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Contents lists available at ScienceDirect
Vaccine
j ournal homepage: www.elsevier.com/locate/vaccine
1 Progress with Plasmodium falciparum sporozoite (PfSPZ)-based
Q1 a,∗ a a b
3 Thomas L. Richie , Peter F. Billingsley , B. Kim Lee Sim , Judith E. Epstein ,
c d e f
4 Kirsten E. Lyke , Benjamin Mordmüller , Pedro Alonso , Patrick E. Duffy ,
g h i j
5 Ogobara K. Doumbo , Robert W. Sauerwein , Marcel Tanner , Salim Abdulla ,
d k a
6 Peter G. Kremsner , Robert A. Seder , Stephen L. Hoffman
a
7 Sanaria Inc., Rockville, MD, United States
b
8 Naval Medical Research Center, Silver Spring, MD, United States
c
9 Center for Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, United States
d
10 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
e
11 World Health Organization Global Malaria Program, Geneva, Switzerland
f
12 Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD, United States
g
13 Malaria Research and Training Center, University of Bamako, Bamako, Mali
h
14 Radboud University Medical Center, Nijmegen, The Netherlands
i
15 Swiss Tropical and Public Health Institute, Basel, Switzerland
j
16 Ifakara Health Institute, Bagamoyo, United Republic of Tanzania
k
17 Vaccine Research Center, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, United States
18
3119 a r t i c l e i n f o a b s t r a c t
20
21 Article history: Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falcip-
22 Available online xxx
arum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based
23 vaccine that provides high grade, durable protection against infection with Pf malaria. Several candidate
24 Keywords:
vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by
irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant adminis-
26 Plasmodium falciparum
tration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout.
27 Sporozoite
Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-
28 PfSPZ vaccine
C), are collaborating to advance this program by providing intellectual, clinical, and financial support.
29 PfSPZ-CVac
Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are
30 PfSPZ challenge
underway and at least 12 more are planned for 2015–2016 in the US (four trials), Germany (2 trials), Tan-
zania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license
a first generation product in late 2017, initially to protect adults, and in 2018 to protect all persons >6
months of age for at least six months. Improved vaccine candidates will be advanced as needed until
the following requirements have been met: long-term protection against natural transmission, excellent
safety and tolerability, and operational feasibility for population-wide administration. Here we describe
the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licen-
sure and deployment, and long-term objectives for a final product suitable for mass administration to
achieve regional malaria elimination and eventual global eradication.
© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
32 1. Background the SPZ during their journey from the mosquito proboscis to the 36
Q3 liver or during development in the liver (pre-erythrocytic stages 37
33 The Plasmodium sporozoite (SPZ), transmitted to the human host of the parasite life cycle), there would be no blood stage infection 38
34 by female Anopheles mosquitoes, is an attractive vaccine candi- and no production of gametocytes. This would address an urgent 39
35 date. If immune responses induced by such a vaccine could kill public health priority, namely protecting people in endemic areas 40
from clinical malaria, especially those susceptible to severe dis- 41
ease such as infants and young children. A pre-erythrocytic stage 42
∗ vaccine would also benefit travelers, obviating the difficulties of 43
Q2 Corresponding author. Tel.: +1 301 770 3222; fax: +1 301 770 5554.
http://dx.doi.org/10.1016/j.vaccine.2015.09.096
0264-410X/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.
0/).
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.09.096
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44 prophylactic drug compliance and side effects. Ultimately, a highly
45 effective pre-erythrocytic stage vaccine, serving as a vaccine to Box 1: Targeting the SPZ.
Whole SPZ were one of the first malaria immunogens tested
46 interrupt malaria transmission (VIMT), would be the ideal tool to
as a malaria vaccine, described by Sergent and Sergent in a
47 eliminate malaria and contain spread of malaria parasites from
report published in 1910 by the Academy of Sciences, Paris,
48 defined geographic regions, leading to global eradication [1].
on the avian parasite Plasmodium relictum [2]. In the early
1940s, Mulligan, Russell and Mohan at the Pasteur Institute
in Coonoor, India partially protected fowl against another bird
49 1.1. Targeting the sporozoite
parasite, P. gallinaceum, by administering five intravenous
injections of a crude preparation of dried, ground thoraces
50Q4 Several approaches have been taken to induce protective immu-
from infected mosquitoes (220 thoraces per fowl) [3,4]. Vacci-
51 nity against SPZ. Forty years ago injection of attenuated whole
nated animals and controls were challenged by the bites of two
52 SPZ was shown to protect rodents against malaria infection, fol-
infected Aëdes albopictus mosquitoes, and while all immu-
53 lowed quickly by proof-of-concept that the same approach works
nized fowl developed asexual blood stage infections (thus
54
in humans (Box 1). However, the SPZ had to be administered to protection against infection was nil), prior SPZ vaccination
55 humans by mosquito bite, limiting feasibility as a vaccine approach. halved the parasite density in the blood, and reduced mortal-
56 The alternative, producing large numbers of infected mosquitoes, ity from 55% to 30% or less. Similar results were obtained with
57 harvesting the SPZ, and purifying them from contaminating sali- SPZ dissected from salivary glands and inactivated by a 30-min
exposure to ultraviolet light. The partial protection by killed
58 vary gland antigens, also appeared to be difficult if not impossible,
SPZ in the avian model was confirmed in subsequent stud-
59 especially as the purified sporozoites would have to be aseptic for
ies [5]. It was shown that protected fowl were still susceptible
60 injection. All in all, immunization with whole sporozoites was felt
to blood stage challenge, indicating that the partially effective
61 to be “too crude and impractical to produce a vaccine for wide
immune response induced by whole killed SPZ vaccination
62 application” [27].
targeted the pre-erythrocytic stages.
A significant improvement in protection was reported by
Nussenzweig and colleagues in 1967 by using attenuated,
63 1.2. Whole sporozoites for parenteral injection
rather than killed SPZ, this time in a rodent model. X-irradiation
was used to damage P. berghei SPZ dissected from infected
64 Sanaria Inc., a biotechnology company in Rockville, Maryland,
Anopheles stephensi mosquitoes [6]. SPZ receiving this sub-
65 spent the last 10 years addressing the challenges of production,
lethal irradiation remained metabolically active and motile,
66
purification and cryopreservation, and now routinely manufactures could invade hepatocytes and round up (a morphological
67 vials of highly purified, aseptic P. falciparum (Pf) SPZ that are in com- change signifying the earliest stage of development in the
68 pliance with regulatory standards for purity, potency, safety and hepatocyte), but could not develop into hepatic trophozoites
or schizonts. When mice immunized by IV administration
69 consistency [28]. 2082 doses of PfSPZ (doses as high as 2.2 million
of 75,000 SPZ irradiated with 80–100 gray (Gy) were chal-
70 PfSPZ) have now been administered to 789 adults by the intrader-
lenged by IV injection of non-irradiated SPZ two weeks after
71 mal (ID), subcutaneous (SC), intramuscular (IM), intravenous (IV) or
immunization, infection rates were 37% compared to 90% in
72 direct venous inoculation (DVI) routes, and have shown excellent
controls, indicating that more than half were sterilely immune.
73 safety and tolerability. In blinded, randomized, placebo-controlled
Those animals becoming infected despite vaccination showed
74 trials, the PfSPZ have caused no detectable systemic reactogenicity
delays in the prepatent period. Eleven protected mice were
75 (Sissoko et al., unpublished; Mordmüller et al., unpublished) [29]
re-challenged at 36 days, and most were again protected, indi-
76 and no allergic responses, indicating that PfSPZ may be suitable for cating a degree of durability and also ruling out non-specific
77 mass administration campaigns for malaria elimination. protection mediated by the innate immune system. The murine
78 Because Plasmodium is a eukaryotic organism, the PfSPZ need model thus established that attenuated, metabolically active
parasites could induce antigen-specific, sterile immunity to
79 to be cryopreserved and stored in liquid nitrogen vapor phase
malaria.
80 (LNVP) to maintain viability, like other cellular therapies or prod-
The radiation-attenuated SPZ approach was rapidly translated
81 ucts (mammalian sperm, eggs, embryos, cellular cancer vaccines),
to humans in a series of studies in the early 1970s carried
82 as well as eleven veterinary vaccines including the Theileria parva
out by Clyde and colleagues [7–11], and Rieckmann and col-
83 vaccine used in Africa. Indeed, LNVP storage may prove to be advan-
leagues [12–14] and to non-human primates [15]. A review of
84 tageous, enhancing delivery to remote areas since no electricity is
these studies and subsequent work by the US military [16]
85
needed to maintain the cold chain (compared to refrigerated vac- and the University of Maryland [17,18] by Hoffman et al. [19]
86 cines), and the vaccine can remain stable for weeks to months in concluded that administration of more than 1000 bites from
87 a free-standing container. LN is widely available across Africa and irradiated, infected mosquitoes consistently protected >90%
(13/14) of recipients undergoing CHMI by mosquito bite within
88 other tropical areas, with infrastructure in place to support veteri-
10 weeks of immunization, and 5/6 volunteers were still pro-
89 nary vaccine applications, artificial insemination of cattle, oil and
tected on repeat CHMI up to 42 weeks later. Furthermore, 4
90 mining applications, and the brewing industry. Distribution of the
subjects underwent CHMI with 7 heterologous strains of Pf,
91 vaccine in LNVP is feasible in malaria endemic countries using a
and there was 100% protection. 15 Gy was established as a
92 hub and spoke model, and projected costs are roughly equivalent
sufficiently attenuating radiation dose to prevent blood stage
93 to those required for adding a new vaccine to current distribution
infection without over-irradiating the parasites.
◦
94 networks for refrigerated (2–8 C) vaccines [30].
This work provided proof-of-concept for high-grade protection
95 PfSPZ, the core Sanaria product, are manufactured in accordance against parasitemia in humans by targeting the SPZ (and/or the
96 with Title 21 of the Code of Federal Regulations (21 CFR) and in early liver stage parasites they become), and inspired efforts
97 accordance with International Conference on Harmonization (ICH) to develop pre-erythrocytic stage malaria vaccines. It was rea-
soned that if the antigenic components of whole SPZ could
98 guidelines. Manufacturing of PfSPZ products is performed follow-
be identified and suitably formulated as vaccines, it should
99 ing current Good Manufacturing Practice (cGMP) guidelines where
be possible for subunits to reproduce the high-grade protec-
100 processes are defined and controlled to ensure consistency and
tion induced by whole SPZ. The identification and cloning
101 compliance with specifications. PfSPZ products have excellent sta-
in 1983/1984 of the major surface protein of the P. knowlesi
102 bility profiles when stored for more than 4 years. Sanaria maintains
and P. falciparum (Pf) SPZ, the circumsporozoite protein (CSP)
103 Biologics Master Files with the US FDA, and all clinical trials are
[20,21], galvanized this effort, and led to the clinical testing of
104 conducted with US FDA oversight under investigational new drug
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
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a series of recombinant constructs [22,23], the most successful the highest total dose (Table 1) demonstrated that the PfSPZ were 149
being RTS,S, a recombinant protein containing a portion of potent and provided the critical proof-of principle that the model 150
PfCSP fused to hepatitis B surface antigen, produced in yeast,
of protection by mosquito bite with radiation-attenuated SPZ (Box 151
assembled into virus-like particles, and formulated in adjuvant.
1) could indeed be translated into a human injectable product. 152
RTS,S has been extensively tested in Africa, and the results of
There was a clear dose-threshold effect, with the three lower doses 153
a large Phase 3 trial recently reported [24]. In addition to RTS,S,
showing limited, but dose-related protection, and the highest dose 154
several other subunit approaches using pre-erythrocytic stage
conferring high-grade sterile immunity (Table 1). There was a dose 155
antigens are being pursued, including gene-based approaches;
response for antibody and cellular immune responses, and antibody 156
some, like RTS,S, have sterilely protected volunteers against
157
CHMI [25,26]. While these subunit approaches are promising, responses to PfSPZ were associated with protection. The most sig-
they present the immune system with only a small number of nificant association was with antibodies to PfSPZ measured by the 158
pre-erythrocytic immunogens, and have provided only modest inhibition of invasion into hepatocytes (ISI) assay [36]. 159
protection. With the development by Sanaria of technologies
for the manufacture and administration of whole SPZ, many
2.2. PfSPZ challenge 160
in the malaria vaccine development field have begun to direct
their efforts back toward this more empiric whole organism
®
161
approach (see Box 2). Sanaria PfSPZ challenge is manufactured identically to PfSPZ
Vaccine except that the PfSPZ are not irradiated, and are therefore 162
fully infectious. CHMI with injectable PfSPZ can replace traditional 163
CHMI by the bite of mosquitoes to measure vaccine and drug 164
105 applications (IND), and with appropriate host nation regulatory
efficacy, as well as to increase understanding of factors (genetic, 165
106 oversight.
immune) that affect Pf infectivity. The optimal dose and route 166
for administering PfSPZ Challenge were worked out in a series of 167
107 2. Products
eight clinical trials conducted from 2010 to 2014, with the first five 168
testing ID and IM routes. These were conducted at Radboud Uni- 169
108 Sanaria’s first PfSPZ products are based on the NF54 strain of
versity Medical Center (RUMC), Nijmegen, the Netherlands [37], 170
109 Pf, isolated in 1981 from a Dutch farmer living near Amsterdam’s
the University of Oxford, Oxford, UK [38], the Ifakara Health Insti- 171
110 Schiphol airport and originating in Africa [31,32]. Pf NF54 strain
tute (IHI), Bagamoyo, Tanzania [29], UMB CVD (Lyke et al., in 172
111 is chloroquine sensitive. More recently, Sanaria has manufactured
press, AJTMH), and the Kenya Medical Research Institute (KEMRI), Q5 173
112 PfSPZ derived from a clone of a Brazilian isolate, 7G8 [33], as well
Nairobi, Kenya [39,40]. The aim of all these studies was to admin- 174
113 as PfSPZ from a Cambodian clone, NF135.C10 [34].
ister a dose of PfSPZ Challenge that reproduced the infectivity 175
114 Controlled human malaria infection (CHMI) and exposure to
and prepatent period of five PfSPZ-infected mosquitoes, namely 176
115 natural transmission have been used to test the efficacy of Sanaria’s
100% of volunteers infected and a prepatent period by thick smear 177
116 vaccine products. CHMI has been performed by mosquito bite, using
microscopy of <12 days. ID administration has achieved 100% infec- 178
117 mosquitoes infected with NF54, 3D7 (a clone of NF54) or 7G8, or
tion rates, but not the target prepatent period. IM administration of 179
118 by the direct injection of infectious PfSPZ (NF54) manufactured 4
7.5 × 10 PfSPZ achieved both attributes [41]. IV inoculation using 180
119 by Sanaria. When NF54 or 3D7 are used, the CHMI is considered
an in-dwelling intravenous catheter was first tested at the Uni- 181
120 homologous, since the parasite is identical or highly similar to the
versity of Tübingen, Germany, and achieved 100% infection rate 182
121 vaccine. When other strains are used to assess efficacy, the CHMI is 3
after administering only 3.2 × 10 PfSPZ [42]. The geometric mean 183
122 considered heterologous, and a potentially better predictor of effi-
(GM) prepatent period was 11.2 days (range 10.5–12.5 days). These 184
123 cacy under conditions of natural transmission, where mosquitoes
results were then reproduced at the Barcelona Centre for Interna- 185
124 harbor highly diverse strains of Pf. 3
tional Health (CRESIB), Spain [41,42], establishing 3.2 × 10 PfSPZ 186
of PfSPZ Challenge as the new gold standard for “mosquito-free” 187
125 2.1. PfSPZ vaccine
CHMI. In Barcelona the PfSPZ were administered by DVI, insert- 188
ing the 25 g needle of a tuberculin syringe directly into a vein 189
126 The first PfSPZ product developed using Sanaria’s manufactur-
® and rapidly injecting the PfSPZ in a volume of 0.5 mL (Fig. 1). This 190
127 ing technology was Sanaria PfSPZ Vaccine, which is composed of
standard dose and DVI administration were used by the Lambaréné 191
128 aseptic, purified, live (metabolically active), radiation attenuated,
129 cryopreserved PfSPZ. Several clinical trials of PfSPZ Vaccine have
130 been completed in the USA. In the first trial, conducted by the
131 Naval Medical Research Center (NMRC), the University of Mary-
132 land, Baltimore Center for Vaccine Development (UMB CVD), and
133 the Walter Reed Army Institute of Research (WRAIR), the vaccine
134 was administered ID or SC, was poorly immunogenic and protected
135 at best only 2 of 16 volunteers at one dosage against CHMI [35]. A
136 concurrent study in non-human primates (NHP) at the NIH Vac-
137 cine Research Center (VRC) administered the vaccine SC, as in the
138 clinical trial, and by direct venous inoculation (DVI), as done in
139 the original rodent experiments (Box 1). DVI induced far supe-
140 rior immune responses: 3.2% of CD8+ T cells in the livers of the
141 three NHPs immunized by DVI responded with IFN␥ production to
142 PfSPZ stimulation, compared with low to undetectable frequencies
143 in SC-immunized monkeys [35]. This finding provided the proof
144 of concept for the second trial, conducted at the VRC, where the Fig. 1. Direct venous inoculation (DVI) of PfSPZ [42]. Once the injection is prepped
with an antiseptic such as 70% isopropyl alcohol, needle insertion, loosening the
145 vaccine was given IV through an in-dwelling catheter. This trial
tourniquet and vaccine injection taken only about 10–15 s. Note the small size of
146 escalated through five increasing doses of the vaccine, adminis-
the needle (25 gauge) and syringe (1 mL), and blood flashback confirming successful
147 tering four to six injections to the volunteers over the course of
puncture of, in this case, the median cubital or cephalic vein. Veins in the back of
148 20–26 weeks. Sterile protection in 6/6 (100%) subjects receiving the hand or side of the wrist may also be used. Photo by B. Mordmüller.
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Table 1
Summary of protective efficacy and antibody responses in volunteers immunized in the VRC 312 clinical trial with PfSPZ vaccine [36].
a
Dosage regimen Anti-PfCSP Antibodies (OD 1.0) Number of volunteers Protective efficacy
5 5
Dose (PfSPZ × 10 ) Number of doses Maximum total dose (PfSPZ × 10 ) Challenged Protected
0.075 4 or 6 0.45 13 6 0 0%
0.3 4 or 6 1.8 324 11 1 9%
b
1.35 4 5.4 3454 9 6 60%
1.35 5 6.75 6716 6 6 100%
a
Anti-PfCSP antibody level 2 weeks after the last dose and before CHMI by ELISA (geometric mean of the inverse of the serum dilution at which the optical density (OD)
was 1.0).
b
5/6 controls developed parasitemia.
192 Centre for Medical Research in Gabon to study the effect of natu- route was by far the most efficient for infecting volunteers. Thus 243
193 rally acquired immunity and sickle cell trait on the growth rate of for each objective – inducing protective immunity with PfSPZ Vac- 244
194 Pf in vivo (Lell et al., unpublished). These studies were performed cine or the PfSPZ-CVac approach, or inducing infection with PfPSZ 245
195 using different PfSPZ Challenge lots, some of which were manu- Challenge – there was a multi-fold difference in potency between 246
196 factured years apart. In summary, these studies of PfSPZ Challenge the IV/DVI routes of administration and the more traditional ID, SC 247
197 demonstrated that the purified, cryopreserved PfSPZ produced by and/or IM routes. 248
198 Sanaria were potent (infectious) and highly stable, and that IV or
199 DVI routes were the most efficient means of administration.
2.4. Comparative potency of PfSPZ vaccine and PfSPZ-CVac 249
200 Having established a standard route and dose, injections of
3
201 3.2 × 10 PfSPZ of PfSPZ Challenge, administered by DVI, have now
Our cumulative experience using PfSPZ Vaccine shows that it 250
202 been used successfully in seven CHMIs in Tanzania and Germany
requires several hundred thousand PfSPZ to induce high-grade 251
203 to test the efficacy of PfSPZ Vaccine and PfSPZ-CVac respectively,
protection, while the same or better can be achieved using the 252
204 infecting all control volunteers (n = 43) (Mordmüller et al., unpub-
PfSPZ-CVac approach using a fraction of the dose. This parallels ear- 253
205 lished; Shekalaghe et al., unpublished). CHMI by PfSPZ Challenge
lier experience using mosquito bite immunization: with CPS, it took 254
206 reduces costs and streamlines the logistics compared with CHMI
exposure to ∼45 PfSPZ-infected mosquitoes to achieve durable, 255
207 by mosquito bite. It also allows repeated CHMIs and adaptive clin-
high level protective efficacy. In contrast, it required exposure to 256
208 ical trial designs, since the timing of CHMI is independent of the
the bites of at least 1000 mosquitoes carrying radiation-attenuated 257
209 complex process needed to produce a batch of infected mosquitoes.
PfSPZ to consistently achieve high-level protection (Box 1). The 258
210 Since each inoculation is identical, PfSPZ Challenge also standard-
likely reason for this is that radiation-attenuated PfSPZ invade 259
211 izes the dose of infectious PfSPZ, which cannot be done with CHMI
hepatocytes and begin the process of development, and although 260
212 by mosquito bite.
they express ∼1000 proteins their replication arrests early in liver 261
stage development. In contrast, the infectious PfSPZ in PfSPZ-CVac 262
invade hepatocytes, but then replicate 10,000–40,000-fold and 263
213 2.3. PfSPZ-CVac
express ∼4500 different proteins, including blood stage proteins. 264
Thus there are dramatically more parasites and antigens presented 265
214 In a seminal study of chemoprophylaxis with SPZ (CPS)
to the immune system per PfSPZ injected with PfSPZ-CVac than 266
215 conducted at RUMC in Nijmegen [43], 3 × 12–15 bites from
with PfSPZ Vaccine. 267
216 non-irradiated Anopheles stephensi mosquitoes harboring PfSPZ
217 administered to malaria-naïve adults concurrently taking chloro-
2.5. PfSPZ-GA1 268
218 quine resulted in 100% sterile protection against CHMI (10/10
219 volunteers protected). The protection persisted for at least 28
®
Sanaria PfSPZ-GA1 consists of purified, aseptic, cryopreserved 269
220 months in the majority of volunteers undergoing a second
Pf sporozoites (NF54 strain) genetically attenuated by removal of 270
221 CHMI, with 4/6 sterilely protected and 2/6 showing prolonged
the b9 and slarp genes to halt development in the early liver stages 271
222 prepatent periods [44]. The Sanaria team and collaborators rea-
[46,47]. The parasite line was generated by the Leiden University 272
223 soned that PfSPZ Challenge should be able to substitute for the
Medical Center (LUMC) and RUMC in collaboration with Sanaria. 273
224 mosquito bites, and accordingly, PfSPZ Challenge was tested as the
®
Pf b9 slarp parasites invade hepatocytes but are incapable of sus- 274
225 immunogen in a CPS vaccine approach called Sanaria PfSPZ-CVac
taining liver stage development, similar to radiation-attenuated 275
226 (CVac = Chemoprophylaxis Vaccine).
PfSPZ. The potential advantages of PfSPZ-GA1 are that (1) the PfSPZ 276
227 The first PfSPZ-CVac trial was conducted at RUMC; PfSPZ Chal-
are homogenous and have a precisely characterized genetic basis 277
228 lenge was administered ID with chloroquine as the drug partner.
for attenuation; (2) manufacturing PfSPZ-GA1 cannot result in acci- 278
229 Disappointingly, but in hindsight not unexpectedly, three or four ID
dental exposure of staff to clinical malaria, thereby simplifying 279
230 administrations of 75,000 PfSPZ induced minimal immunogenicity
the approach to safety of operators and lowering costs. PfSPZ-GA1 280
231 and little or no protection [45]. Once the superiority of the IV route
also has the potential to induce more efficient protection than the 281
232 was demonstrated for PfSPZ Vaccine in the VRC314 trial, however,
radiation-attenuated PfSPZ Vaccine due to a different pattern of 282
233 there was justification for a second trial of PfSPZ-CVac, which was
developmental arrest and antigen expression. 283
234 conducted at the University of Tübingen. PfSPZ were administered
235 by DVI rather than ID, chloroquine was retained as the partner drug,
236 and this time the outcome was dramatically reversed [Mordmüller 2.6. Safety and tolerability 284
237 et al., unpublished]. The transformation from low- to high-grade
238 immunogenicity and efficacy mirrored the similar transformation 2082 doses of cryopreserved PfSPZ from Sanaria products have 285
239 for PfSPZ Vaccine when the route of administration was changed been administered to 789 adult volunteers in 17 clinical trials via 286
240 from ID or SC to IV. The finding that IV or DVI administration was a variety of routes (Richie et al., unpublished). Several of these 287
241 needed to reveal the potency of PfSPZ for immunizing volunteers trials included randomized, double-blind allocation to PfSPZ or 288
242 parallels experience with PfSPZ Challenge for which the IV or DVI normal saline (NS) placebo, and data are available from three 289
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
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290 such trials, involving 97 PfSPZ recipients and 68 placebo recipi- by repeated malaria infections. The specific results from these trials 352
291 ents in total. The two groups were compared in each trial after will be published by the investigators. 353
292 unblinding the adverse event data; there were no differences in Stage 2 of the clinical development plan, launching in mid-2015, 354
293 adverse event profiles between volunteers receiving PfSPZ and will address the following objectives: 355
294 placebo during the first seven days after injection [29] (Sissoko
295 et al., unpublished; Mordmüller et al., unpublished). Moreover,
(1) Demonstrate high-grade sterile protection in malaria-naïve 356
296 there have been no allergic reactions to PfSPZ, nor any serious
adults, including durable (≥6 month) protection against het- 357
297 adverse events attributed to PfSPZ. Experience includes 30 IV injec-
5 6 erologous CHMI following a simplified (e.g., three dose) 358
298 tions of 9 × 10 PfSPZ and 36 IM injections of 2.2 × 10 PfSPZ (Lyke
regimen. These studies will finalize the regimen for licensure 359
299 et al., unpublished). The absence of clinically significant side effects
to protect travelers, including military personnel, during stays 360
300 linked to PfSPZ administration applies also to laboratory abnormal-
in malarious areas. 361
301 ities, including liver function tests.
(2) Demonstrate high-grade sterile protection in malaria-exposed 362
302 DVI is rapid and efficient (Fig. 1). If the veins in the arm are
African adults, including durable (6 month) protection against 363
303 suitable for obtaining blood via standard venipuncture, they are
naturally transmitted malaria following a similarly simplified 364
304 suitable for administration of PfSPZ by DVI. The procedure involves
regimen. These studies are aimed at defining a regimen that 365
305 the insertion of a 25 g needle into the vein, a slight withdrawal
can be used in malaria elimination campaigns to halt infection 366
306 on the plunger to demonstrate blood “flashback,” loosening of the
and transmission. 367
307 restricting band and immediate injection of 0.5 mL of diluted PfSPZ
(3) Evaluate the tolerability, immunogenicity and efficacy of trun- 368
308 (or placebo), typically taking less than 10 s. More than half (in some
cated regimens: 0, 1, and 4 weeks; 0 and 1 week; 0, 2, 4 and 369
309 trials >90%) of subjects have rated the injections as painless on a
6 days or even a single immunization. These studies aim to 370
310 four-point scale (painless, mild pain, moderate pain, severe pain).
improve the operational feasibility of using the vaccine for all 371
311 DVI may cause slight bruising at the injection site if there is extrava-
indications. 372
312 sation of blood from the vein, but there are no persistent local signs
(4) Demonstrate safety, immunogenicity and protection in African 373
313 or symptoms such as tenderness, erythema or induration, since
infants 5 months or older and in young children. These stud- 374
314 the vaccine is dispersed on injection. ID and SC injections are also
ies aim to protect the most vulnerable age group from malaria 375
315 well tolerated, indicating that if any inoculum is deposited into the
and will optimize dose of vaccine with respect to age and body 376
316 surrounding tissues during DVI, it does not affect tolerability. The
weight. We hypothesize that because African infants have had 377
317 vaccine contains no adjuvant or pro-inflammatory material.
5 limited exposure to malaria, vaccinations will result in better 378
318 The demonstrated safety of PfSPZ at doses up to 9 × 10 PfSPZ by
protective responses than for African adults thereby providing 379
319 DVI has enabled plans for further dose escalation, in order to max-
an effective vaccine for the most vulnerable populations. 380
320 imize the degree and duration of sterile immunity, and this will be
(5) Demonstrate safety in the elderly and in HIV-infected individ- 381
321 conducted for both PfSPZ Vaccine and PfSPZ-CVac. An interesting
uals. These studies aim to show that screening for diminished 382
322 aspect of the latter approach when using chloroquine as the anti-
health or immunodeficiency will not be required when 383
323 malarial is that 5.5–7 days after injection merozoites are released
conducting mass administration campaigns. Since radiation- 384
324 into the blood and are detectable by qPCR, providing a transient
attenuated parasites cannot replicate, they should prove safe 385
325 low-grade parasite density that is rapidly cleared by chloroquine.
in all individuals, including the immunocompromised. 386
326 The kinetics of transient parasitemia allows an estimate of the
(6) Evaluate efficacy against P. vivax by CHMI and natural trans- 387
327 number of infected hepatocytes, which can be used to correlate
mission. Pv and Pf share tens of thousands of minimal T cell 388
328 immunogen dose (number of sporozoites infecting hepatocytes)
epitopes, and PfSPZ may induce cross-protective cell mediated 389
329 with protective efficacy.
immunity [48,49]. 390
(7) Establish immunological correlates of infection; all immune 391
responses measured in these trials will be assessed as potential 392
330 3. Clinical development plan
correlates. 393
(8) Continue with operational research in preparation for phase 394
331 3.1. PfSPZ vaccine
3 clinical trials and elimination campaigns with the licensed 395
vaccine. 396
332 Springboarding off the two completed trials of PfSPZ Vaccine
333 [35,36], particularly following the high-grade protection in VRC 312
334 and ongoing studies, there are five trials completed or underway of There are eight funded trials that will address these objectives 397
335 this product that constitute “Stage 1” of the PfSPZ Vaccine clinical in the USA, Germany (2 trials), Tanzania, Mali, Burkina Faso, Kenya 398
336 development plan (CDP) (Fig. 2). Each of these trials was initiated by and Equatorial Guinea (Table 2), plus one additional trial of a new 399
337 the primary performing institutions (Table 2), which also provided strain of PfSPZ Challenge. A program for studying PfSPZ Vaccine in 400
338 funding and developed protocols in close partnership with Sanaria. pregnancy is in the planning stages. 401
339 Preliminary analysis of the data has shown that these studies have Stage 3 of the CDP will include expanded safety testing and large 402
340 reproduced the high-grade efficacy seen in VRC 312, demonstrated scale CHMI trials in malaria-naïve adults using one or more het- 403
341 that PfSPZ Vaccine induces heterologous and durable (6 month) erologous parasites for CHMI, and will also include large-scale field 404
342 protection against CHMI and against naturally transmitted malaria, efficacy trials in malaria endemic areas including all age groups 405
343 and that a three-dose regimen can be highly protective. We have older than six months. These studies are planned for 2016–18. 406
344 also learned that malaria-naïve individuals in the U.S. respond The studies in malaria-naïve adults will support the targeted sub- 407
345 better to the vaccine than malaria-exposed individuals in Africa mission of a biologics license application (BLA) late in 2017 for a 408
346 after receiving an identical dose and regimen, exhibiting multifold traveler’s vaccine, and the studies in endemic areas will support an 409
347 higher titers of antibodies to PfCSP by ELISA. This indicates that additional indication for use in endemic areas subsequently. Opera- 410
348 increased doses of PfSPZ, and potentially interval changes between tionally we intend to initially target infants, age 6–12 months, to 411
349 doses, will be required to achieve high-level immunogenicity and reduce morbidity and mortality, and mass administration projects 412
350 sterile protection in malaria-exposed individuals. This difference intended to achieve halting of transmission and elimination of 413
351 in responsiveness may result from the immune modulation caused malaria will follow. 414
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.09.096
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Fig. 2. Clinical development plan for PfSPZ vaccine. Current activities fall into Stage 2.
415 3.2. PfSPZ-CVac regimen of the partner drug. Development is being prioritized 418
and accelerated because of PfSPZ-CVac’s increased potency com- 419
416 The CDP for PfSPZ-CVac parallels that of PfSPZ Vaccine with pared to PfSPZ Vaccine. One clinical trial is ongoing (TÜCHMI-002 420
417 the added necessity of optimizing the administration, dose and trial at the University of Tübingen), and four additional trials are 421
Table 2
Summary of Stage 1 and Stage 2 PfSPZ Vaccine Clinical Trials. The performing institutions are core members of the expanding International PfSPZ Consortium (see Table 4).
Stage 1
Country Protocol name Primary performing institutions ClinTrials.gov Identifier
USA VRC 314 NIAID Vaccine Research Center (VRC), UMB CVD NCT02015091
Mali 14-I-N010 Malaria Research & Training Center (MRTC), University of Bamako NCT01988636
NIAID Laboratory for Malaria Immunology and Vaccinology (LMIV)
Tanzania BSPZV01 Ifakara Health Institute (IHI) NCT02132299
Swiss Tropical and Public Health Institute (Swiss TPH)
USA WRAIR 2080 NMRC NCT02215707
WRAIR
Equatorial Guinea EGSPZV1 Equatorial Guinea Ministry of Health and Social Welfare (MOHSW) NCT02418962 IHI
Swiss TPH
Medical Care Development International (MCDI)
La Paz Hospital, Malabo, EG
Stage 2
Country Primary performing institutions Objectives Challenge method
Germany University of Tübingen Condensed regimens in adults CHMI – PfSPZ
Challenge
Comparison with PfSPZ-CVac CHMI – PfSPZ
Challenge
Tanzania IHI Age de-escalation to infants CHMI – PfSPZ Challenge
Swiss TPH
Mali MRTC Dose escalation and efficacy in adults CHMI – PfSPZ
Challenge + Natural exposure
LMIV
Burkina Faso CNRFP Dose escalation and efficacy in adults Natural exposure
UMB CVD
USA NMRC Finalized regimen for adult travelers CHMI – Mosquito bite UMB-CVD
WRAIR
Equatorial Guinea Equatorial Guinea MOHSW Efficacy in adults CHMI – PfSPZ
Challenge
IHI Age escalation
Swiss TPH Safety in HIV positive subjects
MCDI
Kenya KEMRI Safety and efficacy in infants Natural exposure
US Centers for Disease Control (CDC)
NIAID VRC
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
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Table 3
Summary of current and planned PfSPZ-CVac clinical trials.
Country Primary performing institutions Objectives Challenge method
Germany University of Tübingen Condensed regimens CHMI – PfSPZ Challenge
(ClinicalTrials.gov NCT02115516) Alternative drug partner
USA LMIV Alternative partner drug CHMI – PfSPZ Challenge
NIAID Division of Microbiology and Infectious Disease (DMID) Dose escalation Condensed regimen CHMI – PfSPZ Challenge
Seattle Group Health, Seattle BioMed
Ghana Kintampo Health Research Centre US Navy Dose escalation CHMI – PfSPZ Challenge
Indonesia Eijkman Institute Field efficacy Natural exposure
Indonesian Military Pv cross-protection
Table 4
Box 2, Table 1 Members of the International PfSPZ Consortium. Partners and funding organizations are listed by country and do not necessarily match.
Location Collaborative and funding partners Funding organizations
USA NMRC, DoD Military Infectious Disease Research Program (MIDRP)
WRAIR, DoD US Navy Advanced Medical Development Program
a
VRC, NIAID, NIH USAMMDA
a
LMIV, NIAID, NIH DMID, NIAID, NIH
University of Maryland Baltimore, CVD PATH MVI (BMGF)
Centers for Disease Control Marathon Oil Corporation
Medical Care Development International Noble Energy
AMPCO
Institute for OneWorld Health (BMGF)
Europe European Vaccine Initiative
a
Switzerland Swiss TPH Swiss State Secretariat for Education, Research and Innovation
a
Germany University of Tübingen German Centre for Infection Research
The Netherlands Radboud University Medical Center (RUMC), Top Institute Pharma
Leiden University Medical Center
a
Spain ISGlobal, Barcelona Centre for International Health Research (CRESIB) CRESIB, Spanish Government
a,b
UK Jenner Institute, Oxford University The Wellcome Trust
Africa
Tanzania Ifakara Health Institute (IHI) Tanzania Commission on Science and Technology (COSTECH)
Equatorial Guinea Ministry of Health and Social Welfare Government of Equatorial Guinea
Equatorial Guinea LNG
Kenya Kenya Medical Research Institute
Wellcome Trust Laboratories
Centre for Research in Therapeutic Sciences (CREATES)
Gabon Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital
Mozambique Manhica Center
Ghana Kintampo Health Research Center Ghana Ministry of Health
Mali University of Bamako (MRTC)
Burkina Faso Centre National de Recherche et de Formation sur le Paludisme (CNRFP)
Asia
Indonesia Eijkman-Oxford Clinical Research Unit (EOCRU), Jakarta
a
Invested institutional funds in clinical trials of PfSPZ-based products.
b
Only involved with PfSPZ Challenge.
422 planned for 2015–2016 (Table 3). These include trials of condensed immediately after release of parasites into the blood is also being 442
423 regimens (as few as 3 doses in 10 days) and alternative drug part- actively pursued, as such parasites will mimic PfSPZ-CVac without 443
424 ners (atovaquone/proguanil). Close attention is being paid to safety the need for administering anti-malarial drugs. 444
425 considerations, since the PfSPZ-CVac approach includes injecting
426 healthy individuals with a human pathogen, notwithstanding the 3.4. International SPZ consortium 445
427 fact that PfSPZ Challenge (NF54) is highly sensitive to chloroquine
428 and other antimalarials. Any regimen will require ingestion and A key aspect of the CDPs for PfSPZ Vaccine, PfSPZ-CVac and 446
429 retention of a protective drug before the PfSPZ are administered. PfSPZ-GA1 are their reliance on an informed and proactive consor- 447
430 This will be done under direct observation. The challenge during tium of research and funding institutions that together constitute 448
431 development is to demonstrate that vaccination with PfSPZ-CVac the International PfSPZ Consortium (I-PfSPZ-C) (Table 4). Mem- 449
432 is as safe as any other approach to vaccination. PfSPZ-CVac may bers meet periodically to share and critique data, and to discuss 450
433 be most appropriate for use in elimination campaigns in endemic plans. The most recent meeting was held 11–12 March 2015, in 451
434 areas, where the population is already exposed to natural malaria Tübingen (Box 2). The enthusiasm and aggressive research strate- 452
435 transmission. gies of the I-PfSPZ-C have propelled innovative approaches and 453
greatly accelerated the development and testing of PfSPZ-based 454
436 3.3. PfSPZ-GA1 products. Sanaria acts as sponsor for nearly all the trials, which 455
are conducted under US FDA oversight, as well as the oversight 456
437 Clinical lots of PfSPZ-GA1 have been manufactured. A proposal of regulatory authorities in the countries outside the US where 457
438 for the first trial has been submitted for funding. The first step will the trials are conducted. Sanaria also serves as lead organizer for 458
439 be to establish adequate attenuation and to compare protective the I-PfSPZ-C and as a repository for information. Of particular 459
440 efficacy with PfSPZ Vaccine. A vaccine based on genetically atten- importance is the dissemination of clinical data among sites, to 460
441 uated Pf designed to arrest development late in the liver stage or provide alerts in case of adverse events, and to inform all partners 461
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
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underlying protection. Moreover, the whole organism approach 501
Box 2: The International PfSPZ Consortium. mirrors that of many other live, attenuated vaccine products, nearly 502
The International PfSPZ Consortium (I-PfSPZ-C) has evolved
all of which are highly protective. 503
to integrate the planning and governance of development
The fact remains, however, that there are no vaccines licensed 504
among the organizations collaborating to take PfSPZ Vaccine
to protect humans against parasites, which are far more complex 505
and PfSPZ-CVac through to licensure. The I-PfSPZ-C has an
than viral or bacterial pathogens. It is therefore to be expected that 506
inclusive structure in which all individuals, groups, institutions
numerous innovations have been required, and these have included 507
and funding organizations involved in studies with Sanaria’s
novel manufacturing process steps for the production of highly 508
PfSPZ-based products participate in the planning of trials, and
509
reviewing data on safety, immunogenicity and protective effi- PfSPZ-infected, aseptic mosquitoes, harvesting infected glands, and
cacy of PfSPZ vaccines. They also contribute to the efforts to purifying and cryopreserving the PfSPZ. On the clinical side, it has 510
raise funds to support the program. The I-PfSPZ-C has met been necessary to develop new immunization regimens, and to 511
two to three times per year since November 2011, including
develop DVI as a method for efficient PfSPZ administration. Fur- 512
sessions organized in association with the annual meeting
ther process refinements are anticipated in the coming years after 513
of the American Society of Tropical Medicine and Hygiene.
licensure of the first generation PfSPZ vaccine(s), and these include 514
The most recent meeting was at the University of Tübingen,
robotic extraction of PfSPZ from mosquitoes and in vitro develop- 515
Germany, in March 2015. The meeting was attended by 81
ment of PfSPZ from sexual stage parasites. Although the worldwide 516
individuals from 35 different institutions based in 14 different
need for a malaria vaccine can be met using current methods for 517
countries in the USA, Europe and Africa. In addition to clin-
manufacture, such innovations will simplify scale-up and reduce 518
ical investigators, participants included representatives from
African governments, policy agencies, regulatory authorities the cost of goods. 519
and funding agencies. The rapid progress achieved by the I-PfSPZ-C would not have 520
been possible without the open-minded and creative approaches 521
adopted by Sanaria and collaborators. Members of the I-PfSPZ- 522
C have provided leadership in key developments including DVI 523
462 regarding outcomes, which may impact the design and manage-
administration, condensed immunization regimens, and novel 524
463 ment of other trials. In the case of the meeting in Tübingen, results
vaccine concepts such as PfSPZ-CVac. Remarkably, our clinical 525
464 of five clinical trials were reported to members long before publi-
experience has demonstrated excellent safety and tolerability, 526
465 cation in a scientific journal.
regardless of route of administration. This allows for the testing 527
of higher doses, which appear needed to achieve our objectives in 528
466 3.5. Malaria elimination campaigns
those with prior malaria exposure. As new technologies for man- 529
ufacturing, formulation, cryopreservation and administration are 530
467 A remarkable aspect of the PfSPZ development story has been
developed, and as indicated by the results of ongoing clinical test- 531
468 the financial support by African partner countries, first Tanzania,
ing, optimized vaccine candidates and immunization regimens will 532
469 then Equatorial Guinea and, most recently, Ghana; this is an impor-
be advanced under appropriate regulatory guidance. The long-term 533
470 tant milestone in malaria vaccine development. A striking example
goal is durable, cross-strain, sterile immunity in >90% of vaccine 534
471 is occurring in Equatorial Guinea, which will support four trials
recipients with the fewest numbers of PfSPZ in the fewest num- 535
472 of PfSPZ Vaccine and associated operational research in Equato-
bers of doses in the shortest period of time. The target product 536
473 rial Guinea and Tanzania to optimize vaccine administration for
must also demonstrate operational, safety and tolerability char- 537
474 later use in malaria elimination campaigns. The Equatorial Guinea
acteristics suitable for use in mass administration campaigns. The 538
475 Government, Marathon Oil Corporation, Noble Energy, AMPCO,
I-PfSPZ-C is working toward these long-term objectives, aiming for 539
476 Medical Care Development International (MCDI) and Sanaria have
a PfSPZ vaccine to be the cornerstone for malaria elimination and 540
477 partnered to conduct a malaria elimination campaign after a PfSPZ-
eradication. 541
478 based vaccine is licensed for this indication. The collaboration in
479 Equatorial Guinea involves not only Equatorial Guinea Ministry of
480 Health and Social Welfare and Sanaria investigators, but also a team
Acknowledgements 542
481 from the Ifakara Health Institute in Bagamoyo, Tanzania, and collab-
482 orators from the Swiss Tropical and Public Health Institute, Medical
We warmly thank the many institutions, investigators and 543
483 Care Development International (MCDI), and La Paz Medical Cen-
their teams who were or are involved in the conduct of com- 544
484 tre. The first phase of the demonstration will target elimination
pleted, ongoing and planned trials of PfSPZ products, for their 545
485 of malaria from Bioko Island. The population of >250,000 endure
collaboration and, in many cases, financial support (listed by insti- 546
486 ongoing malaria transmission and significant malaria-related mor-
tution in alphabetical order): Armed Forces Research Institute of 547
487 bidity and mortality despite a well-funded and executed malaria
Medical Sciences, Bangkok, Thailand: Ratawan Ubalee; Center for 548
488 control program [50]. Plans for this campaign will be developed
Malaria Research, Institute for Global Health, University of Mary- 549
489 during the coming years, anticipating launch of the campaign
land School of Medicine, Baltimore, MD, United States: Matthew 550
490 immediately after licensure.
Laurens, Andrea Berry, Robert Edelman, Christopher Plowe; CER- 551
MEL (Centre de Recherches Médicales de Lambaréné), Lambaréné, 552
491 4. Conclusions Gabon: Jean-Claude Dejon Agobe, Jeannot Zinzou, Bertrand Lell; 553
Centers for Disease Control, Atlanta, GA, United States: Mary Hamel, 554
492 With the development of PfSPZ-based products for parenteral Laurence Slutsker; Centre National de Recherche et de Forma- 555
493 injection, the field of malaria vaccines is returning to principles tion sur le Paludisme (CNRFP), Burkina Faso: Sodiomon Sirima; 556
494 of highly protective immunization first established in birds in the Eijkman-Oxford Clinical Research Unit (EOCRU), Jakarta, Indonesia: 557
495 early 1900s, in mice in the 1960s and in humans in the 1970s Kevin Baird; Equatorial Guinea Ministry of Health and Social Wel- 558
496 (Box 1). The focus has been to reproduce the same durable protec- fare, Malabo, Equatorial Guinea: Diosdado Nsue Milang, Vicente 559
497 tive immunity using an injectable product that is safe for human Urbano Nsue Ndong Nchama, Eka Ondó Martín; Fred Hutchin- 560
498 use. This approach, unencumbered by a priori restrictions on vac- son Cancer Research Center: James Kublin Group Health, Seattle, 561
499 cine design, has led to rapid progress, and should translate into a WA, United States: Lisa Jackson Ifakara Health Institute, Bagamoyo, 562
500 more thorough understanding of the immunological mechanisms United Republic of Tanzania: Seif Shekalaghe, Said Abdallah Jongo, 563
Please cite this article in press as: Richie TL, et al. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.
Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.09.096
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600 We gratefully acknowledge the past and current support of the
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605
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614Q7 have participated to date in trials of Sanaria products.
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