1. So tell me,
this physician of whom
you were just speaking,
Is he a money maker,
an earner of fees,
or a healer of the sick?
Plato, The Republic

2. This formidable array of defense mechanisms
Allows HIV to avoid being suppressed by our immune system
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
How can we help
the body fight back?

3. This formidable array of defense mechanisms
Allows HIV to avoid being suppressed by our immune system
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
How about an
AIDS vaccine?

4. Even 2,500 Years Ago,
People Knew Immunity Worked.
• Greek physicians
noticed that people who
survived smallpox
never got it again.
• The insight: Becoming
infected by certain
diseases gives
immunity.

5. Fast forward 2300 years
Vaccination
• Edward Jenner 1796 :
Cowpox/Swinepox
• 1800’s Compulsory childhood
vaccination

6. Variolation was a huge advance
Smallpox
•1% v. 25% mortality
•Life-long immunity
• UK: 1700’s
• China 1950
• Pakistan/Afghanistan/Ethiopia
1970
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

7. Smallpox presented many advantages that made this possible
Smallpox•
No animal reservoir
• Lifelong immunity
• Subclinical cases rare
• Infectivity does
not precede overt symptoms
• One Variola serotype
•
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

8. Smallpox As a result, after a world-wide effort
Smallpox was eliminated as a human disease in 1979
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

9. making once feared diseases a thing of the past
Reported cases per 100000 population
Other vaccines have followed,
100
10
1
0.1
0.01
0.00
1
Inactivated
(Salk) vaccine
Oral
vaccine
Cases per 100,000
population United
States
1950 1960 1970 1980 1990

10. How does vaccination
work?
Expose the patient to an Antigen
• A live or inactivated substance (e.g.,
protein, polysaccharide) derived from a
pathogen (e.g bacteria or virus) capable
of producing an immune response

11. How does vaccination
work?
Expose the patient to an Antigen
• A live or inactivated substance (e.g.,
protein, polysaccharide) derived from a
pathogen (e.g bacteria or virus)capable of
producing an immune response
If the patient is subsequently exposed
to infectious agent carrying this
Antigen they will mount a faster
immune response

12. It works like this
Patient exposed to pathogen
Carrying antigens A and B
Molecular Biology of the Cell Alberts et al

13. Vaccines can be divided
into two types
• Live attenuated
• Inactivated

14. Inactivated Vaccines
fall into different categories
Whole
• viruses
• bacteria
Fractional
• Individual proteins from pathogen
• Pathogen specific complex sugars

15. Live Attenuated Vaccines
have several advantages
• Attenuated (weakened) form of the
"wild" virus or bacterium
• Can replicate themselves so the
immune response is more similar to
natural infection
• Usually effective with one dose

16. Live Attenuated Vaccines
also have several
disadvantages
• Severe reactions possible
especially in
immune compromised
patients
• Worry about recreating
a wild-type pathogen
that can cause disease
• Fragile – must be
stored carefully
MMWR, CDC

17. A number of the vaccines you
received
were live Attenuated Vaccines
• Viral measles, mumps,
rubella, vaccinia,
varicella/zoster,
yellow fever, rotavirus,
intranasal influenza,
oral polio
• Bacterial BCG (TB), oral typhoid

18. Inactivated Vaccines are the
other option
Pluses
• No chance of recreating live pathogen
• Less interference from circulating antibody
than live vaccines

19. Inactivated Vaccines are the
other option
Minuses
• Cannot replicate and thus generally not as
effective as live vaccines
• Usually require 3-5 doses
• Immune response mostly antibody based

20. Inactivated Vaccines are also
a common approach today
Whole-cell vaccines
• Viral polio, hepatitis A,
rabies, influenza*
• Bacterial pertussis*, typhoid*
cholera*, plague*
*not used in the United States

21. Other Inactivated Vaccines
now contain purified proteins
rather than whole bacteria/viruses
• Proteins hepatitis B, influenza,
acellular pertussis,
human papillomavirus,
anthrax, Lyme
• Toxins diphtheria, tetanus

22. Sabin Polio Vaccine
Attenuated by passage in foreign host (monkey kidney cells)
Selection to grow in new host makes virus
less suited to original host

23. Sabin Polio Vaccine
Attenuated by passage in foreign host (monkey kidney cells)
Selection to grow in new host makes virus
less suited to original host
• Grows in epithelial cells
• Does not grow in nerves
• No paralysis
•Local gut immunity (IgA)

24. Salk Polio Vaccine
• Formaldehyde-fixed
• No reversion

25. Polio Vaccine illustrates the pluses
and minuses of live vaccines
US: Sabin attenuated vaccine
~ 10 cases vaccine-associated polio per year =
1 in 4,000,000 vaccine infections
Scandinavia: Salk dead vaccine
• No gut immunity
• Cannot wipe out wt virus
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

26. Modern molecular biology
has offered new approaches
to make vaccines

27. Modern molecular biology
has offered new approaches
to make vaccines
1. Clone gene from virus or bacteria
and express this protein antigen
in yeast, bacteria or
mammalian cells in culture

28. Modern molecular biology
has offered new approaches
to make vaccines
2. Clone gene from virus or bacteria
Into genome of another virus (adenovirus, canary pox, vaccinia)
And use this live virus as vaccine

29. Cloned protein antigens
have pluses and minuses
Pluses
•Easily manufactured and often relatively stable
•Cannot “revert” to recreate pathogen
Minuses
• Poorly immunogenic
•Poor T cell response

30. Viral vectors
have pluses and minuses
Pluses
• Infects human cells but some do not replicate
• Better presentation of antigen
• Generate T cell response
Minuses
•Can cause bad reactions
•Can be problems with pre-exisiting immunity to virus
•Often can only accommodate one or two antigens

31. Given that introduction,
should we search for a
vaccine against HIV and
how would we do so?
30 million deaths caused by HIV
33 million living with HIV/AIDS
2.7 million new infections in 2008

32. An effective vaccine could have a MAJOR
Impact on the future prognosis
iavi.org

33. This allows An T cells effective to vaccine recognize must get HIV around
infected cells,
for example, and even internal proteins
the strategies HIV uses to evade the immune system
like reverse transcriptase can serve as antigens

34. This allows T cells to recognize HIV infected cells,
The vaccine must be able to target conserved
and essential parts of the viruses machinery
for example, and even internal proteins
like reverse transcriptase can serve as antigens
Inaccessible epitopes
Antigenic escape
+ existence of many viral strains

35. This allows T cells to recognize HIV infected cells,
The vaccine must act early in the process
Before the virus becomes firmly established
for example, and even internal proteins
And destroys the immune system
like reverse transcriptase can serve as antigens
Integration and latency
Destruction of CD4+ T cells
Molecular Biology of the Cell Alberts et al

36. There are many possible
HIV Vaccine Approaches
Protein subunit
Synthetic peptide
Naked DNA
Inactivated Virus
Live-attenuated
Virus
Live-vectored Vaccine
Ramil Sapinoro, University of Rochester Medical Center

37. To begin we need to
ask some key questions
What should vaccine elicit?

38. To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virus

39. To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virus
T cell response to
kill infected cells
OR

40. To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virus
T cell response to
kill infected cells
OR
OR BOTH?

41. The biology of HIV provides some clues

42. Remember the long term non-progressors
Infected with a Nef mutant virus?

43. This would generate both
an antibody and a T cell response
Could this be used to generate a vaccine?

44. This prompted an experiment
that demonstrated
the feasibility of a vaccine

45. This prompted an experiment
that demonstrated
the feasibility of a vaccine
December 1992: Live attenuated SIV vaccine
Lacking the gene Nef
protected all monkeys for 2 years against
massive dose of virus
• All controls died
• cell mediated immunity was key

46. However, this approach is still
viewed as too risky to try on
human subjects
December 1992: Live attenuated SIV vaccine
Lacking the gene Nef
protected all monkeys for 2 years against
massive dose of virus
• All controls died
• cell mediated immunity was key

47. Another effort attempted to
use recombinant viral proteins as antigens
in an effort to generate neutralizing antibodies

48. VaxGen made two different forms
of gp120 from different HIV strains
and began human trials after chimp testing

49. Human vaccine trials are large
and very expensive

50. The trial was viewed as a failure,
with only minor effects seen
that were interpreted
as statistically insignificant
NY Times

51. Or was it a failure?
A variant on the same vaccine was
tried in Thailand
combination of two vaccines:
Patients were primed with ALVAC® HIV vaccine
= live canarypox vector expressing gp120
and boosted with
the recombinant gp120 protein VacGen AIDSVAX® B/E
The vaccine combination was based on HIV strains
common in Thailand.

52. Or was it a failure?
A variant on the same vaccine was
tried in Thailand
combination of two vaccines:
Canarypox virus (CNPV) is an Canarypox is an
avipoxvirus and the etiologic agent of
canarypox, a disease of wild and captive birds
that can cause significant losses. Canarypox
can enter human cells, but it cannot survive
and multiply
No thanks!

53. The results suggested
it was partially effective!!

54. Data suggest the effect depended
on generating antibodies to a
variable loop on gp120

55. The next approach involved using
viral vectors to try to
also boost the T cell response

56. Many different viral vectors are
being investigated but this trial used
the human cold virus called
adenovirus

57. They actually used three
adenoviruses carrying three
different viral proteins
Gag
Pol
Nef

58. Early results suggested the immune
system was being stimulated

59. The hotly awaited results were
released at the 2007 AIDS Meeting

60. You be the judge—what happened?

62. This stunning failure
led to a re-thinking
of the approach

63. However trials continue,
but with more focus
on the details of how they affect immunity