Immunization with cocktail of HIV-derived peptides in Montanide ISA-51 is immunogenic, but causes sterile abscesses and Unacceptable Reactogenicity

Abstract

Background: A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund'sadjuvant (IFA).Methods: Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, andselected using criteria specifying that 50% in each study group would be HLA-B7+. Immunizations were scheduled at 0, 1,and 6 months using a total peptide dose of 1 or 4 mg. Adaptive immune responses in16 vaccine recipients and two placeborecipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays ofcryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, 51Cr release assays were performed on freshPBMCs following 14-day stimulation with individual vaccine peptide antigens.Results: 24 subjects were enrolled; 18 completed 2 injections. The study was prematurely terminated because 4 vaccineesdeveloped prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two othersubjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurredafter the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectableMN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, usingboth ELISpot and ICS, 8/16 vaccinees (5/7 HLA-B7+) and 0/2 controls had detectable vaccine-specific CD8 T-cell responses.Subjects with moderate or severe systemic or local reactions tended to have more frequent T cell responses and higherantibody responses than those with mild or no reactions.Conclusions: The severity of local responses related to the formulation of these four peptides in IFA is clinicallyunacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitudeof response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunitvaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimizethe risk of adverse events.