Failures of Previous Vaccination Methods

In spite of two centuries of vaccine development, many parasitic, bacterial and viral diseases, such as Chagas, malaria, tuberculosis and hepatitis C,  have eluded protection through vaccines. Modern times have also brought new diseases, such as HIV, SARS, MERS and cancer which similarly have evolved to evade vaccine protection.

 

There are two types of vaccines: prophylactic and therapeutic:

  • Prophylactic or preventative vaccines: Only two such vaccines for cancer are currently in use, and neither directly prevents cancer. Instead, the vaccines work by killing viruses that may lead to cancer. The human papillomavirus (HPV) vaccine, for example, targets potent strains of HPV that cause the majority of cervical, throatanal and several other cancers. The hepatitis B vaccine is designed to help prevent some cases of liver cancer. These vaccines prevent viruses that cause inflammation that may lead to cancer. 

 

  • Therapeutic or treatment vaccines: These are designed to stimulate the immune system to attack cancer cells. Two therapeutic cancer vaccines are now in use: Sipuleucel-T (Provenge®), which was approved for treatment of advanced prostate cancer; and, the Bacillus Calmette–Guérin (BCG) vaccine, which was originally developed for prevention of tuberculosis and has since been approved to treat bladder cancer.

 

We believe the lack of success in developing effective therapeutic cancer vaccines is because simple re-exposure of tumor antigens to the same immune system that failed to originally protect against the disease, only serves to amplify the original failed response.  A therapeutic cancer vaccine must elicit a new and different effective immune response upon re-exposure to the tumor and then this new response must imprint to dominate over the resident failed response. 

Albert Einstein stated:

“The definition of insanity is doing the same thing over and over again, but expecting different results."

We believe that a common problem with past attempts to develop cancer vaccines has been to mistakenly try to elicit an anti-cancer immune response of the same type that was successful in childhood vaccines that protect against diseases such as chicken pox (varicella), diphtheria, measles, mumps, tetanus and pertussis. These vaccines are given to healthy children to prevent disease by stimulating an antibody immune response that neutralizes the pathogens before they develop into disease.  However, antibodies neutralize pathogens found outside of cells. Some viruses such as HIV and hepatitis C that reside inside of cells are not responsive to antibodies.  Some viruses like hepatitis B can be neutralized by antibodies if present prior to infection, however once the disease is established the vaccine is unable to provide a therapeutic effect through eliciting an antibody response.

The immune system can respond to vaccines with either a humoral (antibody) response or a cellular response (or mixture).  As the antibody and cellular responses can cancel each other, a strong cellular response is generally considered the preferred immune response against cancers and modern pathogens. It is much more technically difficult to elicit a cellular immune response to an antigen than it is to elicit an antibody response.

The first decision when designing a cancer vaccine is to determine the antigen to be used for immune education. For decades researchers have unsuccessfully attempted to identify antigens on the surface of tumors that distinguish the cancer cells from normal cells so that these surface targets can be used to direct a neutralizing antibody response. To date, no tumor-specific surface molecules have been identified. There have been some surface molecules identified which are expressed in higher densities on tumors than on normal cells (so called “tumor associated antigens or TAA”).  However, vaccination with TAA has not translated into effective therapeutic immune responses. 

A persistent technical problem is to determine what antigen a cancer vaccine should target. Cancers are caused by a multitude of gene mutations, so developing a vaccine to target all possible mutations is likely impossible.