Towards an HIV Vaccine

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					TOWARDS AN HIV VACCINE
  why is it so hard to make an HIV
  vaccine and where are we now?



          Neal Nathanson, MD
          Emeritus Professor
       Department of Microbiology
       University of Pennsylvania
          School of Medicine



                                     1
Estimated number of persons living with
HIV/AIDS, December, 2004




                                                          1 million



                                              8 million




                      26.8 million


                 Global total: 39.4 million



                                                                      2
    TOWARDS AN HIV VACCINE


g   Why is it so hard to make an AIDS vaccine?
g   ‘Sterilizing’ or ‘partial’ immunity?
g   Immune correlate of protection?
g   Cellular immunity: provides protection?
g   Neutralizing antibody: a daunting challenge
g   Cross-clade immunity?
g   Current status of AIDS vaccines?

                                                  3
TOWARDS AN HIV VACCINE




  WHY IS IT SO HARD TO
 MAKE AN AIDS VACCINE?



                         4
    TOWARDS AN HIV VACCINE

RESEARCH EXPERIENCE
•   HIV env protein fails to induce neutralizing Ab
•   Live attenuated SIVs protect but cause AIDS
BIOLOGICAL ISSUES
•   First HIV infection may not attenuate a second HIV infection?
•   Persistence of HIV and progression to AIDS
IMPLICATION
•   Immunobiological questions must be addressed
•   Mechanisms of vaccine protection?



                                                                    5
   TOWARDS AN HIV VACCINE
                    VAXGEN TRIAL OF rgp120
   multiple immunizations, 3 year cumulative infection percentage
                      Science 2003, 299: 1290



GROUP          TREATMENT      SUBJECTS       INFECTIONS    PERCENT

TOTAL          PLACEBO           1679            98          5.8%
               VACCINE           3330            191         5.7%

WHITE,         PLACEBO           1508            81          5.4%
HISPANIC       VACCINE           3003            179         6.0%

BLACK,         PLACEBO            171            17          9.9%
ASIAN, OTHER   VACCINE            327            12          3.7%



                                                                     6
                                TOWARDS AN HIV VACCINE
FIRST HIV INFECTION MAY NOT PROTECT AGAINST SECOND INFECTION?

                                                HIV INFECTION IN SEX WORKERS, NAIROBI, KENYA
                                                                   CASE # 3
                                                     OVERBAUGH ET AL, 2005, UNPUBLISHED


                                                      D                               A
     HIV-1 viral RNA levels




                                                4.5
                                                                                                                 4.1
                                                        3.9
                                                4.0
                              log10 copies/ml




                                                3.5
                                                3.0
                                                2.5
                                                              2.4
                                                2.0                       1.7
                                                1.5
                                                1.0
                                                0.5
                                                                                Estimated days since infection
                                                0.0




                                                                                                                    2
                                                  -50         150   350         550       750    950     1150          1350
                                                                          485
                                                        101




                                                                                                                 126
                                                  0


                                                                                                                              7
TOWARDS AN HIV VACCINE
THE DAUNTING TRIAD: FAILURE TO PREVENT INFECTION;
        PERSISTENCE; LOSS OF CD4 T CELLS

                                         DYNAMICS OF HIV INFECTION ILLUSTRATING
                                         PROBLEMS IN PRE-EXPOSURE IMMUNIZATION


                           6
  VIREMIA (LOG10 PER ML)




                                                       HIV
                           5                           TRANSIENT INFECTION
                                                       HIV (IMMUNIZED)
                           4

                           3

                           2
                                                                                  ?
                           1

                           0
                               0     4      8             5                  10
                                   WEEKS                          YEARS

                                                                                      8
TOWARDS AN HIV VACCINE




    “STERILIZING” OR
  “PARTIAL” IMMUNITY?




                         9
  TOWARDS AN HIV VACCINE

            “STERILIZING” OR “PARTIAL” IMMUNITY?

For viruses causing acute infections, subjects who have been
adequately immunized usually undergo an abortive infection when
exposed to a potentially virulent wildtype virus

  Will such ‘partial’ protection confer adequate resistance to an
  HIV challenge or is ‘absolute’ protection (‘sterilizing’ immunity)
  needed?

  Do studies of immunized monkeys challenged with SIV provide a
  useful reference?

  Do studies of viral set points and survival curves in HIV-infected
  humans provide a useful predictor?


                                                                       10
TOWARDS AN HIV VACCINE

                                  PROTECTION OF RHESUS MACAQUES
                                  AGAINST SIV SM E660 IV CHALLENGE
                             BY RECOMBINANT VACCINIA (MVA) IMMUNIZATION
                                   Ourmanov, J Virology, 2000, 74: 2740

                                                            CONTROL
                             6                              RAPID PROGRESSORS 2
  RNA COPIES PER ML PLASMA




                                                            PROGRESSORS 3
                             5
      GEOMETRIC MEAN




                             4

                             3

                                     MVA gag-pol-env
                             2       PROGRESSORS 1
                                     NONPROGRESSORS 5
                             1
                                 0         4            8            12           16
                                          WEEKS AFTER CHALLENGE
                                                                                       11
 TOWARDS AN HIV VACCINE

VIRUS SETPOINT DETERMINES THE COURSE OF THE INFECTION
                         Mellors et al, Science, 1996, 272: 1167; Whittle et al, COI, 1998, 10: 382.



                        100                                               <0.5
                         90                                                             HIV-2
    PERCENT SURVIVING




                         80
                         70                                               0.5-4
                         60
                         50
                                                                                          HIV-1
                         40
                                                                          4-12
                         30
                                  VIRAL
                         20       SETPOINT
                         10                                               12-29
                          0                                               29-250

                              0      2       4       6       8       10      12      14       16       18
                                                         YEARS OF STUDY
                                                                                                            12
TOWARDS AN HIV VACCINE




  IMMUNE CORRELATES
    OF PROTECTION?




                         13
 TOWARDS AN HIV VACCINE

CORRELATE HYPOTHESIS?
  Does protection correlate with a specific immune response
  parameter, such as antibody, CTL killing, or CD4+
  proliferation?
BARRIER HYPOTHESIS?
  Might a combination of antibody plus CTLs plus
  associated cytokine responses act in concert to constitute
  a sufficient barrier?
  Could different immunizing protocols protect by a different
  mix of immune defenses?




                                                                14
TOWARDS AN HIV VACCINE




   CELLULAR IMMUNITY
    PROVIDES PARTIAL
      PROTECTION



                         15
 TOWARDS AN HIV VACCINE
CD8 CELLULAR IMMUNE RESPONSE GOVERNS VIRUS SETPOINT
           Schmitz et al, Science 1999, 238: 857.
      VIRAL RNA (COPIES PER ML)




                                  7         MONKEY A                                         7


                                  6                                                          6
                                                                             MONKEY B

                                  5                                                          5


                                  4                                                          4
                                                        CD8 DEPRESSED


                                  3                                                          3
                                      -10   -5      0      5     10     15   20   25    30
                                                 DAYS AFTER IMMUNOSUPPRESSION
                                                                                                 16
TOWARDS AN HIV VACCINE
VACCINE FAILURE DUE TO ESCAPE FROM A SINGLE CD8 EPITOPE
     recombinant env-gag DNA/IL-2 vaccine; SHIV challenge
                                      Barouche et al, Nature 2002, 415: 335.


                                                   SHIV
                              7
                                                   ESCAPE MUTANT
   LOG10 mRNA PER ML PLASMA




                                                   (p11C DOMINANT EPITOPE)

                              6                                                     1200


                              5




                                                                                          CD4 PER µL
                              4                                                     800


                              3


                              2                                                     400
                                  0    10        20         30        40       50
                                        WEEKS AFTER INFECTION
                                                                                                       17
TOWARDS AN HIV VACCINE




NEUTRALIZING ANTIBODY:
A DAUNTING CHALLENGE



                         18
  TOWARDS AN HIV VACCINE
     NEUTRALIZING ANTIBODY INFLUENCES VIRUS SETPOINT
chimp anti-HIV passive antibody; challenge: iv virulent SHIV (matched gp120)
    Shibata et al, Nature Medicine, 1999, 5: 204; Nishimura et al, JV, 2002 76: 2123




                      SHIV DNA (LOG 10 COPIES PER 105 PBMC)   3

                                                                             CONTROL (4)
                                                                             N AB TITER <2
                                                              2



                                                              1
                                                                                                     PARTIAL (4)
                                                                                                     N AB TITER 2.5-4

                                                              0

                                                                        COMPLETE (2)
                                                                        N AB TITER 5-8
                                                              -1

                                                                   0   20     40         60   80   100     120
                                                                            DAYS AFTER INFECTION


                                                                                                                        19
TOWARDS AN HIV VACCINE
PASSIVE ANTIBODY PROTECTS MONKEYS AGAINST SUBSEQUENT
             CHALLENGE WITH VIRULENT SHIV
                     Nishimura, 2002

                             100
    AGAINST SHIV CHALLENGE
     PERCENT PROTECTION




                              80


                              60


                              40


                              20


                               0
                                   0     20   40   60   80   100   120
                                           SERUM DILUTION (1/X)
                                       PROVIDING 99% NEUTRALIZATION
                                              IN CELL CULTURE
                                                                         20
      TOWARDS AN HIV VACCINE

                                                MHC II

                            SIV
                                                gp120

THE NEUTRALIZING ANTIBODY ENIGMA
  Using gp120, it is difficult to raise neutralizing antibody
  Using MHC Class II, anti-SIV neutralizing antibody can be readily induced
INFERENCE?
  the problem lies with gp120 and not in any intrinsic ability of SIV to resist
  neutralization
  Query: is SIV gp120 a poor target for neutralization? Do gp120 neutralization
  escape mutants play a role?


                                                                                  21
TOWARDS AN HIV VACCINE
   HIV INFECTION INDUCES AUTOLOGOUS NEUTRALIZING
     ANTIBODY THAT SELECTS FOR ESCAPE VARIANTS
                Richman et al, PNAS 2003, 100: 4144

                               PLASMA NEUTRALIZING TITER
                                MONTHS AFTER INFECTON

                          0           6           12        18

           0            <100         675        2670       2190

           6            <100        <100        1769       2247
 VIRUS
MONTHS
           12           <100        <100        <100       556

           18           <100        <100         117       122


                                                                  22
           TOWARDS AN HIV VACCINE

             THE NEUTRALIZING ANTIBODY ENIGMA




             gp120                      IgG binding
                                        domain targets near
                                        the CD4 binding site
   CD4                    CD4           permitting viral escape
binding                   ligand        mutants
    site                  domain




    if CD4 can dock why can’t IgG block attachment?
                                                           23
  TOWARDS AN HIV VACCINE

Influenza virus has a
receptor site on each
trimer head and can be
neutralized by antibodies
that bind to any of four
different sites that are
near the receptor binding
site. Viral escape
mutants can be selected
for each of these
neutralizing antibody
sites



                            24
TOWARDS AN HIV VACCINE




     CROSS CLADE
      IMMUNITY?




                         25
   TOWARDS AN HIV VACCINE
THERE ARE ABOUT 10 DISTINCT CLADES (GENOTYPES) OF HIV-1




                                                    26
    TOWARDS AN HIV VACCINE



    ARE THE ~10 CLADES DISTINCT IMMUNOTYPES?

•   Will neutralizing antibody cross clades?
•   Will cellular immunity cross clades?
•   Relevance of conserved vs variable epitopes?
•   Are multivalent HIV-1 vaccines needed?



                                                   27
     TOWARDS AN HIV VACCINE
     MULTICLADE VACCINE IS EQUAL TO MONOCLADE VACCINE
Rhesus monkeys immunized with env DNA @ 0, 4, 8 wks; rAdV env DNA @ 26 wks
                       Tested 1 week post vaccine
                            Letvin et al, 2003




          env IMMUNOGEN                  env RESPONSES
             BY CLADE                       BY CLADE
               mg DNA                  IFN ELISPOT/106 PBL
           A       B       C             A         B        C

           -      4.5       -           1200     2900     1300
           -       -       4.5          1500     1200     2700
          1.5     1.5      1.5          2500     2200     2600

                                                                        28
TOWARDS AN HIV VACCINE




  CURRENT STATUS OF
    AIDS VACCINES




                         29
              TOWARDS AN HIV VACCINE
                   vaccine provides partial protection in SIV model
                   rDNA plus rAdv (SIV239 gag, pol, env) immunization
                          iv SIV 251 (heterologous) challenge
                             Letvin et al, unpublished, 2005




             100
                                                                        Vaccinated
             80                                                         (n = 24)
% Survival




             60                                                         Control
                                                                        (n = 6)
             40

             20
                                                       p=0.007
              0
                   0   50   100   150   200   250   300     350   400
                                                                        P=0.007
                            Days Post-SIVmac251 Challenge
                                                                         p=0.007
                                                                                     30
   TOWARDS AN HIV VACCINE

lessons from poliovirus vaccine
“In 1945, Professor Burnet of Melbourne wrote ‘While I was in
America recently I had good opportunity to meet with most of the
men actively engaged on research in poliomyelitis…The part played
by acquired immunity to poliomyelitis is still completely uncertain,
and the practical problem of preventing infantile paralysis has not
been solved. It is even doubtful whether it ever will be solved.’

…most of us doing research on poliomyelitis in 1945 were mainly
motivated by curiosity, rather than by the hope of a practical
solution in our lifetime.”

                                                 David Bodian, 1976


                                                                       31
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