Status of malaria vaccine R&D in 2007

The First International Conference on Malaria Vaccines for the World was convened from 17–19th September, 2007, at the Royal Society of Medicine in London, UK. Recurrent themes included progress in clinical testing and further development or exclusion of existing vaccine candidates based on clinical performance, preclinical development of new candidates including progress towards new vaccine platforms, methods for the identification of new antigens for the next generation of vaccine candidates, and immunological findings that can help inform development. Special symposia were devoted to the plans for Phase III testing of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP)-based vaccine RTS,S and to advances in the attenuated sporozoite approach.

The conference was attended by 151 individuals from 16 countries. Attendees included researchers from academia, government and industry, individuals interested in the regulatory or policy aspects of vaccine development, and representatives of funding organizations. Perspectives and portfolio updates were provided by some of the key funders (R Rabinovitch, BMGF; C Loucq and J McNeil, PATH MVI; O Leroy, EMVI; L Hall, NIAID/NIH). It was estimated that US$3–7 billion would be required per annum to achieve and sustain maximum malarial disease impact, based on a scenario of 80% population coverage with the current tools and implementation and advocacy systems (R Rabinovitch); the current global commitment is approximately US$2 billion per annum. Effective global control of malaria will require innovative research and development, better understanding of the parasite, vector and host response, enhanced implementation, and stronger advocacy. Although up to 31 candidates are expected to be in clinical trials by 2009, no candidate other than RTS,S is expected to reach Phase III evaluation by 2012. The potential competition for Phase IIb trial sites and the need to carefully manage infant enrollments was recognized (M Moran, The George Institute for International Health, Australia), as was the need for greater coordination to ensure the long-term stability of the field-site infrastructure that already exists. This is particularly important given the number of blood-stage candidates in clinical development and the need to assess such candidates in the field, where impact on clinical disease can be evaluated. The publication of a review of these and other topics was announced, entitled The Malaria Product Pipeline: Planning for the Future. Regulatory perspectives to the problems facing the field as a whole were provided (M Moran; J Daugherty, US FDA; C Peterson, Carolyn Peterson Consulting, USA).

Clinical progress

Current candidate vaccines are based on several different technological platforms, including recombinant proteins, synthetic peptides, viral vectors, bacterial vectors, plasmid DNA and attenuated organisms. Recombinant protein antigens formulated in adjuvant represent the majority of the pipeline (∼80% of the candidates). However, the development of a number of recombinant protein vaccine candidates has been halted due to inadequate clinical efficacy or immunogenicity, problems with scalability, or concerns regarding adjuvant safety (C Loucq; O Leroy; G Heppner; US Military Malaria Vaccine Program, USA).

The most significantly advanced malaria vaccine candidate is the pre-erythrocytic stage PfCSP-based vaccine RTS,S being developed by GlaxoSmithKline and PATH MVI, known as Mosquirix™ [1]. This vaccine, when formulated with the adjuvant AS02A, was demonstrated in 1–4-year-olds in Mozambique to have an excellent safety profile and partial efficacy against clinical malaria [2]. Subsequent Phase I/II trials in children (six studies; 2790 participants) have been completed recently or are ongoing. Results of these studies will drive final formulation and delivery decisions prior to the initiation of the planned multicenter Phase III efficacy trial. This trial, anticipated to start in the second half of 2008, is expected to enroll 16,000 infants and young children in seven African countries (S Abdullah, Ifikara Health Research and Development Centre, Tanzania). Three key topics were reviewed: clinical case definitions of malaria disease for efficacy trials (P Bejon, Kenya Medical Research Institute, Kenya); statistical analysis plan (P Milligan, London School of Hygiene and Tropical Medicine, UK); and vaccine effect on nonmalaria comorbidities (B Greenwood, LSHTM). If this Phase III trial is successful, the current projection is that Mosquirix could be available in 5 years.

The US Military Malaria Vaccine Program (USMMVP) at WRAIR/NMRC (USA) has shelved several recombinant protein candidates following nonefficacious Phase II trials, including recombinant PfLSA1 and a first-generation recombinant PfMSP1₄₂/3D7 (G Heppner). The USMMVP is continuing to focus on enhancements to RTS,S, including combination with additional candidates that must be proven to have some clinical effect individually. Phase Ia and Ib clinical evaluations of PfMSP1₄₂ (FVO strain, AS01B) are planned in the USA and Kenya, and a Phase IIb trial of PfAMA1 (3D7 strain, AS02) in children aged 1–6 years in Mali is currently in progress (G Heppner).

The intramural NIH/NIAID program has multiallelic vaccines for both PfMSP1 and PfAMA1 in clinical development (L Miller). A Phase I trial of PfMSP1₄₂/FVO or PfMSP1₄₂/3D7 formulated in Alhydrogel^® showed that the vaccines were safe but not sufficiently immunogenic to generate a biologic effect, and that vaccine-induced cytokine responses were allele specific (C Long).

The most rapidly developing technologies for malaria vaccine development are viral vector platforms. The University of Oxford, UK (A Hill) has extensively evaluated a TRAP-ME based fowlpox (FP9)/modified vaccinia Ankara (MVA) prime–boost vaccine, which induced good IFN-γ responses and reduced liver stage parasite burden following Pf sporozoite challenge in some malaria-naive adults in the UK, but had no efficacy in a Phase IIb field trial in Kenyan children. A cocktail of two Ad5-serotype adenovirus vaccines expressing PfCSP and PfAMA1 antigens is currently being evaluated in malaria-naive adults (T Richie, USMMVP), and is highly immunogenic as evidenced by robust IFN-γ responses vectors following a single dose (M Sedegah, USMMVP).

Preclinical development

Very limited access to next-generation human-use adjuvants (for business reasons) is a major problem for many developers of recombinant protein-based vaccines. Current candidates in the clinic utilize only three modern adjuvants (ASO1, ASO2 and ISA70), in addition to traditional alum formulations. Inadequate consideration of protein/adjuvant formulation issues is also a significant problem. Success with novel adjuvant formulations was reported in animal models: CPG 7909 significantly enhanced the functional immune response of a recombinant PfAMA1-based vaccine formulated in Alhydrogel (G Mullen, NIAID/NIH), and a synthetic TLR7 agonist, imiquimod, acted as a potent topical adjuvant for a PfCSP repeat synthetic peptide vaccine (E Nardin, New York University, USA). The use of self-adjuvanting nanobeads, which rely on the capacity of dendritic cells to take up particulate antigens of a restricted size range, was also reported (M Plebanski, The Austin Research Institute, Australia).

Preclinical data with viral vector platforms in animal models are very encouraging. The Oxford group is actively developing the next generation of pox/adenoviral heterologous combinations, including both pre-erythrocytic and blood-stage targets (A Hill and S Draper). A second-generation five-antigen Ad5-based vaccine that targets both the pre-erythrocytic stage (PfCSP, PfLSA1 and PfAg2) and the blood-stage (PfAMA1 and PfMSP1₄₂) is being developed by GenVec Inc., USMMVP, and PATH MVI) with promising preclinical responses (D Doolan, USMMVP). Both the use of non-Ad5 vectors serotypes, which are not as prevalent as Ad5, including Ad35 (Crucell Inc., The Netherlands; GenVec Inc., USA) and chimpanzee adenoviruses (A Hill), as well as modifications to the hexon hypervariable regions of Ad5 vector (J Bruder, GenVec Inc.), are being developed to overcome the problems of pre-existing immunity to Ad5. Other strategies, such as heterologous prime–boost with adenovirally vectored antigens followed by recombinant proteins, have produced greater than log increases in cellular responses over RTS,S/AS01B in preclinical evaluation (V Stewart, USMMVP).

The use of bacterial vectors, a recombinant Lactococcus lactis vaccine candidate, known as GMZ2, expressing a long synthetic peptide representing conserved epitopes from GLURP and MSP3 targeted by ADCI-effective antibodies, was also reported (M Theisen, Statens Serum Institut, Denmark; M Esen, Institute of Tropical Medicine, Germany).

A novel approach using inplanta engineering and Agrobacterium (Icon Genetics, Germany) was presented by R Coppel (Monash University, Australia).

In response to the resurgence of interest in whole-parasite vaccines, J Vanderberg (NYU) gave an enthralling historical perspective of malaria vaccine research in general and the irradiated sporozoite model in particular. A special symposium was devoted to the process development, manufacture, regulatory approach and plans for testing the metabolically active, nonreplicating whole parasite Pf sporozoite vaccine (irradiated sporozoite vaccine) by Sanaria Inc. (S Hoffman et al., USA). Preclinical data supporting the use of double-knockout, genetically attenuated sporozoites and their mechanisms of protection, and the goals for future clinical testing of genetically attenuated plasmodium parasites, were presented (S Kappe, Seattle Biomedical Research Institute, USA; U Krzych, USMMVP). The Queensland Institute of Medical Research (Australia) is developing an ultra-low-dose parasitized merozoite vaccine (M Good). To support regulatory aspects of the whole-parasite vaccines, the FDA (S Kumar) is developing methods for generating and testing mutant parasites and biomarkers of virulence.

Target antigens

In recognition of the past focus on a very limited number of antigens and vaccine platforms, and in response to the recent disappointing clinical results for some of them, a notable new emphasis by funding organizations was the diversification of portfolios to include additional vaccine platforms and target antigens, with enough products at different stages of development (discovery research through clinical testing) to ensure the smooth flow of products through the pipeline. PATH MVI is supporting the process development of PfMSP4 and PfMSP5 (S Kovacevic, Monash University), and EMVI is supporting the development of PfLSA3 and GLURP (O Leroy), as well as a Pfs48/45 transmission-blocking vaccine (R Sauerwein, UMC Nijmegen, The Netherlands). A chimeric Plasmodium vivax CSP vaccine that incorporates both the 210 and 247 alleles is also in development (A Yadava, USMMVP).

Innovative molecular immunological approaches aimed at leveraging the Plasmodium genome sequence for vaccine development were reported, including gene-knockout studies (S Kappe), protein arrays (D Doolan, USMMVP/QIMR; P Corran, LSHTM), protein structural motifs studies (α-helical coiled coil analysis; G Corradin, University of Lausanne, Switzerland), bioinformatic identification and testing of erythrocyte surface-expressed Plasmodium antigens (M Shuaibu, Nagasaki University, Japan), and large-scale DNA-vaccine approaches (R Coppel). However, these antigen discovery efforts are still in early stages and it will be a number of years before data regarding the potential efficacy of such antigens in humans are available.

Even previously discovered targets are being explored in new ways. Ancora Pharmaceuticals (USA) is developing an antidisease vaccine directed against the Plasmodium glycosylphosphatidylinositol (GPI) toxin glycan (S Campbell). G Brown et al. (Melbourne University, Australia) are reassessing the Var gene complex to see if those variants reactive with CSA could have potential to protect young women from the devastating effects of primiparous malaria.

Vaccine immunology

The importance to next-generation malaria vaccine development of collecting information about naturally and artificially induced immunity during vaccine trials, regardless of efficacy success or failure, was emphasized. E Riley (LSHTM) entreated the funder’s consortium to fund field and experimental challenge studies adequately to allow for the inclusion of tertiary and ancillary immunological end point data. There is increasing consensus that blood-stage challenges may have a role in Phase IIa studies of blood-stage vaccine candidates (A Hill). As an example of clinical vaccinology, the measurement of antigen-specific gene expression changes following candidate malaria vaccine regimens was presented (S Dunachie, University of Oxford). Several papers discussed the fine specificities of functionalities of antibodies to blood stage antigens PfMSP1, PfAMA1, or both (R Curd, National Institute of Medical Research, UK; E Angov and S Dutta, USMMVP), and the interaction of antibodies with specific Fc receptors (R Pleass, University of Nottingham, UK). The ability of antisporozoite antibodies to immobilize Plasmodium sporozoites in the skin and block their invasion of the blood was presented (J Vanderberg).

In addition to the plethora of antigenically diverse Plasmodium strains, a major challenge facing the vaccine community is the complex variability in local epidemiology. The prevalence and dynamics of allelic polymorphisms in PfMSP1₁₉ and PfAMA1 at a study site in Mali (S Takala, University of Maryland, USA) reinforced the concept that highly allele-specific response may be inadequate against field challenge.

Summary

Malaria is responsible for approximately 5 billion clinical episodes, 500 million cases of morbidity, 10–20 million cases of severe disease and 1–3 million deaths each year [3,4,101]. An effective vaccine against malaria is considered by many to be the best hope of reducing the tremendous public health burden of this disease. It is apparent that significant advances have been made in understanding mechanisms of immunity, identifying target antigens, developing platform technologies, and designing and testing candidate vaccines in preclinical models and clinical trials. Although many challenges are yet to be overcome, there is considerable optimism in the field that the development of an effective malaria vaccine is not only feasible but is highly likely.

Acknowledgements

The Scientific Advisory Panel would like to thank John Herriot and the staff of Meetings Management for organizing the meeting; and PATH MVI, EMVI, GSK, Aldevron, PlasmidFactory, DNAvaccine.com, and Hindawi Publishing Corporation for financial support. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the US Department of the Army or the Department of Defense.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.