Impairment by Mucosal Adjuvants and Cross-Reactivity with Variant Peptides of the Mucosal Immunity Induced by Injection of the Fusion Peptide PADRE-ELDKWA

Abstract

Secretory immunity protects against mucosal transmission of viruses, as demonstrated with the oral poliovirus vaccine. In a previous study we showed that this immunity could be induced in mice by injection of a fusion peptide consisting of an unnatural peptide-like sequence (PADRE) and a viral epitope (ELDKWASLW). PADRE is a T-helper-cell epitope able to bind most major histocompatibility complex class II molecules of different haplotypes in mice and humans and to increase antibody responses. ELDKWA is a well-known consensual sequence of gp41 involved in a key structure of human immunodeficiency virus (HIV) type 1. Here, the antibody response to the native form of ELDKWA was mainly of the immunoglobulin A isotype and selectively occurred in mucosa. Adjuvants, such as cholera toxin and cytosine polyguanine, were useless and even competed with PADRE for the response. Interestingly, these antibodies were cross-reactive with the three major variants of the epitope, as shown both by direct enzyme-linked immunosorbent assay and by inhibition. This unconventional route of mucosal immunization allows control of the administered dose. The lack of adjuvant and the cross-reactivity of the antibodies increase the safety and the spectrum of the candidate vaccine, respectively. The drug-like nature of the construct suggests further improvements by synthesis of more antigenic sequences. The reasonable cost of short peptides at the industrial level and their purity make this approach of interest for future vaccines against mucosal transmission of HIV or other pathogens.

Mucosal and Systemic Adjuvant Effects of Cholera Toxin and Cry1Ac Protoxin on the Specific Antibody Response to HIV-1 C4/V3 Peptides Are Different and Depend on the Antigen Co-administered

“…Several studies support the notion that CT has potent mucosal adjuvant effects (23,54,56), but there are also data in the literature showing its lack of adjuvanticity against some DIFFERENT ADJUVANTICITY TO HIV PEPTIDES immunogenic (3,25,45) as well as nonimmunogenic antigens (14). The present data showing that a different number of antigen doses were required to attain adjuvanticity against the distinct HIV peptides tested indicate that the adjuvant effects of CT and Cry1Ac are not equal for all antigens.…”

“…It has been proposed that this reduction in antibody response might be characteristic of whole-cell vaccines or other particulate antigens, possibly because CT, which itself is a strong immunogen, induces tolerance to the coadministered strong immunogens or redirects the immune response toward itself (3). However adjuvants such as CT and cytosine polyguanine also did not induce mucosal immunity to the fusion peptide PADRE-ELDKWA consisting of an unnatural peptide-like sequence (PADRE) and a viral epitope (ELDKWA) of HIV1, which is not a potent immunogen (14).…”

Induction of Homologous Rather than Heterologous Antigen-Specific CD4 T Cell Responses Is Critical for Functional CD8 T Cell Responses in Mice Transgenic for a Foreign Antigen

“…Only the combination of PADRE and CpG or cholera toxin in an HIV peptide-based vaccine reduced the IgA response (45). However, we observed an increase in OVA-specific IgG titer after OVA-P immunization.…”

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

“…In addition, Abs can be directed against the carrier protein and away from the peptide, as was observed by Ho et al, in which anti-HLA-DR reactivity exceeded reactivity to gp120 (100). There are several other examples describing immunization with 2F5 peptides, including 2F5 peptides conjugated to a carrier such as tetanus toxoid (53), bovine serum albumin (127), a CD4 helper T-cell epitope (54), and multivalent peptides on a carbohydrate scaffold (166). The studies described here show the trend that immunization with the 2F5 epitope peptide elicits antipeptide antibodies but does not produce Nt Abs.…”