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A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccine Adjuvants".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 26911

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Prof. Dr. Olga Borges

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Center for Neurosciences and Cell Biology (CNC), Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
Interests: preparation methods to obtain antigen and/or immunopotentiator-loaded polymeric nanoparticles; physicochemical characterization of the nanoparticles using standardized methods and protocols; interaction studies of the nanoparticles with biological membranes and with immune cells; immunotoxicological tests with nanoparticles; immunization studies and evaluation of the cellular and humoral immune response
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Dear Colleagues,

After the introduction of the first successful vaccine for smallpox by Edward Jenner in 1798, other vaccines were discovered and, gradually, the perception of the importance of the vaccines has been decreasing as the most feared infectious diseases have decreased or disappeared. The appearance of the SARS-CoV-2 virus in 2020 brings, again, to public discussion, the importance of being prepared for the development of vaccines in a short period of time. Reverse vaccinology and proteomic approaches have allowed rapid identification of the antigenic structures and, thus, the design of a successful vaccine. Less than 3 months from the appearance of the SARS-CoV-2, a huge number of vaccines have entered preclinical and clinical trials—a historic and unprecedented achievement. A huge diversity of vaccines is being tested, based on RNA, DNA, recombinant proteins, inactivated and attenuated virus, and viral vectors. Appropriate adjuvants for these vaccines are not approved and need to be developed not only for injectable vaccines but, also, to obtain more stable, needle-free, oral, and intranasal vaccines. These last modalities would help to not only increase the vaccine coverage but also more rapidly, and to decrease the infections associated with bad clinical practice during the administration of injectables, especially in developing countries. The objective of this Special Issue of Vaccines is to cover the most recent developments in vaccine adjuvants and formulations.

Prof. Dr. Olga Borges
Guest Editor

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Keywords

vaccines
adjuvants
immunopotentiators
immunomodulators
immune response
immunization
vaccination
immunomodulatory agents

Published Papers (11 papers)

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15 pages, 2558 KiB

Open AccessArticle

Uptake Quantification of Antigen Carried by Nanoparticles and Its Impact on Carrier Adjuvanticity Evaluation

by Yupu Zhu, Minxuan Cui, Yutao Liu, Zhengjun Ma, Jiayue Xi, Yi Tian, Jinwei Hu, Chaojun Song, Li Fan and Quan Li

Vaccines 2024, 12(1), 28; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines12010028 - 26 Dec 2023

Viewed by 894

Abstract

Nanoparticles have been identified in numerous studies as effective antigen delivery systems that enhance immune responses. However, it remains unclear whether this enhancement is a result of increased antigen uptake when carried by nanoparticles or the adjuvanticity of the nanoparticle carriers. Consequently, it is important to quantify antigen uptake by dendritic cells in a manner that is free from artifacts in order to analyze the immune response when antigens are carried by nanoparticles. In this study, we demonstrated several scenarios (antigens on nanoparticles or inside cells) that are likely to contribute to the generation of artifacts in conventional fluorescence-based quantification. Furthermore, we developed the necessary assay for accurate uptake quantification. PLGA NPs were selected as the model carrier system to deliver EsxB protein (a Staphylococcus aureus antigen) in order to testify to the feasibility of the established method. The results showed that for the same antigen uptake amount, the antigen delivered by PLGA nanoparticles could elicit 3.6 times IL-2 secretion (representative of cellular immune response activation) and 1.5 times IL-12 secretion (representative of DC maturation level) compared with pure antigen feeding. The findings above give direct evidence of the extra adjuvanticity of PLGA nanoparticles, except for their delivery functions. The developed methodology allows for the evaluation of immune cell responses on an antigen uptake basis, thus providing a better understanding of the origin of the adjuvanticity of nanoparticle carriers. Ultimately, this research provides general guidelines for the formulation of nano-vaccines. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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15 pages, 2031 KiB

Open AccessArticle

Expression of E. coli FimH Enhances Trafficking of an Orally Delivered Lactobacillus acidophilus Vaccine to Immune Inductive Sites via Antigen-Presenting Cells

by Allison C. Vilander, Kimberly Shelton, Alora LaVoy and Gregg A. Dean

Vaccines 2023, 11(7), 1162; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines11071162 - 27 Jun 2023

Cited by 2 | Viewed by 1563

Abstract

The development of lactic acid bacteria as mucosal vaccine vectors requires the identification of robust mucosal adjuvants to increase vaccine effectiveness. The E. coli type I fimbriae adhesion protein FimH is of interest as a mucosal adjuvant as it targets microfold (M) cells enhancing vaccine uptake into Peyer’s patches and can activate the innate immune system via Toll-like receptor (TLR) 4 binding. Here, we displayed the N-terminal domain of FimH on the surface of a Lactobacillus acidophilus vaccine vector and evaluated its ability to increase uptake of L. acidophilus into Peyer’s patches and activate innate immune responses. FimH was robustly displayed on the L. acidophilus surface but did not increase uptake into the Peyer’s patches. FimH did increase trafficking of L. acidophilus to mesenteric lymph nodes by antigen-presenting cells including macrophages and dendritic cells. It also increased transcription of retinaldehyde dehydrogenase and decreased transcription of IL-21 in the Peyer’s patches and mesenteric lymph nodes. The N-terminal domain of FimH did not activate TLR4 in vitro, indicating that FimH may stimulate innate immune responses through a not-yet-identified mechanism. These results indicate that E. coli FimH alters the innate immune response to L. acidophilus and should be further studied as an adjuvant for lactic acid bacterial vaccine platforms. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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21 pages, 4490 KiB

Open AccessArticle

Astragalus Saponins, Astragaloside VII and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation

by Nilgun Yakubogullari, Ali Cagir, Erdal Bedir and Duygu Sag

Vaccines 2023, 11(3), 495; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines11030495 - 21 Feb 2023

Cited by 2 | Viewed by 1886

Abstract

Astragaloside VII (AST VII), a triterpenic saponin isolated from Astragalus species, shows promise as a vaccine adjuvant, as it supported a balanced Th1/Th2 immune response in previous in vivo studies. However, the underlying mechanisms of its adjuvant activity have not been defined. Here, we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed using ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1β in PMA/ionomycin-stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1β and IL-12, and the expression of MHC II, CD86, and CD80. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4⁺ and CD8⁺ T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses and support dendritic cell maturation and T cell activation in vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as a vaccine adjuvant. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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20 pages, 3031 KiB

Open AccessArticle

Adjuvant Effects of a New Saponin Analog VSA-1 on Enhancing Homologous and Heterosubtypic Protection by Influenza Virus Vaccination

by Noopur Bhatnagar, Ki-Hye Kim, Jeeva Subbiah, Bo Ryoung Park, Pengfei Wang, Harvinder Singh Gill, Bao-Zhong Wang and Sang-Moo Kang

Vaccines 2022, 10(9), 1383; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10091383 - 24 Aug 2022

Cited by 4 | Viewed by 1875

Abstract

Adjuvants can increase the magnitude and durability of the immune response generated by the vaccine antigen. Aluminum salts (Alum) remain the main adjuvant licensed for human use. A few new adjuvants have been licensed for use in human vaccines since the 1990s. QS-21, a mixture of saponin compounds, was included in the AS01-adjuvanted Shingrix vaccine. Here, we investigated the adjuvant effects of VSA-1, a newly developed semisynthetic analog of QS-21, on promoting protection in mice after vaccination with the inactivated split virus vaccine. The adjuvant effects of VSA-1 on improving vaccine efficacy after prime immunization were evident as shown by significantly higher levels of hemagglutination-inhibiting antibody titers and enhanced homologous protection compared to those by QS-21 and Alum adjuvants. The adjuvant effects of VSA-1 on enhancing heterosubtypic protection after two doses of adjuvanted vaccination were comparable to those of QS-21. T cell immunity played an important role in conferring cross-protection by VSA-1-adjuvanted vaccination. Overall, the findings in this study suggest that VSA-1 exhibits desirable adjuvant properties and a unique pattern of innate and adaptive immune responses, contributing to improved homologous and heterosubtypic protection by inactivated split influenza vaccination in mice. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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17 pages, 1723 KiB

Open AccessArticle

Kinome Analysis to Define Mechanisms of Adjuvant Action: PCEP Induces Unique Signaling at the Injection Site and Lymph Nodes

by Sunita Awate, Erin Scruten, George Mutwiri and Scott Napper

Vaccines 2022, 10(6), 927; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10060927 - 11 Jun 2022

Cited by 1 | Viewed by 1777

Abstract

Understanding the mechanism of action of adjuvants through systems biology enables rationale criteria for their selection, optimization, and application. As kinome analysis has proven valuable for defining responses to infectious agents and providing biomarkers of vaccine responsiveness, it is a logical candidate to define molecular responses to adjuvants. Signaling responses to the adjuvant poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP) were defined at the site of injection and draining lymph node at 24 h post-vaccination. Kinome analysis indicates that PCEP induces a proinflammatory environment at the injection site, including activation of interferon and IL-6 signaling events. This is supported by the elevated expression of proinflammatory genes (IFNγ, IL-6 and TNFα) and the recruitment of myeloid (neutrophils, macrophages, monocytes and dendritic cells) and lymphoid (CD4+, CD8+ and B) cells. Kinome analysis also indicates that PCEP’s mechanism of action is not limited to the injection site. Strong signaling responses to PCEP, but not alum, are observed at the draining lymph node where, in addition to proinflammatory signaling, PCEP activates responses associated with growth factor and erythropoietin stimulation. Coupled with the significant (p < 0.0001) recruitment of macrophages and dendritic cells to the lymph node by PCEP (but not alum) supports the systemic consequences of the adjuvant. Collectively, these results indicate that PCEP utilizes a complex, multi-faceted MOA and support the utility of kinome analysis to define cellular responses to adjuvants. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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26 pages, 6257 KiB

Open AccessArticle

Adjuvant Curdlan Contributes to Immunization against Cryptococcus gattii Infection in a Mouse Strain-Specific Manner

by Patrícia Kellen Martins Oliveira-Brito, Gabriela Yamazaki de Campos, Júlia Garcia Guimarães, Letícia Serafim da Costa, Edanielle Silva de Moura, Javier Emílio Lazo-Chica, Maria Cristina Roque-Barreira and Thiago Aparecido da Silva

Vaccines 2022, 10(4), 620; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10040620 - 15 Apr 2022

Cited by 5 | Viewed by 2326

Abstract

The low efficacy and side effects associated with antifungal agents have highlighted the importance of developing immunotherapeutic approaches to treat Cryptococcus gattii infection. We developed an immunization strategy that uses selective Dectin-1 agonist as an adjuvant. BALB/c or C57BL/6 mice received curdlan or β-glucan peptide (BGP) before immunization with heat-killed C. gattii, and the mice were infected with viable C. gattii on day 14 post immunization and euthanized 14 days after infection. Adjuvant curdlan restored pulmonary tumor necrosis factor- α (TNF-α) levels, as induced by immunization with heat-killed C. gattii. The average area and relative frequency of C. gattii titan cells in the lungs of curdlan-treated BALB/c mice were reduced. However, this did not reduce the pulmonary fungal burden or decrease the i0,nflammatory infiltrate in the pulmonary parenchyma of BALB/c mice. Conversely, adjuvant curdlan induced high levels of interferon-γ (IFN-γ) and interleukin (IL)-10 and decreased the C. gattii burden in the lungs of C57BL/6 mice, which was not replicated in β-glucan peptide-treated mice. The adjuvant curdlan favors the control of C. gattii infection depending on the immune response profile of the mouse strain. This study will have implications for developing new immunotherapeutic approaches to treat C. gattii infection. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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14 pages, 2135 KiB

Open AccessArticle

Enhanced Potency and Persistence of Immunity to Varicella-Zoster Virus Glycoprotein E in Mice by Addition of a Novel BC02 Compound Adjuvant

by Junli Li, Lili Fu, Yang Yang, Guozhi Wang and Aihua Zhao

Vaccines 2022, 10(4), 529; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines10040529 - 29 Mar 2022

Cited by 3 | Viewed by 3258

Abstract

Herpes zoster (HZ) is one of two distinct syndromes caused by Varicella-zoster virus (VZV). A primary infection with VZV causes varicella in susceptible young children. After resolution of the primary infection, VZV establishes a lifelong latency within the cranial or dorsal root ganglia. With increasing age, family history of shingles, immunosuppression or other risk factors, there is a decline in the virus-specific T-cell-mediated immune (CMI) response which allows reactivation of latent VZV in the root ganglia resulting in HZ. There are currently two vaccines that have been approved to prevent HZ and postherpetic neuralgia (PHN) but one is a live attenuated vaccine, the protective effect of which is considered to decrease significantly with the age of the recipient. However, a recombinant subunit vaccine may provide targeted VZV-specific cellular and humoral immunity, giving it a more potent and longer-lasting protective effect against HZ. The current study reports the development of a novel adjuvant, BC02 (BCG CpG DNA compound adjuvants system 02), composed of Al(OH)₃ inorganic salt adjuvant and BC01 (BCG CpG DNA compound adjuvants system 01), a Toll-like receptor 9 (TLR9) agonist. Immunogenicity and compatibility with recombinant VZV glycoprotein E (gE) in mice were studied. The BC02-adjuvanted gE experimental vaccine was highly effective in eliciting both humoral and cellular immune responses to the recombinant gE glycoprotein and VZV-Oka in a mouse model. The efficient production and long-term persistence of gE and VZV-Oka-specific IFN-γ, IL-2-specific T cells and memory B cells in the early (1W), middle (7W), middle-late (15W), and final (27W) immune stages were established. Results of fluorescent antibody to membrane antigen (FAMA) and serum antibody plaque reduction tests also showed that the BC02 adjuvanted-gE experimental vaccine induced mice to secrete neutralizing antibodies against clinically isolated VZV strains. In combination, the current data suggest that the BC02 compound adjuvant offers a strategy to induce an appropriately strong cellular and humoral immunity against the VZV gE protein subunit to improve vaccine efficacy. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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12 pages, 3483 KiB

Open AccessArticle

A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice

by Qiao Li, Zhihua Liu, Yi Liu, Chen Liang, Jiayi Shu, Xia Jin, Chuanyou Li and Zhihua Kou

Vaccines 2021, 9(12), 1408; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9121408 - 29 Nov 2021

Viewed by 1775

Abstract

TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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20 pages, 19118 KiB

Open AccessArticle

Vaccine Composition Formulated with a Novel Lactobacillus-Derived Exopolysaccharides Adjuvant Provided High Protection against Staphylococcus aureus

by Haochi Zhang, Na Pan, Cheng Ma, Bohui Liu, Lei Xiu, He Tong, Shouxin Sheng, Yanchen Liang, Haotian Li, Fangfei Ma, Xuemei Bao, Wei Hu and Xiao Wang

Vaccines 2021, 9(7), 775; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9070775 - 12 Jul 2021

Cited by 5 | Viewed by 2679

Abstract

A vaccine that effectively targets methicillin-resistant Staphylococcus aureus (MRSA) is urgently needed, and has been the focus of studies by numerous research groups, but with limited success to date. Recently, our team found that exopolysaccharides derived from probiotic Lactobacilluscasei strain WXD030 as an adjuvant-formulated OVA could upregulate IFN-γ and IL-17 expression in CD4⁺ T cells. In this study, we developed a vaccine (termed rMntC-EPS) composed of S. aureus antigen MntC and Lactobacillus casei exopolysaccharides, which conferred high levels of protection against S. aureus infection. Methods: Six–eight-week-old female mice were vaccinated with purified rMntC-EPS30. The immune protection function of rMntC-EPS30 was assessed by the protective effect of rMntC-EPS30 to S. aureus-induced pulmonary and cutaneous infection in mice, bacterial loads and H&E in injury site, and ELISA for inflammation-related cytokines. The protective mechanism of rMntC-EPS30 was assessed by ELISA for IgG in serum, cytokines in the spleen and lungs of vaccinated mice. In addition, flow cytometry was used for analyzing cellular immune response induced by rMntC-EPS30. For confirmation of our findings, three kinds of mice were used in this study: IL-17A knockout mice, IFN-γ knockout mice and TCRγ/δ knockout mice. Results: rMntC-EPS30 conferred up to 90% protection against S. aureus pulmonary infection and significantly reduced the abscess size in the S. aureus cutaneous model, with clearance of the pathogen. The rMntC-EPS vaccine could induce superior humoral immunity as well as significantly increase IL-17A and IFN-γ production. In addition, we found that rMntC-EPS vaccination induced robust Th 17/γδ T 17 primary and recall responses. Interestingly, this protective effect was distinctly reduced in the IL-17A knockout mice but not in IFN-γ knockout mice. Moreover, in TCRγ/δ knockout mice, rMntC-EPS vaccination neither increased IL-17A secretion nor provided effective protection against S. aureus infection. Conclusions: These data demonstrated that the rMntC formulated with a novel Lactobacillus-derived Exopolysaccharides adjuvant provided high protection against Staphylococcus aureus. The rMntC-EPS vaccine induced γδ T cells and IL-17A might play substantial roles in anti-S. aureus immunity. Our findings provided direct evidence that rMntC-EPS vaccine is a promising candidate for future clinical application against S. aureus-induced pulmonary and cutaneous infection. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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14 pages, 2096 KiB

Open AccessArticle

Designing a SARS-CoV-2 T-Cell-Inducing Vaccine for High-Risk Patient Groups

by Hans-Georg Rammensee, Cécile Gouttefangeas, Sonja Heidu, Reinhild Klein, Beate Preuß, Juliane Sarah Walz, Annika Nelde, Sebastian P. Haen, Michael Reth, Jianying Yang, Ghazaleh Tabatabai, Hans Bösmüller, Helen Hoffmann, Michael Schindler, Oliver Planz, Karl-Heinz Wiesmüller and Markus W. Löffler

Vaccines 2021, 9(5), 428; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines9050428 - 24 Apr 2021

Cited by 17 | Viewed by 4374

Abstract

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively. The first set of peptides contained eight peptides predicted to bind to the individual’s HLA molecules. The second set consisted of ten peptides predicted to bind promiscuously to several HLA-DR allotypes. The vaccine formulation contained the new TLR 1/2 agonist XS15 and was administered as an emulsion in Montanide as a single subcutaneous injection. Peripheral blood mononuclear cells isolated from blood drawn before and after vaccinations were assessed using Interferon-γ ELISpot assays and intracellular cytokine staining. We detected vaccine-induced CD4 T cell responses against six out of 11 peptides predicted to bind to HLA-DR after 19 days, following vaccination, for one peptide already at day 12. We used these results to support the design of a T-cell-inducing vaccine for application in high-risk patients, with weakened lymphocyte performance. Meanwhile, an according vaccine, incorporating T cell epitopes predominant in convalescents, is undergoing clinical trial testing. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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Review

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17 pages, 688 KiB

Open AccessReview

Adjuvants for COVID-19 Vaccines

by Javier Castrodeza-Sanz, Iván Sanz-Muñoz and Jose M. Eiros

Vaccines 2023, 11(5), 902; https://0-doi-org.brum.beds.ac.uk/10.3390/vaccines11050902 - 26 Apr 2023

Cited by 4 | Viewed by 2768

Abstract

In recent decades, the improvement of traditional vaccines has meant that we have moved from inactivated whole virus vaccines, which provoke a moderate immune response but notable adverse effects, to much more processed vaccines such as protein subunit vaccines, which despite being less immunogenic have better tolerability profiles. This reduction in immunogenicity is detrimental to the prevention of people at risk. For this reason, adjuvants are a good solution to improve the immunogenicity of this type of vaccine, with much better tolerability profiles and a low prevalence of side effects. During the COVID-19 pandemic, vaccination focused on mRNA-type and viral vector vaccines. However, during the years 2022 and 2023, the first protein-based vaccines began to be approved. Adjuvanted vaccines are capable of inducing potent responses, not only humoral but also cellular, in populations whose immune systems are weak or do not respond properly, such as the elderly. Therefore, this type of vaccine should complete the portfolio of existing vaccines, and could help to complete vaccination against COVID-19 worldwide now and over the coming years. In this review we analyze the advantages and disadvantages of adjuvants, as well as their use in current and future vaccines against COVID-19. Full article

(This article belongs to the Special Issue Vaccine Adjuvants Research)

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