 range of follow up was three to 59 weeks.14,19,20,21,22 There were higher incidence of generalised convulsive seizures within The first field trial of this vaccine was seven days post vaccination with conducted by Sissoko et al. in Mali in 93 RTS,S/AS01 booster dose in both non-malaria naived adults. The double children and infants when compared blind, randomised placebo controlled with those who received control vaccine phase 1 trial aimed to assess the safety, (in children, the incidence were 2.5 per tolerability, as well as efficacy of the 1000 doses in R3R group, 1.2 per 1000 vaccine against naturally acquired doses in the R3C group and 0.4 per Plasmodium falciparum malaria.23 1000 doses in the C3C group; whereas in infants the incidence were 2.2 per The vaccine group received five doses 5 1000 doses in the R3R group, 0.0 per of 2.7 x 10 PfSPZ while normal saline 1000 doses in the R3C group and 0.5 was given to the control group and was per 1000 doses in the C3C group).16 followed up for six months. Sixty six percent (27 of 41 participants) in the The frequency of serious adverse vaccine group and 93% (37 of 40 events reported was almost similar participants) in the placebo group were between the vaccine and the control infected with Plasmodium falciparum group.16,17 malaria.23 The vaccine gave 48.3% (95% CI: 14.5, 68.7) efficacy by time to PfSPZ VACCINE first infection analysis and gave 28.8% (95% CI: 8.2, 47.2) when measured ∑ EFFICACY AND SAFETY against all . 23,24 This vaccine is still in the early stage of The safety and tolerability of PfSPZ development. Numerous completed and vaccine has been proven good with on-going phase 1 and 2 clinical trials minimal local or systemic events were conducted in United States of reported.20,23 America, Germany and several African countries in healthy volunteers from However, the optimal vaccine doses and 18 various age categories. regime has yet to be established.

In earlier studies, the vaccine efficacy A phase 1 study is ongoing in Equatorial showed to be dose dependent. These Guinea and is estimated to be studies involved healthy malaria-naive completed in August 2017. This study volunteers who subjected to different participants involves healthy adults, doses, regimens and length of follow up, adolescents, children and infants.25 and subsequently underwent controlled human malaria infection. The efficacies While in western Kenya, the phase 1 were higher, which were more than 55% and 2 trial recruits healthy children and

6 | P a g e infants aged 5 months to 9 years and inoculation.20,22,23 Hence, the practicality approximated to complete in December of repeated venous injection especially 2018.26 in infants and children need to be considered further.23 ESTIMATED COST The logistic concern rises in view of this RTS,S/AS01 (MOSQUIRIX) MALARIA vaccine which requires liquid nitrogen VACCINE for storage and transport. Thus, a reliable liquid nitrogen cold chain logistic The exact price of RTS,S/SAS01 is necessary.23 vaccine is not yet finalised.4 Despite that, the RTS,S/SAS01 vaccine is Furthermore, manually dissecting the anticipated to be priced around USD5 mosquito’s salivary gland to harvest the (±RM 21.64) per unit. The estimated sporozoites is a slow and tedious cost is about USD20 (±RM 86.55) per process that seems impossible for mass regimen which includes three doses scale production. In order to overcome plus a booster, excluding a delivery this, Sanaria Inc. is working on cost.27 Sporobot, a robot dissecting the mosquito to automate the sporozoites There was no information retrieved on collecting process.28 cost for PfSPZ vaccine.

*(USD 1 = RM 4.33) POTENTIAL IMPACT ORGANIZATIONAL ISSUES Both RTS,S/AS01 and PfSPZ malaria vaccine candidates showed promising RTS,S/AS01 (MOSQUIRIX) MALARIA results. VACCINE Although RTS,S/AS01 vaccine is The study showed that the vaccine leading the race, nonetheless it still has needs to be given in full four doses to be issues of low vaccine protection and effective. Hence, there will be a serious adverse effects that one should challenge to ensure the children get the look into before it can go further into full course of vaccination. If adoption of mass vaccination programme. this vaccine is a must, it is preferable to include this vaccine in national Less than half of the children may be vaccination programme specifically for protected against clinical malaria with children living in malaria endemic area. RTS,S/AS01, but the efficacy became much lower in infants. From the study, PfSPZ VACCINE the efficacy waned over time in which The regime for PfSPZ has not yet been the RTS,S/AS01 vaccination may need optimised. In the early trials, this vaccine to be repeated in another four years’ was given either in three, four or five time.16,17 doses via direct venous

7 | P a g e Both vaccines were only shown to 3. Sabbatani S, Fiorino S & Manfredi R. protect against Plasmodium falciparum The Emerging of the Fifth Malaria infection, but different strain of malaria Parasite (Plasmodium knowlesi). A namely, Plasmodium vivax and Public Health Concern? Braz J Infect Plasmodium knowlesi are of high Dis. 2010;14(3):299-309. importance in Malaysia. 4. Fact sheet: RTS,S malaria vaccine The need for full course of four doses of candidate (Mosquirix™). Malaria RTS,S/AS01 to confer immunity and the Vaccine Initiative. Available at route of administration via direct venous http://www.malariavaccine.org/sites/ inoculation for PfSPZ in multiple doses www.malariavaccine.org/files/content may influence the feasibility and /page/files/RTSS%20vaccine%20ca compliance towards the vaccines. ndidate%20Factsheet_FINAL.pdf. Accessed on 8 February 2017.

The occurrence of serious adverse 5. Arama C & Troye-Blomberg M. The events such as meningitis post Path of Malaria Vaccine RTS,S/AS01 vaccination warrants Development: Challenges and further study to investigate the causality. Perspectives. J Intern Med. 2014;275(5):456-66. Furthermore, there could be potential for the vaccines to give false sense of 6. Tables of Malaria Vaccine Projects security to the population and lead to Globally. , Vaccines reduction in the use of other preventive and Biologicals. World Health measures such as insecticide treated Organization. Available at bed net. Whereas, the vaccines are http://www.int/immunization/research intended only as an addition to the /development/Rainbow_tables/en/. existing measures. Accessed on 4 April 2017. REFERENCES 7. Epstein JE & Richie TL. The Whole Parasite, Pre-erythrocytic Stage 1. Fact Sheet: World Malaria Report Approach to Malaria Vaccine 2016. Malaria. World Health Development: A Review. Curr Opin Organisation. Available at Infect Dis. 2013 Oct;26(5):420-428. http://www.who.int/malaria/media/wo 8. First Malaria Vaccine Receives rld-malaria-report-2016/en/. Positive Scientific Opinion from Accessed on 8 February 2017. EMA. Press Release. European 2. Management Guidelines of Malaria Medicines Agency. 24 July 2015. in Malaysia. Vector Borne Disease Available at Sector. Disease Control Division. http://www.ema.europa.eu/docs/en_ Ministry of Health Malaysia. 2014. GB/document_library/Press_release/ 2015/07/WC500190447.pdf. Accessed on 4 April 2017.

8 | P a g e 9. MosquirixTM. Assessment Report. Nonreplicating Sporozoite Vaccine. European Medicines Agency. 23 July Science. 2013;341(6152):1359-65. 2015. Available at www.ema.europa.eu/docs/en_GB/do 15.Mosquirix. Summary of Opinion cuments_lirary/Medicine_for_use_ou Committee for Medicinal Products for tside_EU/2015/10/WC500194577.pd Human Use. European Medicines f. Accessed on 4 April 2017. Agency. 23 July 2015. EMA/CHMP/464758/2015. Available 10.Pilot Implementation of First Malaria at http://www.ema.europa.eu/docs/ Vaccine Recommended by WHO en_GB/document_library/Medicine_f Advisory Group. News Release. or_use_outside_EU/2015/07/WC500 Media Centre. World Health 190452.pdf. Accessed on 23 Organization. 23 October 2015. February 2017. Available at http://www.who.int/mediacentre/new 16.RTS,S Clinical Trials Partnership. s/releases/2015/sage/en/. Accessed Efficacy and Safety of RTS,S/AS01 on 28 February 2017. Malaria Vaccine with or without a Booster dose in Infants and Children 11.Sanaria - Malaria Eradication in Africa: Final Results of a Phase 3, Through Vaccination. Available at Individually Randomised, Controlled http://www.sanaria.com/index.php?s Trial. . =1. Accessed on 12 April 2017. 2015;386(9988):31-45.

12.Schayk IV. Progress with Sanaria’s 17.Olutu A, Fegan G, Wambua J et al. Plasmodium falciparum sporozoite Seven Year Efficacy of RTS,S/AS01 vaccines. Malaria World. March Malaria Vaccine among Young 2017. Available at African Children. N Engl J Med. https://malariaworld.org/blog/progres 2016;374(26):2519-2529. s-sanaria%E2%80%99s-plasmodium -falciparum-sporozoite-vaccines. 18.Phase 2 Trial Of Radiation- Accessed on 10 April 2017. Attenuated Malaria Vaccine Debuts in Kenya. The Foundation for 13.Sanaria PfSPZ Vaccina Against vaccine Research. January 2017. Malaraia Receives FDA Fast tract Available at http://www.vaccine Designation. Available at foundation.org/. Accessed on 3 May http://www.sanaria.com/pdf/Fast%20 2017. Track%20Press%20Release%2022 SEP2016.pdf. Accessed on 12 April 19.Epstein JE, Paolino KM, Richie TL et 2017. al. Protection Against Plasmodium Malaria by PfSPZ Vaccine. JCI 14.Seder RA, Chang LJ, Enama ME et Insight. 2017;2(1):e89154. al. Protection Against Malaria By Intravenous Immunization With A

9 | P a g e 20.Mordmueller B, Surat G, Lagler H et an Age De-escalation Trial in al. Sterile Protection Against Human Equatorial Guinea. ClinicalTrials.gov. Malaria by Chemoattenuated PfSPZ Available at Vaccine. https://clinicaltrials.gov/ct2/show/NC 2017;542(7642):445-449. T02859350. Accessed on 11 May 2017. 21.Lyke KE, Ishizuka AS, Berry AA et al. Attenuated PfSPZ Vaccine 26.Safety, Tolerability and Efficacy of Induces Strain-transcending T cells PfSPZ Vaccine in Healthy Children and Durable Protection Against and Infants 5 Months - 9 Years Heterologous Controlled Human Living in Kenya. ClinicalTrials.gov. Malaria Infection. Proc Natl Acad Sci Available at USA. 2017;114(10):2711-2716. https://clinicaltrials.gov/ct2/show/NC T02687373. Accessed on 11 May 22.Ishizuka AS, Lyke KE, DeZure A et 2017. al. Protection Against Malaria At 1 Year And Immune Correlates 27.Gosling R & von Seidlein L. The Following PfSPZ Vaccination. Nat Future of the RTS,S/AS01 Malaria Med. 2016;22(6):614-23. Vaccine: An Alternative Development Plan. PLoS Med. 23.Sissoko MS, Healy SA, Katile A et al. 2016;13(4):e1001994. Safety and Efficacy of PfSPZ Vaccine Against Plasmodium 28.Sanaria Inc. to launch crowdfunding falciparum via Direct Venous campaign for SporoBotTM, a Inoculation in Healthy Malaria- Mosquito-Dissecting Robot for Exposed Adults in Mali: A Accelerating Manufacture of Randomised, Double Blind Phase 1 Sanaria’s Malaria Vaccine. Available Trial. Lancet Infect at Dis. 2017;17(5):498-509. http://www.sanaria.com/pdf/Press%2 0Release%2029APR2014.pdf. 24.Greenwood B. Progress with the Accessed on 11 May 2017. PfSPZ Vaccine for Malaria. Lancet Infect Dis. 2017;17(5):463-464.

25.Safety, Tolerability and of PfSPZ Vaccine in

10 | P a g e Appendix

Table 2: Vaccine efficacy against clinical malaria

Number of clinical Vaccine efficacy (95% CI), p value malaria episodes C3C R3C R3R R3C vs C3C R3R vs C3C Children group (age five to 17 months) Month 0 to 9585 7396 6616 28.3% (23.3,32.9), <0.0001 36.35% (31.8,40.5), <0.0001 study end Young infants group (age six to 12 weeks) Month 0 to 6170 5444 4993 18.3% (11.7,24.4), <0.0001 25.9% (19.9,31.5), <0.0001 study end C3C = control group, R3C = primary vaccine without booster group, R3R = primary vaccine plus booster group. Vaccine efficacy = 1 – relative risk for clinical malaria.

Table 3: Vaccine efficacy against severe malaria

Number of participants with at least Vaccine efficacy (95% CI), p value one episodes of severe malaria C3C R3C R3R R3C vs C3C R3R vs C3C Children group (age 5 to 17 months) Month 0 to 171 169 116 1.1% (-23.0, 20.5), 0.96 32.2% (13.7, 46.9), 0.0009 study end Young infants group (age 6 to 12 weeks) Month 0 to 116 104 96 10.3% (-17.3, 31.8),0.45 17.3% (-9.4, 37.5), 0.16 study end C3C = control group, R3C = primary vaccine without booster group, R3R = primary vaccine plus booster group. Vaccine efficacy = 1 – relative risk for severe malaria.

11 | P a g e Table 4: Incremental vaccine efficacy after booster dose against clinical malaria

Incremental vaccine efficacy Vaccine efficacy (95% CI) (during 12 months after booster (month 33 to study end) vaccination) R3C vs C3C R3R vs C3C R3R Children group (age 5 to 17 months) 2.9% (-6.4, 11.4) 12.3% (3.6, 20.1) 25.6% (18.2, 32.3) Young infants group (age 6 to 12 weeks) 4.4% (-6.7, 14.3) 10.5% (0.2, 19.7) 22.3% (14.0, 29.8) C3C = control group, R3C = primary vaccine without booster group, R3R = primary vaccine plus booster group. Incremental efficacy = 1 – (incident rate ratio between the R3R and R3C groups).

Table 5: Number of cases averted per 1000 participants

Number of cases averted per 1000 participants (95% CI) (from month 0 to study end) Type of cases Children group Young infants group (age 5 to 17 months) (age 6 to 12 weeks) R3C R3R R3C R3R Clinical malaria 1363 (995, 1797) 1774 (1387, 2186) 558 (158, 926) 983 (592, 1337)

Severe malaria 8 (-9, 26) 19 (4, 35) 8 (-13, 28) 12 (-6, 32) Malaria hospital 26 (4, 51) 40 (19, 64) 14 (-13, 39) 18 (-8, 42) admission C3C = control group, R3C = primary vaccine without booster group, R3R = primary vaccine plus booster group.

12 | P a g e