Enhanced Immunogenicity and Protective Efficacy of aCampylobacter jejuniConjugate Vaccine Coadministered with Liposomes Containing Monophosphoryl Lipid A and QS-21

ABSTRACTCampylobacter jejuniis among the most common causes of diarrheal disease worldwide and efforts to develop protective measures against the pathogen are ongoing. One of the few defined virulence factors targeted for vaccine development is the capsule polysaccharide (CPS). We have developed a capsule conjugate vaccine againstC. jejunistrain 81-176 (CPS-CRM) that is immunogenic in mice and nonhuman primates (NHPs) but only moderately immunogenic in humans when delivered alone or with aluminum hydroxide. To enhance immunogenicity, two novel liposome-based adjuvant systems, the Army Liposome Formulation (ALF), containing synthetic monophosphoryl lipid A, and ALF plus QS-21 (ALFQ), were evaluated with CPS-CRM in this study. In mice, ALF and ALFQ induced similar amounts of CPS-specific IgG that was significantly higher than levels induced by CPS-CRM alone. Qualitative differences in antibody responses were observed where CPS-CRM alone induced Th2-biased IgG1, whereas ALF and ALFQ enhanced Th1-mediated anti-CPS IgG2b and IgG2c and generated functional bactericidal antibody titers. CPS-CRM + ALFQ was superior to vaccine alone or CPS-CRM + ALF in augmenting antigen-specific Th1, Th2, and Th17 cytokine responses and a significantly higher proportion of CD4+IFN-γ+IL-2+TNF-α+and CD4+IL-4+IL-10+T cells. ALFQ also significantly enhanced anti-CPS responses in NHPs when delivered with CPS-CRM compared to alum- or ALF-adjuvanted groups and showed the highest protective efficacy against diarrhea following orogastric challenge withC. jejuni. This study provides evidence that the ALF adjuvants may provide enhanced immunogenicity of this and other novelC. jejunicapsule conjugate vaccines in humans.IMPORTANCECampylobacter jejuniis a leading cause of diarrheal disease worldwide, and currently no preventative interventions are available.C. jejuniis an invasive mucosal pathogen that has a variety of polysaccharide structures on its surface, including a capsule. In phase 1 studies, aC. jejunicapsule conjugate vaccine was safe but poorly immunogenic when delivered alone or with aluminum hydroxide. Here, we report enhanced immunogenicity of the conjugate vaccine delivered with liposome adjuvants containing monophosphoryl lipid A without or with QS-21, known as ALF and ALFQ, respectively, in preclinical studies. Both liposome adjuvants significantly enhanced immunity in mice and nonhuman primates and improved protective efficacy of the vaccine compared to alum in a nonhuman primateC. jejunidiarrhea model, providing promising evidence that these potent adjuvant formulations may enhance immunogenicity in upcoming human studies with thisC. jejuniconjugate and other malaria and HIV vaccine platforms.

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Erratum for Ramakrishnan et al., “Enhanced Immunogenicity and Protective Efficacy of a Campylobacter jejuni Conjugate Vaccine Coadministered with Liposomes Containing Monophosphoryl Lipid A and QS-21”

mSphere ◽

10.1128/msphere.00440-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 2

Author(s):

Amritha Ramakrishnan ◽

Nina M. Schumack ◽

Christina L. Gariepy ◽

Heather Eggleston ◽

Gladys Nunez ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Conjugate Vaccine ◽

Lipid A ◽

Protective Efficacy ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

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Correction for Ramakrishnan et al., “Enhanced Immunogenicity and Protective Efficacy of a Campylobacter jejuni Conjugate Vaccine Coadministered with Liposomes Containing Monophosphoryl Lipid A and QS-21”

mSphere ◽

10.1128/msphere.00351-19 ◽

2019 ◽

Vol 4 (3) ◽

Cited By ~ 1

Author(s):

Amritha Ramakrishnan ◽

Nina M. Schumack ◽

Christina L. Gariepy ◽

Heather Eggleston ◽

Gladys Nunez ◽

...

Keyword(s):

Campylobacter Jejuni ◽

Conjugate Vaccine ◽

Lipid A ◽

Protective Efficacy ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

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The Combinations Chitosan-Pam3CSK4 and Chitosan-Monophosphoryl Lipid A: Promising Immune-Enhancing Adjuvants for Anticaries Vaccine PAc

Infection and Immunity ◽

10.1128/iai.00651-19 ◽

2019 ◽

Vol 87 (12) ◽

Author(s):

Yongli Bi ◽

Qingan Xu ◽

Lingkai Su ◽

Jiantao Xu ◽

Zhongfang Liu ◽

...

Keyword(s):

Lipid A ◽

Vaccine Development ◽

Protection Effect ◽

Content Type ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Tooth Surfaces ◽

Antibody Titers

ABSTRACT We previously demonstrated that recombinant protein PAc could be administered as an anticaries vaccine. However, the relatively weak immunogenicity of PAc limits its application. In the present study, we investigated the effect of two adjuvant combinations of chitosan plus Pam3CSK4 (chitosan-Pam3CSK4) and of chitosan plus monophosphoryl lipid A (chitosan-MPL) in the immune responses to the PAc protein in vivo and in vitro. PAc-chitosan-Pam3CSK4 or PAc-chitosan-MPL promoted significantly higher PAc-specific antibody titers in serum and saliva, inhibited Streptococcus mutans colonization onto the tooth surfaces, and endowed better protection effect with significantly less caries activities than PAc alone. Chitosan-Pam3CSK4 and chitosan-MPL showed no statistically significant differences. In conclusion, our study demonstrated that the chitosan-Pam3CSK4 and chitosan-MPL combinations are promising for anticaries vaccine development.

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Combining Monophosphoryl Lipid A (MPL), CpG Oligodeoxynucleotide (ODN), and QS-21 Adjuvants Induces Strong and Persistent Functional Antibodies and T Cell Responses against Cell-Traversal Protein for Ookinetes and Sporozoites (CelTOS) ofPlasmodium falciparumin BALB/c Mice

Infection and Immunity ◽

10.1128/iai.00911-18 ◽

2019 ◽

Vol 87 (6) ◽

Cited By ~ 5

Author(s):

Sakineh Pirahmadi ◽

Sedigheh Zakeri ◽

Akram A. Mehrizi ◽

Navid D. Djadid ◽

Abbas-Ali Raz ◽

...

Keyword(s):

Lipid A ◽

Enzyme Linked Immunosorbent Assay ◽

Vaccine Adjuvants ◽

Content Type ◽

Quillaja Saponaria ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Cpg Oligodeoxynucleotide ◽

Membrane Feeding ◽

Functional Antibodies

ABSTRACTPlasmodium falciparumcell-traversal protein for ookinetes and sporozoites (PfCelTOS) is an advanced vaccine candidate that has a crucial role in the traversal of the malaria parasite in both mosquito and mammalian hosts. As recombinant purified proteins are normally poor immunogens, they require to be admixed with an adjuvant(s); therefore, the objective of the present study was to evaluate the capacity of different vaccine adjuvants, monophosphoryl lipid A (MPL), CpG, andQuillaja saponariaMolina fraction 21 (QS-21), alone or in combination (MCQ [MPL/CpG/QS-21]), to enhance the immunogenicity ofEscherichia coli-expressed PfCelTOS in BALB/c mice. This goal was achieved by the assessment of anti-PfCelTOS IgG antibodies (level, titer, IgG isotype profile, avidity, and persistence) and extracellular Th1 cytokines using an enzyme-linked immunosorbent assay (ELISA) on postimmunized BALB/c mouse sera and PfCelTOS-stimulated splenocytes, respectively. Also, an assessment of the transmission-reducing activity (TRA) of anti-PfCelTOS obtained from different vaccine groups was carried out in femaleAnopheles stephensimosquitoes by using a standard membrane feeding assay (SMFA). In comparison to PfCelTOS alone, administration of PfCelTOS with three distinct potent Th1 adjuvants in vaccine mouse groups showed enhancement and improvement of PfCelTOS immunogenicity that generated more bias toward a Th1 response with significantly enhanced titers and avidity of the anti-PfCelTOS responses that could impair ookinete development inA. stephensi. However, immunization of mice with PfCelTOS with MCQ mixture adjuvants resulted in the highest levels of induction of antibody titers, avidity, and inhibitory antibodies in oocyst development (88%/26.7% reductions in intensity/prevalence) inA. stephensi. It could be suggested that adjuvant combinations with different mechanisms stimulate better functional antibody responses than adjuvants individually against challenging diseases such as malaria.

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Parenterally Administered Norovirus GII.4 Virus-Like Particle Vaccine Formulated with Aluminum Hydroxide or Monophosphoryl Lipid A Adjuvants Induces Systemic but Not Mucosal Immune Responses in Mice

Journal of Immunology Research ◽

10.1155/2018/3487095 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Suvi Heinimäki ◽

Maria Malm ◽

Timo Vesikari ◽

Vesna Blazevic

Keyword(s):

Aluminum Hydroxide ◽

Mucosal Immunity ◽

Lipid A ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Virus Like Particle ◽

Iga Antibodies ◽

Nasal Secretions ◽

Sparing Effect ◽

Norovirus Gii

Norovirus (NoV) is a main cause of acute gastroenteritis across all ages worldwide. NoV vaccine candidates currently in clinical trials are based on noninfectious highly immunogenic virus-like particles (VLPs) delivered intramuscularly (IM). Since NoV is an enteric pathogen, it is likely that mucosal immunity has a significant role in protection from infection in the intestine. Due to the fact that IM delivery of NoV VLPs does not generate mucosal immunity, we investigated whether NoV genotype GII.4 VLPs coadministered with aluminum hydroxide (Al(OH)3) or monophosphoryl lipid A (MPLA) would induce mucosal antibodies in mice. Systemic as well as mucosal IgG and IgA antibodies in serum and intestinal and nasal secretions were measured. As expected, strong serum IgG, IgG1, and IgG2a antibodies as well as a dose sparing effect were induced by both Al(OH)3and MPLA, but no mucosal IgA antibodies were detected. In contrast, IN immunization with GII.4 VLPs without an adjuvant induced systemic as well as mucosal IgA antibody response. These results indicate that mucosal delivery of NoV VLPs is needed for induction of mucosal responses.

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Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.00574-16 ◽

2017 ◽

Vol 24 (3) ◽

Cited By ~ 8

Author(s):

Katharina Richard ◽

Barbara J. Mann ◽

Aiping Qin ◽

Eileen M. Barry ◽

Robert K. Ernst ◽

...

Keyword(s):

Francisella Tularensis ◽

Subunit Vaccine ◽

Lipid A ◽

Ex Vivo ◽

The United States ◽

Content Type ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Ifn Γ ◽

Schu S4

ABSTRACT Francisella tularensis, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated F. tularensis LVS or fully virulent F. tularensis Schu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4-V, respectively) protected fully against F. tularensis LVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection against F. tularensis Schu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti-F. tularensis IgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected more F. tularensis antigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death against F. tularensis Schu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-γ)-secreting activated helper T cells, IFN-γ production, and the ability of splenocytes to control intramacrophage F. tularensis LVS replication ex vivo. Active LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n. F. tularensis Schu S4 challenge (to ∼60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains.

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Gamma Interferon and Monophosphoryl Lipid A-Trehalose Dicorynomycolate Are Efficient Adjuvants for Mycobacterium tuberculosis Multivalent Acellular Vaccine

Infection and Immunity ◽

10.1128/iai.73.1.250-257.2005 ◽

2005 ◽

Vol 73 (1) ◽

pp. 250-257 ◽

Cited By ~ 21

Author(s):

Avi-Hai Hovav ◽

Yolanta Fishman ◽

Herve Bercovier

Keyword(s):

Mycobacterium Tuberculosis ◽

Lipid A ◽

Protective Efficacy ◽

Gamma Interferon ◽

No Production ◽

Adjuvant Effect ◽

Recombinant Antigens ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Ifn Γ

ABSTRACT In this study, we examined the immunogenicity and protective efficacy of six immunodominant Mycobacterium tuberculosis recombinant antigens (85B, 38kDa, ESAT-6, CFP21, Mtb8.4, and 16kDa) in a multivalent vaccine preparation (6Ag). Gamma interferon (IFN-γ) and monophosphoryl lipid A-trehalose dicorynomycolate (Ribi) adjuvant systems were used separately or in combination for immunization with the recombinant antigens. Our results demonstrate that immunization of mice with Ribi emulsified antigens in the presence of IFN-γ (Ribi+6Ag+IFN-γ) resulted after challenge with a virulent M. tuberculosis strain in a significant reduction in the CFU counts that was comparable to that achieved with the BCG vaccine (∼0.9-log protection). Antigen-specific immunoglobulin G (IgG) titers in the Ribi+6Ag+IFN-γ-immunized mice were lower than in mice immunized with Ribi+6Ag and were oriented toward a Th1-type response, as confirmed by elevated IgG2a levels. In addition, splenocyte proliferation, IFN-γ secretion, and NO production were significantly higher in splenocytes derived from Ribi+6Ag+IFN-γ-immunized mice, whereas IL-10 secretion was decreased. These findings confirm the induction of a strong cellular immunity in the vaccinated mice that correlates well with their enhanced resistance to M. tuberculosis. The adjuvant effect of IFN-γ was dose dependent. A dose of 5 μg of IFN-γ per mouse per immunization gave optimal protection, whereas lower or higher amounts (0.5 or 50 μg/ mouse) of IFN-γ failed to enhance protection.

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A Comparison of Intramuscular and Subcutaneous Administration of LigA Subunit Vaccine Adjuvanted with Neutral Liposomal Formulation Containing Monophosphoryl Lipid A and QS21

Vaccines ◽

10.3390/vaccines8030494 ◽

2020 ◽

Vol 8 (3) ◽

pp. 494 ◽

Cited By ~ 1

Author(s):

Teerasit Techawiwattanaboon ◽

Christophe Barnier-Quer ◽

Tanapat Palaga ◽

Alain Jacquet ◽

Nicolas Collin ◽

...

Keyword(s):

Survival Rate ◽

Subunit Vaccine ◽

Lipid A ◽

Protective Efficacy ◽

Protein A ◽

Subcutaneous Administration ◽

Protective Effects ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

The Impact

Leptospirosis vaccines with higher potency and reduced adverse effects are needed for human use. The carboxyl terminal domain of leptospiral immunoglobulin like protein A (LigAc) is currently the most promising candidate antigen for leptospirosis subunit vaccine. However, LigAc-based vaccines were unable to confer sterilizing immunity against Leptospira infection in animal models. Several factors including antigen properties, adjuvant, delivery system, and administration route need optimization to maximize vaccine efficacy. Our previous report demonstrated protective effects of the recombinant LigAc (rLigAc) formulated with liposome-based adjuvant, called LMQ (neutral liposome combined with monophosphoryl lipid A and Quillaja saponaria fraction 21) in hamsters. This study aimed to evaluate the impact of two commonly used administration routes, intramuscular (IM) and subcutaneous (SC), on immunogenicity and protective efficacy of rLigAc-LMQ administrated three times at 2-week interval. Two IM vaccinations triggered significantly higher levels of total anti-rLigAc IgG than two SC injections. However, comparable IgG titers and IgG2/IgG1 ratio was observed for both routes after the third immunization. The route of vaccine administration did not influence the survival rate (60%) and renal colonization against lethal Leptospira challenge. Importantly, the kidneys of IM group showed no pathological lesions while the SC group showed mild damage. In conclusion, IM vaccination with rLigAc-LMQ not only elicited faster antibody production but also protected from kidney damage following leptospiral infection better than SC immunization. However, both tested routes did not influence protective efficacy in terms of survival rate and the level of renal colonization.

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The Immunogenicity of Capsid-Like Particle Vaccines in Combination with Different Adjuvants Using Different Routes of Administration

Vaccines ◽

10.3390/vaccines9020131 ◽

2021 ◽

Vol 9 (2) ◽

pp. 131

Author(s):

Christoph M. Janitzek ◽

Philip H. R. Carlsen ◽

Susan Thrane ◽

Vijansh M. Khanna ◽

Virginie Jakob ◽

...

Keyword(s):

Aluminum Hydroxide ◽

Lipid A ◽

Antibody Responses ◽

Bacterial Protein ◽

Adjuvant Effect ◽

Water Emulsion ◽

Routes Of Administration ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Vaccine Antigens

Capsid-like particle (CLP) displays can be used to enhance the immunogenicity of vaccine antigens, but a better understanding of how CLP vaccines are best formulated and delivered is needed. This study compared the humoral immune responses in mice elicited against two different vaccine antigens (a bacterial protein and a viral peptide) delivered on an AP205 CLP platform using six different adjuvant formulations. In comparison to antibody responses obtained after immunization with the unadjuvanted CLP vaccine, three of the adjuvant systems (neutral liposomes/monophosphoryl lipid A/quillaja saponaria 21, squalene-in-water emulsion, and monophosphoryl lipid A) caused significantly increased antibody levels, whereas formulation with the three other adjuvants (aluminum hydroxide, cationic liposomes, and cationic microparticles) resulted in similar or even decreased antibody responses. When delivering the soluble bacterial protein in a squalene-in-water emulsion, 4-log lower IgG levels were obtained compared to when the protein was delivered on CLPs without the adjuvant. The AP205 CLP platform promoted induction of both IgG1 and IgG2 subclasses, which could be skewed towards a higher production of IgG1 (aluminum hydroxide). Compared to other routes, intramuscular administration elicited the highest IgG levels. These results indicate that the effect of the external adjuvant does not always synergize with the adjuvant effect of the CLP display, which underscores the need for empirical testing of different extrinsic adjuvants.

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