Project Title:
Gardasil Vaccine

Group No.:

2

Group Name:

GARDASIL VACCINE1

News URL:

http://www.msnbc.msn.com/id/16948093

Author:

Associated Press

News Paper:

N/A

Area Key Word:

HPV, amino acids, zwitter ion, immunochemistry, catalytic antibodies

Chemistry Key Word:

sterile preparation, aluminium hydrophosphate sulfate, L-histidine, polysorbate 80

Editorial Comment:

Gardasil (quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine) is a controversial vaccine that has been on the market a little over a year now. The vaccine is given to adolescent girls to prevent certain strains of cervical cancer and genital warts. The disease can be prevented through a simple vaccination; however the vaccination has become quite controversial. Does the vaccine prevent all forms of cervical cancer? The idea of a "cancer vaccine" is quite new, and Gardasil is currently the most expensive vaccine on the market. Texas is one of the first states to make it mandatory for women to recieve the vaccination. Is Colorado next? HPV Vaccine Bill approved by Colorado Senate

The Gardasil vaccination is a unique vaccination because it is composed of proteins and does not have a chemical structure. The vaccination is composed of virus like particles or VLP's. The proteins are synthesized by the bacteria Saccharomyces cerevisiae.
Gardasil remains a hotly debated topic in government and in school systems across the United States. The vaccine is attributed to preventing cancer, but is also known for leading to the deaths of some young women. As research continues, society will be presented with the challenge of accepting this controversial vaccine.
This project highlights the chemical ingredients in Gardasil and addresses important, yet different aspects of the vaccine. The chemical focus lies within the proteins of the vaccine. The reaction diagram represented here explains the zwitterion which is explained in detail in question #2.
The zwitterion is essential in understanding amino acids, proteins and the way these correspond to organic chemistry.
The diagram shows an unionized amino acid (left) converting to a zwitterion (right).Note: Not all proteins have "S" stereochemistry. Although the zwitterion exists as "S", some proteins exist as "L".


Gardasil information in Spanish

Question 1:

The Gardasil vaccine is made up of proteins, but how are these proteins made?

Answer 1:

All papillomaviruses have a capsid, or shell that is made up of proteins.
The Gardasil vaccine contains purified L1 proteins for the 4 types of human papillomaviruses: 6,11,16,18.
Further, proteins are made up of amino acids:

picture courtesy of: http://en.wikipedia.org/wiki/aminoacids

Each amino acid contains an amino group (NH2), a carboxyl group (COOH) and a hydrogen atom. How are amino acids formed? Four DNA nucleotides (G,C,A,T) code for the 20 different amino acids. More specifically, 3 nucleotides form a codon. It is the codon that specifies which amino acid will be formed.Through transcription and translation amino acids are converted to proteins. Amino acids join together through peptide bonds when the -NH2 end of one amino acid joins to the -COOH end of another amino acid. Chains of amino acids are called polypeptides. Proteins, then, are long chains of polypeptides. The shape of a protein is very important because it determines the protein's function.

Question 2:

When discussing proteins, how might one connect the topic to Organic Chemistry?

Answer 2:


picture courtesy of: http://en.wikipedia.org/wiki/Zwitterion

In the human body (pH=7.35-7.45) an amino acid exists as a dipolar ion. Such a compound is called a zwitterion. The picture depicts the before and after of a neutral molecule converting to a zwitter ion. The carboxylic acid end of the amino acid has a proton (H+) to donate and the Amino Group (N) can accept a proton, leaving their respective charges of positive and negative. This allows the amino acid to be more soluble in solution because like dissolves like. The zwitter ion has a net zero charge. The zwitter ion is a biologically and chemically important molecule because it allows modification for the behaviors of a protein. The pH of the solution plays an important role in determining whether the zwitter ion will exist or not. This is important to Organic Chemistry because we have studied pKa's. An amino acid does not exist as an uncharged compound. To be uncharged, an amino acid would need to lose a proton from an [+NH3] group with a pKa of 9 more readily than it would lose a proton from a [COOH] group with a pKa of 2. We know this is impossible because a weak acid cannot be more acidic than a strong acid.This brings us back to the idea that at physiology pH (7.35-7.45) an amino acid will exist as a dipolar ion, or a zwitterion.

Question 3:

How do the components of the Gardasil vaccine make it effective?

Answer 3:

Gardasil contains inactive proteins from the HPV Virus (6,11,16,18). Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine , 50 mcg of polysorbate 80, 35 mcg of sodium borate, and water for injection. The product does not contain a preservative or antibiotics. The Gardasil vaccine is a sterile preparation for injection into the muscle tissue. The proteins in Gardasil are produced by recombinant DNA technology. The proteins are manufactured by a yeast that has received DNA. This specific DNA produces the L1 proteins, which are assembled in virus-like particles. These particles resemble the HPV virus. When a patient is given the vaccine, the immune system makes antibodies against these proteins. The antibodies untimately help destroy the virus.
A photo of the amino acid Histidine, found in Gardasil, is shown:



Currently, two prophylactic HVP vaccines are on the market will target HPV virus 6,11,16,18. This vaccine contains HPVL1 proteins synthesized from the virus itself, with the inorganic products, sodium borate and Aluminium adjuvant and NaCl. picture courtesy of: http://www.biology.arizona.edu

Question 4:

Why has the Gardasil vaccine become a subject of controversy? Doesn't it protect against a virus that causes cancer?

Answer 4:

The Gardasil vaccine has become extremely controversial because the Federal Government allows the vaccine to be administered to females at the early age of 9 years old. The government recommends, however, that the vaccine be administered to females that are 11 and 12 years old. Because of the vaccine's effectiveness, some states are considering making the vaccine a requirement before attending school. HPV is linked to 3,700 deaths each year, and even though the vaccine prevents HPV, many people are concerned that a vaccine like this encourages adolescent sexual activities. In addition, some people also feel the vaccine should be administered on a case by case basis since the long-term side effects of the vaccine are not entirely clear at this time. In fact, the chemical ingredients of Gardasil are questionable. Sodium borate is a toxic substance used in roach, rodent, and insect killers, antiseptics, some paints and enamels. The link between Amorphous aluminum hydroxyphosphate sulfate and Alzheimer's disease and brain degeneration is still being researched by scientists. Higher levels of aluminum have been found in the brains of Alzheimer's patients. Furthermore, L-histidine supplements carry warnings that such supplements should be avoided by children, pregnant women, and nursing mothers. The effectiveness of Gardasil is available to the general public. Merck (who solely carried out testing for the drug) released a statement claiming that the duration of immunity following a complete schedule of immunization with GARDASIL has not been established.

Click here for more information.
above picture courtesy of http://www.gardasil.com

Question 5:

How is Gardasil on the cutting edge of modern health issues?

Answer 5:

Before addressing the immunochemistry of the vaccine, some background information is necessary. Studies have shown that approximately 90% of infected women will produce antibodies against HPV strains. The other 10% that will exhibit symptoms of warts and cancerous lesions, that is why the drug companies are aggressively doing the research and development of the protein synthesized vaccines.
Immunochemistry has historically focused on the nature of antibody-antigen recognition. However, in the last 5 years, the field of immunochemistry has taken a new direction shown by the Gardasil vaccine. With the aid of mechanistic and synthetic chemistry, the vast network of molecules and cells of the immune system has been utilized to produce antibodies with a new function- catalytic antibodies. Antibodies in Gardasil can be generated to selectively bind almost any molecule of interest, this new technology offers the potential to tailor-make highly selective catalysts for applications in biology, chemistry, and medicine. In addition, catalytic antibodies provide fundamental insight into important aspects of biological catalysis, including the importance of transition-state stabilization, general acid and base catalysts, electrophilic and nucleophilic catalysis, and strain. This transitional state enzyme is a key to making an effective vaccine because it takes the entire protein molecule and speeds up the manufacturing process of the vaccine itself. These innovations led directly to Gardasil and provided the rationale for future prophylactic vaccines against other virus-induced cancers.
Addressing another aspect of the health issue, researchers postulated that HPV played a role in cervical cancer as early as 1974. The beginning stages of development started out with several studies of population: women and cervical lesions, men and rectum cancerous lesions, oral cancers associated with HPV, and warts on external genitalia. Keeping in mind, the current vaccine treats 4 HPV types, there are currently over 90 genotypes at present and new types discovered every few months. The newest, HPV 58, is now being rigorously tested and will be ready for FDA approval within the year.
One key questions related to the health issue of Gardasil, is the cost of implementing a vaccination program. A family member of one of our group members received the vaccine 2 years ago. The cost was $325.00, not covered by insurance. She was the first to receive it in the OB/GYN practice. We were fortunate to interview one of the office managers, and she described the criteria used to evaluate the pro's and con's of the Gardasil vaccine: (South Denver OB/GYN)
1.) What proportion of cervical cancer and other HPV related disease in our region, i.e. Colorado, are attributed to HPV types used in the vaccine?
2.) What is the overall protection from cervical cancer afforded by the current vaccine?
3.) Specifically, would the vaccine alter any other HPV types not yet addressed by the current vaccine? (Given that the patient is immunized against the HPV types 6,11,16,18)
4.) Will a vaccination program against sexually transmitted disease be accepted by the parents of children who are not sexually active?
5.) What about a booster program?
As you can see, the cutting edge of modern technology is being constantly re-evaluated by health care professionals. Since this is the first cancer vaccine available for cervical cancer, the scrutiny is constant, with articles being written and studies evaluated continuously.

©2004 Dr. Rainer Glaser's group