Wednesday, 10 May 2017 16:39

Scientists Identify Novel Technique To Build Better Vaccine Adjuvants

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Published in mBiosphere

The World Health Organization has touted the urgent need to develop more effective vaccines for various infectious diseases worldwide. These include HIV/AIDS, malaria, and tuberculosis, as well as debilitating, neglected tropical diseases such as respiratory syncytial virus (RSV).

At the University of Maryland, Baltimore, researchers are using a practical method, bacterial enzymatic combinatorial chemistry (BECC), to generate functionally diverse molecules that can potentially be used as adjuvants. Vaccines often combine a well-characterized recombinant protein antigen with an adjuvant to increase the immunogenic response of the vaccine. To date, vaccine adjuvants have been developed using an empirical trial-and-error approach. Aluminum gels and salts have been used since the 1930’s, and monophosphoryl lipid A (MPLA), a modified glycolipid from the outer membrane of a bacterium, has been used since 2009.

“Using BECC, we have identified many promising compounds that could potentially serve as adjuvants for vaccines,” said Robert Ernst, PhD, professor in the Department of Microbial Pathogenesis in the School of Dentistry and an adjunct professor in the School of Medicine, at the University of Maryland, Baltimore. He recently published results from his work in the journal mBio and said his team has formulated the molecules with various vaccines, including one for RSV, with positive results.

mBio: Rationally Designed TLR4 Ligands for Vaccine Adjuvant Discovery

The envelope of gram-negative bacteria is composed of two distinct lipid membranes, with the outer consisting predominantly of lipopolysaccharides (LPS), of which lipid A is a key component. Lipid A is the anchor that holds the LPS molecule in the bacterial membrane. Roughly fifteen years ago, scientists learned that lipid A is recognized by the toll-like receptor 4 (TLR4), which is instrumental in determining an individual’s immune response. For some time, scientists have known that some bacteria make specific structures of lipid A that are very pro-inflammatory. The body recognizes them easily, quickly, and at very low amounts. Work in Dr. Ernst’s lab, however, showed that many other bacteria had lipid A molecules that were not immunostimulatory.

The researchers used the normal bacterial LPS biosynthesis pathway in gram-negative bacteria to synthesize unique lipid A structures based on the presence or absence of specific phosphate, acyl, and carbohydrate groups from a variety of species, to generate novel, rationally-designed lipid A molecules. “Bacteria are very good at what they do. Their enzymes are very specific for which modification can be synthesized, so we engineered bacterial strains that produced the molecules we wanted,” said Dr. Ernst. The researchers applied BECC within an avirulent strain of Yersinia pestis to develop structurally distinct LPS molecules and then screened them for their ability to induce pro-inflammatory responses.

Lead candidates demonstrated potent immunostimulation in mouse splenocytes, human primary blood, mononuclear cells, and human monocyte-derived dendritic cells. “We have narrowed down our list of 50 to 70 molecules down to approximately six that have potential adjuvant activity,” said Dr. Ernst. “What we are finding is that at this point, they are probably a bit better than the current TLR ligand which is MPL, so we are moving in the right direction.” The molecules will be tested in a wide variety of vaccine formulations with different potential antigens, both viral, bacterial, and parasitic.

The view for the future, said Dr. Ernst, “is that someone could say I want a TH1 or TH2 response or some kind of adaptive immune response, and we can say, ‘ molecule X should be good or this is molecule Y that may be better for this antigen,’ and you can start to mix and match potentially in a checkerboard to potentially find the best combination.”

The new system has the potential to generate a diverse array of potential vaccine adjuvants and an opportunity to build a better vaccine. Currently approved adjuvants in human vaccines skew the immune response toward T-helper 2 immunity, but adjuvants that spark a TH1 immune response may be more effective. TH1 responses are characterized by cytotoxic T-cell response, whereas TH2 responses are characterized by the production of interleukin 4 and antibody isotypes/subclasses that strongly promote complement fixation and opsonization of pathogens (where bacteria are targeted for destruction by phagocytes).

The researchers are ramping up to write up a contract to the National Institute of Allergy and Infectious Diseases to move the molecules towards licensure. “It is a lot of work, looking at toxicities, and trying to rule out all of the adverse responses. We haven’t had any failures in moving these forward,” said Dr. Ernst. “Several molecules have moved into some very nice data in a number of animal models, both with viral and bacterial antigens. If we want to get to FDA licensure, that would be great.”

mBio is an open-access journal of the American Society for Microbiology.

Last modified on Thursday, 11 May 2017 15:45

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