Matt Gethers/20.380 HIV Project/Meeting Notes/4.29.09 Peer Critique

Peer Critique Meeting

Matt's Reading: Design

• There are a few small issues: typo on page 10 "furhter" as well as missing figure numbers throughout the section.
• One point not addressed in the design section (though maybe elsewhere) is the need for record-keeping if several courses of the vaccination is necessary.
• Major criticism: Argument is that by targeting a highly conserved epitope, you can eliminate all quasispecies at once. The idea is, of course, that a highly conserved epitope is so critical that the virus cannot survive without it, so it will be present across all strains. You then go on to do some modeling/combinatorial work to predict common escape mutants. These escape mutants should also require this highly conserved epitope in order to be viable (otherwise the epitope isn't really that conserved). So either the planning for escape mutants should be unnecessary or if there are escape mutants, that means the domain you've targeted isn't so highly conserved (and suggests that the quasispecies problem may not be solved by that epitope). Either way, I think that planning for the possibility of escape mutants undermines the "broadly neutralizing antibody" thrust. Even so, if you were to plan for these mutants, then the antibodies you develop to attack the mutants could be similarly ineffective. You could have an indefinite number of rounds of different antibodies if you allow for the possibility of escape mutants. If this argument were to be effective, there would have to be some data/modeling to show that only one round of escape mutant-directed antibodies would increase the probability of ablation manifold.
• Never clearly define what an adjuvant is. "Adjuvants are (fill in the blank) used to promote antigen presentation to dendritic cells..."

Jessie: In Vivo/Clinical

• Safety/Tolerability Tests in Chimpanzees - While you can get a general idea of appropriate dosage from rodent studies, perhaps it may also be useful to vary the dosages among some of your chimpanzees. At the same time, you may not need to have 5 controls. Since chimpanzees are so costly, it may be okay to just have 3.
• Immunogenicity Tests - Go into more detail about the certain assays. For example, how exactly would an ELISA determine anti-E2 antibody levels? While you can assume people reading the paper understand the various assays, some people may simply understand the ELISA to be an assay that tests the binding kinetics, so you need to do more than just state what assays you will use.
• Clinical Trials -
• Overall - Sentences tended to be a little too choppy in the clinical trials section. Once again, it may have been better to explain the use of certain assays with a short phrase as opposed to just stating their use.