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Tuesday, March 25, 2008

HIV Vaccine

Experimental HIV vaccines have failed. Oddly, when I looked for a recent Washington Post story, the Washington Post sent me to this old ABC news story

The evidence suggests that, if anything*, the vaccine increases the risk of infection and speed progression of the disease. The result is horrible, but it is not astonishing (OK I was shocked when I learned about it back then but I am an irrational optimist). It is known that stimulating the immune system speeds the progression from HIV infection to AIDS. I think this is understood at the molecular level by now. So it seems, on balance, for infection.

Also, before the vaccine trials, it was widely noted that successful vaccines cause the production of antibodies which block virus binding to host cells. Of course, it is well known that anti-HIV antibodies don't do this (they are the first symptom of infection). It had been hoped that vaccines would work by stimulating Killer T-cells to kill the first virus infected cells. This would have been a first if it had worked.

So why don't we make antibodies which block HIV infection of cells ? One possibility is that there is no such antibody in our repertoire. That would mean we are out of luck. Another, however, is that we have B-cells which would make the antibody but don't have helper T-cells which would stimulate them. In that case, it might be possible to make a vaccine which will cause us to make an HIV blocking antibody by linking the key bit of the HIV surface protein (gp120) to another protein. A hapten. Such an approach is the basis of the H influenza vaccine which actually works (here it is H influenza polysaccharide linked to a protein).

Now it makes sense that helper T-cells which would help make exactly the right antibodies are missing. The reason is that we have proteins which bind to CD-4 just as HIV does. Therefore, it is possible that the helper T-Cells needed to make antibodies which bind to the HIV binding site are deleted, because they would help us make antibodies to our own proteins.

In fact, blocking antibodies exist in the human repertoire.

A fairly recent review is here.

Permanently promising perhaps, but not hopeless.

Previous googling sent me to the original now very old articles.
First Chimpanzees definitely do make antibodies which protect Monkeys from SIV (monkey HIV).

This article is 9 years old !

This seems much more promising and it is 13 years old !

B-12 a human antibody cloned from a long time HIV infected survivor blocks infection of human cells ! There must be something wrong.

They were still publishing about B-12 in 2003 and getting published in top journals.

HIV binding and infection has been understood in gruesome detail for over a decade.

OOh this is interesting. It is about how HIV evades blocking antibodies. The claim is that gp-120 is glycosylated (sugar stuck on it) when it reproduces in monocytes (not the helper t-cells which it kills but other cells in which it grows). If the virus made from helper T-Cells and monocytes are different, then an antibody which blocks one won't block the other. The authors don't say if the protein is glycoslyated when HIV grows in T-cells, but there must be some reason people were convinced that the antibody blocks infection.

I would say that

known and boring

In fact the evidence tends to suggest that the Merck experimental vaccine was worse than worthless

One of the possibilities is that the increase in the number of infections was related to the vaccine," meaning it could have made people more susceptible to HIV infection, said Dr. Keith Gottesdiener, vice president of clinical research at Merck Research Laboratories. He couldn't say how likely that was but said other factors, even coincidence, could be the explanation.


"New data released Wednesday showed that to date, 49 of 914 vaccinated men became infected with HIV, compared with 33 of the 922 men who got dummy shots.

First what would the probability that as many as 49 or 82 infected men were vaccinated if the probability of infection were the same with and without the vaccine ?

The expected number would be 914/(914+922)= 40.821351
the variance 82*914*922/(914+922)^2 = 20.499611
the standard deviation (82*914*922)^0.5/(914+922)= 4.5276496

z score = (number - expected number)/standard deviation = 1.8063786

This should be distributed very very nearly like a unit normal under the null so the probability of a z score that high or higher is 0.035429612

Typically one considers a two tailed test, that is the probability that the absolute value of the z-score is that high that is 0.070859225.

I think that, during the interview with ABC, Dr. Gottesdiener was quite relieved that the standard confidence level for statistical significance is 5%.

However, the researchers found that volunteers with pre-existing immunity to this particular cold virus were much more likely to get infected with HIV if they got the AIDS vaccine than if they got the dummy shot.

To me that settles it.

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