https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(96)09339-7.pdf

HIV vaccines: where we are and where we are going

Background 
A peptide vaccine was produced containing B and T cell epitopes from the V3 and C4 Envelope domains of 4 subtype B HIV-1 isolates (MN, RF, CanO, & Ev91). The peptide mixture was formulated as an emulsion in incomplete Freund's adjuvant (IFA).
Methods 
Low-risk, healthy adult subjects were enrolled in a randomized, placebo-controlled dose-escalation study, and selected 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 placebo recipients after the 2nd immunization were evaluated using neutralization assays of sera, as well as ELISpot and ICS assays of cryopreserved PBMCs to assess CD4 and CD8 T-cell responses. In addition, 51Cr release assays were performed on fresh PBMCs 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 vaccinees developed prolonged pain and sterile abscess formation at the injection site-2 after dose 1, and 2 after dose 2. Two other subjects experienced severe systemic reactions consisting of headache, chills, nausea, and myalgia. Both reactions occurred after the second 4 mg dose. The immunogenicity assessments showed that 6/8 vaccinees at each dose level had detectable MN-specific neutralizing (NT) activity, and 2/7 HLA-B7+ vaccinees had classical CD8 CTL activity detected. However, using both 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 higher antibody 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 clinically unacceptable for continued development. Both HIV-specific antibody and T cell responses were induced and the magnitude of response correlated with the severity of local and systemic reactions. If potent adjuvants are necessary for subunit vaccines to induce broad and durable immune responses, careful, incremental clinical evaluation is warranted to minimize the risk of adverse events.
Trial Registration 
ClinicalTrials.gov NCT00000886

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Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity.

Identification of most frequent HLA class I antigen specificities in Botswana: relevance for HIV vaccine design.

The development of new vaccines against pathogens is an important part of infectious disease control In the last decade, a variety of proteins giving rise to naturally processed pathogen-derived antigenic peptides, representing B-cell and T-cell epitopes, have been characterized Numerous candidate vaccines consisting of synthetic peptides are being designed and evaluated, with encouraging results In this context, the application of mass spectrometry based on the isolation and identification of pathogen-derived peptides from the human leukocyte antigen (HLA) molecules is a major focus of peptide-based vaccine development Dramatic improvements have been made in mass spectrometer performance for peptide sequencing in terms of increased sensitivity, the ability to rapidly obtain data-directed tandem mass spectra, and the accuracy of mass measurement This review focuses on the efforts to identify T-cell epitopes for viral and microbial pathogens for directed vaccine development

Mass Spectrometry and Peptide-based Vaccine Development

Antibody formation in response to antigen stimulation remains the basis for measuring an individual's response and protection for most viral vaccines. A significant proportion of the variation in individual humoral immune response to vaccination appears to be genetic. The collection of genes found on chromosome 6 forming the human leukocyte antigen system provides one of the greatest sources of genetic variation in individuals with respect to their immunological responses. Recent research has demonstrated significant associations between vaccine response and human leukocyte antigen alleles. These associations not only explain why vaccine-induced humoral immune responses vary among individuals and between populations, but these variations may also hold the key to the development of future generations of vaccines.

Human leukocyte antigen polymorphisms: variable humoral immune responses to viral vaccines.

Use of synthetic peptides in primates to induce high-titered neutralizing antibodies and MHC class I-restricted cytotoxic T cells against acquired immunodeficiency syndrome retroviruses: an HLA-based vaccine strategy.

M. B. Gardner

Papers

Use of synthetic peptides in primates to induce high-titered neutralizing antibodies and MHC class I-restricted cytotoxic T cells against acquired immunodeficiency syndrome retroviruses: an HLA-based vaccine strategy.