Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP

Carly M Bliss,Alison M Lawrie,Sarah C Gilbert,Navin Venkatraman,Adrian V S Hill,Simone C De Cassan,Rachel Roberts,Claudia M Snudden,Huw Davies,Pooja B Mange,Prateek Choudhary,Saul N Faust ,Nicholas Anagnostou ,Stefano Colloca,Ian Poulton ,Tom Havelock,Amy Grobbelaar,Georgina Bowyer,Alfredo Nicosia,Katie Ewer

doi:10.1038/s41598-018-21630-4

Abstract

Heterologous prime-boost vaccination with viral vectors simian adenovirus 63 (ChAd63) and Modified Vaccinia Ankara (MVA) induces potent T cell and antibody responses in humans. The 8-week regimen demonstrates significant efficacy against malaria when expressing the pre-erythrocytic malaria antigen Thrombospondin-Related Adhesion Protein fused to a multiple epitope string (ME-TRAP). We tested these vaccines in 7 new 4- and 8- week interval schedules to evaluate safety and immunogenicity of multiple ChAd63 ME-TRAP priming vaccinations (denoted A), multiple MVA ME-TRAP boosts (denoted M) and alternating vectors. All regimens exhibited acceptable reactogenicity and CD8+ T cell immunogenicity was enhanced with a 4-week interval (AM) and with incorporation of additional ChAd63 ME-TRAP vaccination at 4- or 8-weeks (AAM or A_A_M). Induction of TRAP antibodies was comparable between schedules. T cell immunity against the ChAd63 hexon did not affect T cell responses to the vaccine insert, however pre-vaccination ChAd63-specific T cells correlated with reduced TRAP antibodies. Vaccine-induced antibodies against MVA did not affect TRAP antibody induction, and correlated positively with ME-TRAP-specific T cells. This study identifies potentially more effective immunisation regimens to assess in Phase IIa trials and demonstrates a degree of flexibility with the timing of vectored vaccine administration, aiding incorporation into existing vaccination programmes.

Highlights

Adenovirus vectors induce high levels of both T cells and antibodies, CD8+ effector and effector memory responses[9,10]
The safety profiles of chimpanzee adenovirus serotype 63-derived viral vector (ChAd63) malaria epitopes (ME)-Thrombospondin-Related Adhesion Protein (TRAP) and Modified Vaccinia Ankara (MVA) ME-TRAP observed in this trial were similar to previous clinical studies of these vaccines, with MVA ME-TRAP more reactogenic than ChAd63 ME-TRAP27–30
There was no difference in vaccine-related adverse event profiles with repeated homologous administration of ChAd63 ME-TRAP or MVA ME-TRAP or with the alternating administration of each vector, as compared with previous studies

Summary

Schedule Abbreviation

Antibodies to ChAd63 is lower than to human adenovirus vectors, such as AdHu5, in many populations including African children[13,14]. A 67% reduction in malaria infection was measured in ChAd63.MVA ME-TRAP vaccinated adults in a malaria endemic region of coastal Kenya In this setting, IFN-γ-secreting T cell responses measured in an ex vivo ELISpot assay, directed towards the mid-section of the TRAP antigen correlated with protection[21]. IFN-γ-secreting T cell responses measured in an ex vivo ELISpot assay, directed towards the mid-section of the TRAP antigen correlated with protection[21] It has been previously demonstrated in mice that the phenotype of T cell memory may differ depending on number of vaccinations. In mice primed with adenovirus and boosted with MVA both encoding ME-TRAP, blood CD8+ T cells of an effector memory phenotype correlate with protection against malaria liver-stage infection following Plasmodium berghei challenge[16].

Results

Discussion

Materials and Methods