I need to design a peptide vaccine which act against a pathogen. This pathogen can have several type of proteins like location: secretory, membrane bound, cytosolic..or funtionally: virulence, structural, metabolic..What should be the criteria for selecting the best protein candidate for peptide vaccine development?
Hi Deepiyoti
Unfortunately the immune system of real animals do not know about or care at all about the rules and theories we have.
First, it makes little sense to make a vaccine against a single bacterial isolate.
In my experience the first step is always understanding the diversity and pathobiology of your isolate group "species". Currently the initial step is to pick a couple of relatively stable genes such as cytochrome ubiquinol oxidase I and design a PCR test for your bacterial isolates. Then sequence all the PCR products you get and create a guess at the diversity and relationships in your group. You can do MLVA too and compare results.
Then it is time to do some smartly chosen genome sequencing of isolates to get an accurate measure of the diversity of your group of isolates and thier gene content. Line up all the genomes and study diversity, core genomes, plasmids and islands. Then you can start looking for potential candidates based on gene location and predicted function.
Next it is time to ask yourself, "does this bacterial group burn down the house to keep warm?" OR is it a trigger pathogen? If it seems to "burn down the house" meaning it spreads through the host population like a fire, almost always causing illness and death... Then there is a good chance you can find a few bacterial gene products that will be protective. If the bacterial isolates can colonize the host and live for years without causing issues but can be triggered to cause disease, then chances are making a protein based vaccine will not be protective as the bacterial diversity of the group will be too high and the isolates will have a repitiore of methods to blunt host humoral immunity. It can be done, but it will be much harder and the vaccine may only work against some members of the group. You may need 10 vaccines in different combinations for protection against the whole group.
It is possible to model the immunogenicity of a given protein in-silico using predicted MHC groove interactions but I don't have enough confidence in this yet to exclude or focus on any given protein.
And immunogenicity does not equal protection... And sometimes it makes things worse. If the bacteria have a long history with the host there may be natural selection for a strong humoral immune response or no immune response that may be appropriate or inappropriate.
And last ask yourself if your disease condition is really a polymicrbial interaction, or groups of isolates battling for the same niche on the host with disease a peripheral consequence.
I completely agree with Glenn, just would like to add that you Need to know what kind of immune respone you would like to elicit: humoral, cellular, or both. Thus, it depends on the pathogen and its Habitat, route of infection etc. This again will have major influence on the choice of adjuvant you need to employ.
Once you select peptide candidate you will need to link the peptide to a protein carrier. Early on BSA, OVA & KLH are often used but for clinical development you will need an acceptable carrier protein like TT or CRM197.
Instead conjugation to protein carrier you can synthesize peptides in form of MAPs. Four peptide MAP had shown very nice results.
Agreed with above suggestions!!
Epitopes should be accessible on the surface of protein or better secretory for antibodies to interact. Therefore, Membrane bound and secretory are preferred for Humoral immunity.
Cell mediated immunity (CMI) needs processing, therefore it is better we our peptide is protected from lysosomal and proteosomal cleavage.
The pathogen itself may reside intracellular, therefore, we should also consider the property of pathogen.
Virulence factor are always a plus for selection.
Hope it may help you !!!
Good luck,
Sandeep
Hello Deepjyoti Kumar Das
The criteria for selecting a protein candidate is a huge study and infact, turns out to be crucial in determining your vaccine efficacy.
Rather than being merely surface available, it is necessary for the candidate to be an effective immune-evoking molecule. Be it a glycoprotein, liporotein or a secretory protein for that matter, the main objective is that the protein candidate should effectively evoke a response. This can be known by literature survey, for selecting the best ones based on previous works done on the organism and its pathogenicity. But, it doesnt stop here. The protein candidate chosen should also fulfil additional criteria such as , should be antigenic, should be a non-allergen, should possess high immunnogenicity, should be promiscuous and also, it should cover the supertypes inimmune molecules of most of the world population, in order to be effective across all ethnicities.
If all these criteria are met, the protein has to be then assessed based on its structural features such as stability, flexibility, lesser number of transmembrane helices etc.
The ones showing the best results can be chosen as potent protein candidates.
Hope it helps.
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