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.

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.