Professor Andrew McMichael

Transcription

1 BHIVA AUTUMN CONFERENCE 2011 Including CHIVA Parallel Sessions Professor Andrew McMichael University of Oxford November 2011, Queen Elizabeth II Conference Centre, London BHIVA AUTUMN CONFERENCE 2011 Including CHIVA Parallel Sessions Professor Andrew McMichael University of Oxford COMPETING INTEREST OF FINANCIAL VALUE > 1,000: Speaker Name Statement Andrew McMichael None declared Date 3 November November 2011, Queen Elizabeth II Conference Centre, London 1

2 HIV Vaccines: Lessons Learnt and Future Promise Andrew McMichael University of Oxford Human Papilloma Virus : Harald Zur Hausen identified HPV16 and 18 as causes of cervical cancer 2006: HPV vaccines licensed for use, Gardasil and Cervarix. Near 100% protective 2008 Nobel Prize in Medicine with Luc Montagnier and Francoise Barre-Sinoussi 2

3 : Only three HIV Vaccines tested in Efficacy Trials VAX004 gp120 (AIDSVAX B/B) No protection STEP rad5 gag,pol,nef No protection -? Enhancement RV144 CpEnv + gp120 31% protection Why is an HIV vaccine so difficult? HIV variability Limited neutralizing epitopes for antibody on HIV Envelope Latency of HIV Cell to cell transmission Immunosuppression by HIV BUT The transmitted/founder virus is single in 70+% of intections 3

4 Why is an HIV vaccine so difficult? HIV variability Limited neutralizing epitopes on HIV Envelope Latency of HIV Cell to cell transmission Immunosuppression by HIV HPV -? ++?+?- BUT The transmitted/founder virus is single in 70+% of intections Current Vaccine Approaches Improve RV144 New Env Immunogens New T cell vaccines eg UKHVC DNA-Ad5-MVA-gp120 Replic vectors Mosaics Conserved regions 4

5 Thai Trial RV144 Alvac - HIV: Weeks Vaxgen gp120: Weeks Rerks-Ngarm et al NEJM October RV144 Correlates of Protection: Bart Haynes et al; Int AIDS Vaccine, Thailand vaccinated HIV infected vs 205 vaccinated uninfected participants 6 measurements: Serum IgA binding to Env IgG avidity to A244 gp120 ADCC AE infected CD4 T cells Tier one neutralizing antibodies IgGbinding to gp70 V1V2 CD4 T cell intracellular cytokines 5

6 Slides not yet published Conclude: A non-classical IgGantibody response was associated with protection. Serum IgA effect unexplained. But also unknown role for canarypox priming? Innate immunity Therefore: Improve RV144 approach: eg UKHVC: DNA-Ad5-MVA-gp120 Use of Persisting vectors Novel vector combinations Question: Do repeat studies need to be made in low risk as well as high risk cohorts? 6

7 Approach 2: Improve Envelope Vaccines to get broadly neutralizing antibodies: mabs PG9, PG16 (V1/V2 and V3 loops) mab 2G12 (glycans) mabs b12, VRC01, HJ16 (CD4bs) mabs 2F5, 4E10, Z13e1 (MPER) gp41 gp120 Viral membrane Burton, D.R., and R.A. Weiss. AIDS/HIV. A boost for HIV vaccine design. Science 329:

8 Recent findings: Many HIV-1 infected people make broadly neutralizing antibodies But only after 3-5 years Not associated with good virus control higher VL associated with such antibodies Antibodies have accumulated somatic mutations from germ line Germ line ancestor of antibody binds with low affinity Good targets CD4 binding site Membrane proximal region Glycans Obstacles How to design of immunogens that will drive B cells down the right mutational pathway SCHEMA OF B CELL MATURATION IN THE GERMINAL CENTRE V genes D and J C genes pre B cell B cell Somatic hyper-mutation Affinity maturation B cell H L Plasma Cell Broad neutralizing antibodies are rare amongst the repertoire of anti Env antibodies Have multiple randomly generated somatic mutations How can a vaccine select out these antibodies???? 8

9 Approach 3: T cell vaccines: STEP Vaccine (Ad5 gag,pol,nef): Elicited mean of 3 T cell responses, to gag, pol, nef Focus on variable regions HIV-1 specific T cells per million PBMC No protection (McElrath et al, Rolland et al) Enhanced acquisition associated with pre-vaccination antibodies to the Ad5 vector New SIV / NHP data Hansen et al Nature 2011;473:523-7 Macaques vaccinated with CMV vectored SIV antigens, or CMV + Ad5 boost or DNA + Ad5 Then challenged with homologous SIVmac 239 Half of CMV vaccinated animals clear virus Correlates with CD8+ T cell response, NOT neutralizing antibodies. 9

10 CD8 T Cells cannot prevent infection but can control the virus: SA (III) SA (IV) SA (I-II) SA (I-II) SA (1-II) MAL (I-II) MAL (V) MAL (I-II) T.PAIR MAL (I-II) T. PAIR MAL (I-II) US (III) * US (IV) TWIN US (II) US (II) US-077 (II) Slides not yet published 10

11 Therefore: Strong but narrow T cell responses to variable epitopes likely to select escape mutations rapidly and be ineffective: STEP Ideal vaccine should stimulate broad T cell responses (eg CMV expt) and/or responses to epitopes that only escape with a fitness cost Note that the protective HLA types B57, B58, B27, B51, B81 all select epitopes that are highly conserved and escape with fitness cost. T cell vaccines and virus variability Vaccine match to transmitted/founder virus at entry Virus escape from vaccine stimulated T cell responses Two solutions: Mosaic (Bette Korber) Good coverage and broad T cell responses But no focus on conserved regions Conserved region (Hanke, Mullins, Brander) Strong focus on conserved regions 11

12 Conclusions: 3 Approaches RV144 type of vaccine being pursued. May lead to first useable vaccine Envelope structure being understood to high level. May lead to new Env immunogen design T cell vaccines look more feasible compared to post-step era. Conserved immunogenand Mosaic approaches can deal with variability and escape. ACKNOWLEDGMENTS: RV144 Immune Correlates Working Group David Evans Susan Zolla-Pazner/Tim Cardozo Georgia Tomaras David Montefiori Chitraporn Kanasuta Julie McElrath Munir Alam Philip Berman Anthony DeVico Steve De Rosa Nicole Frahm Ruengpung Sutthent George Lewis Guido Ferrari Richard Koup Robert Bailer Mangala Rao Nicos Karasavva Viseth Ngauy Barton Haynes CHAVI Acute Infection Team Nilu Goonetilleke Michael Liu Victoria Bourne Kati Digleria Guido Ferrari Mike Betts Jesus Salazar Maria Salazar Brandon Keele Beatrice Hahn George Shaw Feng Gao Bette Korber Vitaly Ganusov Alan Perelson Steve Self Natalie Hawkins Myron Cohen David Margolies Joe Eron Charles Hicks Volunteers HIV Consv Vaccine Tomas Hanke Sven Letourneau Max Rosario Lucy Dorrell MRC 12