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"Stephenson, Rachel J"
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Advances in Infectious Disease Vaccine Adjuvants
Vaccines are one of the most significant medical interventions in the fight against infectious diseases. Since their discovery by Edward Jenner in 1796, vaccines have reduced the worldwide transmission to eradication levels of infectious diseases, including smallpox, diphtheria, hepatitis, malaria, and influenza. However, the complexity of developing safe and effective vaccines remains a barrier for combating many more infectious diseases. Immune stimulants (or adjuvants) are an indispensable factor in vaccine development, especially for inactivated and subunit-based vaccines due to their decreased immunogenicity compared to whole pathogen vaccines. Adjuvants are widely diverse in structure; however, their overall function in vaccine constructs is the same: to enhance and/or prolong an immunological response. The potential for adverse effects as a result of adjuvant use, though, must be acknowledged and carefully managed. Understanding the specific mechanisms of adjuvant efficacy and safety is a key prerequisite for adjuvant use in vaccination. Therefore, rigorous pre-clinical and clinical research into adjuvant development is essential. Overall, the incorporation of adjuvants allows for greater opportunities in advancing vaccine development and the importance of immune stimulants drives the emergence of novel and more effective adjuvants. This article highlights recent advances in vaccine adjuvant development and provides detailed data from pre-clinical and clinical studies specific to infectious diseases. Future perspectives into vaccine adjuvant development are also highlighted.
Journal Article
Recent Scientific Advancements towards a Vaccine against Group A Streptococcus
Group A Streptococcus (GAS), or Streptococcus pyogenes, is a gram-positive bacterium that extensively colonises within the human host. GAS is responsible for causing a range of human infections, such as pharyngitis, impetigo, scarlet fever, septicemia, and necrotising fasciitis. GAS pathogens have the potential to elicit fatal autoimmune sequelae diseases (including rheumatic fever and rheumatic heart diseases) due to recurrent GAS infections, leading to high morbidity and mortality of young children and the elderly worldwide. Antibiotic drugs are the primary method of controlling and treating the early stages of GAS infection; however, the recent identification of clinical GAS isolates with reduced sensitivity to penicillin-adjunctive antibiotics and increasing macrolide resistance is an increasing threat. Vaccination is credited as the most successful medical intervention against infectious diseases since it was discovered by Edward Jenner in 1796. Immunisation with an inactive/live-attenuated whole pathogen or selective pathogen-derived antigens induces a potent adaptive immunity and protection against infectious diseases. Although no GAS vaccines have been approved for the market following more than 100 years of GAS vaccine development, the understanding of GAS pathogenesis and transmission has significantly increased, providing detailed insight into the primary pathogenic proteins, and enhancing GAS vaccine design. This review highlights recent advances in GAS vaccine development, providing detailed data from preclinical and clinical studies across the globe for potential GAS vaccine candidates. Furthermore, the challenges and future perspectives on the development of GAS vaccines are also described.
Journal Article
Utilizing murine dendritic cell line DC2.4 to evaluate the immunogenicity of subunit vaccines in vitro
Subunit vaccines hold substantial promise in controlling infectious diseases, due to their superior safety profile, specific immunogenicity, simplified manufacturing processes, and well-defined chemical compositions. One of the most important end-targets of vaccines is a subset of lymphocytes originating from the thymus, known as T cells, which possess the ability to mount an antigen-specific immune response. Furthermore, vaccines confer long-term immunity through the generation of memory T cell pools. Dendritic cells are essential for the activation of T cells and the induction of adaptive immunity, making them key for the in vitro evaluation of vaccine efficacy. Upon internalization by dendritic cells, vaccine-bearing antigens are processed, and suitable fragments are presented to T cells by major histocompatibility complex (MHC) molecules. In addition, DCs can secrete various cytokines to crosstalk with T cells to coordinate subsequent immune responses. Here, we generated an in vitro model using the immortalized murine dendritic cell line, DC2.4, to recapitulate the process of antigen uptake and DC maturation, measured as the elevation of CD40, MHC-II, CD80 and CD86 on the cell surface. The levels of key DC cytokines, tumor necrosis alpha (TNF-α) and interleukin-10 (IL-10) were measured to better define DC activation. This information served as a cost-effective and rapid proxy for assessing the antigen presentation efficacy of various vaccine formulations, demonstrating a strong correlation with previously published in vivo study outcomes. Hence, our assay enables the selection of the lead vaccine candidates based on DC activation capacity prior to in vivo animal studies.
Journal Article
Self-Assembling Peptides for Vaccine Adjuvant Discovery
Vaccination is credited as a significant medical achievement contributing to the decline in morbidity and mortality of infectious diseases. Traditional vaccines composed of inactivated and live-attenuated whole pathogens confer the induction of potent and long-term immune responses; however, traditional vaccines pose a high risk of eliciting autoimmune and allergic responses as well as inflammations. New modern vaccines, such as subunit vaccines, employ minimum pathogenic components (such as carbohydrates, proteins, or peptides), overcome the drawbacks of traditional vaccines and stimulate effective immunity against infections. However, the low immunogenicity of subunit vaccines requires effective immune stimulants (adjuvants), which are an indispensable factor in vaccine development. Although there are several approved adjuvants in human vaccines, the challenges of matching and designing appropriate adjuvants for specific vaccines, along with managing the side effects and toxicity of existing adjuvants in humans, are driving the development of new adjuvants. Self-assembling peptides are a promising biomaterial rapidly emerging in the fields of biomedicine, vaccination and material science. Here, peptides self-assemble into ordered supramolecular structures, forming different building blocks in nanoparticle size, including fibrils, tapes, nanotubes, micelles, hydrogels or nanocages, with great biostability, biocompatibility, low toxicity and effectiveness at controlled release. Self-assembling peptides are effective immunostimulatory agents used in vaccine development to enhance and prolong immune responses. This review describes the predominant structures of self-assembling peptides and summarises their recent applications as vaccine adjuvants. Challenges and future perspectives on self-assembled peptides as vaccine adjuvants are also highlighted.
Journal Article
Liposomal Formulations of a Polyleucine–Antigen Conjugate as Therapeutic Vaccines against Cervical Cancer
Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant.
Journal Article
Identification of Host Insulin Binding Sites on Schistosoma japonicum Insulin Receptors
Schistosoma japonicum insulin receptors (SjIRs) have been identified as encouraging vaccine candidates. Interrupting or blocking the binding between host insulin and the schistosome insulin receptors (IRs) may result in reduced glucose uptake leading to starvation and stunting of worms with a reduction in egg output. To further understand how schistosomes are able to exploit host insulin for development and growth, and whether these parasites and their mammalian hosts compete for the same insulin source, we identified insulin binding sites on the SjIRs. Based on sequence analysis and the predicted antigenic structure of the primary sequences of the SjIRs, we designed nine and eleven peptide analogues from SjIR-1 and SjIR-2, respectively. Using the Octet RED system, we identified analogues derived from SjIR-1 (10) and SjIR-2 (20, 21 and 22) with insulin-binding sequences specific for S. japonicum. Nevertheless, the human insulin receptor (HIR) may compete with the SjIRs in binding human insulin in other positions which are important for HIR binding to insulin. However, no binding occurred between insulin and parasite analogues derived from SjIR-1 (2, 7 and 8) and SjIR-2 (14, 16 and 18) at the same locations as HIR sequences which have been shown to have strong insulin binding affinities. Importantly, we found two analogues (1 and 3), derived from SjIR-1, and two analogues (13 and 15) derived from SjIR-2, were responsible for the major insulin binding affinity in S. japonicum. These peptide analogues were shown to have more than 10 times (in KD value) stronger binding capacity for human insulin compared with peptides derived from the HIR in the same sequence positions. Paradoxically, analogues 1, 3, 13 and 15 do not appear to contain major antigenic determinants which resulted in poor antibody responses to native S. japonicum protein. This argues against their future development as peptide-vaccine candidates.
Journal Article
A synthetic cyclic peptide for promoting antigen presentation and immune activation
Cyclic peptides are often used as scaffolds for the multivalent presentation of drug molecules due to their structural stability and constrained conformation. We identified a cyclic deca-peptide incorporating lipoamino acids for delivering T helper and B cell epitopes against group A
Streptococcus
(GAS), eliciting robust humoral immune responses. In this study, we assessed the function-immunogenicity relationship of the multi-component vaccine candidate (referred to as VC-13) to elucidate a mechanism of action. We identified a potential universal delivery platform, not only capable of adjuvanting different peptide epitopes (e.g., NS1 and 88/30 from group A
Streptococcus
, gonadotropin hormone releasing hormone [GnRH]), but also protein antigens (e.g., bovine serum albumin [BSA], receptor binding domain (RBD) of the SARS-CoV-2 protein responsible for COVID-19 infection [SARS-CoV-2 RBD]) and small molecular haptens (e.g., cocaine). All vaccine candidates self-assembled into sub-500 nm nanoparticles and induced high antigen-specific systemic IgG titers and opsonic potential compared to the antigen co-administered with a commercial adjuvant, complete Freund’s adjuvant. Notably, presence of the cyclic decapeptide in this vaccine increased accumulation in the draining inguinal lymph nodes, facilitating cellular uptake of peptide antigens. Furthermore, the lipoamino acid promoted dendritic cell activation, acting as both toll-like receptors 2 and 4 -targeting moiety. Our study revealed the importance of the cyclic decapeptide and lipoamino acid presence in antigen presentation and immune response activation, leading onto the development of a fully synthetic, self-assembled, and promising platform for the delivery of subunit vaccines and anti-drug vaccines.
Journal Article
Peptide-Based Nanovaccines in the Treatment of Cervical Cancer: A Review of Recent Advances
Persistent infection with high-risk human papillomaviruses (HPVs), such as HPV-16 and HPV-18, can induce cervical cancer in humans. The disease carries high morbidity and mortality among females worldwide. Inoculation with prophylactic HPV vaccines, such as Gardasil
or Cervarix
, is the predominant method of preventing cervical cancer in females 6 to 26 years of age. However, despite the availability of commercial prophylactic HPV vaccines, no therapeutic HPV vaccines to eliminate existing HPV infections have been approved. Peptide-based vaccines, which form one of the most potent vaccine platforms, have been broadly investigated to overcome this shortcoming. Peptide-based vaccines are especially effective in inducing cellular immune responses and eradicating tumor cells when combined with nanoscale adjuvant particles and delivery systems. This review summarizes progress in the development of peptide-based nanovaccines against HPV infection.
Journal Article
Opsonic Activity of Conservative Versus Variable Regions of the Group A Streptococcus M Protein
Group A Streptococcus (GAS) and GAS-associated infections are a global challenge, with no licensed GAS vaccine on the market. The GAS M protein is a critical virulence factor in the fight against GAS infection, and it has been a primary target for GAS vaccine development. Measuring functional opsonic antibodies against GAS is an important component in the clinical development path for effective vaccines. In this study, we compared the opsonic activity of two synthetic, self-adjuvanting subunit vaccines containing either the J8- or 88/30-epitope in Swiss outbred mice using intranasal administration. Following primary immunization and three boosts, sera were assessed for IgG activity using ELISA, and opsonization activity against seven randomly selected clinical isolates of GAS was measured. Vaccine constructs containing the conservative J8-epitope showed significant opsonic activity against six out of the seven GAS clinical isolates, while the vaccine containing the variable 88/30-epitope did not show any significant opsonic activity.
Journal Article