A Multi-Stage Malaria Vaccine
Malaria vaccine development has proved difficult1. Since the 1980s over 30 vaccine candidates have entered clinical trials, and proceeded as far as a phase II efficacy trial, often using the well-established sporozoite challenge model. In recent years there has been substantial progress in the development of single antigen pre-erythrocytic vaccines that point to the feasibility of developing a high efficacy vaccine that could make a major impact on malaria control. A highly effective malaria vaccine is still a major objective of global health research, and will likely require a multi-stage product.
MultiMalVax will develop a highly effective multi-stage malaria vaccine to the point of proof-of-concept phase II testing in Europe, prior to clinical trials in malaria-endemic areas. Remarkable recent advances in vaccine design for all four stages of the P. falciparum parasite’s life-cycle allow testing of a multi-stage multi-component vaccine for the first time, with strong chances of success. These advances are:
1) The availability of a new vectored vaccination regime based on the chimpanzee adenovirus (ChAd63)–modified vaccinia Ankara (MVA) prime-boost approach to induce exceptionally potent CD8+ T cell responses and high titre antibodies against multiple malaria antigens.
2) The development of a potentially improved version of the leading partially protective pre-erythrocytic-stage protein (RTS,S) vaccine candidate, termed R21, that lacks the excess of the Hepatitis B virus antigen (HBsAg) in RTS,S. Both vaccines are based on the P. falciparum circumsporozoite protein (CSP) fused to HBsAg surface antigen, a protein capable of forming virus-like particles.
3) The identification, using a viral vector technology screen, of the blood-stage reticulocyte-binding protein homologue 5 antigen (PfRH5) as the first antigen to induce potent strain-transcending neutralisation of blood-stage parasites in in vitro growth inhibition assays.
4) The demonstration that vector-induced antibodies against two mosquito-stage antigens can induce very potent transmission blocking against field isolates of P. falciparum in Africa.
MultiMalVax will undertake four phase I / II clinical trials to assess the pre-erythrocytic, blood-stage and mosquito-stage components individually, and in combination.
The collaboration of academic and industrial partners together with the major European product development partnership for malaria vaccines will provide complementary and highly relevant abilities to accelerate development of this promising product.
The overall overarching aim of this four year clinical development programme is to show safety, immunogenicity and efficacy at each stage of the parasite‘s life cycle using a multi-stage malaria vaccine, that could provide a deployable high efficacy product for use in malaria-endemic areas.
Individual objectives are to:
- Manufacture viral vector vaccines based on ChAd63 and MVA expressing the PfRH5 blood-stage and the Pfs25 mosquito stage antigens.
- Manufacture an improved version of RTS,S (termed R21), displaying a higher number of antibody target epitopes per particle.
- Conduct phase I/II clinical trials addressing safety, immunogenicity and efficacy of all four formulations: (1) a virus-like particle pre-erythrocytic-stage vaccine, alone and in combination with viral vector vaccine expressing the thrombospondin related adhesive protein (TRAP); (2) a PfRH5 blood-stage vaccine; (3) a Pfs25 mosquito-stage vaccine; (4) a combination of vaccines targeting two or more life-stages, depending on the success of earlier trials targeting individual life-stages.
Pre-erythrocytic stage malaria vaccine candidate R21
In the phase I clinical trial VAC056 (NCT02600975), safety and immunogenicity of the protein particle malaria vaccine candidate R21 - adjuvanted with AS01B - was assessed in 20 healthy volunteers in Oxford and Southampton. All vaccinations were administered intramuscularly in a three-dose regime with vaccinations given 4 weeks apart. Participants were followed up for 6 months after their final vaccination. There were no safety concerns relating to R21 in GSK’s AS01B adjuvant and both doses were well tolerated. R21 in AS01B was immunogenic and induced good antibody responses to the pre-erythrocytic circumsporozoite protein at both 10 and 50µg doses tested, which was comparable to levels induced by the leading malaria vaccine candidate, RTS,S. R21 was administered to healthy human volunteers and the safety profile is very reassuring. Initial immunogenicity profiles observed are very encouraging and adjuvanted R21 induces strong antibody responses to the CSP central repeat, at levels comparable to those induced by the leading malaria vaccine candidate, RTS,S.
Blood-stage malaria vaccine candidate RH5
Targeting the blood-stage, in another phase I clinical trial (NCT02181088), ChAd63 -a replication-deficient simian adenovirus- and MVA -a modified vaccinia virus Ankara which is also unable to replicate in humans- were evaluated as vectors. Both encode the P. falciparum reticulocyte-binding protein homologue 5 (RH5), which is one of the proteins involved in parasite invasion of red blood cells. This protein is vital for survival of the parasite and the binding of this protein to its receptor (basigin) mediates an essential interaction required for red blood cell invasion by all tested strains of P. falciparum to date. Pre-clinical testing of the vaccine demonstrated high efficacy against a heterologous strain challenge. ChAd63/MVA RH5 vaccines were shown to be safe and immunogenic (humoral immunogenicity) in healthy volunteers. Purified IgG from trial volunteers inhibited P. falciparum growth, as assessed by a growth inhibition assay (GIA). This is the first antigen to induce substantial GIA following viral vectored vaccination in a clinical trial. An effective RH5 vaccine is likely to require higher levels of antibodies than were induced by ChAd63/MVA RH5. In a follow-up project protein-in-adjuvant formulation (RH5.1) is currently being evaluated in a phase I clinical trial in the UK.
Transmission blocking/Mosquito stage malaria vaccine candidate Pfs25
For the mosquito stage vaccine, the phase I clinical trial (VAC062) is the first clinical use of the viral vectored transmission blocking/mosquito stage vaccines ChAd63 Pfs25-IMX313 and MVA Pfs25-IMX313. The transmission-blocking Pfs25 antigen is fused to the Imaxio IMX313 carrier protein. Fusion to the IMX313 DNA sequence leads to oligomerisation of the recombinant protein as the IMX313 carrier protein spontaneously auto-assembles into a heptamer. The oligomerisation of the antigen is expected to induce significant B cell and T cell immunogenicity. This phase I trial in healthy volunteers aged 18 – 50 began in 2015 in Southampton and Oxford, UK (NCT02532049). To date, all of the clinical trial participants have been enrolled, all vaccinations are complete with the final volunteer follow-up in June 2017. There have been no safety concerns relating to the vaccines and they have been well tolerated. Immunogenicity analysis is ongoing and we have demonstrated that antigen-specific T cells are induced after vaccination.
Combination malaria vaccine candidate
A phase I/IIa sporozoite challenge study to assess the safety and protective efficacy of adjuvanted R21 at two different doses in combination with the malaria vaccine candidate ChAd63 and MVA encoding ME-TRAP was performed safely (VAC065; NCT02905019). The safety, immunogenicity and efficacy of R21 adjuvanted with Matrix-M1 were compared to R21/Matrix-M1 in combination with vectored ME-TRAP, enrolling a total of 36 volunteers plus 6 unvaccinated controls. The promising results showing safety, immunogenicity and also efficacy will soon be reported via an open access scientific publication.
- The MultiMalVax Kick-off Meeting was held in Oxford, UK, 08 November 2012
- 1st Annual meeting held in Heidelberg, Germany, 7th-8th November 2013
- 2nd Annual meeting held in Siena, Italy, 15th-16th September 2014
- 3rd Annual meeting held in Ottignies-Louvain-la-Neuve, Belgium, 17th-18th November 2015
- 4th Annual meeting held in Oxford, UK, 22 March 2017
Li Y, Leneghan DB, Miura K, Nikolaeva D, Brian IJ, Dicks MD, Fyfe AJ, Zakutansky SE, de Cassan S, Long CA, Draper SJ, Hill AV, Hill F, Biswas S. Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology. Sci Rep. 2016 Jan 8;6:18848. doi: 10.1038/srep18848.
Ewer KJ, Sierra-Davidson K, Salman AM, Illingworth JJ, Draper SJ, Biswas S, Hill AV. Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity". Vaccine. 2015 Dec 22;33(52):7444-51. doi: 10.1016/j.vaccine.2015.09.094. Epub 2015 Oct 21.
Hill, A.V. Vaccines against malaria. Philos Trans R Soc Lond B Biol Sci 366, 2806-2814 (2011)