Prime-boost strategies for malaria vaccine development
Centre for Clinical Vaccinology and Tropical Medicine,, University of Oxford, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK
* Author for correspondence (e-mail: susie.dunachie{at}ndm.ox.ac.uk)
Accepted 1 July 2003
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Summary |
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Key words: vaccine, malaria, prime-boost strategy, T-cell
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Introduction |
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An important potential role for CD8+ T-cells in protection against P.
falciparum malaria was suggested by studies in mice
(Schneider et al., 1998) and
humans (Hill et al., 1991
).
Established vaccines in current clinical use act predominantly by induction of
antibodies, and stimulating strong cellular immunity has proved harder to
achieve. In particular, many studies have shown that non-particulate antigens
adjuvanted with alum do not induce significant levels of CD8+ cytotoxic
T-lymphocytes (CTLs). A number of alternative antigen delivery systems have
the potential to activate cell-mediated immunity, including DNA vaccines,
recombinant viral and bacterial vectors, protein-in-adjuvant formulations and
recombinant virus-like particles. For DNA and recombinant virus subunit
vaccines, the DNA sequence for the antigen(s) of choice is inserted into an
Escherichia coli-derived purified plasmid or the genome of a
double-stranded DNA virus such as vaccinia. Host CD4+ and CD8+ responses can
then be induced following intracellular synthesis, processing and HLA (Human
Leukocyte Antigen) presentation of class I and II T-cell epitopes.
In the mid-1990s there was much international optimism about the potential
for DNA vaccines to be effective preventative and therapeutic vaccines for a
range of intracellular diseases including malaria, tuberculosis, HIV and
cancer. Many murine studies demonstrated their ability to stimulate both
humoral and cellular immunity, including protection against Plasmodium
yoelii by PyCSP, a DNA vaccine encoding the P. yoelii
circumsporozoite antigen (Hoffman et al.,
1994). Human studies confirmed the safety of the approach and the
ability to elicit antigen-specific CD8+ CTLs
(Wang et al., 1998
). However,
a much more limited magnitude of T-cell response, which was insufficient to be
protective against malaria challenge, was observed in these clinical trials.
Strategies to improve the immunogenicity of DNA vaccines have been reported by
many groups, including co-administration of cytokine- and chemokine-encoding
plasmids (Doolan and Hoffman,
2001
; Gurunathan et al.,
1998
; Sedegah et al.,
2000
) and ubiquitination approaches such as N-end rule targeting
(Tobery and Siliciano, 1999
).
However, these modifications have yet to result in enhanced cellular immunity
of sufficient magnitude to confer protection of humans against challenge.
In parallel with the development of DNA vaccines has been the emergence of
recombinant viral vectors, such as poxviruses and adenoviruses, as vaccine
delivery systems. Ideally such vaccines should be unable to replicate in human
cells, to minimise side effects and allow use in immunocompromised
individuals. Poxviruses are good candidates as they show high species
specificity; for example, avipox viruses are unable to replicate in mammalian
cells (Paoletti, 1996).
Protective T-cell responses in small animals induced by recombinant vaccinia
viruses were first reported in the 1980s
(Panicali and Paoletti, 1982
;
Smith et al., 1983
). The
highly attenuated recombinant vaccinia viruses MVA (modified vaccinia virus
Ankara) (Sutter and Moss,
1992
) and NYVAC (New York vaccinia)
(Tartaglia et al., 1992
) have
been shown to have excellent immunogenicity. MVA was developed by over 500
serial passages in chicken embryo fibroblasts and was used as a smallpox
vaccine in 120 000 people in the 1970s, including immunocompromised
individuals (Mayr et al.,
1978
), and appears to have an excellent safety profile. Due to an
acquired replication defect at a late stage of virion assembly MVA does not
replicate in human cells, but is able to express recombinant genes, making it
an excellent candidate viral vector, like NYVAC, which was derived from the
Copenhagen strain of vaccinia virus and is molecularly attenuated. However,
these recombinant viruses when used singly or with repeated administration
(homologous boosting) do not produce the levels of CD8+ T-cells required for
high-level protection against malaria in murine models
(Lanar et al., 1996
;
Pye et al., 1991
;
Schneider et al., 1998
;
Sedegah et al., 1990
).
Induction of CD8+ T-cells requires introduction of antigen into the MHC
(Major Histocompatibility Complex) class I presenting pathway. Soluble
proteins and peptides do not induce CD8+ T-cells when administered alone,
probably because the antigen does not enter class I processing pathways and
does not provide a sufficient `danger signal' to trigger innate immune
responses. Therefore protein-based vaccines frequently employ adjuvants for
delivery, to act as immune stimulants. Other approaches to facilitate
intracellular delivery of protein material include the use of bacterial toxins
(Donnelly et al., 1993),
liposomes (Lipford et al.,
1994
), lipopeptides (Deres et
al., 1989
) and virus-like particles (VLPs) such as the
yeast-derived Ty-VLP (Gilbert et al.,
1997
).
Heterologous prime-boost strategy
Much research has been conducted into ways of improving the efficacy of DNA
and recombinant viruses, and it was logical to try combining different
approaches. Li et al. (1993)
reported protection of mice against P. yoelii challenge when a
priming immunisation with a recombinant influenza virus expressing an epitope
from the circumsporozoite protein of P.yoelii was followed by a
boosting immunisation of a recombinant vaccinia virus expressing the same
epitope (Li et al., 1993
).
This sequence of immunisation was crucial because homologous boosting or the
opposite order of immunisation failed to induce protection. This early example
of protection by heterologous prime-boost immunisation appeared to be mediated
by predominantly CD8+ T-cells, as the anti-malaria immunity was abolished by
treatment of the immunised mice with anti-CD8 monoclonal antibody. In some
other studies in the field of HIV vaccine research, combining different
antigen vectors (DNA vaccine boosted by a protein-in-adjuvant formulation)
resulted in enhanced antibody function, but by an additive rather than
synergistic effect, which did not result in greatly enhanced effector T-cell
induction (Gorse et al., 1994
;
Letvin et al., 1997
),
signifying that not all heterologous prime-boost strategies are effective at
generating a synergistic enhancement of T-cell responses.
Other heterologous combinations have emerged that confirm the ability of
certain prime-boost approaches to enhance cellular immunity with a variety of
antigen delivery systems. Although many vector agents are able to prime an
immune response, not all are effective at boosting. Priming the response
requires induction of specific T-cells, including a population that persists
as antigen-specific memory cells beyond elimination of the antigen, which then
undergoes rapid expansion upon re-exposure to the same antigen in a boosting
immunisation. The nature of an antigen delivery system determines its ability
to boost the cell-mediated immune response. In general DNA plasmids,
protein-in-adjuvant formulations, virus-like particles and lipopeptides are
excellent priming agents but relatively ineffective as boosting agents.
Recombinant viruses including MVA, NYVAC, attenuated fowlpox strain 9 (FP9)
and non-replicating adenovirus strains appear capable of either priming or
boosting when used in heterologous regimens. Immunisation with recombinant
viruses results in expression of the vaccine antigens inside infected cells,
and hence their efficient delivery to MHC class I and II antigen-processing
pathways via endogenous pathways. Protein-in-adjuvant and other
particulate vaccines that result in exogenous antigen delivery may not access
the class I antigen processing pathway as efficiently
(Belshe et al., 2001). However,
this does not explain why delivery systems that prime well fail to boost as
well as poxviruses and adenoviruses
(Gilbert et al., 2002
). Part
of the explanation may be simply an immunodominance effect. The overall
immunogenicity of a recombinant poxvirus
(Harrington et al., 2002
) or
adenovirus is substantially greater that that of a plasmid DNA or a
lipopeptide vaccine. However, when used alone or in homologous prime-boost
regimes, much of the immunogenicity of these recombinant viruses is targeted
at vector components. By priming with a different vector, synergistic
prime-boost immunisation may generate memory T-cells to the insert with the
priming immunisation that are then amplified by the booster immunisation in
preference to vector-specific T-cell responses that were not primed. Many
groups have now reported enhanced CD4+ and CD8+ T-cell induction by
prime-boost strategies in a range of disease models, including tuberculosis
(McShane et al., 2001
), HIV
(Hanke et al., 1998
), human
papillomavirus (van der Burg et al.,
2001
) and Ebola (Sullivan et
al., 2000
).
Assays of cellular immunity
Evaluation of T-cell immunity has improved in recent years, due to
development of sensitive quantitative assays. The chromium release assay was
previously the established assay of effector function, but had the
disadvantages of low sensitivity, requirement of radio-labelling of target
cells, and the need for in vitro culture over several days. Sensitive
assays now available include the ex vivo and cultured ELISPOT
(enzyme-linked immunospot) assays of cytokine secretion
(Herr et al., 1996),
intracellular cytokine staining by FACS analysis
(Murali-Krishna et al., 1998
),
tetramer staining studies (Altman et al.,
1996
) and commercially available multiple simultaneous cytokine
detection systems (De Jager et al.,
2003
). Due to its relative ease of use, low cost, good
reproducibility and ability to detect responses across a 1000- fold range, the
ex vivo
-interferon ELISPOT is now widely used to quantify
CD4+ and CD8+ T-cell responses in pre-clinical and clinical studies.
Antigen selection
The recent publication of the entire P. falciparum genome sequence
identified about 5300 probable genes
(Gardner et al., 2002),
highlighting the difficulties in selecting the best antigen(s) for inclusion
in a vaccine. The parasite life cycle involves multiple stages, expressing
largely different antigens at different times, and with so many antigens it is
difficult to know which to focus on. Many major antigens show genetic
variation and a few major blood stage antigens display antigenic variation, or
clonal switching, further aiding evasion by the parasite of the host immune
response. Identification of immune correlates of protection against malaria
would greatly aid antigen selection. Studies of T-cell effector function in
mice (Doolan and Hoffman,
2000
), malaria-exposed humans
(Dodoo et al., 2002
) and
vaccinated malaria-naïve populations
(Lalvani et al., 1999
) have
highlighted the complexity and diversity of T-cell immunity. Many candidate
vaccines in pre-clinical and clinical studies have used whole or part of the
well-characterised circumsporozoite protein (CS), which is expressed on the
extracellular sporozoite and the intracellular hepatic stages of the parasite
(Nardin and Nussenzweig, 1993
;
Nardin et al., 1982
).
Thrombospondin-related adhesion protein (TRAP), a pre-erythrocytic antigen
necessary for gliding motility and infectivity of liver cells
(Sultan, 1999
) is a protective
antigen in both P. berghei and P. yoelii and has been used
in several candidate vaccines to date. T-cell responses to this antigen
generated by natural exposure to malaria have been characterised in studies in
The Gambia and Kenya (Flanagan et al.,
1999
).
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Murine studies |
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|
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These studies underlined the importance of immunisation order, as priming
with the MVA vector and boosting with the DNA vaccine resulted in no
improvement in immunogenicity or protection over MVA alone. The route of
inoculation for the MVA vector was shown to be a factor, with intravenous and
intradermal significantly better than intramuscular, subcutaneous or
intraperitoneal delivery. Additionally the boosting ability of the two
non-replicating vaccinia recombinant viruses MVA and NYVAC were compared the
replication-competent WR (Western Reserve) strain, when delivered after the
DNA vaccine. Interestingly, high levels of protection were only seen when
boosting with the non-replicating poxviruses. Further murine studies in Oxford
demonstrated enhanced immunogenicity and protection using Ty-virus-like
particles followed by MVA boosting
(Gilbert et al., 1997;
Plebanski et al., 1998
), and
recently even better protection with recombinant adenovirus priming followed
by MVA boosting (Gilbert et al.,
2002
). Importantly, the latter study demonstrated that a
non-replicating adenovirus vector could boost efficiently as well as acting as
a strong priming vaccine vector. The induced T-cell responses have been shown
to persist to some extent. In the DNA-MVA prime-boost regimen in mice,
protective efficacy against P. berghei fell from 100% at 14 days post
MVA to 60% at day 150 (J. Schneider, personal communication). Durability of
protection was characterised in more detail for prime-boost regimens in the
P. yoelii model, with a drop in efficacy from 70-100% at 20 weeks to
30-40% at 28 weeks (Sedegah et al.,
2002
).
Additional vectors have also been evaluated. Studies at the New York School
of Medicine revealed that non-replicating adenoviruses expressing CS can prime
to induce complete protection against P. yoelii, when followed by a
boosting recombinant vaccinia virus expressing the same protein
(Bruna-Romero et al., 2001). As
noted above, studies with P. berghei CS antigen demonstrated that
such non-replicating adenoviruses can either prime or boost CD8+ T-cell
responses (Gilbert et al.,
2002
). Recombinant FP9, an attenuated fowlpox, has also been
developed in Oxford, and in murine studies this was also more immunogenic than
DNA as a priming agent, with higher levels of induced T-cells and better
protection against P. berghei challenge (R. J. Anderson, C. M.
Hannen, S. G. Gilbert, S. M. Laidlaw, E. G. Sheu, S. Korten, R. Sinden, M. A.
Skinner and A. V. S. Hill, submitted). Triple vector immunisation with
sequential delivery of three heterologous vectors encoding the same antigen is
an appealing next step but, perhaps surprisingly, there is no evidence from
studies using triple combinations of DNA, MVA, FP9 and adenovirus for any
improvement over the best regimens employing two vaccines
(Gilbert et al., 2002
).
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Non-human primate studies |
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Experience with non-human primate models in other intracellular diseases is
of potential relevance to malaria. The efficacy of synergistic heterologous
prime-boost strategies against SIV (simian immunodeficiency virus) and SHIV
(simian-human immunodeficiency virus) has been assessed in rhesus monkeys, as
a model for HIV. Several studies have reported impressive boosting of CD4+ and
CD8+ T-cell responses primed with DNA and boosted with recombinant poxviruses
(Allen et al., 2000;
Kent et al., 1998
), and in one
case survival from challenge 7 months after challenge with the highly virulent
SHIV 89.6P virus (Amara et al.,
2001
). The observed protection appeared to be mediated by cellular
immunity, as no neutralising antibodies were detected
(Robinson et al., 1999
).
Promising data from studies of prime-boost immunisation in non-human primates
have been generated for other diseases including hepatitis B
(Pancholi et al., 2001
) and
Ebola (Sullivan et al.,
2000
).
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Human clinical trials |
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Cellular immune responses were assessed chiefly by the summed ex
vivo -IFN ELISPOT to overlapping peptide pools covering the entire
vaccine insert (McConkey et al.,
2003
). Responses after repeated vaccination with DNA alone were
small, but were markedly increased following boosting with MVA, with summed
pools of over 1000 S.F.C. (spot forming cells) 10-6 PBMCs
(peripheral blood mononuclear cells) in some cases using high doses
(Fig. 2). These changes from
baseline were highly significant (P=0.0006, adjusted for multiple
comparisons). CD8+ and CD4+ responses were detected, mostly to TRAP antigen
rather than the polyepitope string, and were detectable to all peptide pools
tested. There was substantial cross-reactivity of the T-cell response to
peptide pools from the heterologous Pf3D7 strain. Depletion studies suggested
the responses were mainly CD4+ rather than CD8+, and antibody responses to the
antigen insert were low or not detected. Stronger responses were seen when the
interval between DNA and MVA was three weeks rather than eight weeks
(P=0.026). Although the peak level of induced response dropped
significantly from one to 4 weeks after the MVA vaccination, the elicited
immune responses were persistent and were still detectable 5-11 months after
the peak.
|
Vaccine efficacy was assessed using an adapted P. falciparum
sporozoite challenge model (Chulay et al.,
1986). The challenge was heterologous because the strain of
parasite used for challenge (Pf3D7) differed from the strain of the vaccine
TRAP antigen (PfT9/96) by approximately 6% of the TRAP amino acid sequence
(Robson et al., 1990
).
Subjects immunised with DNA prime-MVA boost regimens showed a highly
significant delay in time to blood-stage parasitaemia (thick film positive)
compared to subjects receiving homologous regimens and unvaccinated control
subjects (P=0.013). Although this does not represent sterile
immunity, based on a presumed eightfold multiplication rate of blood-stage
parasites in one 48 h cycle in human blood
(Simpson et al., 2002
), a 2
day delay to parasitaemia can be estimated to correspond to an approximately
87% reduction in parasites emerging from the liver. The best estimate of the
mean reduction induced by DNA-MVA vaccination in this study was 78%. Such
evidence of vaccine efficacy against the parasite is encouraging, given that
this challenge model may deliver ten times more sporozoites than a natural
mosquito bite in the field. Nevertheless this level of protection does not
reach the levels of sterile immunity achieved by vaccination of
malaria-naïve subjects with RTS,S/AS02A
(Kester et al., 2001
), where
antibody-induced protection may be of most importance.
On the basis of the Oxford studies, Phase I trials have been undertaken in semi-immune adults in The Gambia (V. S. Moorthy, T. Imoukhuede, M. Pinder, W. H. H. Reece, K. Watkins, S. Atabani, C. Hannan, K. Bojang, K. P. W. J. McAdam, J. Schneider, S. C. Gilbert et al., submitted). The DNA and MVA vaccines have shown good safety profiles in this population. As expected from previous immunological studies in endemic areas, baseline levels of T-cell responses to the TRAP insert in these subjects were low; at approximately 25 S.F.C. 106 PBMCs. Prime-boost vaccination enhanced the immunogenicity to levels at least as high as achieved in the Oxford trials. A double-blind phase IIb study of 372 semi-immune Gambian adults receiving either DNA-DNA-MVA or rabies vaccine has been conducted successfully (V. S. Moorthy, T. Imoukhuede, M. Pinder, W. H. H. Reece, K. Watkins, S. Atabani, C. Hannan, K. Bojang, K. P. W. J. McAdam, J. Schneider, S. C. Gilbert et al., manuscript in preparation) very recently.
In 2001 clinical trials commenced in Oxford evaluating recombinant fowlpox (FP9) encoding the same `ME-TRAP' insert as the DNA and MVA vaccines. Several combinations were assessed and challenged (D. Webster, S. Dunachie, J. Vuola, S. McConkey, I. Poulton, L. Andrews, R. Ebensen, T. Berthoud, S. Keating, P. Bejon, et al., manuscript submitted for publication). Further studies have commenced using MVA encoding the circumsporozoite protein (CS) and RTS,S/AS02A in prime-boost combinations, as well as trials to evaluate ICC-1132, a recombinant protein vaccine comprising of several CS epitopes fused to the Hepatitis B core antigen, produced by Apovia Inc. Ongoing work includes a collaboration with the US Navy employing DNA and MVA vaccines encoding CS, and prime-boost studies using FP9-CS.
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Discussion |
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Although prime-boost immunisations can induce strong CD8+ responses, in some cases depletion studies have revealed predominantly a CD4+ response. The precise pattern and levels of cellular immunity required for protection against malaria remain unknown. A major obstacle in malaria vaccine research is the identification of correlates of response to vaccination and protection against malaria. As a result of multiple prior episodes of parasitaemia, semi-immune people living in endemic areas show a repertoire of humoral and cell-mediated immune responses to malaria that varies between individuals. The opportunity to conduct malaria challenge studies in malaria-naïve subjects allows greater scrutiny of the relationships between vaccination, induced immunity and protection.
Heterologous prime-boost immunisation can be seen as the sequel to the widespread use of DNA vaccines in the 1990s. Intensive research continues to further improve both the priming and boosting components of this approach, for example by vector modification, and significant advances are likely. The sequencing of the P. falciparum genome heralds a new age in the identification of vaccine antigens, and combining pre-erythrocytic vaccines with blood-stage and transmission-blocking vaccines could amplify the progress to powerful efficacy. Some of the regimens currently under study may appear too complex for widespread use across Africa, requiring a range of vaccines delivered by a variety of routes at different times. However, given the enormity of the malaria problem internationally, and decades of thwarted efforts to find a vaccine, the current strategy is to obtain good efficacy first and then develop ways to simplify the regimen. Novel delivery devices allowing reliable intradermal delivery, and technology allowing controlled product release over a time period of weeks are under development, which could facilitate deployment of the regimens described in this review. Although most deployed vaccines prevent a significant majority from getting any disease, a vaccine protecting 50% of recipients for 6 months in children less than 5 years of age in Africa would be worthwhile given the high mortality from malaria. This is a realistic goal, but will require much greater international financial support than that currently available. Clearly the final product must be affordable to those who need it most, namely children in developing countries. Increased international collaboration in recent years has accelerated progress, and further advances in immunology and vaccine design are expected to contribute enormously over the next few years. There is therefore good reason to look forward to the next few years of malaria vaccine development with great anticipation, although the timeline is unpredictable.
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