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PHADs, or Phosphorylated Hexa Acyl Disaccharides, are a type of synthetic lipid A-like molecule used as Toll-like receptor 4 (TLR4) agonists. 

PHAD, 3D-PHAD, 3D(6-acyl)-PHAD are very similar and only vary in the presence and location of acyl chains. PHAD has a total of 6 acyl chains connected to the disaccharide backbone. 3D-PHAD only has 5 acyl chains, missing the 3rd connection to the disaccharide backbone. 3D(6-acyl)-PHAD has a total of 6 acyl chains with the additional chain connected via the ester group on the far right. 

The role of PHADs is particularly interesting because they are designed to mimic the immune-stimulating effects of bacterial LPS (lipopolysaccharide), but typically with a lower toxicity profile. This makes PHADs an attractive option for vaccine adjuvants because they can enhance immune responses without causing the severe inflammatory reactions often associated with natural LPS. 

Toll-like receptors (TLRs) are a class of proteins that recognize specific patterns found on microbial pathogens. When TLRs bind to these patterns, they trigger an innate immunity response - the body's first line of defence against pathogens. Their discovery was honoured with the 2011 Nobel Prize. 

The use of TLR agonists as adjuvants is particularly significant in vaccine development. Adjuvants are substances included in vaccines to enhance the immune response to the vaccine's antigen (the part of the vaccine that stimulates the body's immune response to produce immunity). By mimicking the structural components of pathogens, TLR agonists effectively "trick" the immune system into reacting as if a real infection was present, thus enhancing the overall immune response elicited by the vaccine. 

Several vaccines incorporate TLR agonists as adjuvants, including those for cervical cancer, shingles, and Hepatitis B. 

Current adjuvant systems used in vaccine research and development include Glucopyranosyl Lipid Adjuvants (GLA-LSQ, GLA-SE, GLA-AF) which were developed by Access to Advance Health Institute, second group of systems - Army Liposome Formulations (ALF, ALFA, ALFQ) were developed by Walter Reed Army Institute of Research, one more group of Adjuvant Systems (AS01, AS04) is the only one in the marketed vaccines and were developed by GSK.

*this content is derived from a broad spectrum of research papers

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. It is contributing to the structural integrity of the bacteria and protecting the membrane from certain kinds of chemical attacks. When bacteria breach our initial defence barriers it induces a strong immune system response targeting several PRRs (pattern recognition receptors) including TLR2 and TLR4. LPS is a potent activator of the immune system and pyrogen (agent that causes fever). In severe cases, LPS can play a role in causing septic shock. 

Monophosporyl Lipid A (MPLA) is bacterial derived detoxified version of Salmonella minnesota LPS. MPLA specifically targets Toll-like receptor 4 (TLR4) on immune cells. Activation of TLR4 triggers a cascade of signaling pathways that lead to the activation of innate immune responses. 

PHADs (Phosphorylated Hexa Acyl Disaccharides) were developed as a synthetic alternative to the bacterial-derived MPLA, given its desirable vaccine design profile of low reactogenicity and high efficacy.