Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial

Abstract

Trial design: HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported.

Methods: Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination.

Results: Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern.

Conclusions: These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies.

Trial registration: ClinicalTrials.gov NCT01151319.

Conflict of interest statement

Competing Interests: The authors declare no conflict of interest except for MdS and SC, who were employees of OKAIROS AG from 2007 to 2013. Subsequently OKAIROS AG was acquired by GlaxoSmithKline (GSK), who now hold commercial rights on the work described in the manuscript. Presently MdS and SC have no financial or commercial interests and are not GSK employees. LC reports grants from MRC during the conduct of the study, and TH who reports grants from MRC and European and Developing Countries Clinical Trial Partnership obtained during the conduct of the study and is an inventor on patent WO06123256. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT flow diagram for HIV-CORE 002.

Each vaccine and placebo dose was delivered by two injections, one into each arm.

Figure 2. Summary of local reactions.

Volunteers received vaccines pSG2.HIVconsv DNA (D), ChAdV63.HIVcocnsv (c – low dose and C – standard dose) and MVA.HIVconsv (M) in 4 groups using regimens c, (n  =  2), CM, DDDCM and DDDMC (n  =  10) and in Groups 2–4, were randomized between 8 and 2 recipients of vaccine and placebo, respectively. Local reactions were recorded by the volunteers themselves and assessed and scored by the clinical team. ‘Other’ - one placebo recipient reported a ‘slightly stiff left shoulder’.

Figure 3. Summary of systemic reactions.

Following administration of the pSG2.HIVconsv DNA (D), ChAdV63.HIVconsv (c – low dose and C – standard dose) and MVA.HIVconsv (M) vaccines (Groups 1–4) or placebo (Groups 2, 3 and 4), the volunteers themselves and the clinical team recorded and scored systemic reactions. ‘Other’ encompasses allergic reaction, chills/rigors, headache, vomit, stomach cramps and syncope.

Figure 4. Vaccine-elicited neutralizing antibodies to ChAdV-63.

Volunteers were given ChAdV63.HIVconsv alone or as a part of a heterologous prime-boost regimen and their sera were tested before and 2 weeks after the ChAdV63.HIVconsv administration for ChAdV-63 neutralizing antibodies. Boxed volunteer numbers indicate placebo recipients.