Biomedical subjects

M Balusubramanian

Publications and source records attributed to M Balusubramanian.

5 recordsLinked to original sources

PubMed1998

Development of adjuvant-active nonionic block copolymers.

Nonionic block copolymers are surfactants synthesized using propylene oxide (PO) and ethylene oxide (EO) which are organized as 'blocks' of polyoxyethylene (POE) and polyoxypropylene (POP). These copolymers can be designed and synthesized using variable amounts of the PO and EO and with differential arrangement of the POP and POE blocks so that individual products have unique physicochemical properties. The copolymers that have been most thoroughly evaluated in vaccine research are linear with the polymer blocks organized as POE-POP-POE. Low molecular weight (MW) copolymers, 3-6 kDa, of this type have been used in oil-based emulsion formulations, whereas high-MW copolymers, >9 kDa, can be used in aqueous formulations. The adjuvant activity of nonionic block copolymers is influenced greatly by the size of the POP core block. As the size of this block is increased so is the adjuvant activity of the copolymer; peak activity is achieved using copolymers with POP cores that are 12-15 kDa. However, adjuvant activity is also affected by the amount of POE with low concentrations, 5-10%, being optimal. The type of immune responses produced is also influenced by the POE content. Copolymers with 10% POE preferentially augment Type 2 helper T-lymphocyte responses which support antibody responses, including mucosal antibody responses. Copolymers with <10% POE augment both Type 1 and Type 2 helper T-lymphocyte responses, which support a broader range of antibody responses and cellular immune responses. This property may allow for vaccines to be 'customized' by using adjuvant-active nonionic block copolymers that will augment the most appropriate types of immune responses.

Journal Article↗

PubMed1998

Design and development of adjuvant-active nonionic block copolymers.

Nonionic block copolymers are surfactants synthesized using propylene oxide and ethylene oxide, and they can be designed so that individual copolymers have unique vaccine adjuvant properties. We have designed and produced nonionic block copolymers based on high molecular weight (MW), 9-15 kDA, cores of poly(oxypropylene) (POP) coupled with smaller poly(oxyethylene) (POE) end blocks. Copolymers synthesized with less than 10% (w/w) POE will spontaneously assemble into 300 nm-3 microm micelles or microparticles in aqueous solutions at physiological pH, and when formulated with protein, complex microparticles consisting of both the protein and copolymers are formed. The adjuvant activity of nonionic block copolymers is influenced by both size and POE content; maximal activity is associated with low POE content, 5-10%, and a molecular size of 11-12 kDa. The type of immune response produced is also influenced by the POE content. Copolymers with 10% POE significantly augmented Type 2 helper T-lymphocyte responses whereas copolymers with lower POE contents augmented both Type 1 and Type 2 helper T-lymphocyte responses. This property allows for vaccines to be "customized" by using adjuvant-active nonionic block copolymers that will augment the most appropriate types of immune responses.

Animals↗

PubMed1998

Use of nonionic block copolymers in vaccines and therapeutics.

Nonionic block copolymers synthesized from ethylene oxide and propylene oxide were developed specifically for use as surfactants. Because the sizes and relative positions of the hydrophobic polyoxypropylene (POP) and hydrophilic polyoxyethylene (POE) blocks can be altered during synthesis, copolymers with significantly different surfactant characteristics can be produced. Copolymers of this type are currently used as excipients in a wide variety of pharmaceutical products where they act as emulsifying, wetting, thickening, stabilizing, and dispersing agents. Copolymers with unique physicochemical properties have recently been developed through the use of new manufacturing and purification techniques, and these copolymers are being used as drug-active and drug-delivery components. In this review, we summarize the current status of these new copolymers in terms of research and product development. This includes the use of new, high molecular weight copolymers as vaccine adjuvants and as vaccine-delivery vehicles. The use of purified, pharmaceutical-grade copolymers as anti-infectives and as antibiotic-delivery systems for the treatment of established bacterial and viral infections is also reviewed. These novel uses for copolymers are significantly different from the excipient uses common to this type of product and demonstrate the widespread utility of synthetic surfactant polymers.

Adjuvants, Immunologic↗

PubMed1998

Systematic development of a block copolymer adjuvant for trivalent influenza virus vaccine.

The current influenza virus vaccines induce systemic humoral immunity and short lived cellular immunity in young adults. Unfortunately these vaccines are only 50% efficacious in the elderly (> 65 years) and high risk groups of the very young. The use of a vaccine adjuvant to correct this deficit would therefore be very beneficial to these population groups. We have developed high molecular weight synthetic non-ionic block copolymers with adjuvant activity. These copolymers are compatible with, and active in, aqueous, physiological formulations in which they spontaneously assemble into 500-3000 nm particles. By varying both the molecular weight and the proportions of hydrophilic and hydrophobic components of the molecule, we have designed the optimal copolymer adjuvant for use with influenza hemagglutinin. This copolymer, termed CRL-1005, was investigated for its ability to augment the immune response of mice to the commercially-available human influenza vaccine, Fluogen. Co-formulation of CRL-1005 with the vaccine resulted in markedly increased antibody titres measured by both ELISA and the functional haemagglutination inhibition assay, indicating that critical immunogen epitopes were not destroyed. A single dose of copolymer and vaccine produced both long term rising antibody titres (six months) and primed for a potent secondary response. This high molecular weight copolymer is non-toxic and should therefore be well suited for widespread use.

Adjuvants, Immunologic↗

PubMed1997

Increasing the immunogenicity of a trivalent influenza virus vaccine with adjuvant-active nonionic block copolymers for potential use in the elderly.

High molecular weight nonionic block copolymers consisting of a large hydrophobic core made from repeat oxypropylene units and smaller hydrophilic blocks of oxyethylene repeat units were evaluated as adjuvants in experimental influenza virus vaccine formulations. The goal was to identify a copolymer that would increase the immunogenicity of the commercial Fluogen trivalent influenza virus vaccine. Vaccine experiments done using BALB/c mice provided data that allowed us to identify a copolymer that increased both antibody titers specific for total virus proteins as well as antibodies with hemagglutination inhibition (HAI) activity. This copolymer, termed CRL1005, increased the production of IgG1, IgG2a and IgG2b which suggested it increased the activity of both Type-1 and Type-2 T-helper lymphocytes. The CRL1005 copolymer was tested further in rhesus monkeys with similar results. Levels of antibodies specific for total virus protein preparations were increased as were HAI antibody titers following vaccination with the copolymer-supplemented Fluogen vaccine. Thus, the CRL1005 copolymer adjuvant appears to be compatible for use with the current generation of inactivated viron-based influenza vaccines and useful for increasing the immunogenicity. A more potent influenza virus vaccine could well be more efficacious in the aged segment of our population than current vaccines.

Adjuvants, Immunologic↗