Immunity ≠ Immunological Memory

Rolf Zinkernagel University of Zurich

IMI Stakeholder Forum - 13 May 2013 - Brussels

• Protective vaccines imitate co-evolution of infectious agents and hosts. • We cannot do better than evolution by using the same tools, only when introducing ‘new’ tools (antibiotics, antivirals, autoantibodies, behavioural changes) • Vaccines against solid tumours (carcinomas, sarcomas) and chronic persistent infections are theoretically not impossible but practically highly unlikely!

Vaccines Not successful available

Polio 1, 2, 3 TB bact. toxins Leprosy measles HIV Haem. infl. malaria (cholera)

Neutr. / effector T cells opsonising antibodies antibodies igG (IgA)

IMMUNITY

• "innate resistance" > 95 % • Ab in eggs • protective memory via Ab (vaccines) • TB: no vaccine • autoimmunity > 30 y, female > male 5 : 1 • tumors > 30 years • Is what we measure biologically important ? (e.g. acad. memory: earlier + greater)

CTL ELISA

nAb

Immunity Immunology Protection

• ‚Memory‘ • Small pox • quicker - higher • Poliomeningitis • Measles • HIV, malaria - • Tuberculosis ± Antibody Memory after immunization with VSV

a) neutralizing antibodies b) ELISA

12 12

)

10 ) 10

2 3

8 8 40 40 log

10 10 log 6 -

- 6 NP binding NP - 4

IND neutralizing IND 4

-

IgG IgG ( IgG ( 2 VSV 2 VSV 0 0 0 20 100 200 300 0 20 100 200 300 days after immunization days after immunization

Why immunological Memory ? Protection (immunity) counts ! • Earlier + better • If first infection survived no need for memory • If first infection kills no need for memory • All vaccines that function protect via preex. neutr. antibodies? (autoantibodies ?) • Protection is antigen dependent

Theoretical vaccines Theoretical HIV Theoretical Influenza (or TB) vaccine vaccine

• persistence at low • combination of levels for T cell all possible activation (TB) hemagglutinins 4 • combination of 10 3 – 107 GP variants, ~ 10 variants? or mutating vaccine • repeat • low-no vaccinations immunopatholgy (TB) • crossprotective vaccine not • anti-virals, possible antibiotics, wait until HIV-1 ~ HIV-2?

Conclusions

• „Memory“, a nice idea, but is a laboratory artefact • Protection depends on preinfect. nAb titers and / or activated T cells (variability: HIV, malaria) • Both are antigen-driven (reencounter, persistence in host, antigen-antibody complexes on FDC) H. Hengartner

A. Althage A. Ochsenbein M. Bachmann B. Odermatt A. Ciurea M. Pericin St. Freigang D. Pinschewer L. Hunziker M. Recher U. Karrer HP. Roost Th. Kündig Th. Rülicke B. Ludewig C. de la Torre M. Martinic M. Whitt

Thank you!

IMI Stakeholder Forum - 13 May 2013 - Brussels