Why Vaccines Directed Against Cancer, HIV Don't Work

In research spanning more than a decade, Gary Clark, associate professor of Obstetrics, Gynecology and Women's Health in the MU School of Medicine, and Anne Dell, an investigator at Imperial College London, found that HIV, aggressive cancer cells, H. pylori, and parasitic worms known as schistosomes carry the same carbohydrate sequences as many proteins produced in human sperm.

"It's our major Achilles heel," Clark said. "Reproduction is required for the survival of our species. Therefore we are 'hard-wired' to protect our sperm and eggs as well as our unborn babies from any type of immune response. Unfortunately, our results suggest that many pathogens and tumor cells also have integrated themselves into this protective system, thus enabling them to resist the human immune response."

During the initial stages of life, the body goes through a process where it "self-identifies," determining which cells and proteins belong in the body, so it can detect those that do not. After this time, anything foreign is deemed as dangerous, unless the immune system is specifically told to ignore those cells and proteins. This situation arises primarily during reproduction.

When sperm are made, they specifically label their glycoproteins with Lewis carbohydrate sequences, a specific chain of carbohydrates. When these "foreign" sperm enter the female body, the female's immune system does not recognize them as foreign probably because of these Lewis sequences. Similarly, the unborn baby also could be seen as foreign by the mother's immune system, but she produces other types of glycoproteins that likely block any type of immune response in the womb. These events are required for successful human reproduction.

H. pylori is a bacteria known for causing stomach ulcers. Schistosomes live inside our bodies, resisting many types of immune responses. Aggressive tumor cells also can defeat the immune system; this killed more than half a million people in the United States last year. HIV-infected immune cells cause AIDS. The common thread is that each carries Lewis sequences. Clark said this evidence suggests that vaccines are likely ineffective against these diseases because Lewis sequences shut down the specific immune response that enables vaccines to work.

"If aggressive cancers and pathogens are using the same system of universally recognizable markers to trick the immune system into 'thinking' they're harmless, we need to determine exactly how this interaction works," Dell said. "This is where we're planning to take this research next. Understanding how these markers work at a basic biological and chemical level could lead to new ways to treat or prevent cancers and these other diseases in the future."

"This work is creating an entirely new way of thinking about how we must combat viruses like HIV and aggressive tumor cells," Clark said. "We have literally spent billions of dollars developing vaccines for AIDS and cancer. However, the latest high profile HIV and tumor vaccine trials have been spectacularly unsuccessful, perhaps for some very good reasons. We must become more clever if we are ever going to solve the problems of cancer and AIDS."

This research is being published in the Dec. 14 edition of The Journal of Biological Chemistry.

Clark's research is funded by grants from the National Institute of Allergy and Infectious Diseases (NIAID), the Breeden-Adams Foundation, and the State of Missouri. Dell is funded by grants from the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust.