RTS,S: Toward a ﬁrst Landmark on the Malaria Vaccine ଝ

Home , Anopheles, Circumsporozoite protein

Vaccine 33 (2015) 7425–7432

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Vaccine

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RTS,S: Toward a ﬁrst landmark on the Malaria Vaccine ଝ

Technology Roadmap

a,∗ b

David C. Kaslow , Sophie Biernaux

PATH, 2201 Westlake Blvd, Suite 200, Seattle, WA 98141, USA

GSK Vaccines, Avenue Fleming, 20, Wavre, 1300, Belgium

a r a

t i b s

c t

l e i n f o r a c t

Article history: The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a ﬁrst-generation malaria vac-

Available online 1 October 2015

cine that has protective efﬁcacy against severe disease and death, lasting longer than one year. This review

focuses on product development efforts over the last ﬁve years of RTS,S, a pre-erythrocytic, recombinant

Keywords:

subunit, adjuvanted, candidate malaria vaccine designed with this goal of a ﬁrst-generation malaria vac-

Malaria vaccines

cine in mind. RTS,S recently completed a successful pivotal Phase III safety, efﬁcacy and immunogenicity

Vaccine efﬁcacy

study. Although vaccine efﬁcacy was found to be modest, a substantial number of cases of clinical malaria

Circumsporozoite protein

were averted over a 3–4 years period, particularly in settings of signiﬁcant disease burden. European reg-

Hepatitis B virus surface antigen

ulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of

active 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-effectiveness

of RTS,S are now anticipated through policy and ﬁnancing reviews at the global and national levels.

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

1. Introduction to 17 months against malaria caused by P. falciparum and against

hepatitis B. If approved by national regulatory authorities and rec-

RTS,S, a subunit malaria vaccine candidate, has now reached the ommended by policy makers in countries of use, development of

scientiﬁc and regulatory milestone of a positive scientiﬁc opin- RTS,S will have taken more than 30 years (see Fig. 1). For a summary

ion from European regulators for the prevention of malaria in of the major milestones achieved during the ﬁrst two dozen years

young children in sub-Saharan Africa and continues to progress of RTS,S development, the reader is referred to reviews published

toward potentially being the ﬁrst malaria vaccine deployed against in 2010 [1,2]. The present review focuses on product develop-

a human parasite. RTS,S is comprised of a liposome-based adjuvant ment efforts and the associated scientiﬁc literature over the last

(AS01) and hepatitis B virus surface antigen (HBsAg) virus-like par- half decade, particularly the Phase III program, the regulatory and

ticles incorporating a portion of the Plasmodium falciparum-derived anticipated policy and ﬁnancing pathways, and the planned post-

circumsporozoite protein (CSP) genetically fused to HBsAg. The approval program/Phase IV studies.

indication is for active immunization of children aged 6 weeks up But ﬁrst, a recapitulation of the rationale for development of

RTS,S in the context of the Malaria Vaccine Technology Roadmap

developed by World Health Organization (WHO) in consultation

with the Scientiﬁc & Public Health Malaria Community [3,4], is

Abbreviations: CHMP, Committee for Medicinal Products for Human Use; CSP, provided.

circumsporozoite protein; EMA, European Medicines Agency; GFATM, Global Fund

to Fight Aids, Tuberculosis and Malaria; HBsAg, hepatitis B virus surface antigen;

2. RTS,S and the Malaria Vaccine Technology Roadmap

ITT, intention-to-treat; JTEG, Joint Technical Expert Group; MPAC, Malaria Policy

2015 Landmark Goal

Advisory Committee; MPL, monophosphoryl lipid A; MVTRM, Malaria Vaccine Tech-

nology Roadmap; PAP, post-approval program; SAGE, Strategic Advisory Group of

Experts; TSP, Thrombospondin-like type I repeat domain; VE, vaccine efﬁcacy; VIS, The Malaria Vaccine Technology Roadmap (MVTRM) was origi-

Vaccine Investment Strategy; WRAIR, Walter Reed Army Institute of Research; WHO,

nally launched in 2006 and focused on the urgent need for vaccines

World Health Organization.

ଝ to alleviate the ongoing severe disease and death due to malaria.

Open Access provided for this article by PATH MVI/Exxon-Mobil.

∗ As such, the priority for the global malaria vaccine development

Corresponding author at: PO Box 900922, Seattle, WA 98109, USA.

efforts was on P. falciparum, children under 5 years of age, and sub-

Tel.: +1 206 302 4588.

E-mail address: [email protected] (D.C. Kaslow). Saharan Africa and other highly endemic regions. Largely driven by

http://dx.doi.org/10.1016/j.vaccine.2015.09.061

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 Army

Institute of Research (WRAIR) initiated in 1984. GSK and the PATH Malaria Vaccine Initiative (MVI) partnership was initiated in 2001. Proof-of-concept (PoC) was established

in 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 Medicines

Agency (EMA) for review under the Article 58 procedure in 2014 [39]. The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in July 2015

[6].

the progress of early clinical development of RTS,S, the MVTRM set hosts having parasite-infected salivary glands. Only a fraction of the

the following landmark goal: “By 2015, develop and license a ﬁrst- sporozoites in the mosquito salivary glands are injected into the cir-

generation malaria vaccine that has a protective efﬁcacy of more culation and ultimately infect hepatocytes in susceptible humans.

than 50 percent against severe disease and death and lasts longer Because the parasite endures a signiﬁcant numerical bottleneck as

than one year” [3]. it is transmitted between hosts, it is thought the parasite is most

The shared vision and strategic goals of the MVTRM were vulnerable to immune attack as it cycles between the deﬁnitive

expanded in 2013 to include development of vaccines against Plas- and intermediate hosts [7]. That protective immunity able to block

modium vivax and development of malaria vaccines that reduce transmission of the parasite as it passes through these numerical

transmission of the parasite [4]. This expansion was driven by bottlenecks is never acquired [8], despite repeated infections, pro-

marked changes in malaria epidemiology associated with the scale- vides an opportunity to induce novel immune responses through

up of malaria control measures and the resultant reductions in active immunization [9].

malaria parasite transmission, a shift in peak age of clinical malaria The circumsporozoite protein (CSP), which is the major surface

to older age groups, and a decline in malaria-related deaths, cou- protein of Plasmodium ssp. sporozoites, forms a dense coat on the

pled with substantial changes in the malaria research agenda. As parasite’s surface and has been proposed to contribute to several

the focus of the RTS,S development program was on the pediatric critical roles as the parasites develops within the female mosquito

indication to prevent clinical malaria, the contribution of RTS,S to and infects the mammalian host [10]. Although the primary amino

the strategic goal of developing vaccines that interrupt malaria acid sequences of CSPs differ between Plasmodium ssp., the basic

parasite transmission (also known as VIMTs) has been largely unex- architectures are similar (Fig. 2): a N-terminus that encodes a sig-

plored to date, other than some recent preliminary ﬁndings that nal peptide sequence, binds heparin sulfate proteoglycans (Region

suggest that serum from RTS,S-vaccinated individuals does not I), and contains a conserved ﬁve amino acid (KLKQP) proteolytic

inhibit sporogony in mosquitoes [5]. That said, the original 2015 cleavage site sequence and Pexel motifs [11]; a middle third that

landmark, which captures the goal of a ﬁrst-generation malaria vac- consists of tandem, species-speciﬁc amino acid repeats that are

cine, remains unchanged in the updated MVTRM [4]. In that regard, immunodominant B-cell epitopes recognized by the neutralizing

on 23 July 2015, the Committee for Medicinal Products for Human antibodies [12] and contributes to sporozoite development in the

Use (CHMP) adopted a positive opinion in accordance with the mosquito [13]; and a C-terminus that contains a thrombospondin-

European Medicines Agency (EMA) Article 58 procedure, recom- like type I repeat domain (TSP) with cell adhesion properties

mending the granting of a marketing authorization for RTS,S for an (Region II), a canonical glycosylphosphatidylinositol (GPI) anchor

indication of active immunization of children aged 6 weeks up to addition sequence, and three known T cell epitopes—a highly vari-

+ +

17 months against malaria caused by Plasmodium falciparum and able CD4 T-cell epitope before the TSP, a highly variable CD8 T-cell

against hepatitis B [6]. epitope within the TSP, and a “promiscuous” CD4 T-cell epitope

whose structure is conserved among all parasite isolates [14].

3. Circumsporozoite protein and RTS,S RTS,S contains 189 amino acids from CSP (NF54 199-387aa),

including the last 18 NANP repeats and the C-terminus exclusive

The sporozoite plays a central role in the parasite life cycle, from of the GPI anchor addition sequence. Approximately 25% of the

the maturing Plasmodium oocyst in the midgut of the deﬁnitive Hepatitis B virus surface antigen (HBsAg) monomers in RTS,S parti-

host to initial infection of the intermediate host. In the case of P. cles are genetically fused to the truncated CSP and serve as protein

falciparum, sporozoites are transmitted to the intermediate human carriers. Despite self-assembly into HBsAg virus-like particles, non-

host through the bites of the deﬁnitive female Anopheles mosquito 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 binds

heparin 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) anchor

addition 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.

Hepatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like particles and approximately 25% of the HBsAg monomers in RTS,S are genetically fused to

the truncated CSP and serve as protein carriers. The CSP fragment in RTS,S contains three known T-cell epitopes: a highly variable CD4 T-cell epitope before the TSP-like

+ +

domain (TH2R), a highly variable CD8 T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 T cell epitope (CS.T3) at the C-terminus.

to improve the magnitude and duration of the immune responses if the vaccine is limiting the complexity of infection (COI) instead

to CSP [15]. The Adjuvant System selected [15], AS01, consists of of selecting for particular parasite variants in the RTS,S vaccinated

two immunostimulants, 3-O-desacyl-4 -monophosphoryl lipid A population. The goal of this study is to determine if RTS,S selects

(MPL) and QS-21 Stimulon Adjuvant (QS-21), in a liposome for- speciﬁc parasite variants or alters the number of parasite types

mulation. Recent studies suggest that one mechanism of action of within a vaccinated subject, and to gain a better understanding of

AS01 is to transiently stimulate the innate immune system and acti- the mechanism of action of the RTS,S [21].

vate a high number of efﬁcient antigen-presenting dendritic cells

in the draining lymph nodes [16]. Also recently published are a 4. Phase III program

repeated dose toxicity study after four administrations of RTS,S at

two-week intervals in New Zealand white rabbits. As expected an The cornerstone of the Phase III program was a pivotal efﬁcacy

acute inﬂammatory reaction was observed at the injection sites; and safety trial, MALARIA-055 (NCT00866619) [22,23]), conducted

however, all affected parameters returned to normal within 28 by the RTS,S Clinical Trials Partnership at 11 clinical trial sites in

days after the last injection, indicating full recovery, and no local or seven African countries (one site in Burkina Faso, Gabon, Malawi

systemic toxicities were observed [17]. and Mozambique; two sites in Ghana and Tanzania; and, three

In the context of RTS,S, the absence of the N-terminal region and sites in Kenya). The trial started in May 2009, enrolled 15,459

the genetic diversity of CSP are worth noting. Immune responses to infants and young children, concluded in January 2014, and the

the CSP N-terminal region which contains two functional domains results summary through study end posted in January 2015 [23].

have been identiﬁed as potential targets for protective antibod- This double-blind, individually randomized, controlled, three-arm

ies [18]. Whether antibodies speciﬁcally directed at the highly trial, in which participants received either three doses of RTS,S

conserved Region I of CSP inhibit parasite binding and/or proteo- one month apart, followed by a booster dose 18 months later;

lytic cleavage, and more importantly confer protective immunity three doses of RTS,S followed by a comparator (or ‘control’)

remains to be deﬁnitively established. Whereas the N-terminal vaccine at the time of booster vaccination; or only control vac-

region of the CSP appears to have limited genetic diversity, the cines throughout, had two age categories: young children aged

central repeat and C-terminal regions are known to be natu- 5–17 months and infants aged 6–12 weeks at the time of enroll-

rally polymorphic, as recently conﬁrmed in Mali [19] and Madhya ment. The younger age category was aligned with the infant cohort

Pradesh, India, where malaria is endemic in a population not pre- targeted for co-administration with routine Expanded Program of

viously exposed to RTS,S [20]. The validation of Region I as a target Immunization oral polio and parenteral DTP-containing vaccines.

of protective immunity may become important in addressing any The details of the trial, designed in consultation with appropriate

issues of genetic diversity associated with the more polymorphic regulatory authorities and the World Health Organization (WHO),

C-terminal portion of CSP. have been published [24–27], as have some key learnings from

To evaluate CSP genetic diversity in populations administered community engagement during the conduct of the trial [28]. Other

RTS,S, an ancillary study to the pivotal Phase III trial of RTS,S trials in the Phase III program were conducted to further assess

(described below) was developed to genotype parasites from the RTS,S in co-administration with other routinely administered vac-

vaccine trial [21]. Approximately 6,000 samples were drawn, rep- cines, to assess its safety and efﬁcacy in HIV-infected infants and

resenting both enrolled age categories, severe disease cases, ﬁrst young children, and to document lot-to-lot consistency of vaccine

clinical episodes, and cross-sectional parasite-positive samples manufacturing [29,30].

collected during study month 20. Parasite variants that infect vac- The pivotal Phase III trial was conducted in two phases: a double-

cinated subjects will be evaluated for known T cell epitope (Th2R, blind phase from Month 0–32 [31–33]; and, an extension phase

Th3R, CS.T3) haplotypes, as well as differences in B cell epitope from Month 33 to study end [34]. The primary aim of the trial was

(NANP) repeat count distributions within the central repeat region to assess the efﬁcacy of a three-dose primary vaccination course of

of CSP. Whether administration of RTS,S is associated with a change RTS,S against clinical malaria over 12 months follow-up in two age

in parasite genetic diversity (within and outside the csp locus) will categories (see above). Secondary aims were to describe the safety

be evaluated by enumerating the parasite genotypes to determine and immunogenicity of RTS,S, to evaluate the efﬁcacy of the vaccine

7428 D.C. Kaslow, S. Biernaux / Vaccine 33 (2015) 7425–7432

candidate against other endpoints of public health importance (4) while administration of a booster dose of RTS,S led to an

(e.g., severe malaria and malaria hospitalization), and to evaluate a increase in anti-circumsporozoite geometric mean titers in both

booster dose of RTS,S received at Month 20 with follow-up through young infants and children, the titers after the booster was lower

a twelve-month period (Month 32). An additional analysis was than concentrations after the primary course and the booster effect

conducted at the end of an extension of the follow-up period, was only transitory; (5) the frequency of SAEs overall was balanced

including an evaluation of safety and efﬁcacy against clinical between groups; however, in the older age category meningitis was

malaria, severe malaria and prevalent parasitemia [34]. reported as an SAE during the entire study period in 11, 10 and one

With respect to the primary aim in the per-protocol popula- child in the four RTS,S dose, three RTS,S dose and control groups,

tion of the pivotal Phase III trial, over the Month 2.5 to Month 14 respectively, while, in contrast, no imbalance in cases of meningi-

follow-up period (i.e., 12 months post-dose 3), in the 5–17 months tis was noted in the younger age category; and, (6) the incidence of

age category, the efﬁcacy of RTS,S calculated by negative binomial generalized convulsive seizures within seven days of RTS,S booster

regression model against ﬁrst or only episode of malaria meet- was observed at a higher rate than controls in both the younger

ing the clinical malaria primary case deﬁnition was 55.8% (with and older age categories (2.2 and 2.5/1000 doses, respectively) [34].

97.5% conﬁdence interval ranging from 50.6% (lower limit) to 60.4% Based on the temporal association and biological plausibility, it was

(upper limit), and p-value <0.0001) [23,31]. Over the Month 2.5 to concluded that there was a reasonable possibility of causal rela-

Month 14 follow-up period, in the 6–12 weeks age category, the tionship between RTS,S and the occurrence of febrile convulsions

efﬁcacy of RTS,S similarly calculated by negative binomial regres- within 7 days post-vaccination [34].

sion model against ﬁrst or only episodes of malaria meeting the A cautionary note: the detailed study analyses contain data from

clinical malaria primary case deﬁnition was 31.3% (with 97.5% con- multiple protocol-speciﬁed and subsequent data analysis plan-

ﬁdence intervals ranging from 23.6% (lower limit) to 38.3% (upper speciﬁed time points, generating hundreds of comparisons and

limit), and p-value <0.0001) [32]. creating the opportunity for unexpected associations to emerge by

With respect to the secondary aims of the pivotal Phase III trial chance. Similarly, the high standard of care provided to all trial par-

prior to a booster (4th) dose of vaccine (Month 20), several results ticipants may have limited the ability of this trial to detect an impact

are worth noting: (1) vaccine efﬁcacy and immunogenicity were on more severe outcomes and mortality. With the former caveat in

lower in young infants than in children [32,33]; (2) vaccine efﬁ- mind and despite a comprehensive analysis, no obvious explana-

cacy waned over time in both age categories (Schoenfeld residuals tion for the meningitis observation has been found, and while a

p < 0.001) [31–33]; (3) despite modest and waning vaccine efﬁcacy, temporal relationship to vaccination is lacking and the biological

the public health impact, reported as the number of cases of clin- plausibility is low, a causal relationship cannot be conﬁrmed or

ical malaria, severe malaria and all cause hospitalizations averted excluded at this point.

per 1000 persons vaccinated [ranging across sites from 37 to 2365, Beyond those highlighted above, additional results of extensive

−1 to 49, and −3 to 131, respectively in the 5–17 month old age analyses of secondary, tertiary and exploratory aims of the trial,

category (ITT), and from −10 to 1402, −13 to 37, and −153 to 145, can be found in the published literature [31–34] and on the open

respectively in the 6–12 week old age category (ITT)] was substan- access GSK clinical study register [23]. With respect to protective

tial, particularly, in the older age category and in the context of immune responses, much is still incompletely understood despite

high disease burden—translated to the population at risk of malaria, numerous recent analyses [36–40]. While antibody levels and to a

cases averted or vaccine preventable disease incidence (VPDI) on lesser extend cell mediated immune responses, have been shown

this scale would have a major public health impact [33,35]; (4) to associate with protection against malaria infection, a deﬁnitive

increased risk for febrile convulsion within 7 days of administer- correlate of protection remains elusive.

ing RTS,S in children over 5 months of age at time of vaccination; Table 1 summarizes on-going clinical trials of RTS,S in support

and (5) meningitis was reported as a serious adverse event and of the pediatric indication. A more comprehensive summary of list

the greater number of cases in the RTS,S group compared with the of trials conducted and results published since 2010 can be found

control vaccine group in the older age category reached statistical in materials reviewed by WHO advisory bodies (see below) in 2013

signiﬁcance [33]. [30].

With respect to the ﬁnal set of results, which included the

efﬁcacy of a 4th dose of RTS,S, and the efﬁcacy, impact, immuno-

genicity, and safety of RTS,S from ﬁrst vaccination to study end (SE) 5. Regulatory, policy, and ﬁnancing pathway

for a median follow-up of 38 months in the younger age category

and 48 months in the older age category, several additional ﬁndings As an initial step in the policy and regulatory process, GSK sub-

are noteworthy: (1) a 4th dose appeared to restore and maintain mitted a regulatory application to EMA in June 2014 [41]. The RTS,S

vaccine efﬁcacy—VE (ITT) from Month 0 to SE was 36.3% (95% CI regulatory application was reviewed under the Article 58 proce-

31.8; 40.5) and 32.2% (95% CI 13.7; 46.9) against all episodes of dure, which allows the EMA to assess the quality, safety and efﬁcacy

clinical malaria and severe malaria, respectively, in the older age of a product intended exclusively for use outside the European

category, and 25.9% (95% CI 19.9; 31.5) and 17.3% (95% CI −9.4; Union (EU) but which is manufactured in a EU member state, to

37.5) against clinical malaria and severe malaria, respectively, in address a disease recognized by the World Health Organization

the younger age category; (2) without a booster, VE (ITT) against (WHO) as of major public health interest [42]. This assessment

clinical malaria continued to wane in both age categories and, in the was done by the EMA in collaboration with the WHO and non-

older age category, severe malaria VE became non-signiﬁcant over EU regulators, and requires products to meet the same standards

the entire study period (VE Month 0–SE = 1.1%, 95% CI −23.0; 20.5) as a vaccine intended for use in the EU. Under the Article 58 pro-

and, in fact, the comparative incidence of severe malaria in the time cedure, the CHMP performed a scientiﬁc evaluation of RTS,S and

period from Month 21 to SE was signiﬁcantly higher [VE Month 21- in July 2015 issued “a European scientiﬁc opinion”, adopting a

SE = −41.0% (95% CI −98.5; −0.8); p = 0.04) than the control group; positive opinion and recommending the granting of a marketing

(3) despite waning efﬁcacy, the number of cases of clinical malaria authorization for active immunization of children aged 6 weeks up

averted continued to accumulate in the older and younger age cat- to 17 months against malaria caused by P. falciparum and against

egories that were administered a 4th dose of RTS,S, reaching an hepatitis B, noting that use should be based on ofﬁcial recommen-

average of 1774 and 980 per 1000 children vaccinated, respectively, dations considering P. falciparum malaria epidemiology in different

with impact greater in sites with higher malaria burden (Fig. 3); geographical areas. It is important to emphasize that a positive

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

Fig. 3. Vaccine efficacy and impact against clinical malaria through study end (Study Month 0-SE). Forest plot of vaccine efficacy with 95% confidence intervals for the group

that received four doses (R3R) of RTS,S and bar graphs of number of cases averted in the three dose (R3C) and four dose (R3R) RTS,S groups by site in the intent-to-treat

population of children age 5–17 months (Panel A) and infants age 6–12 weeks (Panel B) at ﬁrst vaccination, respectively [33].

opinion is not licensure or registration in the EU, but provides a sci- In preparation for such a decision, Gavi included a malaria vaccine

entiﬁc opinion that African national regulatory authorities may use in a recent Vaccine Investment Strategy (VIS) review, an evidence-

in their own regulatory review processes as they consider licensure based prioritization process, undertaken once every ﬁve years, to

and registration in their jurisdictions. identify new vaccines with high priority for inclusion in the Gavi

The positive opinion adopted by CHMP also plays a critical role portfolio [45]. Based on various analyses conducted as part of the

in decision making by WHO normative bodies. The technical group VIS process, including a projection that RTS,S could potentially avert

advising WHO on Phase 3 trials of malaria vaccines is the Joint Tech- approximately 1 million future deaths in Africa over 15 years (Fig. 4)

nical Expert Group (JTEG) on Malaria Vaccines, convened by the [46], and based on meeting certain pre-speciﬁed conditions [45], it

Immunization, Vaccines, and Biologicals Department (IVBD) and is anticipated that the Gavi Secretariat will recommend to the Gavi

the Global Malaria Program (GMP) [43], and reporting jointly to Board the opening of a country support window, albeit highlight-

Strategic Advisory Group of Experts (SAGE) on immunization and ing the importance of coordinating the introduction of a vaccine as

the Malaria Policy Advisory Committee (MPAC) [42,44]. Based on part of integrated malaria control programs and exploring oppor-

the positive opinion adopted by CHMP, JTEG’s evaluation of RTS,S tunities for harmonized global procurement strategies with other

will now be considered jointly by SAGE and MPAC who will advise international ﬁnancing mechanisms (e.g., GFATM) [45].

WHO on recommendation(s) for use, anticipated in the last quar- Given that all clinical trial data from the ﬁeld are from sub-

ter of 2015 [44]. WHO will also consider RTS,S for prequaliﬁcation Saharan Africa and given the scientiﬁc opinion adopted by CHMP,

(PQ), a process “intended to ensure that a speciﬁc vaccine from it is anticipated that any WHO recommendation, public ﬁnancing,

a speciﬁc manufacturer meets international standards of quality, national regulatory authority review and national policy recom-

safety and efﬁcacy and is appropriate for the target population. Only mendations on introduction and use of the vaccine will be restricted

WHO prequaliﬁed vaccines can be supplied to countries through to sub-Saharan Africa, consistent with the ﬁrst landmark goal of the

UN agencies” [43]. MVTRM.

Another critical step after WHO recommendation and PQ will

be decisions by various international ﬁnancing organizations and 6. Post-approval program/Phase IV studies

public–private partnerships, including Gavi—the Vaccine Alliance

(Gavi), and the Global Fund to Fight Aids, Tuberculosis and Malaria Post-approval studies play an important role in the introduction

(GFATM), to open country support windows for public ﬁnancing. and scale-up of vaccines and are critical components of any vaccine

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

Table 1

Ongoing/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 extension

Same study groups as in the primary Long-term efﬁcacy, safety and Tanzania, Kenya, 5–17 months or 3600

study immunogenicity of RTS,S/AS01 over an Burkina Faso 6–12 weeks

•

RTS,S/AS01 (3 doses) + RTS,S/AS01 additional 3-year period.

booster dose • Primary endpoint: incidence of

• RTS,S/AS01 (3 doses) + control vaccine severe malaria.

• Control vaccine (3 doses) + control • Secondary endpoints: clinical

vaccine malaria, parasite prevalence and SAEs

of special interest

Co-administration Ph IIIb study (Measles, yellow fever and rubella vaccines)

•

RTS,S/AS01 at 6, 7.5 and 9m. Yellow Non-inferiority of immune response To be determined 6 months 700

fever and measles-rubella vaccines and safety of the RTS,S/AS01 with or

co-administered at 9 m. without co-administration of measles,

• RTS,S/AS01 at 6, 7.5 and 9 m, Yellow yellow fever and rubella vaccines

fever and measles-rubella vaccines

staggered at 10m.

• Yellow fever and measles-rubella

vaccines at 9m.

All groups receive vitamin A at 6 m

Malaria Transmission Intensity study

6m–4y Annual cross-sectional surveys of P. 6 Sub-Saharan 6 months to 90 6400

5y–19y falciparum parasitemia at peak of African countries; 8 years

20y + transmission in Ph III pivotal efﬁcacy & research centers

safety study catchment areas, during 4

years.

Ph III study on HepB Indication and EPI Integration

• RTS,S/AS01 + CoAd Non-inferiority of Hepatitis B immune Burkina Faso Ghana 8–12 weeks 705

(DTPa/Hib + OPV + rotavirus response.

vaccine) + pneumococcal vaccine Co-administration with 10V S.

staggered (3 groups—3 lots) pneumonia, non-inferiority of immune

• RTS,S/AS01 + CoAd response

(DTPa/Hib + OPV + pneumococcal Co-administration with rotavirus

vaccine) + rotavirus staggered (3 vaccine, non-inferiority of immune

groups—3 lots) response.

•

RTS,S/AS01 + CoAd

(DTPa/Hib + OPV) + rotavirus and

pneumococcal vaccines staggered (3

groups—3 lots)

• HepB + CoAd

(DTPa/Hib + OPV + pneumococcal

vaccine) + rotavirus vaccine staggered

• HepB + CoAd

(DTPa/Hib + OPV + rotavirus

vaccine) + pneumococcal vaccine

staggered

Memory response to the HBs antigen

(booster hepatitis B vaccine given 4

years post primary)

Ph II Schedule optimization study

•

RTS,S/AS01 (≤7d, 10w, 14w) Exploration of various vaccination Malawi ≤7d–14w 480

• RTS,S/AS01 (≤7d, 10w, 26w) schedules around current EPI visits.

• RTS,S/AS01 (6w, 10w, 14w)

• RTS,S/AS01 (6w, 10w, 26w)

• RTS,S/AS01 (6w, 10w, 26w & HepB at

birth)

• RTS,S/AS01 (10w, 14w, 26w)

• RTS,S/AS01 (14w, 26w, 9m)

• HepB at birth (control group)

All groups receive: BCG, OPV at birth

DTPw-HepB/Hib, OPV at 6w, 10w, 14w

Measles vaccine at 9m

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

development program, as they address key questions that cannot in-country, with additional information to assist in deciding on

be readily addressed in Phase III studies. For example, monitoring the use of a new tool in their national vaccine and malaria control

safety and determining effectiveness of vaccines in larger popula- programs.

tions under more “real life” conditions are key data in reﬁning the As it relates to pharmacovigilance and impact, three studies

beneﬁt-risk proﬁle and optimizing the application of new vaccines. are currently envisioned. An epidemiology study (EPI-MAL-002),

In the case of RTS,S, the post-approval program is being developed to “set the baseline” for the incidence of pre-deﬁned diseases

to meet regulatory commitments as part of the EMA Article 58 pro- that may be reported as adverse events following immunization

cedure. It can also be used to provide policy and decision-makers and for malaria morbidity and mortality. This ﬁrst phase will be

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

Fig. 4. Gavi projects that RTS,S could potentially avert around 1 million future deaths in Africa over 15 years (2015–2030) [46]. The point estimate of 1.1 million deaths

averted (y-axis: cumulative deaths averted over a 15 year period) represents the midpoint of the Imperial College and Swiss Tropical Public Health model outputs for a

scenario that includes a booster dose [44].

conducted in several countries, and will follow approximately Sources of support

40,000 children for two years prior to the introduction of RTS,S

in the study communities (this phase will start pre-approval). PATH has received grants from the Bill & Melinda Gates Foun-

This study will be followed by a second phase to be conducted dation to support the clinical development of RTS,S, from the US

after national regulatory approval of RTS,S, such that RTS,S will Agency for International Development to support Decision-Making

be delivered using the immunization system already in place in Framework-related activities, and the ExxonMobil Foundation to

the study area. The vaccination study (EPI-MAL-003) will enroll support research on malaria transmission intensity, health eco-

another approximately 45,000 children to determine the incidence nomics research and modeling, and for the community perceptions

of these same pre-deﬁned diseases after immunization with RTS,S. and VIC projects. All RTS,S studies have been sponsored and

To leverage and further enhance existing infrastructure, these supported by GSK Biologicals SA, the vaccine developer and man-

two studies will be conducted at sites that already monitor the ufacturer.

population in their catchment area through demographic surveys.

A third study (EPI-MAL-005, a malariometric study), concurrent Acknowledgements

to the other two studies, will conduct cross-sectional surveys to

collect data on the use and coverage of other malaria interventions

The authors thank: the thousands of children and their families

and will track changes in disease burden during the period in

and communities, the hundreds of adult trial subjects, and the prin-

which EPI-MAL-002 and EPI-MAL-003 are conducted.

cipal investigators, team members and healthcare workers at each

In addition to these pharmacovigilance/malaria impact stud-

of the trial sites who have participated in the clinical development

ies (baseline and vaccination phases) and concurrent malaria

of RTS,S; the global, national and local organizations and govern-

transmission intensity studies, the RTS,S post-approval program

ment authorities for their input, guidance and support; and the

includes research in health economics and the piloting of com-

hundreds of product R&D professionals who have worked tirelessly

munications materials to support possible introduction. Additional

over decades on the development of RTS,S as a malaria vaccine

studies will be contemplated if deemed needed and feasible.

candidate. The author further thanks the Clinical Trial Partnership

Committee (CTPC) and MVI-GSK partnership for their critical con-

tributions to the late stage development of RTS,S. The authors also

7. Conclusion

thank our colleagues at GSK and PATH MVI for critical review of

this manuscript.

RTS,S, a candidate malaria vaccine, has now been success-

fully evaluated in a Phase III program conducted in eight African

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