Informatics Support for Vaccine Projects Using and extending the UCSC bioinformatics infrastructure

Informatics Support for Vaccine Projects

Using and extending the UCSC bioinformatics infrastructure

Motivation for UCSC Vaccine Work

Part of our increasing emphasis on the medical side of biomedical research.

Involves international collaborations. Potentially beneficial to greater numbers of

people than most drug-related research. Less profitable than drugs, so the

involvement of *public* research institutions such as universities is important.

Personal grudge against HIV. (JK is a San Francisco native.)

Helpful vaccine informatics support

Analysis to help find good molecular targets for vaccines.

Private databases to help collect and organize lab and clinical data.

Public databases and web works to help display and analyse the results of clinical trials.

Integrating in additional data from samples in clinical trials into database.






HIV Vaccine Database and Web Works

HIV Vaccine Database and Web Works

UCSC Status ReportUCSC Status Report






Longitudinal coevolution info

Hopefully will get sequence from representative infected subjects over multiple time points.

Ideally sequence would include both the virus, and from host antibody/T-cell receptor rearranged genes.

Does virus evolve from a more infective form (relatively exposed conserved binding sites on ENV) to a more immune resistant form (conserved areas more hidden inside of VAR regions)?

Genotype Information

For HIV there are 10-100 genetic variants that have a substantial effect on the progress of the disease.

Results on race and sex for GSID trial suggest that genetic variation may have an effect on vaccine response

Integrating in the information on 10-100 genomic regions on each subject is straightforward in existing software.

In our NHGRI-funded work we are developing systems to handle “association studies” that have information on 500,000 genomic SNPs.

Serum analysis data

It would certainly make sense to put the data from the serum neutralization profiling work into the same database.

Should be relatively straightforward and cheap to do. No new views should be required, just extensions of existing views.

Neutralizing antibody characterization?This data is likely to be only on a very

small subset of subjects.Best presented in a different view, one

that relates to the 3-D structure of the protein.

Perhaps best done by a good informatics person hired into Phil’s lab rather than by genome bioinformatics group.






Humoral Response Targets

Want externally accessible parts of virus that don’t mutate too quickly

Variable regions of env proteins make this a challenge with HIV.

Is there a pattern to the more infectious early forms? Antibodies against somewhat buried regions that are

conserved, like receptor binding domains, are neutralizing, but relatively unlikely to develop against normally folded env.

Engineering antigen that exposes receptor binding domains more easily than native ENV?

Make cocktail of diverse, common, env forms, and update vaccine yearly like the flu?

Cellular response targets

Want to target conserved regions, but they don’t need to be exposed on surface.

Conserved peptide fragments *do* need to present on MHC I.

Since MHC I is so variable, may need to make immunizing peptides correspond to HLA haplotypes of person being vaccinated.

A vaccine that targeted *both* humoral and cellular responses would be a good thing!

Conservation work

UCSC informatics could do the conservation work, but the Utah group is doing a very good job of both this and the population genetics. For now suggest they generate multiple alignments and analysis, UCSC just do display web works.






Whether to do databases for organizing data during trials? Pros

UCSC has very effective software development team and strong interest.

We’re aquiring clinical database management expertise as part of NHGRI funded “medical sequencing” projects. This includes handling HIPPA.

Cons Interfacing with the FDA etc. is painful. It would require substantial expansion of the group.

Might spread management too thin. Conclusion - see what other groups can do

this well and want the work before deciding.

Musings on a vaccine strategy

Make antigen cocktail against a dozen of the most prominent ENV surface varients, and a “conserved bits exposed” version of ENV.

Mix in engineered replication-deficient virus (maybe influenza based) that encodes conserved peptides MHC likes to display, also encodes cytokines to really get immune system’s attention without resorting to painful adjuvents.

Software Process

Hire good people, train them well, and rely on their good judgement.

Design in small groups.Code in a peaceful setting.Pair up once a week to proofread each

others code and exchange tips.Separate quality control group tests

code and data.Release updates every two weeks.

UCSC Development Team

Possible vaccine informatics

Extend database with additional data GSID and Berman lab are now generating. ($)

Genotype analysis support. ($) Analysis software to help understand

coevolution of virus/immune response and database to store such studies. ($$$)

Create database system and a curator that would gather post-publication data from HIV research community in general. ($$$$)

Vaccine clinical trial support? ($$$$$$$$)($ = ~100k + 50k/year direct)

Documents

Informatics Support for Vaccine Projects Using and extending the UCSC bioinformatics infrastructure