Abstract
Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers.
Highlights
Tailoring of the immune responses to DNA vaccination via targeting of different tissues has received little attention
A previous comparative clinical study using an inactivated influenza vaccine indicated preferential amplification of CD8 + effector-T cells after TC application in comparison to IM injection, comparable CD4 + responses were induced by both routes of administration, while humoral responses were induced by IM administration only[16,17]
In this Phase I randomised controlled clinical trial we investigate whether the site and mode of DNA vaccination can influence the quality of the cellular immune responses, using a vaccine designed to induce cellular and not antibody responses
Summary
® GTU MultiHIV B clade DNA vaccine is well tolerated in healthy HIV negative adult volunteers when delivered by TC, ID and IM administration with and without EP. Of note 5/11 participants in the TC0.4 + IM4 group reported either hypo or hyperpigmentation over the transcutaneous vaccine site, most likely a post-inflammatory phenomenon to DNA vaccination This has not been previously observed following TC vaccination when using seasonal influenza vaccine[16]. Positive T cell ELISpot IFN-ɣ responses at the primary end point (week 12) were seen in 1/9 participants (11%) who received ID0.4 + IM4 vaccination, and 9/10 (90%) that received EP + IM4 vaccination (Fig. 1A,B). There was no correlation with the number of virus isolates inhibited by positive responders: C036 (4 viruses), C021 and C030 (3 viruses), C049 (2 viruses) and C037 (1 virus) (Fig. 3B) and the magnitude or kinetics of response These data suggest that TC immunization induced a quality of T cell response distinct to EP + IM4 and ID0.4 + IM4
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