Research Area:	Immunology
Technology Exchange:	Cellular immunology and Vaccine production and evaluation
Scientific Themes:	Immunology & Infectious Disease
Keywords:	Malaria, Vaccine, Immunology and Clinical Trials
Web Links:	Jenner Website Merton College Website Podcast 'Progress in Malaria Vaccine Research'

My research interests include studies of vaccine-induced malaria immunity as well as the optimisation of antibody induction by subunit vaccines against the blood-stage of malaria infection.

In recent years, we have developed simian adenovirus (ChAd63) and MVA viral vectored vaccines targeting two major candidate antigens from the human malaria parasite P. falciparum (MSP1 and AMA1) and a leading candidate antigen (PvDBP) from P. vivax. We have demonstrated potent and effective T cell and antibody immunogenicity in preclinical models and have now translated these findings into a series of Phase I/IIa clinical vaccine trials funded by the MRC and EMVDA. The aims of this on-going clinical work are to assess the safety, immunogenicity and protective efficacy of these new vaccines in human volunteers. These studies provide an opportunity to better understand how vaccine-induced responses can protect against malaria infection in humans, and also how exposure to the parasite can modulate immunity. We have a particular interest in B cell clinical immunology and the identification of targets of antibody-mediated immunity. These studies of malaria-exposed volunteers in Oxford are also complemented by similar immunological studies in individuals who are naturally-exposed to malaria in Africa through our collaboration with the KEMRI-Wellcome Institute in Kilifi, Kenya.

More recently, our preclinical vaccine development work has focussed on the identification of improved antigen targets within the blood-stage merozoite parasite. We have established new protein vaccine production platforms that, along with viral vectored delivery, are enabling the generation of a whole new range of vaccines. To-date we have identified the PfRH5 antigen as the first reported target in the P. falciparum merozoite that is highly susceptible to broadly-neutralising vaccine-induced antibodies. This on-going programme of work is now aiming to define further antigens from the malaria genome and new target antigen combinations that should prove to be more successful in inducing protective efficacy against malaria by subunit vaccination in humans. In conjunction we are also undertaking studies to look at the utility of deploying protein-in-adjuvant and viral vectored vaccines in combination immunisation regimes, alongside research focusing on novel vaccine adjuvants. We are currently progressing viral vectored vaccines as well as a protein vaccine based on PfRH5 to Phase I/IIa clinical trials.

Name	Department	Institution	Country
Prof Adrian VS Hill	Jenner Institute	Oxford University	UK
Prof Kevin Marsh	Tropical Medicine	Oxford University	UK
Dr Sumi Biswas	Jenner Institute	Oxford University	UK
Dr Alexander Hal Drakesmith	Experimental Medicine Division	Oxford University	UK
Dr Matt Cottingham	Jenner Institute	Oxford University	UK
Dr Persephone Borrow	Experimental Medicine Division	Oxford University	UK
Prof Sarah C Gilbert	Jenner Institute	Oxford University	UK
Prof Helen McShane	Jenner Institute	Oxford University	UK
Prof Robert Sinden	Jenner Institute	Oxford University	UK

de Cassan SC, Draper SJ. 2013. Recent advances in antibody-inducing poxviral and adenoviral vectored vaccine delivery platforms for difficult disease targets. Expert Rev Vaccines, 12 (4), pp. 365-378. Read abstract | Read more

Viral vectored vaccine delivery platforms have traditionally been used for the induction of cellular rather than humoral immunity. However, in recent years, recombinant adenoviral and poxviral vectored vaccines have been optimized to induce B-cell responses, resulting in the demonstration of high-titer antibody responses in a wide variety of animal species. These approaches have now been translated, confirming the induction of substantial levels of antigen-specific IgG in a series of Phase I human clinical trials targeting HIV-1 and Plasmodium falciparum malaria. To further improve the induction of antibodies, mixed-modality regimens based on recombinant viral and protein/adjuvant vaccines are now being assessed. However, limited data exist about the underlying mechanisms mediating the induction of B-cell responses by these subunit vaccines and their ability to influence the qualitative aspects of vaccine-induced B-cell populations and immunoglobulin. Future studies in this area are needed to guide the rational design of antibody-inducing subunit vaccine strategies. Hide abstract

Elias SC, Collins KA, Halstead FD, Choudhary P, Bliss CM, Ewer KJ, Sheehy SH, Duncan CJ, Biswas S, Hill AV, Draper SJ. 2013. Assessment of immune interference, antagonism, and diversion following human immunization with biallelic blood-stage malaria viral-vectored vaccines and controlled malaria infection. J Immunol, 190 (3), pp. 1135-1147. Read abstract | Read more

Overcoming antigenic variation is one of the major challenges in the development of an effective vaccine against Plasmodium falciparum, a causative agent of human malaria. Inclusion of multiple Ag variants in subunit vaccine candidates is one strategy that has aimed to overcome this problem for the leading blood-stage malaria vaccine targets, that is, merozoite surface protein 1 (MSP1) and apical membrane Ag 1 (AMA1). However, previous studies, utilizing malaria Ags, have concluded that inclusion of multiple allelic variants, encoding altered peptide ligands, in such a vaccine may be detrimental to both the priming and in vivo restimulation of Ag-experienced T cells. In this study, we analyze the T cell responses to two alleles of MSP1 and AMA1 induced by vaccination of malaria-naive adult volunteers with bivalent viral-vectored vaccine candidates. We show a significant bias to the 3D7/MAD20 allele compared with the Wellcome allele for the 33 kDa region of MSP1, but not for the 19 kDa fragment or the AMA1 Ag. Although this bias could be caused by "immune interference" at priming, the data do not support a significant role for "immune antagonism" during memory T cell restimulation, despite observation of the latter at a minimal epitope level in vitro. A lack of class I HLA epitopes in the Wellcome allele that are recognized by vaccinated volunteers may in fact contribute to the observed bias. We also show that controlled infection with 3D7 strain P. falciparum parasites neither boosts existing 3D7-specific T cell responses nor appears to "immune divert" cellular responses toward the Wellcome allele. Hide abstract

Williams AR, Douglas AD, Miura K, Illingworth JJ, Choudhary P, Murungi LM, Furze JM, Diouf A, Miotto O, Crosnier C, Wright GJ, Kwiatkowski DP, Fairhurst RM, Long CA, Draper SJ et al. 2012. Enhancing blockade of Plasmodium falciparum erythrocyte invasion: assessing combinations of antibodies against PfRH5 and other merozoite antigens. PLoS Pathog, 8 (11), pp. e1002991. Read abstract | Read more

No vaccine has yet proven effective against the blood-stages of Plasmodium falciparum, which cause the symptoms and severe manifestations of malaria. We recently found that PfRH5, a P. falciparum-specific protein expressed in merozoites, is efficiently targeted by broadly-neutralizing, vaccine-induced antibodies. Here we show that antibodies against PfRH5 efficiently inhibit the in vitro growth of short-term-adapted parasite isolates from Cambodia, and that the EC(50) values of antigen-specific antibodies against PfRH5 are lower than those against PfAMA1. Since antibody responses elicited by multiple antigens are speculated to improve the efficacy of blood-stage vaccines, we conducted detailed assessments of parasite growth inhibition by antibodies against PfRH5 in combination with antibodies against seven other merozoite antigens. We found that antibodies against PfRH5 act synergistically with antibodies against certain other merozoite antigens, most notably with antibodies against other erythrocyte-binding antigens such as PfRH4, to inhibit the growth of a homologous P. falciparum clone. A combination of antibodies against PfRH4 and basigin, the erythrocyte receptor for PfRH5, also potently inhibited parasite growth. This methodology provides the first quantitative evidence that polyclonal vaccine-induced antibodies can act synergistically against P. falciparum antigens and should help to guide the rational development of future multi-antigen vaccines. Hide abstract

Sheehy SH, Duncan CJ, Elias SC, Choudhary P, Biswas S, Halstead FD, Collins KA, Edwards NJ, Douglas AD, Anagnostou NA, Ewer KJ, Havelock T, Mahungu T, Bliss CM, Miura K, Poulton ID, Lillie PJ, Antrobus RD, Berrie E, Moyle S, Gantlett K, Colloca S, Cortese R, Long CA, Sinden RE, Gilbert SC, Lawrie AM, Doherty T, Faust SN, Nicosia A, Hill AV, Draper SJ et al. 2012. ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans. Mol Ther, 20 (12), pp. 2355-2368. Read abstract | Read more

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets. Hide abstract

Biswas S, Spencer AJ, Forbes EK, Gilbert SC, Holder AA, Hill AV, Draper SJ. 2012. Recombinant viral-vectored vaccines expressing Plasmodium chabaudi AS apical membrane antigen 1: mechanisms of vaccine-induced blood-stage protection. J Immunol, 188 (10), pp. 5041-5053. Read abstract | Read more

Apical membrane Ag 1 (AMA1) is one of the leading candidate Ags for inclusion in a subunit vaccine against blood-stage malaria. However, the efficacy of Ab-inducing recombinant AMA1 protein vaccines in phase IIa/b clinical trials remains disappointing. In this article, we describe the development of recombinant human adenovirus serotype 5 and modified vaccinia virus Ankara vectors encoding AMA1 from the Plasmodium chabaudi chabaudi strain AS. These vectors, when used in a heterologous prime-boost regimen in BALB/c mice, are capable of inducing strong transgene-specific humoral and cellular immune responses. We show that this vaccination regimen is protective against a nonlethal P. chabaudi chabaudi strain AS blood-stage challenge, resulting in reduced peak parasitemias. The role of vaccine-induced, AMA1-specific Abs and T cells in mediating the antiparasite effect was investigated by in vivo depletion of CD4(+) T cells and adoptive-transfer studies into naive and immunodeficient mice. Depletion of CD4(+) T cells led to a loss of vaccine-induced protection. Adoptive-transfer studies confirmed that efficacy is mediated by both CD4(+) T cells and Abs functioning in the context of an intact immune system. Unlike previous studies, these results confirm that Ag-specific CD4(+) T cells, induced by a clinically relevant vaccine-delivery platform, can make a significant contribution to vaccine blood-stage efficacy in the P. chabaudi model. Given that cell-mediated immunity may also contribute to parasite control in human malaria, these data support the clinical development of viral-vectored vaccines that induce both T cell and Abs against Plasmodium falciparum blood-stage malaria Ags like AMA1. Hide abstract

Duncan CJ, Draper SJ. 2012. Controlled human blood stage malaria infection: current status and potential applications. Am J Trop Med Hyg, 86 (4), pp. 561-565. Read abstract | Read more

Controlled human malaria infection by blood stage parasite (BSP) inoculation is an alternative to the well-established model of infection with Plasmodium falciparum sporozoites delivered by mosquito bites. The BSP model has been utilized less frequently, but its use is increasing. Advantages of BSP challenge include greater ease of administration, better standardization of the infecting dose per volunteer, and good inter-study reproducibility of in vivo parasite dynamics. Recently, a surprising reduction in clinical symptoms at microscopic patency in the BSP model has been identified, which has an undefined and intriguing pathophysiologic basis, but may make this approach more acceptable to volunteers. We summarize clinical, parasitologic, and immunologic data from all BSP challenges to date, explore differences between the BSP and sporozoite models, and propose future applications for BSP challenge. Hide abstract

Sheehy SH, Duncan CJ, Elias SC, Collins KA, Ewer KJ, Spencer AJ, Williams AR, Halstead FD, Moretz SE, Miura K, Epp C, Dicks MD, Poulton ID, Lawrie AM, Berrie E, Moyle S, Long CA, Colloca S, Cortese R, Gilbert SC, Nicosia A, Hill AV, Draper SJ et al. 2011. Phase Ia clinical evaluation of the Plasmodium falciparum blood-stage antigen MSP1 in ChAd63 and MVA vaccine vectors. Mol Ther, 19 (12), pp. 2269-2276. Read abstract | Read more

Efficacy trials of antibody-inducing protein-in-adjuvant vaccines targeting the blood-stage Plasmodium falciparum malaria parasite have so far shown disappointing results. The induction of cell-mediated responses in conjunction with antibody responses is thought to be one alternative strategy that could achieve protective efficacy in humans. Here, we prepared chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient vectors encoding the well-studied P. falciparum blood-stage malaria antigen merozoite surface protein 1 (MSP1). A phase Ia clinical trial was conducted in healthy adults of a ChAd63-MVA MSP1 heterologous prime-boost immunization regime. The vaccine was safe and generally well tolerated. Fewer systemic adverse events (AEs) were observed following ChAd63 MSP1 than MVA MSP1 administration. Exceptionally strong T-cell responses were induced, and these displayed a mixed of CD4(+) and CD8(+) phenotype. Substantial MSP1-specific serum immunoglobulin G (IgG) antibody responses were also induced, which were capable of recognizing native parasite antigen, but these did not reach titers sufficient to neutralize P. falciparum parasites in vitro. This viral vectored vaccine regime is thus a leading approach for the induction of strong cellular and humoral immunogenicity against difficult disease targets in humans. Further studies are required to assess whether this strategy can achieve protective efficacy against blood-stage malaria infection. Hide abstract

Goodman AL, Blagborough AM, Biswas S, Wu Y, Hill AV, Sinden RE, Draper SJ. 2011. A viral vectored prime-boost immunization regime targeting the malaria Pfs25 antigen induces transmission-blocking activity. PLoS One, 6 (12), pp. e29428. Read abstract | Read more

The ookinete surface protein Pfs25 is a macrogamete-to-ookinete/ookinete stage antigen of Plasmodium falciparum, capable of exerting high-level anti-malarial transmission-blocking activity following immunization with recombinant protein-in-adjuvant formulations. Here, this antigen was expressed in recombinant chimpanzee adenovirus 63 (ChAd63), human adenovirus serotype 5 (AdHu5) and modified vaccinia virus Ankara (MVA) viral vectored vaccines. Two immunizations were administered to mice in a heterologous prime-boost regime. Immunization of mice with AdHu5 Pfs25 at week 0 and MVA Pfs25 at week 10 (Ad-MVA Pfs25) resulted in high anti-Pfs25 IgG titers, consisting of predominantly isotypes IgG1 and IgG2a. A single priming immunization with ChAd63 Pfs25 was as effective as AdHu5 Pfs25 with respect to ELISA titers at 8 weeks post-immunization. Sera from Ad-MVA Pfs25 immunized mice inhibited the transmission of P. falciparum to the mosquito both ex vivo and in vivo. In a standard membrane-feeding assay using NF54 strain P. falciparum, oocyst intensity in Anopheles stephensi mosquitoes was significantly reduced in an IgG concentration-dependent manner when compared to control feeds (96% reduction of intensity, 78% reduction in prevalence at a 1 in 5 dilution of sera). In addition, an in vivo transmission-blocking effect was also demonstrated by direct feeding of immunized mice infected with Pfs25DR3, a chimeric P. berghei line expressing Pfs25 in place of endogenous Pbs25. In this assay the density of Pfs25DR3 oocysts was significantly reduced when mosquitoes were fed on vaccinated as compared to control mice (67% reduction of intensity, 28% reduction in prevalence) and specific IgG titer correlated with efficacy. These data confirm the utility of the adenovirus-MVA vaccine platform for the induction of antibodies with transmission-blocking activity, and support the continued development of this alternative approach to transmission-blocking malaria subunit vaccines. Hide abstract

Douglas AD, Williams AR, Illingworth JJ, Kamuyu G, Biswas S, Goodman AL, Wyllie DH, Crosnier C, Miura K, Wright GJ, Long CA, Osier FH, Marsh K, Turner AV, Hill AV, Draper SJ et al. 2011. The blood-stage malaria antigen PfRH5 is susceptible to vaccine-inducible cross-strain neutralizing antibody. Nat Commun, 2 (1), pp. 601. Read abstract | Read more

Current vaccine strategies against the asexual blood stage of Plasmodium falciparum are mostly focused on well-studied merozoite antigens that induce immune responses after natural exposure, but have yet to induce robust protection in any clinical trial. Here we compare human-compatible viral-vectored vaccines targeting ten different blood-stage antigens. We show that the full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) is highly susceptible to cross-strain neutralizing vaccine-induced antibodies, out-performing all other antigens delivered by the same vaccine platform. We find that, despite being susceptible to antibody, PfRH5 is unlikely to be under substantial immune selection pressure; there is minimal acquisition of anti-PfRH5 IgG antibodies in malaria-exposed Kenyans. These data challenge the widespread beliefs that any merozoite antigen that is highly susceptible to immune attack would be subject to significant levels of antigenic polymorphism, and that erythrocyte invasion by P. falciparum is a degenerate process involving a series of parallel redundant pathways. Hide abstract

Enhancing Antibody Immunogenicity of Malaria Vaccines

The malaria vaccine group at the Jenner Institute has developed numerous approaches that aim to generate very powerful antibody and T cell responses when used in optimised subunit vaccine immunisation regimes. These approaches have included the use of both viral vectored vaccines as well as protein-in-adjuvant formulations. A series of Phase I/IIa clinical trials are in progress of the most promising new approaches targeting the most virulent malaria parasite Plasmodium falciparum with future ...

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