Natural history of the major histocompatibility complex

https://www.mdpi.com/2076-393X/2/3/515/pdf

Peptide Vaccine: Progress and Challenges.

Peptide-based subunit vaccines are of great interest in modern immunotherapy as they are safe, easy to produce and well defined. However, peptide antigens produce a relatively weak immune response, and thus require the use of immunostimulants (adjuvants) for optimal efficacy. Developing a safe and effective adjuvant remains a challenge for peptide-based vaccine design. Recent advances in immunology have allowed researchers to have a better understanding of the immunological implication of related diseases, which facilitates more rational design of adjuvant systems. Understanding the molecular structure of the adjuvants allows the establishment of their structure-activity relationships which is useful for the development of next-generation adjuvants. This review summarizes the current state of adjuvants development in the field of synthetic peptide-based vaccines. The structural, chemical and biological properties of adjuvants associated with their immunomodulatory effects are discussed.

https://www.tandfonline.com/doi/pdf/10.4161/hv.27332

Recent progress in adjuvant discovery for peptide-based subunit vaccines

The advent of mass vaccination has saved millions of human lives and revolutionized the quality of life. Vaccination is currently one of the most cost effective ways of managing healthcare costs in both emerging and developed countries. Despite the long vaccine history and success, design and development of efficacious and safe vaccines has been tradi-tionally semi-empirical. This is mainly due to our limited understanding of vaccination mechanism and its influencing factors. The most important factor is arguably the type and concentration of vaccine adjuvants. Until recently, however, only one type of adjuvant – aluminum salts, had been widely used within licensed human vaccines in the US, even though a variety of novel adjuvants have been evaluated in the past few decades. This review summarizes the key adju-vants that have been evaluated in recent years with an intention to facilitate more efficient development of vaccine products to combat human diseases.

/pdf/selection-of-adjuvants-for-enhanced-vaccine-potency-4p0s9cayt5.pdf

Selection of Adjuvants for Enhanced Vaccine Potency

B-cell epitope mapping for the design of vaccines and effective diagnostics

The current vaccines for anthrax in the United States and United Kingdom are efficacious in the two most accepted animal models of inhalation anthrax, nonhuman primates and rabbits, but require extensive immunization protocols. We previously demonstrated that a linear determinant in domain 2 of Bacillus anthracis protective Ag (PA) is a potentially important target for an epitope-specific vaccine for anthrax, as Abs specific for this site, referred to as the loop-neutralizing determinant (LND), neutralize lethal toxin in vitro, yet are virtually absent in PA-immunized rabbits. In this study, we evaluated the immunogenicity and protective efficacy in rabbits of multiple antigenic peptides (MAPs) consisting of aa 304-319 from the LND of PA colinearly synthesized at the C terminus (T-B MAP) or N terminus (B-T MAP) with a heterologous T cell epitope from Plasmodium falciparum. Immunogenicity studies demonstrated that both MAPs elicited toxin-neutralizing Ab in rabbits. To evaluate the MAPs as potential anthrax vaccines, we immunized groups of rabbits (n = 7) with each MAP in Freund's adjuvant and then exposed all rabbits to a 200-LD(50) challenge with aerosolized spores of B. anthracis Ames strain. All seven rabbits immunized with the B-T MAP and 89% (six of seven) of rabbits immunized with the T-B MAP survived the spore challenge. Corollary studies with reference sera from human vaccinees immunized with rPA or anthrax vaccine absorbed and nonhuman primates immunized with PA revealed no detectable Ab with specificity for the LND. We conclude that a synthetic peptide vaccine targeting the LND would be a potentially efficacious vaccine for anthrax.

A Synthetic Peptide Vaccine Directed against the 2β2–2β3 Loop of Domain 2 of Protective Antigen Protects Rabbits from Inhalation Anthrax

Current evidence suggests that protective antigen (PA)-based anthrax vaccines may elicit a narrow neutralizing antibody repertoire, and this may represent a vulnerability with PA-based vaccines. In an effort to identify neutralizing specificities which may complement those prevalent in PA antiserum, we evaluated whether sequences within the 2β2-2β3 loop of PA, which are apparent in the crystal structure of heptameric but not monomeric PA, might represent a target for an epitope-specific vaccine for anthrax and, further, whether antibodies to these sequences are induced in rabbits immunized with monomeric PA. We evaluated the immunogenicity in rabbits of a multiple antigenic peptide (MAP) displaying copies of amino acids (aa) 305 to 319 of this region. Overall, four out of six rabbits vaccinated with the MAP peptide in Freund's adjuvant developed high-titer, high-avidity antibody responses which cross-reacted with the immobilized peptide sequence comprising aa 305 to 319 and with PA, as determined by an enzyme-linked immunosorbent assay, and which displayed potent and durable neutralization of lethal toxin (LeTx) in vitro, with peak titers which were 452%, 100%, 67%, and 41% of the peak neutralization titers observed in positive-control rabbits immunized with PA. Importantly, analysis of sera from multiple cohorts of rabbits with high-titer immunity to PA demonstrated a virtual absence of this potent antibody specificity, and work by others suggests that this specificity may be present at only low levels in primate PA antiserum. These results highlight the potential importance of this immunologically cryptic neutralizing epitope from PA as a target for alternative and adjunctive vaccines for anthrax.

Synthetic Peptide Vaccine Targeting a Cryptic Neutralizing Epitope in Domain 2 of Bacillus anthracis Protective Antigen

Low-dose intraperitoneal Freund's adjuvant: Toxicity and immunogenicity in mice using an immunogen targeting amyloid-β peptide

We previously showed that a multiple antigenic peptide (MAP) displaying amino acids (aa) 305 to 319 from the 2beta2-2beta3 loop of protective antigen (PA) can elicit high-titered antibody that neutralizes lethal toxin (LeTx) in vitro and that this loop-neutralizing determinant (LND) specificity is absent in PA-immune rabbits. Some immune rabbits were, however, nonresponders to the MAP. We hypothesized that the immunogen elicited suboptimal major histocompatibility complex (MHC) class II-restricted T-cell help and that introduction of a functional helper T-cell epitope would increase MHC-restricted responsiveness and the magnitude and affinity of the antibody responses. In the current study, we characterized the T- and B-cell responses to LND peptides in mice, then designed second-generation MAP immunogens for eliciting LND-specific immunity, and tested them in rabbits. The 305-319 sequence was devoid of helper T-cell epitopes in three strains of mice; however, a T-B peptide comprising aa 305 to 319, colinearly synthesized with the P30 helper epitope of tetanus toxin, elicited robust LeTx-neutralizing immunity in mice. T-B MAPs displaying B-cell epitopes 304 to 319 (MAP304) or 305 to 319 (MAP305) elicited high-titer, durable antibody responses in rabbits which exhibited potent neutralization of LeTx in vitro. All MAP304-immune rabbits demonstrated neutralization titers exceeding that of hyperimmune sera of rabbits immunized with PA in Freund's adjuvant, with peak neutralization titers 23-, 6-, and 3-fold higher than that of the PA antiserum. Overall, immunization with MAPs containing the P30 epitope elicited higher antibody and toxin neutralization titers and peptide-specific affinity than immunization with an LND MAP lacking a helper epitope. P30-containing MAP304 represents a promising LND-specific vaccine for anthrax.

A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant of Bacillus anthracis Protective Antigen

Fen Yu

Papers

A Synthetic Peptide Vaccine Directed against the 2β2–2β3 Loop of Domain 2 of Protective Antigen Protects Rabbits from Inhalation Anthrax

Synthetic Peptide Vaccine Targeting a Cryptic Neutralizing Epitope in Domain 2 of Bacillus anthracis Protective Antigen

Low-dose intraperitoneal Freund's adjuvant: Toxicity and immunogenicity in mice using an immunogen targeting amyloid-β peptide

A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant of Bacillus anthracis Protective Antigen

Genetic vaccines for anthrax based on recombinant adeno-associated virus vectors.