In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid

Gupta, Rajesh K.; Chang, Alice B.; Griffin, Paul; Rivera, Rachel; Siber, George R.

doi:10.1016/s0264-410x(96)00073-4

Cited by 78 publications

(37 citation statements)

References 21 publications

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“…In one specific case, aluminum adjuvant-adsorbed tetanus toxoid and HIV-gp 120 injected in vivo were rapidly released from the injection site. 42,43 This result is consistent with antigen desorption when exposed to interstitial fluid. 37 Most importantly, the desorbed antigen from the aluminum adjuvants should be assessed using various methods with specific mAbs to demonstrate the integrity of different epitopes.…”

Section: Discussionsupporting

confidence: 83%

Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment

Zhang

Yang

et al. 2015

Human Vaccines & Immunotherapeutics

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Most vaccines require adjuvants for antigen stabilization and immune potentiation. Aluminum-based adjuvants are the most widely used adjuvants for human vaccines. Previous reports demonstrated the preservation of antigen conformation and other antigen characteristics after recovery from adjuvanted Hepatitis B and human papillomavirus vaccines. In this study, we used a combination of various physiochemical and immunochemical methods to analyze hepatitis E vaccine antigen quality attributes after recovery from adjuvants. All biochemical and biophysical methods showed similar characteristics of the p239 protein after recovery from adjuvanted vaccine formulation compared to the antigen in solution which never experienced adsorption/desorption process. Most importantly, we demonstrated full preservation of key antigen epitopes post-recovery from adjuvanted vaccine using a panel of murine monoclonal antibodies as exquisite probes. Antigenicity of p239 was probed with a panel of 9 mAbs using competition/blocking ELISA, surface plasmon resonance and sandwich ELISA methods. These multifaceted analyses demonstrated the preservation of antigen key epitopes and comparable protein thermal stability when adsorbed on adjuvants or of the recovered antigen post-dissolution treatment. A better understanding of the antigen conformation in adjuvanted vaccine will enhanced our knowledge of antigen-adjuvant interactions and facilitate an improved process control and development of stable vaccine formulation.

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Section: Discussionsupporting

confidence: 83%

Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment

Zhang

Yang

et al. 2015

Human Vaccines & Immunotherapeutics

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“…Recent studies evaluating the impact of the kinetics of antigen and adjuvant availability on T-cell and antibody responses suggest sustained exposure of the immune system over a period of several days to both antigen and adjuvant molecules amplifies vaccine immunogenicity (11-13, 16, 17). However, parenterally injected soluble vaccines are rapidly cleared from the injection site and flush through the draining LNs in a time course of minutes to hours (10,23), and here we have shown similar rapid clearance of soluble vaccine components by efferent lymph flow following i.LN injection. To sustain exposure of the immune system to vaccines, parenteral immunization with antigen or adjuvants in controlled release formulations has been explored.…”

Section: Discussionsupporting

confidence: 66%

“…To sustain exposure of the immune system to vaccines, parenteral immunization with antigen or adjuvants in controlled release formulations has been explored. Polymer matrices releasing antigen over days or weeks following parenteral injection have been shown to robustly promote antibody responses (23,24) and biodegradable MPs loaded with TLR agonists can promote CD4 þ and CD8 þ T-cell responses, as well as antibody responses (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles

Jewell

López

Irvine

2011

Proc. Natl. Acad. Sci. U.S.A.

221

216

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Recent studies have demonstrated a simple, potentially universal strategy to enhance vaccine potency, via intralymph node (i.LN) injection. To date, intranodal immunization studies have focused on the delivery of unadjuvanted vaccines (e.g., naked DNA, peptide, or protein). We hypothesized that combining i.LN vaccination with controlled release biomaterials permitting sustained dosing of molecular adjuvants to the local tissue microenvironment would further enhance this promising vaccination strategy. To test this idea, we encapsulated the Toll-like receptor-3 ligand poly(inosinic:cytidylic acid) (polyIC) in biodegradable poly(lactide-co-glycolide) microparticles (MPs) designed to remain extracellular and release polyIC in the LN over several days. Intranodal injection of MPs increased persistence of polyIC in LNs compared to the same dose of soluble polyIC or polyIC formulated in nanoparticles, leading to increased accumulation of Toll-like receptor agonist in LNresident antigen presenting cells and more enduring dendritic cell activation. Intralymph node injection of ovalbumin mixed with polyIC-releasing MPs enhanced the humoral response and expanded ovalbumin-specific T cells to frequencies as high as 18% among all CD8 þ cells following a single injection (8.2-fold greater than the same vaccine given i.m.), a response that could not be matched by antigen mixed with polyIC-loaded nanoparticles or a 10-fold greater dose of soluble polyIC. Thus, i.LN immunization with slow release-formulated adjuvants may be a broadly applicable strategy to enhance therapeutic or prophylactic vaccines.C ompared to live attenuated pathogens, vaccines based on nonreplicating viral/bacterial vectors or subunit antigens offer enhanced safety but elicit weaker, less durable immune responses. Thus, enhancing the potency of these vector/subunit vaccines without sacrificing their excellent safety profile is a central focus of vaccine development. One strategy to enhance vaccine potency is to improve the delivery of antigen and adjuvant molecules to critical antigen presenting cells (APCs) in secondary lymphoid organs. In the "geographic" view of immunity, antigen which does not reach these sites for induction of primary immune responses is ignored by the immune system (1). Following traditional vaccine injection in peripheral tissues, soluble proteins or small particles (<50 nm) drain directly to lymph nodes (LNs), while cell-associated antigen or larger antigen particles access LNs by APC uptake and trafficking (2-4). Recently, intralymph node (i.LN) vaccination-injection of antigens/adjuvants directly into LNs-has shown great promise for vaccine delivery, improving the potency of DNA, RNA, peptide, protein, and dendritic cell-based vaccines (2). Studies have demonstrated as much as 10 6 -fold reductions in antigen dose (5, 6), 100-fold reductions in adjuvant dose (7), and enhanced protection with reduced side effects relative to traditional parenteral immunizations (2). Lymph node injection in humans is readily performed using ultraso...

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“…The adjuvant action of aluminum hydroxide was long attributed to its ability to adsorb antigens onto its surface, thus increasing the release time and therefore the duration of contact between an antigen and antigen-presenting cells. However, it was subsequently shown that adsorbed antigens are released within first few hours after the injection [26]. It has been shown that aluminum adjutants induce strong innate immune responses that consist of an influx of neutrophils, eosinophils, NK cells, CD11b+ monocytes and dendritic cells (DCs) to the site of injection [27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Tabynov¹,

Khairullin²,

Kydyrbayev³

et al. 2013

J Vaccines Vaccin

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We performed a randomized, blinded, dose-dependent placebo-controlled phase I clinical study of single administration of Refluvac®, a monovalent inactivated whole-virion vaccine against pandemic influenza А (Н1N1) pdm09 containing aluminum adjuvant, in healthy volunteers aged 18-60. Single intramuscular injection at doses of 3.75, 7.5, or 15.0 µg hemagglutinin (НА) identified no safety issues in adult volunteers (n=12 per group); no severe or serious vaccination-related adverse events were observed. Only mild/moderate local adverse events (n= 3/12, 25% in 7.5 µg НА arm,) and one moderate systemic reaction (n=1/12, 8.3% in 15.0 µg НА arm) were observed. In volunteers vaccinated at 3.75 µg HA, the proportion of subjects with 4-fold seroconversion was 75%, the level of seroprotection was also 75%, the antibody titer increase was 10.7-fold, and the geometric mean titer (GMT) of antibodies to А/H1N1p-dm09 was 53.4; for the 7.5 µg HA dose, the proportion of 4-fold seroconversion was 75%, the antibody titer increase was 32.0-fold, the GMT was 160.0, and the level of seroprotection was 75%. When administered at a higher dose (15 µg HA), the proportion of subjects with protective antibody titers increased from 75% to 83%; however, the GMT and antibody titer increase were not significantly different (P>0.05) to the group vaccinated at 7.5 µg HA. Phase II clinical studies of the 3.75 and 7.5 µg HA doses of Refluvac® vaccine should be performed in a larger cohort of healthy volunteers aged 18-60. The effective immunogenicity of low doses of Refluvac® vaccine may enable increased production of pandemic influenza vaccines, and thus provide more people with a safe, effective vaccine. Citation: Tabynov K, Khairullin B, Kydyrbayev Z, Sandybayev N, Stukova M, et al. (2013) [16]. Notably, the lowest НА content required to induce a sufficient immune response was seen when whole-virion or adjuvant-containing vaccines were used. The НА content is the most important limiting factor when developing a pandemic vaccine, as existing production capacities for seasonal influenza vaccines are rather limited and are unable to meet the worldwide demand for a pandemic vaccine. Thus, a higher number of doses of vaccines with low antigenic loads can be manufactured. Journal of Vaccines & VaccinationOn this basis, in order to create a pandemic vaccine to protect the population of Kazakhstan and neighbouring Central Asian countries, an inactivated whole-virion vaccine (Refluvac®) against Н1N1pdm09 containing aluminum hydroxide adjuvant was developed at the Research Institute for Biological Safety Problems (Kazakhstan). We previously demonstrated the safety and immunogenicity of this vaccine in preclinical studies conducted at research centers in Russia (The Research Institute of Influenza, Institute of Toxicology, Chemical and Pharmaceutical Academy) and Kazakhstan (The National Center for Expertise on Drugs) [17,18]. On the basis of these preclinical studies, Refluvac® vaccine was recommended for a phase I clinical study of single intra...

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In vivo distribution of radioactivity in mice after injection of biodegradable polymer microspheres containing 14C-labeled tetanus toxoid

Cited by 78 publications

References 21 publications

Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment

Comparable quality attributes of hepatitis E vaccine antigen with and without adjuvant adsorption-dissolution treatment

In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

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