Discovery heralds better adjuvants
immune response to an antigen which have been used for over 80
years - are beginning to be understood by researchers who believe
more effective adjuvants can be designed.
And it may also be possible to design adjuvants that reduce or remove the risk of causing atopic disease, such as atopic dermatitis or asthma. One hypothesis is that adjuvants such as alum can actually increase this risk.
The researchers report in the June 18 issue of Science that the most common adjuvant, alum, provokes a previously unrecognised group of immune-system cells to secrete the protein interleukin-4, which primes B cells for a better response to the vaccine.
The team from the National Jewish Medical and Research Centre were investigating a process known as MHC class II signalling, which occurs between B cells and T cells.
When properly stimulated, B cells mature into plasma cells, which release antibodies, one of the immune system's major disease fighting tools.
Researchers noticed that B cells must be primed if they are to be stimulated through this signalling pathway. The abscence of priming will cause B cell inactivity or even self-destruction. Priming, however has only ever been shown in cell cultures.
The study showed the inclusion of alum could prime B cells in mice and that cells bearing a marker known as Gr1 appeared in the spleen shortly after the injection of alum into mice. Gr1 is a marker found on a variety of immune system cells, including granulocytes.
The researchers demonstrated that the Gr1 cells secrete interleukin-4 and that both the Gr1 cells and the interleukin-4 are necessary for the priming of the B cells. When they inactivated the Gr1 cells, mice responded to a vaccine containing the adjuvant with fewer B cells and fewer antibodies.
John Cambier, chairman of the integrated department of immunology at National Jewish and the University of Colorado Health Sciences Centre told DrugResearcher.com: "It is unclear how alum provokes Gr1+ cells to move to the spleen and produce IL-4. Since these cells can be generated from bone marrow cells by culture in GM-C3F and we can find these cells in the peripheral blood shortly following alum injection."
"We hypothesize that alum may induce production of some cytokine at the site of injection that functions to stimulate release from marrow and maturation of the cells in questions."
"We know something about mode of action and search for other compositions that induce the IL-4 secreting cell without side effects."
"Since we know something about mode of action, we can search for other compositions that induce the IL-4 secreting cell without side effects."
However, he stressed that there is a need to prove the existence of an equivalent function in humans. And unfortunately the GR-1 marker does not occur in humans depriving researchers of an important exploratory tool.
"We are devising strategies to study the phenomenon in humans and hope to collaborate with individuals involved in vaccine trials," said Cambier.
Avoiding atopy
Talking about the benefits this discovery could bring, particularly in children who make up the majority of vaccine recipients, Cambier said:
"If in the human alum has its effect by inducing IL-4, it is possible that alum immunisation promotes Th2 skewing increasing the likelihood of atopic disease. This may be a contraindication for alum in babies. However, knowing how alum works should allow us to make better adjuvants. This will clearly benefit children."
Vaccines containing dead organisms (inactivated vaccines) or pieces of the infectious organisms or their toxins (acellular or recombinant vaccines) generally need adjuvants to boost their effectiveness.
Despite its age, alum remains the most widely used adjuvant, and is the only adjuvant approved for use in the US for routine preventive vaccines. Although alum helps boost antibody responses to vaccine antigens, it is a relatively weak adjuvant for many antigens and is difficult to prepare.
Antigens, normally proteins, are physically precipitated with hydrated insoluble salts of aluminum hydroxide or aluminum phosphate. This process is highly volatile and can be critically influenced by diverse factors including the concentration of materials, presence of salts, and temperature.
This has led immunotherapeutic companies like Corixa, to develop new adjuvants that can be used to boost immune responses after a vaccine is administered.
Corixa's MPL is a derivative of the lipid A molecule found in Gram-negative bacteria that is currently in development in allergy, cancer and infectious disease targets.
The company is now developing synthetic components in building an even broader vaccine adjuvant platform with considerable potential for the prevention and treatment of human diseases. Its small molecule synthetic adjuvant, RC-529, is in Phase III clinical trials in Argentina as part of a hepatitis B vaccine being developed by Rhein Biotech.
Cambier revealed that he hoped his discovery would be noticed by drug companies who may be interested in exploiting this cell for cellular and other vaccine developments.
