06 - February 27, 2013.docx

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Cell and Systems Biology
Gray- Owen

06 – February 27, 2013 Vaccine trials – success and failures Application of vaccines in humans General rules – type of immune response that certain types of vaccines can elicit Extract protein as antigen – or genetically engineer protein in cell culture system, used as protein When inject protein, get neutralizing antibodies – in contrast to vaccine where vaccinate with actual virus particle A live virus – poxviruses and adenoviruses usually – this induces more cellular immunity – CTL and ___ Immune response against virus – use virus vector Immune response against bacteria or toxin – better use protein strategy Know epitopes that T cell responds to – make peptides to match that epitope – to match vaccine strategy – if get peptides alone, not very immunogenic, but add lipid, better immunogenicity DNA plasmids that express antigens – safe, because not infectious – proteins seems to be best at giving antibody responses Vaccines elicit – Vaccine wanted to prevent person from getting infected with infectious agent = sterilizing immunity Antibody binding to virus before entering cell Non-sterilizing – infected but no disease – maybe get localized replication of infection then immune system controls infection and eradicates it – cellular immunity – cytotoxic T lymphocytes play role in non-sterilizing immunity Vaccine give sterilizing or non-sterilizing immunity – does not matter clinically unless do not get disease Can get herd immunity with both kinds of immunity Human papilloma virus DNA virus – infects surface epithelial cells – enveloped – creates proteins that make geometric structure – capsid – protein when produced, self-organizes – lots of genotypes 6 and 11 cause warts; other genotypes written can cause warts that can lead to cancer Success story – does not kill cell infected – proteins self-assemble into particles that look like virus Good for vaccine development because want to mimic actual infectious agent HPV vaccines – two pharma companies Alum is one of FDA approved adjuvants Find population that can do clinical trial in – want population with high incidence of disease – want to make sure most people get effect of vaccine – so can see difference – high incidence of disease Sexually active population with high prevalence of HPV infection – vaccine and placebo (just adjuvant) Do they develop endpoint? Warts, cervical cancer (but cancer takes very long to develop – look for precancerous lesions), look for virus Need long term follow-up to look for rates of cancer development between two arms – need to follow patients Gardasil trial – Intention to treat analysis – if drop out of trial, counted as a negative result (no protection) – people included regardless of whether they have HPV or not – already having HPV, so vaccine may not work – for many virus infections, once get infection, antibodies may not work against virus infection Per-protocol analysis – looks at all the people that have completed the trial - In the experimental group, one person got endpoint In intention to treat analysis – so if have previous HPV, vaccine not necessarily good at protection 219, 266 in the placebo group – endpoint Graphs – Kaplan Myer curve – look at time and cumulative incidence of dysplasia – and see that intention to treat, there is a difference and in the per-protocol analysis, greater difference HPV L1 VLPs mechanism of protection – seem to give protection against cancer of the cervix – some people have pre-existing HPV infection prior to vaccination Did the study without knowing mechanism – just assumed that Old way – inactivate agent and vaccinate to see if has an effect Think it’s antibodies that is mechanism – IgG and IgA: IgG can cross genital tract and provide protection HPV vaccine – how long protection lasts Antibody levels drop with time but higher than actual infection – why is it that natural HPV infection produces no antibodies? If get vaccinated, and get re-exposed to HPV – will re-exposure to HPV boost immune response to HPV antigens Easy to make – capsid is rigid structure, which is easy to make antibodies against; versus enveloped viruses’ antibody responses are difficult to make because envelope not rigid HIV transmission simplied – mucosally transmitted virus – felt that HIV comes into contact with mucosa and some virus gets across mucosa and infects activated T cell, which makes more viruses and they infect other cells – so obviously want vaccine that prevents first event from occurring Neutralizing antibodies work where barrier is; CTL response works where the infected activated T cells are Neutralizing antibodies work there because viruses is free and accessible to antibody; CTL Work on viruses in the infected cell (activated T cell) Global distribution of different subtypes – lot of variability in subtype based on genetic sequence – all subtypes different from each other 25% - vaccine antigen must cover all these genetic strains HIV variation – Large – HIV – in one country Small tree – influenza HIV has more genetic variability than influenzAVIRUSES First vaccine trial against HIV in 2003 – VaxGen trial – used protein – used GP120 protein from 2 different virus strains – tested vaccine in population that had high frequency of different virus strains – followed people for two years and endpoint was percentage of people that developed HIV infection after two years – five point eight percent of placebo group Vaccine efficacy is ZERO – statistics – efficacy range from minus twenty-two – zero efficacy Used monomeric GP120 – GP120 forms trimmers on the virus but didn’t use trimolecular complex in vaccine If given intramuscular, do not make enough IgA Vaccine was designed to make antibodies TANGENT WHA TIS YOUR GROUP? WHAT IS YOUR ENDPOINT? Hen designing trial, decide beforehand what statistically analysis will be done Multiply p-value by six because did six different analyses CTLs can also control viruses – CTL vaccine – with natural infection, get virus in the blood and certain levels of virus in the blood that are being partially controlled by immune system – in HIV, make strong CTL response, can control virus substantially to lower the set point – can still be infected but can control virus to such level that there’s very little virus in the body to cause damage Damage may be caused – but transient Induce only CTL response – so only put antigens that are not on the surface of the virus in the vaccine Make vaccine against HIV not containing envelope proteins – so antigens expressed are not antigens – so what other antibodies made, would not neutralize the virus – so this vaccine was to test CTL – would T cell immune response work? Pre-clinical work before testing in humans – so did some work in the SIV model Vaccinate with DNA – vaccinate w
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