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

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

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
Fast forward 2300 years

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
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
Smallpox
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt

9. Other vaccines have followed,
making once feared diseases a thing of the past
100
Inactivated (Salk) vaccine
Cases per 100,000 population United States 10
Oral vaccine 1
Reported cases per population
0.1
0.01
0.001
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. Carrying antigens A and B
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
Individual proteins from pathogen
Pathogen specific complex sugars
Fractional

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. Grows in epithelial cells Local gut immunity (IgA)
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)
Pasteur rabies vaccine also attenuated

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. Live virus generates a more complete immune response
Killed (Salk) Vaccine
Live (Sabin) Vaccine
Serum IgG
512
Serum IgG
128 32
Serum IgM
Serum IgM
Reciprocal virus antibody titer
Nasal IgA
Serum IgA 8
Serum IgA 2
Duodenal IgA
Nasal and duodenal IgA 1 48 96 48 96
Vaccination
Days
Vaccination

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

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

29. 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

30. Cloned protein antigens have pluses and minuses
Easily manufactured and often relatively stable
Cannot “revert” to recreate pathogen
Minuses
Poorly immunogenic
Post-translational modifications
Poor CTL response

31. Viral vectors have pluses and minuses
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

32. Given that introduction, vaccine against HIV and
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

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

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

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

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

37. There are many possible HIV Vaccine Approaches
Protein subunit
Synthetic peptide
Naked DNA
Inactivated Virus
Live-attenuated
Virus
Past approaches to vaccine strategies directed against HIV have included attenuated and inactivated virus, but the high risk and safety limitations afforded to these traditional approaches have led to the exploration of novel vaccine strategies, such as a viral vector-based approach. The success with vaccination against other viruses is a window of optimism, and the over 10 HIV vaccine trials currently ongoing include the use of alphavirus, vaccinia, and adenoviral vectors, in addition to DNA plasmid, protein subunit, and peptide vaccines.
Live-vectored Vaccine
Ramil Sapinoro, University of Rochester Medical Center

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

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

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

41. 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?

42. The biology of HIV provides some clues

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

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

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

46. 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

47. 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

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

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

50. Human vaccine trials are large and very expensive

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

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

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

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

55. Early results suggested the immune system was being stimulated

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

57. You be the judge—what happened?

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

60. “DNA” vaccines are a novel approach

61. The field has decided in part to go back to the basics: how does HIV work and how can we assess vaccine success?
Questions:
For a vaccine what are the measures of protection?
Can we overcome polymorphism?
What are the key antigens?
Attenuated or killed or neither?
Is Mucosal immunity critical?
Should it Prevent infection or prevent disease?
What are the best Animal models
How does HIV kill cells anyway?

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