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HIV Vaccines and the Immune System

Nicole Frahm, PhD HIV Vaccine Trials Network Laboratory Program

Immunology 101
Our immune system is able to recognize and fight bugs that do not look like self

There are two parts of our immune system:


Innate: recognizes patterns on bugs, can fight them
right away Adaptive: recognizes very specific parts of bugs but

takes a while to learn

Different arms of the adaptive immune system

cellular

humoral
B cell (antibody maker)

CD4+ T cell (helper)

CD8+ T cell (killer)

IgG IgA

Thibodeau GA, Patton KT: Anatomy and physiology, ed 7, St Louis, 2010, Mosby.

Killing of target cells is very specific

Antibody neutralization (IgG)

Antibodies at the site of pathogen entry (IgA)

Antibody-dependent cellular cytotoxicity

Immunologic memory

Vaccines take advantage of immunologic memory


18th century: the observation that milkmaids are less susceptible to smallpox suggests that exposure to cowpox may protect from smallpox
Edward Jenner first inoculates children with cowpox from milkmaids and shows they are protected, but other anecdotal evidence existed previously

From georgiangentleman.posterous.com

How do vaccines work?


The vaccine fools the body into thinking it has been infected, so we will make a primary immune response against the vaccine Once the actual pathogen comes around, our body responds with a secondary immune response that is much faster and stronger The correlate of protection has not been formally defined for most vaccines, but protection is believed to be antibody-mediated for most licensed vaccines

Can a vaccine induce both cellular and humoral responses?


Different vaccine constructs are good at inducing different responses:
Proteins are good at inducing antibodies DNA vaccines are good at inducing CD4+ T cell

responses (but getting better for CD8+ T cells too)


Viral vectors can do everything, but it depends on which virus they are based on:
Pox vectors induce primarily CD4+ T cells Adenovirus vectors induce primarily CD8+ T cells All virus vectors need to be boosted for good antibody responses

What else is important?


What parts of HIV go into the

vaccine
Antibodies can only see the envelope protein on the incoming virus, so envelope is essential for neutralization T cells can see all parts of HIV, but some proteins seem to be better targets for T cells than others

So why do we not have a vaccine for HIV?


HIV is extremely variable
Between humans and apes, there is only 2-5% difference
in sequence between related genes, but Different strains of HIV differ by up to 30% from each

other
Our immune system is very specific, and vaccine-induced antibodies or T cells may not recognize a strain of HIV

that is very different from that used in the vaccine

The durability of the vaccine-induced immune response wanes over time using current candidates

How can we overcome this hurdle?


Current vaccines induce narrow and type-specific immune responses
In the Step trial, a median of only one T-cell epitope was recognized in vaccinees

Antibodies in Vaxgen recognized mainly the vaccine


strains

Two possible ways around:


Increase the breadth of the vaccine-induced immune
response Target regions that are conserved across most virus

strains (e.g. Gag for T cells, V2 or CD4 binding site for Ab)