Abstract
BackgroundIn the development of HIV vaccines, improving immunogenicity while maintaining safety is critical. Route of administration can be an important factor.Methodology/Principal FindingsThis multicenter, open-label, randomized trial, HVTN 069, compared routes of administration on safety and immunogenicity of a DNA vaccine prime given intramuscularly at 0, 1 and 2 months and a recombinant replication-defective adenovirus type 5 (rAd5) vaccine boost given at 6 months by intramuscular (IM), intradermal (ID), or subcutaneous (SC) route. Randomization was computer-generated by a central data management center; participants and staff were not blinded to group assignment. The outcomes were vaccine reactogenicity and humoral and cellular immunogenicity. Ninety healthy, HIV-1 uninfected adults in the US and Peru, aged 18–50 were enrolled and randomized. Due to the results of the Step Study, injections with rAd5 vaccine were halted; thus 61 received the booster dose of rAd5 vaccine (IM: 20; ID:21; SC:20). After the rAd5 boost, significant differences by study arm were found in severity of headache, pain and erythema/induration. Immune responses (binding and neutralizing antibodies, IFN-γ ELISpot HIV-specific responses and CD4+ and CD8+ T-cell responses by ICS) at four weeks after the rAd5 booster were not significantly different by administration route of the rAd5 vaccine boost (Binding antibody responses: IM: 66.7%; ID: 70.0%; SC: 77.8%; neutralizing antibody responses: IM: 11.1%; ID: 0.0%; SC 16.7%; ELISpot responses: IM: 46.7%; ID: 35.3%; SC: 44.4%; CD4+ T-cell responses: IM: 29.4%; ID: 20.0%; SC: 35.3%; CD8+ T-cell responses: IM: 29.4%; ID: 16.7%; SC: 50.0%.)Conclusions/SignificanceThis study was limited by the reduced sample size. The higher frequency of local reactions after ID and SC administration and the lack of sufficient evidence to show that there were any differences in immunogenicity by route of administration do not support changing route of administration for the rAd5 boost.Trial RegistrationClinicalTrials.gov NCT00384787
Highlights
While significant challenges exist in the search for a safe and effective HIV vaccine [1], an important part of the discovery process is testing in humans for safety and immunogenicity
All participants received the first dose of DNA vaccine, 88 (99%) received the second dose of DNA vaccine, 84 (93%) received the third dose of DNA vaccine and 61 (68%) received the booster dose of replication-defective adenovirus type 5 (rAd5) vaccine
This study was designed to determine the effect of route of administration of a boost on safety and immunogenicity of a primeboost regimen of two HIV vaccines in adenovirus serotype 5 (Ad5)-seropositive volunteers
Summary
While significant challenges exist in the search for a safe and effective HIV vaccine [1], an important part of the discovery process is testing in humans for safety and immunogenicity. A significant increase in immunogenicity through use of a particular route may allow for a greater chance of demonstrated efficacy, as well as fewer or lower doses used, which can affect the cost of vaccine development. Administration of vaccines into the skin or subcutaneous tissue may be more immunogenic or provide a different pattern of immune responses than administration by the intramuscular route. Dermal immunization attempts to induce an immunologically efficacious response by providing antigen to a variety of cells, including keratinocytes and dendritic cells (DC). Dermal immunization may provide an advantage over intramuscular immunization if lower doses of the vaccine can be utilized with similar or improved immune responses. In the development of HIV vaccines, improving immunogenicity while maintaining safety is critical.
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