The development of effective vaccines against difficult disease targets will require the identification of new subunit vaccination strategies that can induce and maintain effective immune responses in humans. Here we report on a phase 1a clinical trial using the AMA1 antigen from the blood-stage Plasmodium falciparum malaria parasite delivered either as recombinant protein formulated with Alhydrogel adjuvant with and without CPG 7909, or using recombinant vectored vaccines - chimpanzee adenovirus ChAd63 and the orthopoxvirus MVA. A variety of promising "mixed-modality" regimens were tested. All volunteers were primed with ChAd63, and then subsequently boosted with MVA and/or protein-in-adjuvant using either an 8- or 16-week prime-boost interval. We report on the safety of these regimens, as well as the T cell, B cell, and serum antibody responses. Notably, IgG antibody responses primed by ChAd63 were comparably boosted by AMA1 protein vaccine, irrespective of whether CPG 7909 was included in the Alhydrogel adjuvant. The ability to improve the potency of a relatively weak aluminium-based adjuvant in humans, by previously priming with an adenoviral vaccine vector encoding the same antigen, thus offers a novel vaccination strategy for difficult or neglected disease targets when access to more potent adjuvants is not possible.
Bibliographical noteFunding Information:
We thank M Smith, R Lopez-Ramon, N Anagnostou, R Antrobus, and J Meyer for clinical assistance; N Lella and S French for logistical support; J Furze and D Worth for laboratory assistance; the Jenner Institute Flow Cytometry Core Facility for technical assistance; S Moretz, A Diouf, and G Tullo for technical support performing the GIA assays; Yves Durocher (CNRC-NRC, Canada) for provision of HEK293E cells; and all the study volunteers. This work was supported by the EMVDA (European Malaria Vaccine Development Association), a European Commission (EC) FP6-funded consortium (LSHP-CT-2007–037506); the UK National Institute of Health Research through the Oxford Biomedical Research Centre (NIHR-BRC) (A91301 Adult Vaccine); the Wellcome Trust (084113/Z/07/Z); and EVIMalaR, an EC FP7-funded programme (Grant agreement No. 242095). The GIA work was supported by the PATH Malaria Vaccine Initiative and the Intramural Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. AVSH and SJD are Jenner Investigators; SHH holds a Wellcome Trust Research Training Fellowship (097940/Z/11/Z); SB is a NDM Leadership Fellow and Junior Research Fellow of St Catherine's College, Oxford University; and SJD is a UK MRC Career Development Fellow (G1000527) and Lister Institute Prize Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. A.D.D., J.J.I., S.C.dC., A.V.S.H., and S.J.D. are named inventors on patent applications covering malaria vaccines and immunization regimens. A.N. is an employee of and/or shareholder in Okairòs, which is developing vectored vaccines for malaria and other diseases. The manufacture and QC control of AMA1-C1/Alhydrogel vaccine was supported by the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, USA.
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