Informatics Support for Vaccine Projects

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Informatics Support for Vaccine Projects

• Using and extending the UCSC bioinformatics
  infrastructure

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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.)

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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.

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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.

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HIV Vaccine Database and Web Works
UCSC Status Report
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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.

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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)?

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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.

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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.

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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 Phils lab rather than by genome
  bioinformatics group.

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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.

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Humoral Response Targets

• Want externally accessible parts of virus that
  dont 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?

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Cellular response targets

• Want to target conserved regions, but they dont
  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!

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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.

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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.

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Whether to do databases for organizing data
during trials?

• Pros
• UCSC has very effective software development
  team and strong interest.
• Were 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.

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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 systems attention
  without resorting to painful adjuvents.

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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.

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UCSC Development Team
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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)