A circumsporozoite protein vaccine against malaria using the adenovirus Ch63 vector
The circumsporozoite protein (CSP) is an attractive antigen because four efficacy trials in humans have demonstrated that two vaccines, RTS,S/AS02A and RTS,S/AS02D, which use this antigen alone can partially and temporarily prevent Plasmodium falciparum infection and clinical malaria1-6. Results of the RTS,S clinical trial in southern Mozambique in children showed that a vaccine using CSP was effective for at least 18 months in reducing clinical malaria by 35% and severe malaria by 49%. However, recent results indicate that efficacy against clinical malaria was significantly lower in a parallel trial in Mozambique. These results, while currently the best for any malaria vaccine product, are probably not good enough to make this a marketable useful vaccine, and thus improvement is needed either through modifications to the vaccine, such as by the use of combinations of antigens or vaccine components, or through a distinct approach.
The same antigen (CSP) has been used, but with an alternative delivery system, which uses the non-replicating simian adenovirus Ch63 as a vector along with a heterologous Modified Vaccinia Ankara (MVA) boost. This new vaccine could also, in later clinical trials, be combined in a sequence with the current RTS,S/AS02D, which might produce stronger or more lasting immunity. Alternatively, and more readily, it could be combined with other ChAd63 and MVA vectors encoding any or all the malaria antigens ME-TRAP, MSP1 and AMA1 being developed with support from the European Commission funded European Malaria Vaccine Development Association (EMVDA), the Medical Research Council (MRC), the Wellcome Trust and other funders.
The use of viral vectors rather than or in addition to a protein adjuvant vaccine has several well recognised advantages. In pre-clinical and clinical studies the T cell immunogenicity of viral vectors consistently exceeds that of protein/adjuvant vaccines, both for induction of effector T cell and memory T cell responses7. In pre-clinical models of malaria there is extensive evidence that T cells against the liver- stage parasite induce protective immunity8. However, it is also clear that high level antibodies against the central repeat of the circumsporozoite protein are protective in small animal models9. Moreover, analysis of the immunological correlates of immunity induced by the RTS,S/AS02 vaccine in both phase IIa sporozoite challenge studies2,10 and in a recent clinical trial in Mozambique5 provide evidence that very high levels of antibodies correlate with protection in humans. However, this correlation is relatively weak and there may be a component of T cell mediated protection induced by the vaccine, even though the magnitude of the T cell response measured after vaccination is modest, a level of about 150 SFU / million PBMCs on Enzyme Linked Immuno Spot Assay (ELISpot)11. This has given rise to the assessment of an adenovirus serotype 35 CS-encoding vaccine in a macaques study in a prime-boost combination with RTS,S12. This vector is developed by Crucell and has recently entered a phase I clinical trial in the USA. In parallel an Ad5 serotype encoding the CSP is currentlyin a phase I clinical trial in Maryland, USA sponsored by the US Navy programme and partnered with Genvec13. However, both the Ad5 and Ad35 vectors have problems which make it unlikely that they could become useful deployed malaria vaccines. Ad35 has much weaker immunogenicity than the Ad5 vector backbone and about 20% of Africans have significant antibodies to this vector14. Ad5 is more potent but the high prevalence of Ad5 antibodies in Africa make it very unlikely that this standard vector could be useful in the continent where a malaria vaccine is needed most15.
The ChAd63 vector has several advantages which include:
- Lack of significant pre-existing immunity in most human populations to ChAd63 (unpublished data).
- High yield of viral particles in Good Manufacturing Practice (GMP) manufacture.
- Excellent immunogenicity of ChAd63 recombinants in animal models, matching or exceeding that of the potent Ad5 recombinant vector (Reyes-Sandoval et al. Eur J Immunol. 2008 38:732-41).
- Good safety and encouraging immunogenicity in an ongoing phase I clinical trial of this vector with another malaria insert (ME-TRAP).
The overall aim of this specific project is to use the replication-deficient recombinant viral vectored vaccine, encoding most but not all of the Plasmodium falciparum CSP, to assess immunogenicity and safety in phase I clinical trials.
- To generate a recombinant ChAd63 with a gene encoding most of the CSP (full length minus GPI anchor sequence) and a recombinant MVA encoding the same insert, as well as demonstrating the genetic stability of these constructs, and assess the immunogenicity and safety of the ChAd63 CSP and MVA CSP vaccines in mice.
- To undertake GMP manufacturing of the ChAd63 CSP and MVA CSP construct in parallel and complete requisite pre-clinical toxicology testing of the product at a Good Laboratory Practice facility.
- To conduct a dose escalating Phase I clinical trial at the Royal College of Surgeons in Ireland to assess the safety and immunogenicity of ChAd63 CSP and MVA CSP.
- To measure the cellular and humoral immunogenicity generated by immunisation with ChAd63 CSP and MVA CSP in healthy adults.
Media Coverage March 2012
A podcast interview with Samuel McConkey, Principle Investigator of CSVAC clinical trial, is available to listen to below.
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- Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214-7 (2005).
- Stoute, J. A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group [see comments]. N Engl J Med 336, 86-91 (1997).
- Alonso, P. L. et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 364, 1411-20 (2004).
- Alonso, P. L. et al. Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366, 2012-8 (2005).
- Aponte, J. J. et al. Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet 370, 1543-51 (2007).
- Bojang, K. A. et al. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial. Lancet 358, 1927-34 (2001).
- Hill, A. V. Pre-erythrocytic malaria vaccines: towards greater efficacy. Nat Rev Immunol 6, 21-32 (2006).
- Doolan, D. L. & Hoffman, S. L. The complexity of protective immunity against liver-stage malaria. J Immunol 165, 1453-62 (2000).
- Zavala, F. et al. Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria. Science 228, 1436-40 (1985).
- Stoute, J. A. et al. Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine. J Infect Dis 178, 1139-44 (1998).
- Lalvani, A. et al. Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. J Infect Dis 180, 1656-64 (1999).
- Stewart, V. A. et al. Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone. Infect Immun 75, 2283-90 (2007).
- Genvec. Press release available at http://www.genvec.com/download/press/GNVC_MALARIA%20VACCINES%20CONFEREN…
- Kostense, S. et al. Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector. Aids 18, 1213-6 (2004).
- Xiang, Z. et al. Chimpanzee adenovirus antibodies in humans, sub-Saharan Africa. Emerg Infect Dis 12, 1596-9 (2006).
PLOS one DOI:10.1371/journal.pone.0115161 December 18, 2014
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