Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

Abstract

BackgroundTraditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.MethodologyWe conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4+/CD8+ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.ConclusionsChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.Trial RegistrationClinicalTrials.gov NCT01095055

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…Frozen PBMC samples were used throughout this study and were obtained from phase Ia safety and immunogenicity clinical trials for the MSP1 (24) and AMA1 (25) candidate vaccines, as well as a phase IIa efficacy study where immunized volunteers underwent CHMI with vaccine homologous P. falciparum 3D7 strain sporozoites delivered by mosquito bite (Supplemental Fig. 1) (26).…”

“…with MVA vector (doses, 1.25-5 3 10 8 PFU) recombinant for the same Ag. All necessary regulatory and ethical approvals were granted as previously described (24)(25)(26), and the trials were registered with ClinicalTrials.gov. All volunteers gave written informed consent prior to participation, and the studies were conducted according to the principles of the Declaration of Helsinki and in accordance with Good Clinical Practice.…”

“…The MSP1 42 region is composed of an N-terminal 33-kDa region (MSP1 33 , block 16) followed by a C-terminal 19-kDa region (MSP1 19 , block 17). Peptides were designed as 20-mer overlapping by 10 aa to cover the entire sequence of each transgene insert, and they were pooled according to sequence block for the MSP1 insert or by whether they were 3D7 allele-specific, FVO allele-specific, or common to both in the case of AMA1, all as previously described (24,25). All new peptides used for the studies here are listed in Table I.…”

“…We have thus aimed to develop clinically relevant subunit vaccine delivery platforms that are capable of inducing Ab responses against the transgene of interest in conjunction with strong cellular *The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom; and immunity (22,23), and in a recent series of phase I/IIa clinical trials in Oxford, U.K., we have shown that viral-vectored delivery of the MSP1 and AMA1 blood-stage malaria Ags can achieve this goal (24,25). In these trials, the two Ags were separately delivered utilizing a heterologous prime-boost immunization regimen consisting of a priming vaccination with a recombinant replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) vector, followed 8 wk later by a boosting vaccination with an attenuated modified vaccinia virus Ankara (MVA) vector recombinant for the same Ag (Supplemental Fig.…”

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

“…Уровни IgG были достаточно скромными, дости-гали пика на 14 день после введения AdCh63 CS, однако детектировались и на протяжении всего позднего периода наблюдений [5]. Комбинация вакцины AdCh63 AMA1 и MVA AMA1 также без-опасна и иммуногенна, при этом вызывает обра-зование не только высокого уровня Т-клеточного иммунного ответа, но и значительный AMA1-специфический сывороточный IgG ответ [26]. Вакцины против вируса Эбола (табл.…”