The Vaccine Education Center at the Children’s Hospital of Philadelphia offers a look into how vaccines are made:
Vaccines are made in several ways. However, all vaccines have the same general goal: weaken the virus or bacteria in a way that allows the recipient to develop an immune response without developing any symptoms of infection. Vaccines are made using the same components that are found in the natural virus or bacteria.
Several basic strategies are used to make vaccines. The strengths and limitations of each approach are described below.
Weaken the virus
Using this strategy, viruses are weakened so they reproduce very poorly once inside the body. The measles, mumps, German measles (rubella), rotavirus, oral polio (not used in the U.S.), intranasal influenza, chickenpox (varicella), and shingles vaccines are made this way. Viruses usually cause disease by reproducing themselves many times in the body. Whereas natural viruses reproduce thousands of times during an infection, vaccine viruses usually reproduce fewer than 20 times. Because vaccine viruses don't reproduce very much, they don't cause disease, but vaccine viruses replicate well enough to induce "memory B cells" that protect against infection in the future.
The advantage of live, "weakened" vaccines is that one or two doses provide immunity that is life-long. The limitation of this approach is that these vaccines usually cannot be given to people with weakened immune systems (like people with cancer or AIDS).
Inactivate the virus
Using this strategy, viruses are completely inactivated (or killed) with a chemical. By killing the virus, it cannot possibly reproduce itself or cause disease. The inactivated polio, hepatitis A, influenza (shot), and rabies vaccines are made this way. Because the virus is still "seen" by the body, cells of the immune system that protect against disease are generated.
There are two benefits to this approach:
However, the limitation of this approach is that it typically requires several doses to achieve immunity.
Use part of the virus
Using this strategy, just one part of the virus is removed and used as a vaccine. The hepatitis B and HPV vaccines are made this way. The vaccine is composed of a protein that resides on the surface of the virus. This strategy can be used when an immune response to one part of the virus (or bacteria) is responsible for protection against disease.
These vaccines can be given to people with weakened immunity and appear to induce long-lived immunity after three doses.
Use part of the bacteria
Some bacteria cause disease by making a harmful protein called a toxin. Several vaccines are made by taking toxins and inactivating them with a chemical (the toxin, once inactivated, is called a toxoid). By inactivating the toxin, it no longer causes harm. The diphtheria, tetanus and pertussis vaccines are made this way.
Another strategy to make a bacterial vaccine is to use part of the sugar coating (or polysaccharide) of the bacteria. Protection against infection by certain bacteria is based on immunity to this sugar coating (and not the whole bacteria). However, because young children don't make a very good immune response to the sugar coating alone, the coating is linked to a harmless protein (this is called a "conjugated polysaccharide" vaccine). The Haemophilus influenzae B (or Hib), pneumococcal, and recently licensed meningococcal vaccines are made this way.
Just like for inactivated viral vaccines, bacterial vaccines can be given to people with weakened immune systems, but often require several doses to induce adequate immunity.
Making a vaccine
Before a vaccine can be made, researchers must spend time isolating and studying the virus or bacteria in question and learning how it causes disease. Researchers then begin studying how to protect someone from the disease. Sometimes researchers ask questions like: What is the best quantity of virus to give? Does one dose of the vaccine work? Do additional doses help even more? How long does protection last?
There are three phases of studies that need to be done in people before the vaccine can be used by the general population:
Phase I studies are designed to answer two questions: Is the vaccine safe and does it induce an immune response? If the answer to either of these questions is "No", the vaccine cannot be developed further. People enrolled in these studies are usually healthy adults with a low risk for the infection. These studies usually include fewer than 100 participants.
If a vaccine passes the Phase I studies, larger Phase II studies are designed. They are based on information gained from the Phase I study. Phase II studies are usually done in the type of people who will ultimately use the vaccine. Typically, these studies enroll a few hundred participants. If the vaccine is determined to be unsafe or doesn't consistently induce an immune response, it will not be further developed.
Phase III studies determine whether vaccines work and include thousands to tens of thousands of people studied for many years. In many cases, more than one Phase III trial will be performed. Often, these trials are done across a large geographic area to ensure that the vaccine is working in people with different backgrounds and lifestyles. Phase III studies typically include more than 5,000 people.
If a vaccine appears to be safe and to work, all of the data will be submitted to scientists and regulatory personnel at the U.S. Food and Drug Administration (FDA). They will check the data to be sure the studies were done correctly and the results were consistent.
While much of the early research is done in academic research laboratories using grants obtained from foundations or the government (e.g., the National Institutes of Health), Phase I, II and III studies are performed by pharmaceutical companies. These studies typically cost hundreds of millions of dollars.
Once a vaccine has been reviewed by the FDA and considered to be safe, it is still not ready to be given to people. All of the information generated about how the vaccine works in people is then provided to members of a recommending group of scientists and doctors that advise the Centers for Disease Control and Prevention (CDC). This group, called the Advisory Committee on Immunization Practices or ACIP, then recommends how the vaccine should be used and by whom. The CDC, as well as the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP), then make a final recommendation that doctors and healthcare professionals can follow in deciding who should receive the new vaccine.
Phase IV (After licensure)
Once the vaccine begins to be distributed, additional studies occur. These studies are called Phase IV studies. Because some rare side effects may not have been detected in the phase III trials, vaccine safety is continually monitored by the CDC. These studies take at least four forms:
First, the CDC will have certain health departments (usually in areas where there is a high occurrence of disease and hence, high vaccine distribution) monitor every person who receives the vaccine and report to it regularly.
Second, the CDC monitors disease that is reported to every health department in the country, so they will see if there are any abnormal occurrences of disease after the vaccine is introduced and consider whether the two events may be related.
Third, there is a Vaccine Adverse Event Reporting System (or VAERS). If a doctor, nurse or consumer believes that a person who received a vaccine had a significant negative side effect, he or she can file a report in this system, which is continuously monitored for trends in the data.
Fourth, the Vaccine Safety Datalink (VSD) includes about 6 million people in six large HMOs on the West Coast to look at who did and did not receive the vaccine and answer safety questions. The VSD is one of the most effective post-licensure measures we have.
These systems proved their utility in 1999 when a newly licensed rotavirus vaccine was found to be a rare cause of intussusception, a folding of the intestine into itself that may require emergency surgery and can result in death if untreated. Once the relationship was confirmed, use of that rotavirus vaccine was discontinued. A few years later, safer rotavirus vaccines were developed, and phase III studies were of sufficient size to make sure these newer versions were not also causing intussusception.
Reviewed by: Paul A. Offit, MD
Date: November 19, 2014