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Curr Opin Immunol. Author manuscript; available in PMC 2016 August 01.
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Published in final edited form as:

Curr Opin Immunol. 2015 August ; 35: 98–106. doi:10.1016/[Link].2015.06.008.

Malaria vaccine clinical trials: what’s on the horizon

Alberto Moreno1,2,3 and Chester Joyner1,2
1EmoryVaccine Center, Yerkes National Primate Research Center, Emory University, 954
Gatewood Road, Atlanta, GA 30329, USA
2MalariaHost-Pathogen Interaction Center, Emory University, 954 Gatewood Road, Atlanta, GA
30329, USA
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3Divisionof Infectious Diseases, Department of Medicine, Emory University, 69 Jesse Hill, Jr.
Drive, SE, Atlanta, GA 30303, USA

Abstract
Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been
made in the past few years with the completion of numerous clinical trials. Each trial has utilized a
unique combination of antigens, delivery platforms, and adjuvants, and the data that has been
obtained provides critical information that has poises the research community for the development
of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P.
vivax vaccine research requires more momentum and additional investigations to identify novel
vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials
as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for
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future research using post-genomic mining, nonhuman primate models, and systems biology are
also discussed.

Introduction
Malaria is the most predominant parasitic infection and continues to have a significant
global impact on the health and well-being of hundreds of millions of people annually. In
spite of the enormous progress made with reduction in mortality rates in the past 4 years,
nearly half of the global population, approximately 3.3 billion people, remains at risk of
malaria. About 197 million clinical cases led to 584,000 deaths globally in 2013 [1].
Progress in malaria control interventions, including the use of insecticide-treated nets
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(ITNs), indoor residual spraying (IRS), chemoprevention and case management, and the
growth in funding for malaria control, have resulted in the reduction of transmission
intensities and cases. However, recent reports on the development of parasite resistance to
front-line malaria drugs such as artemisinins with the threat and spreading of emerging

Corresponding author: Alberto Moreno. Emory Vaccine Center, Yerkes National Primate Research Center, Emory University. 954
Gatewood Road. Atlanta, GA 30329. Fax: (404) 727-8199. Phone: (404) 727-8611. [Link]@[Link].
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
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 Moreno and Joyner Page 2

multidrug resistant parasites may result in the reversion of this positive trend. Only a
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combination of malaria prevention tools, diagnostics, chemotherapy and effective vaccines

can ensure continued reduction in cases and fatalities and possibly lead to eradication.

Five species of Plasmodium infect humans: P. falciparum, P. vivax, P. malariae, P. ovale

and P. knowlesi. Plasmodium falciparum and P. vivax are the most prevalent and represent a
significant global health threat. Plasmodium falciparum causes the highest mortality rates
worldwide, but P. vivax has a wider geographical distribution due to its ability to infect
Anopheles mosquitoes at lower temperatures. Plasmodium knowlesi is a simian malaria
parasite that primarily infects humans residing or working in and near forested areas of
South-East Asia, where infected macaques reside. This infection is thought to be a zoonosis
because human P. knowlesi cases have been associated with low density gametocytemia [2].
Low numbers of gametocytes is not advantageous to the parasite because it is less likely to
be transmitted to the vector, supporting the thought that human-to-human transmission does
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not occur. However, more research is needed to determine if these infections are solely
zoonotic or if human-to-human transmission can and does occur. Finally, P. malariae and P.
ovale are human malaria parasites that cause mild forms of the disease and typically are
observed in coinfections with P. falciparum and/or P. vivax. Nonetheless, vaccines and
better diagnostics for these two species will also be needed for eradication efforts as well.

One of the primary challenges of developing an efficacious malaria vaccine is the parasite’s
complex life-cycle (Figure 1). Sporozoites, the infectious form of the parasite, are injected
into the skin of a susceptible host and then migrate to the liver via the circulation. In the
liver, sporozoites invade a host hepatocyte and undergo development and multiplication.
Most Plasmodium species undergo a single phase of pre-erythrocytic development, but a
distinguished feature of P. vivax and P. ovale infections is the development of a dormant
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form in the liver known as hypnozoites [3]. The activation of hypnozoites weeks or months
after a primary infection is responsible for repeat infections known as relapses. After
development in the liver, the parasites are released into the bloodstream where they invade
and multiply within host erythrocytes. After multiplication, daughter parasites are released,
and this cycle continues until some parasites develop into gametocytes, which are ingested
by the vector during a blood meal. Within the Anopheles mosquito, the male and female
gametocytes fuse to form a zygote that undergoes morphological and developmental
changes that result in sporozoites that migrate to the mosquito salivary glands. Each of these
steps (i.e. pre-erythrocytic, erythrocytic, and sexual development) are potential targets for
vaccines aimed to disrupt the life-cycle, thus, preventing transmission, infection, and/or
illness (see below; Figure 1). A multi-stage vaccine targeting two or more of these phases is
likely needed to achieve malaria eradication and sterile protection.
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Vaccine development efforts have been primarily focused on P. falciparum. Changes in

malaria epidemiology with increased reports of severe malaria cases due to P. vivax
infection have been critical factors guiding the malaria research community to establish new
research goals for vaccine development. These goals have been published by the World
Health Organization (WHO) in the context of the Malaria Vaccine Technology Roadmap
[4], which establishes the vision of developing safe and effective vaccines against both P.
falciparum and P. vivax.

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Recent clinical trials of Plasmodium falciparum vaccines

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Pre-erythrocytic vaccines
RTS,S, the most advanced malaria vaccine candidate, has reached phase 3 testing in the
clinical trial development pipeline. This vaccine is based on antigenic components of a P.
falciparum sporozoite surface protein known as the circumsporozoite protein (CSP). The
recombinant vaccine antigen includes the repeat region (R) and the complete carboxyl
terminal region of the CSP protein, which contains several T cell epitopes (T), fused to the
hepatitis B surface antigen (S). To improve the cellular reactivity, the protein is formulated
in AS01, an oil-in-water emulsion that incorporates a mixture of MPL (mycobacterial cell
wall skeleton) and QS21 (saponin derivative from the soap bark tree Quillaja saponaria)
[5]. The double-blind, phase 3 trial has been conducted at eleven sites in seven countries
across Africa. In total, the trial included 6,537 infants aged 6–12 weeks and 8,923 children
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aged 5–17 months who received the protein-in-adjuvant RTS,S/AS01 formulation or a

control vaccine (meningococcal C vaccine for infants or rabies vaccine for children).
Protection against clinical malaria was observed in 46% of children and 27% of infants up to
18 months after vaccination [6]. The vaccine efficacy against severe malaria in children was
34% with no evidence of protection in infants. Interestingly, vaccine efficacy was dependent
upon the study site, and higher efficacy was observed in areas with lower incidence of
malaria. This finding suggests that vaccine-mediated immunity wanes with time. Therefore,
the vaccine’s utility in places of high transmission is limited without vector control
programs such as ITNs and IRS. Despite these factors, the vaccine has been submitted for
regulatory approval by the European Medicine Agency. To improve RTS,S efficacy,
alternative vaccination regimens and adjuvants are being explored. Currently, booster doses
of the vaccine using a different adjuvant system, namely AS01E (clinical trial registration
number (CTRN): NCT02207816), are currently being tested in addition to heterologous
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prime-boost immunization regimens with recombinant adenovirus (Ad) vectors (CTRN:

NCT01366534, Table 1).

Adenovirus vectors have been explored as an alternative to potentiate T cell responses of

malaria vaccine candidates. These vectors when used in heterologous prime-boost
immunization regimens have the combined advantage of skewing the immune response
toward a Th1 profile while also inducing antibody responses and robust CD8 T cells [7]. A
heterologous prime-boost immunization using a mixture of DNA plasmid vaccines encoding
P. falciparum CSP and the P. falciparum apical membrane antigen-1 (AMA-1) for priming
and a mixture of recombinant Ad5 vectors for boosting immunization showed 27%
protective efficacy [8]. However, a subsequent trial including a mixture of the recombinant
Ad5 vectors in a single inoculation failed to induce protective efficacy [9]. Differences in
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protection between these regimens were not linked to the overall magnitude of the cellular
immune response but to the relative magnitudes of memory T cell populations, specifically
increasing CD8 effector memory relative to the CD8 central memory T cell response [10].

The high frequency of preexisting immunity to Ad5 in humans is a major concern for using
recombinant Ad vectors for vaccine development. To address this biological constraint, rare
human serotypes or nonhuman (i.e. bovine, canine, ovine, or simian) adenovirus vectors are

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employed. A codon-optimized vaccine candidate based on the P. falciparum CSP has been
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expressed in a replication-deficient Ad35, a rare human serotype, [11] and tested in phase 1
clinical trials. A dose-escalation study to assess the safety and immunogenicity of three
doses of the vectored vaccine has been reported [12]. The immunization regimens tested
induce poor antibody responses with only a four-fold rise from baseline for the highest dose
tested (1011 virus particles/milliliter). Severe systemic reactogenicity was also reported for
volunteers who received higher doses. A dose-escalation trial in semi-immune adults in
Burkina Faso resulted in poor antibody responses and moderate induction of IFN-γ and
TNF-α secreting CD8 T cells, which are thought to be key correlates of vaccine efficacy
[13]. These trials support the need for additional research in effective prime-boost
immunization regimens able to induce balanced humoral and cellular immune responses by
these vectors.

Multiple epitope-thrombospondin-related adhesion protein (ME-TRAP) is another malaria

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vaccine candidate that has been genetically incorporated into chimpanzee replication
deficient Ad vectors (ChAd63) as well as another common viral vector, the attenuated
modified vaccinia virus Ankara (MVA) [14]. This vaccine construct contains a series of B
and T cell epitope-encoding sequences from multiple P. falciparum liver-stage antigens
genetically linked to trap sequences. This vaccine has induced unprecedented T cell
responses in humans using a heterologous prime-boost immunization regimen [15]. A phase
2a efficacy study using controlled human malaria infections (CHMI) with sporozoites
resulted in sterile protection in three out of 14 volunteers (21%) and delays in patency in
five more (36%) [16]. A recent comparative efficacy trial using the same vectors to deliver
CSP and ME-TRAP demonstrated sterile protection in 13% of the vaccinees immunized
with ME-TRAP with a delay in patency in 33%, in contrast with 7% and 20% reported for
volunteers immunized with CSP [17]. These findings offer hope that RTS,S can be
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improved, and clinical trials are underway to test efficacy of the combination of these
vaccines in a single regimen as well as the use of the ME-TRAP vectored vaccines in co-
administration regimens with RTS,S (CTRN: NCT02252640).

The cell-traversal protein for ookinetes and sporozoites (CelTOS) is the first vaccine target
identified using postgenomic tools, including data mining and differential transcriptome
profiling [18]. A codon-optimized protein for expression in E. coli based on the P.
falciparum sequence induced cross-protection using the rodent malaria model P. berghei
[18]. These results demonstrate promise for such approaches in aiding the identification of
potential malaria vaccine candidates in the future. Currently, a protein-in-adjuvant CelTOS
(FMP012)/AS01B formulation is undergoing testing in clinical trials (CTRN:
NCT02174978).
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The limited efficacy of subunit vaccines reported in clinical trials has provided rationale to
revisit the concept of whole organism approaches for pre-erythrocytic malaria vaccine
development. Three different approaches have been recently developed: radiation attenuated
sporozoites, genetically-attenuated parasites, and sporozoite inoculation under chloroquine
prophylaxis (CPS).

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Clinical trials with radiation-attenuated sporozoites indicated that intradermal or

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subcutaneous routes of immunization were not effective [19]. However when administered
intravenously, 100% protection (six out of six volunteers) was reported using different doses
with the highest being 1.35 × 105 P. falciparum irradiated sporozoites delivered five times
[19]. Although the route and the immunization regimen are impractical for implementation
in endemic areas, several clinical trials in non-immune and semi-immune populations are in
progress [20]. Similarly, genetically-attenuated, live P. falciparum are under investigation
and offer similar prospects in terms of efficacy [21]. A chief obstacle other than dosing
regimens is the major facilities and manpower needed to generate substantial amounts of
genetically-attenuated parasites for mass-administration, regardless of the attenuation
method. Currently, this seems impractical, but through the development of robotics or other
engineering methods to dissect mosquitoes, this challenge may be overcome and result in
the feasibility of this approach, as long as dosing regimens and administration routes can be
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optimized.

Dose-response efficacy has been reported using CPS with complete protection in over 80%
of volunteers exposed to 30–45 P. falciparum infected mosquitoes [22]. High antibody
responses against several pre-erythrocytic and erythrocytic antigens were elicited using this
vaccination approach [23]. However, antibody responses induced by this immunization
strategy were not predictive of protection. Interestingly, this result suggests that immune
responses against less immunodominant antigens are important for protection [23] and
supports the search for novel antigens that are not necessarily immunodominant. This
contrasts with traditional paradigms in vaccinology [24]; however, this approach may be
critical for the realization of a malaria vaccine that induces sterile immunity.

Erythrocytic vaccines
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The P. falciparum erythrocytic-stage merozoite surface protein 1 (MSP-1) and the P.

falciparum AMA-1 (expressed in merozoites and sporozoites) have also been delivered
using ChAd63 and the orthopoxvirus MVA [25]. Protective efficacy against CHMI was
tested in volunteers immunized with individual vectored vaccines, a mixture of vectored
vaccines or MSP-1 vectored vaccines combined with the pre-erythrocytic vectored ME-
TRAP vaccine. Although the vaccines induced robust cellular responses, as expected from
such strategies, and moderate IgG responses, no statistically significant efficacy was
observed. Unexpectedly, co-administration was associated with immune interference
between the two antigens that resulted in reduced antibody and cellular immune responses.
A subsequent phase 1 trial, designed to test the combination of priming with the
recombinant ChAd63 and boosting with the recombinant MVA and protein-in-adjuvant
AMA-1 [26], showed that regimens that include protein-in-adjuvant AMA-1 induced higher
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antibody responses in comparison to the regimen that only used vectored vaccines. These
findings suggest that combined sub-unit and viral-vectored vaccines may be able to induce
the appropriate responses needed for protection and provide critical evidence for exploring
this strategy in the future.

Recombinant AMA-1 expressed in E. coli (FMP2.1) has also been tested in phase 2 clinical
trials using a formulation with AS02A [27]. The study population included 400 Malian

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children aged 1–6 years at the time of enrollment; enrolled individuals received the protein-
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in-adjuvant FMP2.1/AS02A formulation or a control rabies vaccine. Although allelic-

specific efficacy against malaria caused by the homologous parasite was reported during the
first 240 days of follow-up, no efficacy was observed during the follow-up period of 730
days [28]. This lack of efficacy is likely due to the high antigenic diversity of P. falciparum
AMA-1, which is a common feature of Plasmodium proteins that are modulated by host
immune selection pressure. Diverse antigens, such as AMA-1, create a moving target for the
immune system and are another obstacle in malaria vaccine development. To address the
diversity of AMA-1, P. falciparum AMA-1 multivalent vaccines that involve more than a
single allele have been explored using a combination of recombinant [29] and chimeric
proteins that include naturally occurring variants optimized to cover polymorphism [30].
This Diversity Covering (DiCo) vaccine candidate is currently being tested in clinical trials
(CTRN: NCT02014727). Such approaches have the advantage of increasing the breadth of
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antibody responses by redirecting the response toward conserved domains of the protein,
which may increase efficacy [31].

A chimeric protein, known as GMZ2, resulting of the fusion of the P. falciparum

erythrocytic-stage antigens glutamate-rich protein (GLURP) fused to the merozoite surface
protein 3 (MSP-3) has been produced in Lactococcus lactis and is currently in phase 2b of
clinical development. The two components of the vaccine have been previously tested in
phase 1 trials as long synthetic peptides, using Montanide ISA720 or Alum as adjuvants.
Immunization resulted in the induction of cytophilic antibodies with the ability to inhibit
parasite growth in vitro [32,33], and functional antibodies, as determined by antibody-
dependent cellular inhibition assays [34], can be elicited in malaria-naïve adults and malaria-
exposed preschool children after immunization. In contrast to AMA-1, IgG elicited by
GMZ2 immunization had similar inhibitory activity against three geographically and
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genetically diverse P. falciparum isolates; thus, this fusion protein may be able to transcend
the obstacles associated with the complex diversity of Plasmodium antigens.

Transmission blocking vaccines

Transmission-blocking vaccines target pre-fertilization antigens, which are expressed by
gametocytes, or post-fertilization antigens, which are expressed by zygotes/ookinetes
(Figure 1). The vaccines work by preventing infection of the vector and are thought to be
critical for malaria eradication. The P. falciparum Pfs25 post-fertilization antigen is critical
for parasite recognition and attachment to the mosquito midgut, and monoclonal and
polyclonal antibodies directed against Pfs25 block the parasite from infecting the mosquito
[35]. However, these recombinant vaccine constructs are poorly immunogenic. To improve
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the immunogenicity of Pfs25, a clinical-grade conjugated vaccine has been recently

produced that consists of a recombinant Pfs25 protein expressed in Pichia pastoris
conjugated to ExoProtein A (EPA), a detoxified form of exotoxin A from Pseudomonas
aeruginosa produced in E. coli [36]. A phase 1a clinical trial is currently underway in Mali
to test Pfs25-EPA and a pre-fertilization antigen Pfs230-EPA (CTRN: NCT02334462).
Vaccines targeting gametocytes and stages of the parasite within the mosquito are relatively
new but may aid in stopping transmission, which is the only way that eradication will ever
be realized.

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Plasmodium vivax preclinical and clinical vaccine trials

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Even though P. vivax is widespread and has the added disease burden of a hypnozoite
reservoir in the liver, only two P. vivax vaccine candidates are currently in advanced stages
of clinical trial testing (phase 1 or 2). This contrasts with the twelve P. falciparum vaccine
trials registered at [Link] that are currently in a recruiting phase.
Nevertheless, some vaccine development progress remains ongoing against vivax malaria. A
recombinant protein called P. vivax malaria protein 001 (VMP001) that incorporates the
complete amino and carboxyl terminal regions of the native CSP protein and a truncated
repeat region that contains sequences representing the two allelic forms of CSP has been
expressed in Escherichia coli and tested in preclinical trials. The chimeric protein is
immunogenic in mice and rhesus macaques [37,38] and, protein-in-adjuvant VMP001/
Montanide 720 and CpG 10104 formulation induced protective immunity in Aotus
nancymaae monkeys [39]. These animals had 66.7% sterilizing immunity when
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experimentally challenged with P. vivax sporozoites, and the protective efficacy correlated
with anti-repeat antibodies [39]. Phase 1 and 2 clinical trials have been completed for this
vaccine candidate using a protein-in-adjuvant/AS01B formulation, but the results are not yet
available (CTRN: NCT01157897). Another vivax vaccine candidate is based on the
interaction of the parasite’s Duffy binding protein (DBP) and the Duffy antigen/chemokine
receptor (DARC), a critical step in the invasion of red blood cells by P. vivax [40]. A viral
vectored vaccine based on P. vivax DBP using ChAd63 and MVA is currently in clinical
trials (CTRN: NCT01816113).

New Candidates on the Horizon

P. falciparum infected erythrocytes are sequestered in the post-capillary vasculature by a
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mechanism of cytoadherence mediated by adhesive domains expressed by proteins of a

family known as P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1). Sequestration is
directly linked to cerebral malaria, respiratory distress and placental malaria (Reviewed in
[41,42]). Studies in areas of intense transmission have indicated that the natural acquisition
of PfEMP1 variant-specific antibodies is protective against severe malaria and
complications associated with malaria during pregnancy [43,44]. Primigravidas are highly
susceptible to clinical complication during pregnancy in contrast with multigravidas that
exhibit resistance. The adhesion, responsible for compartmentalization of infected
erythrocytes in the placenta, is mediated by the expression of the PfEMP1 variant
VAR2CSA [42], and this protein has become the focus of a placental malaria vaccine [45].
A consortium of laboratories established a Pregnancy Malaria Initiative to study specific
binding domains of VAR2CSA in-depth using a variety of expression systems [46], and a
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vaccine candidate based on VAR2CSA has been advancing to clinical testing with support
from the European Vaccine Initiative.

The P. falciparum reticulocyte-binding protein homolog 5 (PfRh5) has attracted attention as

a vaccine candidate over the past few years. This protein is expressed by merozoites, is
secreted from the apical organelles during erythrocyte invasion [47] and binds basigin [48].
In contrast with other antigens involved in invasion, PfRh5 exhibits limited genetic
diversity. Relevantly, affinity-purified naturally acquired anti-PfRh5 human antibodies

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inhibit parasite growth in vitro and are associated with reduced risk of malaria [49]. A
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preclinical trial in Aotus nancymaae monkeys [50] designed to test the protein’s
immunogenicity and efficacy using protein-in-adjuvant formulations and viral vectored
(ChAd63 and MVA) formulations has been recently reported. However, the best reported
outcome was obtained with the protein-in-adjuvant formulation using Freund’s adjuvant,
which is not suitable for human vaccination. Protective efficacy in this model was correlated
with the induction of functional antibodies active in growth inhibition assays. Clinical trials
are expected to begin in 2016 [50].

The path forward

This year will be critical for determining if a malaria vaccine candidate, which has received
30 years of research efforts, will be licensed. Although the efficacy and durability of the pre-
erythrocytic RTS,S vaccine are far from optimal, the information gathered in the course of
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several clinical trials has paved the way for the development of a second generation of
effective malaria vaccines and has provided continued support for the development of novel
subunit vaccines against Plasmodium.

Nonetheless, more research and development is needed for materializing an efficacious

malaria vaccine using modern technologies. Postgenomic tools have already begun to
demonstrate their power to accelerate and enhance malaria vaccine development through the
identification and current clinical testing of the subunit vaccine PfCelTOS (see above). The
high-throughput technologies that were used to identify this antigen are constantly evolving
and continue to offer immense potential for vaccine development. Proteomics, lipidomics,
functional genomics, metabolomics and immune profiling give us the unprecedented
opportunity to identify novel malaria vaccine candidates, and advance the world towards
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accomplishing the ambitious goal set-forth by the Malaria Vaccine technology roadmap for
developing P. falciparum and P. vivax vaccines by 2030 with at least 75% efficacy [4].
Furthermore, the use of these tools is also critical to identify vaccine-induced correlates of
protection against malaria similarly to what has been done for other vaccines to accelerate
vaccine development and clinical testing [51,52].

Systems biology approaches using high-throughput technologies are also needed to identify
vaccine candidates for P. vivax. Vaccine development for [Link] has lagged behind P.
falciparum due to biological constraints (e.g. the lack of a long-term, in vitro culture system)
faced when studying this parasite’s biology [53,54]. The identification and characterization
of P. vivax antigens for all stages of the life-cycle are needed, but the necessity to further our
knowledge of hypnozoite biology is at the forefront. Understanding hypnozoite biology is
critical to elucidate the underlying mechanism(s) involved in relapse infections and is
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needed to develop correlates of protection against these forms. These correlates of protection
will be essential for assessing the efficacy of [Link] vaccine candidates [55]. Non-human
primate models will be critical for obtaining these goals as recently discussed in Joyner et al.
[56].

The complexity of the Plasmodium life cycle and the mechanisms involved in protection
against malaria continue to be major obstacles for vaccine development. In contrast to other

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pathogens, such as HIV and Mycobacterium tuberculosis, malaria vaccine efficacy can be
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tested using CHMIs. Although several centers have the technical expertise and logistics in
place to run these trials [57–60], anti-malaria chemotherapy is required as soon as parasite
are detected in the blood. Thus, CHMIs are unsuitable to characterize the dynamics of the
infection, which is needed to understand immune responses resulting in the control and
elimination of the parasite and associated disease. Although simian malaria parasites and
NHP models have been extensively used in malaria research, their value to characterize the
mechanisms involved in malaria pathogenesis and protection has been underestimated.

The impact of genome-based antigen discovery on vaccine development has been recently
reviewed by Proietti & Doolan [61]. Such endeavors require major resource investment, but
are necessary to capitalize on the extreme benefits of current technologies and move towards
systems biology approaches for discovery. The Malaria Host-Pathogen Interaction Center
(MaHPIC, [Link] is an example of a multi-institutional
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consortium uniquely created to use systems biology approaches to investigate and compare
malaria in both humans and non-human primates [62,63]. This consortium is generating
unprecedented ‘omics and immune-profiling datasets, for eventual online distribution to the
research community, using systems biology tools and several non-human primate - parasite
infection combinations as models of malaria. High-throughput technologies are being
utilized to capture diverse datasets during the course of infection using simian and human
malaria parasite species, and close clinical follow-up involves multiple hematological and
parasitological parameters. The integration of the data generated from such infections is
supporting systems biology-based antigen and biochemical pathway discovery pipelines,
which are essential for the continued search for effective vaccines and new
chemotherapeutic agents.
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Acknowledgments
The authors acknowledge funding in part by Federal funds from the US National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Department of Health and Human Services under grant # R56AI103382 and
contract HHSN272201200031C, and support in part by the Office of Research Infrastructure Programs /OD
P51OD011132 (formerly National Center for Research Resources P51RR000165). We thank Dr. Mary Galinski for
critical reading of the manuscript. We would also like to thank members of the MaHPIC consortium for their
insights towards the use of systems biological approaches for malaria vaccine discovery and development.

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Highlights
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Progress towards a P. falciparum malaria vaccine continues with the completion of

several trials.

Plasmodium vivax vaccine development needs to be prioritized and pursued.

NHP models and definition of correlates of protection are critical foundations for
new vaccines.

Systems biology and post-genomic data mining are essential for the new generation
of vaccines.
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 Moreno and Joyner Page 16
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Figure 1. Malaria Vaccine candidates in clinical trials

Each major stage of the Plasmodium life cycle is color-coded, and current vaccines targeting
that stage correspond with the colors of the life-cycle. The schematic representation does not
include the liver-stage dormant forms known as hypnozoites produced during the pre-
erythrocytic stage of P. vivax and P. ovale infections. Pf, Plasmodium falciparum vaccine
candidates; Pv, Plasmodium vivax vaccine candidates.
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 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 1

Malaria vaccine clinical trials pipeline

Antigen Vaccine platform References

P. falciparum CSP (RTS,S) VLP-in-adjuvant [5,6]

P. falciparum CSP + P. falciparum AMA-1 DNA/Ad5 prime-boost regimen [8,9]

Moreno and Joyner

P. falciparum CSP Ad35 vectored [12,13]

P. falciparum ME-TRAP ChAd63/MVA prime-boost regimen [14–17]

P. falciparum ME-TRAP + RTS,S ChAd63/MVA vectored + VLP-in-adjuvant coadministration NCT02252640*

P. falciparum CelTOS Protein-in-adjuvant NCT02174978*

P. falciparum radiation-attenuated sporozoites Whole organism [19,20]

P. falciparum genetically-attenuated sporozoites Whole organism [21]

P. falciparum sporozoite inoculation under prophylaxis Whole organism [22,23]

P. falciparum MSP-1/P. falciparum AMA-1 ChAd63/MVA prime-boost regimens [25,26]

P. falciparum AMA-1 (FMP2.1) Protein-in-adjuvant [27,28]

P. falciparum AMA-1 (DiCo) Protein-in-adjuvant NCT02014727*

P. falciparum hybrid GLURP+MSP-3 (GMZ2) Protein-in-adjuvant [34]

P. falciparum Pfs25-EPA Conjugated vaccine NCT02334462*

P. falciparum Pfs230-EPA Conjugated vaccine NCT02334462*

P. vivax CSP (VMP001) Protein-in-adjuvant NCT01157897*

P. vivax DBP ChAd63/MVA prime-boost regimen NCT01816113*

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Clinical Trial Registration Number
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