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Vaccine 33 (2015) 7425–7432

Contents lists available at ScienceDirect

Vaccine

j our na l ho me page: www.elsev ier .com/ locate /vacc ine

TS,S: Toward a first landmark on the Malaria Vaccineechnology Roadmap�

avid C. Kaslowa,∗, Sophie Biernauxb

PATH, 2201 Westlake Blvd, Suite 200, Seattle, WA 98141, USAGSK Vaccines, Avenue Fleming, 20, Wavre, 1300, Belgium

r t i c l e i n f o

rticle history:vailable online 1 October 2015

eywords:alaria vaccines

accine efficacyircumsporozoite protein

a b s t r a c t

The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vac-cine that has protective efficacy against severe disease and death, lasting longer than one year. This reviewfocuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinantsubunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vac-cine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicitystudy. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria

epatitis B virus surface antigenwere averted over a 3–4 years period, particularly in settings of significant disease burden. European reg-ulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication ofactive immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium fal-ciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectivenessof RTS,S are now anticipated through policy and financing reviews at the global and national levels.

© 2015 Published by Elsevier Ltd. This is an open access article under the CC BY license

. Introduction

RTS,S, a subunit malaria vaccine candidate, has now reached thecientific and regulatory milestone of a positive scientific opin-on from European regulators for the prevention of malaria inoung children in sub-Saharan Africa and continues to progressoward potentially being the first malaria vaccine deployed against

human parasite. RTS,S is comprised of a liposome-based adjuvantAS01) and hepatitis B virus surface antigen (HBsAg) virus-like par-

icles incorporating a portion of the Plasmodium falciparum-derivedircumsporozoite protein (CSP) genetically fused to HBsAg. Thendication is for active immunization of children aged 6 weeks up

Abbreviations: CHMP, Committee for Medicinal Products for Human Use; CSP,ircumsporozoite protein; EMA, European Medicines Agency; GFATM, Global Fundo Fight Aids, Tuberculosis and Malaria; HBsAg, hepatitis B virus surface antigen;TT, intention-to-treat; JTEG, Joint Technical Expert Group; MPAC, Malaria Policydvisory Committee; MPL, monophosphoryl lipid A; MVTRM, Malaria Vaccine Tech-ology Roadmap; PAP, post-approval program; SAGE, Strategic Advisory Group ofxperts; TSP, Thrombospondin-like type I repeat domain; VE, vaccine efficacy; VIS,accine Investment Strategy; WRAIR, Walter Reed Army Institute of Research; WHO,orld Health Organization.

� Open Access provided for this article by PATH MVI/Exxon-Mobil.∗ Corresponding author at: PO Box 900922, Seattle, WA 98109, USA.el.: +1 206 302 4588.

E-mail address: dkaslow@path.org (D.C. Kaslow).

ttp://dx.doi.org/10.1016/j.vaccine.2015.09.061264-410X/© 2015 Published by Elsevier Ltd. This is an open access article under the CC B

(http://creativecommons.org/licenses/by/4.0/).

to 17 months against malaria caused by P. falciparum and againsthepatitis B. If approved by national regulatory authorities and rec-ommended by policy makers in countries of use, development ofRTS,S will have taken more than 30 years (see Fig. 1). For a summaryof the major milestones achieved during the first two dozen yearsof RTS,S development, the reader is referred to reviews publishedin 2010 [1,2]. The present review focuses on product develop-ment efforts and the associated scientific literature over the lasthalf decade, particularly the Phase III program, the regulatory andanticipated policy and financing pathways, and the planned post-approval program/Phase IV studies.

But first, a recapitulation of the rationale for development ofRTS,S in the context of the Malaria Vaccine Technology Roadmapdeveloped by World Health Organization (WHO) in consultationwith the Scientific & Public Health Malaria Community [3,4], isprovided.

2. RTS,S and the Malaria Vaccine Technology Roadmap2015 Landmark Goal

The Malaria Vaccine Technology Roadmap (MVTRM) was origi-nally launched in 2006 and focused on the urgent need for vaccines

to alleviate the ongoing severe disease and death due to malaria.As such, the priority for the global malaria vaccine developmentefforts was on P. falciparum, children under 5 years of age, and sub-Saharan Africa and other highly endemic regions. Largely driven by

Y license (http://creativecommons.org/licenses/by/4.0/).

7426 D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432

Fig. 1. The timeline for development of RTS,S through 2015 spans 30 years. The effort by GlaxoSmithKline (GSK) can be traced back to a collaboration with Walter Reed ArmyInstitute of Research (WRAIR) initiated in 1984. GSK and the PATH Malaria Vaccine Initiative (MVI) partnership was initiated in 2001. Proof-of-concept (PoC) was establishedin 2004 and the pivotal Phase III trial was initiated in 2009 (reviewed in [1]) and completed in 2014 [34]. GSK submitted a regulatory application to the European MedicinesA ee for

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he progress of early clinical development of RTS,S, the MVTRM sethe following landmark goal: “By 2015, develop and license a first-eneration malaria vaccine that has a protective efficacy of morehan 50 percent against severe disease and death and lasts longerhan one year” [3].

The shared vision and strategic goals of the MVTRM werexpanded in 2013 to include development of vaccines against Plas-odium vivax and development of malaria vaccines that reduce

ransmission of the parasite [4]. This expansion was driven byarked changes in malaria epidemiology associated with the scale-

p of malaria control measures and the resultant reductions inalaria parasite transmission, a shift in peak age of clinical malaria

o older age groups, and a decline in malaria-related deaths, cou-led with substantial changes in the malaria research agenda. Ashe focus of the RTS,S development program was on the pediatricndication to prevent clinical malaria, the contribution of RTS,S tohe strategic goal of developing vaccines that interrupt malariaarasite transmission (also known as VIMTs) has been largely unex-lored to date, other than some recent preliminary findings thatuggest that serum from RTS,S-vaccinated individuals does notnhibit sporogony in mosquitoes [5]. That said, the original 2015andmark, which captures the goal of a first-generation malaria vac-ine, remains unchanged in the updated MVTRM [4]. In that regard,n 23 July 2015, the Committee for Medicinal Products for Humanse (CHMP) adopted a positive opinion in accordance with theuropean Medicines Agency (EMA) Article 58 procedure, recom-ending the granting of a marketing authorization for RTS,S for an

ndication of active immunization of children aged 6 weeks up to7 months against malaria caused by Plasmodium falciparum andgainst hepatitis B [6].

. Circumsporozoite protein and RTS,S

The sporozoite plays a central role in the parasite life cycle, from

he maturing Plasmodium oocyst in the midgut of the definitiveost to initial infection of the intermediate host. In the case of P.

alciparum, sporozoites are transmitted to the intermediate humanost through the bites of the definitive female Anopheles mosquito

Medicinal Products for Human Use (CHMP) adopted a positive opinion in July 2015

hosts having parasite-infected salivary glands. Only a fraction of thesporozoites in the mosquito salivary glands are injected into the cir-culation and ultimately infect hepatocytes in susceptible humans.Because the parasite endures a significant numerical bottleneck asit is transmitted between hosts, it is thought the parasite is mostvulnerable to immune attack as it cycles between the definitiveand intermediate hosts [7]. That protective immunity able to blocktransmission of the parasite as it passes through these numericalbottlenecks is never acquired [8], despite repeated infections, pro-vides an opportunity to induce novel immune responses throughactive immunization [9].

The circumsporozoite protein (CSP), which is the major surfaceprotein of Plasmodium ssp. sporozoites, forms a dense coat on theparasite’s surface and has been proposed to contribute to severalcritical roles as the parasites develops within the female mosquitoand infects the mammalian host [10]. Although the primary aminoacid sequences of CSPs differ between Plasmodium ssp., the basicarchitectures are similar (Fig. 2): a N-terminus that encodes a sig-nal peptide sequence, binds heparin sulfate proteoglycans (RegionI), and contains a conserved five amino acid (KLKQP) proteolyticcleavage site sequence and Pexel motifs [11]; a middle third thatconsists of tandem, species-specific amino acid repeats that areimmunodominant B-cell epitopes recognized by the neutralizingantibodies [12] and contributes to sporozoite development in themosquito [13]; and a C-terminus that contains a thrombospondin-like type I repeat domain (TSP) with cell adhesion properties(Region II), a canonical glycosylphosphatidylinositol (GPI) anchoraddition sequence, and three known T cell epitopes—a highly vari-able CD4+ T-cell epitope before the TSP, a highly variable CD8+ T-cellepitope within the TSP, and a “promiscuous” CD4+ T-cell epitopewhose structure is conserved among all parasite isolates [14].

RTS,S contains 189 amino acids from CSP (NF54 199-387aa),including the last 18 NANP repeats and the C-terminus exclusiveof the GPI anchor addition sequence. Approximately 25% of the

Hepatitis B virus surface antigen (HBsAg) monomers in RTS,S parti-cles are genetically fused to the truncated CSP and serve as proteincarriers. Despite self-assembly into HBsAg virus-like particles, non-adjuvant RTS,S is weakly immunogenic and requires an adjuvant

D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432 7427

Fig. 2. Graphical depiction of circumsporozoite (CSP) and RTS,S structures. CSP comprises an N-terminal region containing a signal peptide sequence and Region I that bindsheparin sulfate proteoglycans and has embedded within it a conserved five amino acid (KLKQP) proteolytic cleavage site sequence; a central region containing four-amino-acid (NANP/NVDP) repeats; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchoraddition sequence. The region of the CSP included in the RTS,S vaccine includes the last 18 NANP repeats and C-terminus exclusive of the GPI anchor addition sequence.H articlet s thred H3R),

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epatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like phe truncated CSP and serve as protein carriers. The CSP fragment in RTS,S containomain (TH2R), a highly variable CD8+ T-cell epitope within the TSP-like domain (T

o improve the magnitude and duration of the immune responseso CSP [15]. The Adjuvant System selected [15], AS01, consists ofwo immunostimulants, 3-O-desacyl-4′-monophosphoryl lipid AMPL) and QS-21 Stimulon® Adjuvant (QS-21), in a liposome for-

ulation. Recent studies suggest that one mechanism of action ofS01 is to transiently stimulate the innate immune system and acti-ate a high number of efficient antigen-presenting dendritic cellsn the draining lymph nodes [16]. Also recently published are aepeated dose toxicity study after four administrations of RTS,S atwo-week intervals in New Zealand white rabbits. As expected ancute inflammatory reaction was observed at the injection sites;owever, all affected parameters returned to normal within 28ays after the last injection, indicating full recovery, and no local orystemic toxicities were observed [17].

In the context of RTS,S, the absence of the N-terminal region andhe genetic diversity of CSP are worth noting. Immune responses tohe CSP N-terminal region which contains two functional domainsave been identified as potential targets for protective antibod-

es [18]. Whether antibodies specifically directed at the highlyonserved Region I of CSP inhibit parasite binding and/or proteo-ytic cleavage, and more importantly confer protective immunityemains to be definitively established. Whereas the N-terminalegion of the CSP appears to have limited genetic diversity, theentral repeat and C-terminal regions are known to be natu-ally polymorphic, as recently confirmed in Mali [19] and Madhyaradesh, India, where malaria is endemic in a population not pre-iously exposed to RTS,S [20]. The validation of Region I as a targetf protective immunity may become important in addressing anyssues of genetic diversity associated with the more polymorphic-terminal portion of CSP.

To evaluate CSP genetic diversity in populations administeredTS,S, an ancillary study to the pivotal Phase III trial of RTS,Sdescribed below) was developed to genotype parasites from theaccine trial [21]. Approximately 6,000 samples were drawn, rep-esenting both enrolled age categories, severe disease cases, firstlinical episodes, and cross-sectional parasite-positive samplesollected during study month 20. Parasite variants that infect vac-inated subjects will be evaluated for known T cell epitope (Th2R,h3R, CS.T3) haplotypes, as well as differences in B cell epitope

NANP) repeat count distributions within the central repeat regionf CSP. Whether administration of RTS,S is associated with a changen parasite genetic diversity (within and outside the csp locus) wille evaluated by enumerating the parasite genotypes to determine

s and approximately 25% of the HBsAg monomers in RTS,S are genetically fused toe known T-cell epitopes: a highly variable CD4+ T-cell epitope before the TSP-like

and a conserved “universal” CD4+ T cell epitope (CS.T3) at the C-terminus.

if the vaccine is limiting the complexity of infection (COI) insteadof selecting for particular parasite variants in the RTS,S vaccinatedpopulation. The goal of this study is to determine if RTS,S selectsspecific parasite variants or alters the number of parasite typeswithin a vaccinated subject, and to gain a better understanding ofthe mechanism of action of the RTS,S [21].

4. Phase III program

The cornerstone of the Phase III program was a pivotal efficacyand safety trial, MALARIA-055 (NCT00866619) [22,23]), conductedby the RTS,S Clinical Trials Partnership at 11 clinical trial sites inseven African countries (one site in Burkina Faso, Gabon, Malawiand Mozambique; two sites in Ghana and Tanzania; and, threesites in Kenya). The trial started in May 2009, enrolled 15,459infants and young children, concluded in January 2014, and theresults summary through study end posted in January 2015 [23].This double-blind, individually randomized, controlled, three-armtrial, in which participants received either three doses of RTS,Sone month apart, followed by a booster dose 18 months later;three doses of RTS,S followed by a comparator (or ‘control’)vaccine at the time of booster vaccination; or only control vac-cines throughout, had two age categories: young children aged5–17 months and infants aged 6–12 weeks at the time of enroll-ment. The younger age category was aligned with the infant cohorttargeted for co-administration with routine Expanded Program ofImmunization oral polio and parenteral DTP-containing vaccines.The details of the trial, designed in consultation with appropriateregulatory authorities and the World Health Organization (WHO),have been published [24–27], as have some key learnings fromcommunity engagement during the conduct of the trial [28]. Othertrials in the Phase III program were conducted to further assessRTS,S in co-administration with other routinely administered vac-cines, to assess its safety and efficacy in HIV-infected infants andyoung children, and to document lot-to-lot consistency of vaccinemanufacturing [29,30].

The pivotal Phase III trial was conducted in two phases: a double-blind phase from Month 0–32 [31–33]; and, an extension phasefrom Month 33 to study end [34]. The primary aim of the trial was

to assess the efficacy of a three-dose primary vaccination course ofRTS,S against clinical malaria over 12 months follow-up in two agecategories (see above). Secondary aims were to describe the safetyand immunogenicity of RTS,S, to evaluate the efficacy of the vaccine

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428 D.C. Kaslow, S. Biernaux /

andidate against other endpoints of public health importancee.g., severe malaria and malaria hospitalization), and to evaluate aooster dose of RTS,S received at Month 20 with follow-up through

twelve-month period (Month 32). An additional analysis wasonducted at the end of an extension of the follow-up period,ncluding an evaluation of safety and efficacy against clinical

alaria, severe malaria and prevalent parasitemia [34].With respect to the primary aim in the per-protocol popula-

ion of the pivotal Phase III trial, over the Month 2.5 to Month 14ollow-up period (i.e., 12 months post-dose 3), in the 5–17 monthsge category, the efficacy of RTS,S calculated by negative binomialegression model against first or only episode of malaria meet-ng the clinical malaria primary case definition was 55.8% (with7.5% confidence interval ranging from 50.6% (lower limit) to 60.4%upper limit), and p-value <0.0001) [23,31]. Over the Month 2.5 to

onth 14 follow-up period, in the 6–12 weeks age category, thefficacy of RTS,S similarly calculated by negative binomial regres-ion model against first or only episodes of malaria meeting thelinical malaria primary case definition was 31.3% (with 97.5% con-dence intervals ranging from 23.6% (lower limit) to 38.3% (upper

imit), and p-value <0.0001) [32].With respect to the secondary aims of the pivotal Phase III trial

rior to a booster (4th) dose of vaccine (Month 20), several resultsre worth noting: (1) vaccine efficacy and immunogenicity wereower in young infants than in children [32,33]; (2) vaccine effi-acy waned over time in both age categories (Schoenfeld residuals

< 0.001) [31–33]; (3) despite modest and waning vaccine efficacy,he public health impact, reported as the number of cases of clin-cal malaria, severe malaria and all cause hospitalizations averteder 1000 persons vaccinated [ranging across sites from 37 to 2365,1 to 49, and −3 to 131, respectively in the 5–17 month old age

ategory (ITT), and from −10 to 1402, −13 to 37, and −153 to 145,espectively in the 6–12 week old age category (ITT)] was substan-ial, particularly, in the older age category and in the context ofigh disease burden—translated to the population at risk of malaria,ases averted or vaccine preventable disease incidence (VPDI) onhis scale would have a major public health impact [33,35]; (4)ncreased risk for febrile convulsion within 7 days of administer-ng RTS,S in children over 5 months of age at time of vaccination;nd (5) meningitis was reported as a serious adverse event andhe greater number of cases in the RTS,S group compared with theontrol vaccine group in the older age category reached statisticalignificance [33].

With respect to the final set of results, which included thefficacy of a 4th dose of RTS,S, and the efficacy, impact, immuno-enicity, and safety of RTS,S from first vaccination to study end (SE)or a median follow-up of 38 months in the younger age categorynd 48 months in the older age category, several additional findingsre noteworthy: (1) a 4th dose appeared to restore and maintainaccine efficacy—VE (ITT) from Month 0 to SE was 36.3% (95% CI1.8; 40.5) and 32.2% (95% CI 13.7; 46.9) against all episodes oflinical malaria and severe malaria, respectively, in the older ageategory, and 25.9% (95% CI 19.9; 31.5) and 17.3% (95% CI −9.4;7.5) against clinical malaria and severe malaria, respectively, inhe younger age category; (2) without a booster, VE (ITT) againstlinical malaria continued to wane in both age categories and, in thelder age category, severe malaria VE became non-significant overhe entire study period (VE Month 0–SE = 1.1%, 95% CI −23.0; 20.5)nd, in fact, the comparative incidence of severe malaria in the timeeriod from Month 21 to SE was significantly higher [VE Month 21-E = −41.0% (95% CI −98.5; −0.8); p = 0.04) than the control group;3) despite waning efficacy, the number of cases of clinical malaria

verted continued to accumulate in the older and younger age cat-gories that were administered a 4th dose of RTS,S, reaching anverage of 1774 and 980 per 1000 children vaccinated, respectively,ith impact greater in sites with higher malaria burden (Fig. 3);

ne 33 (2015) 7425–7432

(4) while administration of a booster dose of RTS,S led to anincrease in anti-circumsporozoite geometric mean titers in bothyoung infants and children, the titers after the booster was lowerthan concentrations after the primary course and the booster effectwas only transitory; (5) the frequency of SAEs overall was balancedbetween groups; however, in the older age category meningitis wasreported as an SAE during the entire study period in 11, 10 and onechild in the four RTS,S dose, three RTS,S dose and control groups,respectively, while, in contrast, no imbalance in cases of meningi-tis was noted in the younger age category; and, (6) the incidence ofgeneralized convulsive seizures within seven days of RTS,S boosterwas observed at a higher rate than controls in both the youngerand older age categories (2.2 and 2.5/1000 doses, respectively) [34].Based on the temporal association and biological plausibility, it wasconcluded that there was a reasonable possibility of causal rela-tionship between RTS,S and the occurrence of febrile convulsionswithin 7 days post-vaccination [34].

A cautionary note: the detailed study analyses contain data frommultiple protocol-specified and subsequent data analysis plan-specified time points, generating hundreds of comparisons andcreating the opportunity for unexpected associations to emerge bychance. Similarly, the high standard of care provided to all trial par-ticipants may have limited the ability of this trial to detect an impacton more severe outcomes and mortality. With the former caveat inmind and despite a comprehensive analysis, no obvious explana-tion for the meningitis observation has been found, and while atemporal relationship to vaccination is lacking and the biologicalplausibility is low, a causal relationship cannot be confirmed orexcluded at this point.

Beyond those highlighted above, additional results of extensiveanalyses of secondary, tertiary and exploratory aims of the trial,can be found in the published literature [31–34] and on the openaccess GSK clinical study register [23]. With respect to protectiveimmune responses, much is still incompletely understood despitenumerous recent analyses [36–40]. While antibody levels and to alesser extend cell mediated immune responses, have been shownto associate with protection against malaria infection, a definitivecorrelate of protection remains elusive.

Table 1 summarizes on-going clinical trials of RTS,S in supportof the pediatric indication. A more comprehensive summary of listof trials conducted and results published since 2010 can be foundin materials reviewed by WHO advisory bodies (see below) in 2013[30].

5. Regulatory, policy, and financing pathway

As an initial step in the policy and regulatory process, GSK sub-mitted a regulatory application to EMA in June 2014 [41]. The RTS,Sregulatory application was reviewed under the Article 58 proce-dure, which allows the EMA to assess the quality, safety and efficacyof a product intended exclusively for use outside the EuropeanUnion (EU) but which is manufactured in a EU member state, toaddress a disease recognized by the World Health Organization(WHO) as of major public health interest [42]. This assessmentwas done by the EMA in collaboration with the WHO and non-EU regulators, and requires products to meet the same standardsas a vaccine intended for use in the EU. Under the Article 58 pro-cedure, the CHMP performed a scientific evaluation of RTS,S andin July 2015 issued “a European scientific opinion”, adopting apositive opinion and recommending the granting of a marketingauthorization for active immunization of children aged 6 weeks up

to 17 months against malaria caused by P. falciparum and againsthepatitis B, noting that use should be based on official recommen-dations considering P. falciparum malaria epidemiology in differentgeographical areas. It is important to emphasize that a positive

D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432 7429

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ig. 3. Vaccine efficacy and impact against clinical malaria through study end (Studhat received four doses (R3R) of RTS,S and bar graphs of number of cases avertedopulation of children age 5–17 months (Panel A) and infants age 6–12 weeks (Pan

pinion is not licensure or registration in the EU, but provides a sci-ntific opinion that African national regulatory authorities may usen their own regulatory review processes as they consider licensurend registration in their jurisdictions.

The positive opinion adopted by CHMP also plays a critical rolen decision making by WHO normative bodies. The technical groupdvising WHO on Phase 3 trials of malaria vaccines is the Joint Tech-ical Expert Group (JTEG) on Malaria Vaccines, convened by the

mmunization, Vaccines, and Biologicals Department (IVBD) andhe Global Malaria Program (GMP) [43], and reporting jointly totrategic Advisory Group of Experts (SAGE) on immunization andhe Malaria Policy Advisory Committee (MPAC) [42,44]. Based onhe positive opinion adopted by CHMP, JTEG’s evaluation of RTS,Sill now be considered jointly by SAGE and MPAC who will adviseHO on recommendation(s) for use, anticipated in the last quar-

er of 2015 [44]. WHO will also consider RTS,S for prequalificationPQ), a process “intended to ensure that a specific vaccine from

specific manufacturer meets international standards of quality,afety and efficacy and is appropriate for the target population. Only

HO prequalified vaccines can be supplied to countries throughN agencies” [43].

Another critical step after WHO recommendation and PQ will

e decisions by various international financing organizations andublic–private partnerships, including Gavi—the Vaccine AllianceGavi), and the Global Fund to Fight Aids, Tuberculosis and MalariaGFATM), to open country support windows for public financing.

th 0-SE). Forest plot of vaccine efficacy with 95% confidence intervals for the groupe three dose (R3C) and four dose (R3R) RTS,S groups by site in the intent-to-treatt first vaccination, respectively [33].

In preparation for such a decision, Gavi included a malaria vaccinein a recent Vaccine Investment Strategy (VIS) review, an evidence-based prioritization process, undertaken once every five years, toidentify new vaccines with high priority for inclusion in the Gaviportfolio [45]. Based on various analyses conducted as part of theVIS process, including a projection that RTS,S could potentially avertapproximately 1 million future deaths in Africa over 15 years (Fig. 4)[46], and based on meeting certain pre-specified conditions [45], itis anticipated that the Gavi Secretariat will recommend to the GaviBoard the opening of a country support window, albeit highlight-ing the importance of coordinating the introduction of a vaccine aspart of integrated malaria control programs and exploring oppor-tunities for harmonized global procurement strategies with otherinternational financing mechanisms (e.g., GFATM) [45].

Given that all clinical trial data from the field are from sub-Saharan Africa and given the scientific opinion adopted by CHMP,it is anticipated that any WHO recommendation, public financing,national regulatory authority review and national policy recom-mendations on introduction and use of the vaccine will be restrictedto sub-Saharan Africa, consistent with the first landmark goal of theMVTRM.

6. Post-approval program/Phase IV studies

Post-approval studies play an important role in the introductionand scale-up of vaccines and are critical components of any vaccine

7430 D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432

Table 1Ongoing/planned RTS,S clinical and epidemiological studies.

Study groups Study and objectives Location Age at enrollment Sample size

Pivotal Ph III efficacy and safety study extensionSame study groups as in the primarystudy• RTS,S/AS01 (3 doses) + RTS,S/AS01booster dose• RTS,S/AS01 (3 doses) + control vaccine• Control vaccine (3 doses) + controlvaccine

Long-term efficacy, safety andimmunogenicity of RTS,S/AS01 over anadditional 3-year period.• Primary endpoint: incidence ofsevere malaria.• Secondary endpoints: clinicalmalaria, parasite prevalence and SAEsof special interest

Tanzania, Kenya,Burkina Faso

5–17 months or6–12 weeks

3600

Co-administration Ph IIIb study (Measles, yellow fever and rubella vaccines)• RTS,S/AS01 at 6, 7.5 and 9m. Yellowfever and measles-rubella vaccinesco-administered at 9 m.• RTS,S/AS01 at 6, 7.5 and 9 m, Yellowfever and measles-rubella vaccinesstaggered at 10m.• Yellow fever and measles-rubellavaccines at 9m.All groups receive vitamin A at 6 m

Non-inferiority of immune responseand safety of the RTS,S/AS01 with orwithout co-administration of measles,yellow fever and rubella vaccines

To be determined 6 months 700

Malaria Transmission Intensity study6m–4y5y–19y20y +

Annual cross-sectional surveys of P.falciparum parasitemia at peak oftransmission in Ph III pivotal efficacy &safety study catchment areas, during 4years.

6 Sub-SaharanAfrican countries; 8research centers

6 months to 90years

6400

Ph III study on HepB Indication and EPI Integration• RTS,S/AS01 + CoAd(DTPa/Hib + OPV + rotavirusvaccine) + pneumococcal vaccinestaggered (3 groups—3 lots)• RTS,S/AS01 + CoAd(DTPa/Hib + OPV + pneumococcalvaccine) + rotavirus staggered (3groups—3 lots)• RTS,S/AS01 + CoAd(DTPa/Hib + OPV) + rotavirus andpneumococcal vaccines staggered (3groups—3 lots)• HepB + CoAd(DTPa/Hib + OPV + pneumococcalvaccine) + rotavirus vaccine staggered• HepB + CoAd(DTPa/Hib + OPV + rotavirusvaccine) + pneumococcal vaccinestaggered

Non-inferiority of Hepatitis B immuneresponse.Co-administration with 10V S.pneumonia, non-inferiority of immuneresponseCo-administration with rotavirusvaccine, non-inferiority of immuneresponse.

Burkina Faso Ghana 8–12 weeks 705

Memory response to the HBs antigen(booster hepatitis B vaccine given 4years post primary)

Ph II Schedule optimization study• RTS,S/AS01 (≤7d, 10w, 14w)• RTS,S/AS01 (≤7d, 10w, 26w)• RTS,S/AS01 (6w, 10w, 14w)• RTS,S/AS01 (6w, 10w, 26w)• RTS,S/AS01 (6w, 10w, 26w & HepB atbirth)• RTS,S/AS01 (10w, 14w, 26w)• RTS,S/AS01 (14w, 26w, 9m)• HepB at birth (control group)All groups receive: BCG, OPV at birthDTPw-HepB/Hib, OPV at 6w, 10w, 14w

Exploration of various vaccinationschedules around current EPI visits.

Malawi ≤7d–14w 480

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Measles vaccine at 9m

= days, w = weeks; m = months, y = years of age.

evelopment program, as they address key questions that cannote readily addressed in Phase III studies. For example, monitoringafety and determining effectiveness of vaccines in larger popula-ions under more “real life” conditions are key data in refining the

enefit-risk profile and optimizing the application of new vaccines.

n the case of RTS,S, the post-approval program is being developedo meet regulatory commitments as part of the EMA Article 58 pro-edure. It can also be used to provide policy and decision-makers

in-country, with additional information to assist in deciding onthe use of a new tool in their national vaccine and malaria controlprograms.

As it relates to pharmacovigilance and impact, three studies

are currently envisioned. An epidemiology study (EPI-MAL-002),to “set the baseline” for the incidence of pre-defined diseasesthat may be reported as adverse events following immunizationand for malaria morbidity and mortality. This first phase will be

D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432 7431

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ig. 4. Gavi projects that RTS,S could potentially avert around 1 million future deverted (y-axis: cumulative deaths averted over a 15 year period) represents the

cenario that includes a booster dose [44].

onducted in several countries, and will follow approximately0,000 children for two years prior to the introduction of RTS,S

n the study communities (this phase will start pre-approval).his study will be followed by a second phase to be conductedfter national regulatory approval of RTS,S, such that RTS,S wille delivered using the immunization system already in place inhe study area. The vaccination study (EPI-MAL-003) will enrollnother approximately 45,000 children to determine the incidencef these same pre-defined diseases after immunization with RTS,S.o leverage and further enhance existing infrastructure, thesewo studies will be conducted at sites that already monitor theopulation in their catchment area through demographic surveys.

third study (EPI-MAL-005, a malariometric study), concurrento the other two studies, will conduct cross-sectional surveys toollect data on the use and coverage of other malaria interventionsnd will track changes in disease burden during the period inhich EPI-MAL-002 and EPI-MAL-003 are conducted.

In addition to these pharmacovigilance/malaria impact stud-es (baseline and vaccination phases) and concurrent malariaransmission intensity studies, the RTS,S post-approval programncludes research in health economics and the piloting of com-

unications materials to support possible introduction. Additionaltudies will be contemplated if deemed needed and feasible.

. Conclusion

RTS,S, a candidate malaria vaccine, has now been success-ully evaluated in a Phase III program conducted in eight Africanountries and undergone a stringent evaluation by a regulatorygency. Although vaccine efficacy may be modest, the number ofases averted in settings of significant disease burden, be it clini-al malaria, severe malaria or malaria hospitalizations, on the scaleeen in MALARIA-055 would have a major public health impact. Buto do so will no doubt require that all available tools be brought toear in an optimal way to prevent and treat malaria. In the end, theenefit, risk, feasibility and cost-effectiveness will be used to deter-ine the impact of RTS,S. The former has initially been evaluated

hrough EMA’s Article 58 procedure with a positive opinion for ages

weeks to 17 months, noting that subsequent evaluations are stilleeded by national regulatory authorities. The latter will now bevaluated through policy and financing reviews at the global andational levels.

Africa over 15 years (2015–2030) [46]. The point estimate of 1.1 million deathsint of the Imperial College and Swiss Tropical Public Health model outputs for a

Sources of support

PATH has received grants from the Bill & Melinda Gates Foun-dation to support the clinical development of RTS,S, from the USAgency for International Development to support Decision-MakingFramework-related activities, and the ExxonMobil Foundation tosupport research on malaria transmission intensity, health eco-nomics research and modeling, and for the community perceptionsand VIC projects. All RTS,S studies have been sponsored andsupported by GSK Biologicals SA, the vaccine developer and man-ufacturer.

Acknowledgements

The authors thank: the thousands of children and their familiesand communities, the hundreds of adult trial subjects, and the prin-cipal investigators, team members and healthcare workers at eachof the trial sites who have participated in the clinical developmentof RTS,S; the global, national and local organizations and govern-ment authorities for their input, guidance and support; and thehundreds of product R&D professionals who have worked tirelesslyover decades on the development of RTS,S as a malaria vaccinecandidate. The author further thanks the Clinical Trial PartnershipCommittee (CTPC) and MVI-GSK partnership for their critical con-tributions to the late stage development of RTS,S. The authors alsothank our colleagues at GSK and PATH MVI for critical review ofthis manuscript.

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