Preparation of measles vaccine
The first human vaccines against viruses were based using weaker or attenuated viruses to generate immunity. The smallpox vaccine used cowpox, a poxvirus that was similar enough to smallpox to protect against it but usually didn’t serious illness. Rabies was the first virus attenuated in a lab to create a vaccine for humans.
Vaccines are made using several different processes. They may contain live viruses that have been attenuated (weakened or altered so as not to cause illness); inactivated or killed organisms or viruses; inactivated toxins (for bacterial diseases where toxins generated by the bacteria, and not the bacteria themselves, cause illness); or merely segments of the pathogen (this includes both subunit and conjugate vaccines).
Live, attenuated vaccines currently recommended as part of the U.S. Childhood Immunization Schedule include those against measles, mumps, and rubella (via the combined MMR vaccine), varicella (chickenpox), and influenza (in the nasal spray version of the seasonal flu vaccine). In addition to live, attenuated vaccines, the immunization schedule includes vaccines of every other major type—see the table above for a breakdown of the vaccine types on the recommended childhood schedule.
The different vaccine types each require different development techniques. Each section below addresses one of the vaccine types.
Live, Attenuated Vaccines
Attenuated vaccines can be made in several different ways. Some of the most common methods involve passing the disease-causing virus through a series of cell cultures or animal embryos (typically chick embryos). Using chick embryos as an example, the virus is grown in different embryos in a series. With each passage, the virus becomes better at replicating in chick cells, but loses its ability to replicate in human cells. A virus targeted for use in a vaccine may be grown through—“passaged” through—upwards of 200 different embryos or cell cultures. Eventually, the attenuated virus will be unable to replicate well (or at all) in human cells, and can be used in a vaccine. All of the methods that involve passing a virus through a non-human host produce a version of the virus that can still be recognized by the human immune system, but cannot replicate well in a human host.
When the resulting vaccine virus is given to a human, it will be unable to replicate enough to cause illness, but will still provoke an immune response that can protect against future infection.
One concern that must be considered is the potential for the vaccine virus to revert to a form capable of causing disease. Mutations that can occur when the vaccine virus replicates in the body may result in more a virulent strain. This is very unlikely, as the vaccine virus’s ability to replicate at all is limited; however, it is taken into consideration when developing an attenuated vaccine. It is worth noting that mutations are somewhat common with the oral polio vaccine (OPV), a live vaccine that is ingested instead of injected. The vaccine virus can mutate into a virulent form and result in rare cases of paralytic polio. For this reason, OPV is no longer used in the United States, and has been replaced on the Recommended Childhood Immunization Schedule by the inactivated polio vaccine (IPV).
Protection from a live, attenuated vaccine typically outlasts that provided by a killed or inactivated vaccine.
Killed or Inactivated Vaccines
One alternative to attenuated vaccines is a killed or inactivated vaccine. Vaccines of this type are created by inactivating a pathogen, typically using heat or chemicals such as formaldehyde or formalin. This destroys the pathogen’s ability to replicate, but keeps it “intact” so that the immune system can still recognize it. (“Inactivated” is generally used rather than “killed” to refer to viral vaccines of this type, as viruses are generally not considered to be alive.)
Because killed or inactivated pathogens can’t replicate at all, they can’t revert to a more virulent form capable of causing disease (as discussed above with live, attenuated vaccines). However, they tend to provide a shorter length of protection than live vaccines, and are more likely to require boosters to create long-term immunity. Killed or inactivated vaccines on the U.S. Recommended Childhood Immunization Schedule include the inactivated polio vaccine and the seasonal influenza vaccine (in shot form).
Toxoids
Some bacterial diseases are not directly caused by a bacterium itself, but by a toxin produced by the bacterium. One example is tetanus: its symptoms are not caused by the Clostridium tetani bacterium, but by a neurotoxin it produces (tetanospasmin). Immunizations for this type of pathogen can be made by inactivating the toxin that causes disease symptoms. As with organisms or viruses used in killed or inactivated vaccines, this can be done via treatment with a chemical such as formalin, or by using heat or other methods.
Immunizations created using inactivated toxins are called toxoids. Toxoids can actually be considered killed or inactivated vaccines, but are sometimes given their own category to highlight the fact that they contain an inactivated toxin, and not an inactivated form of bacteria.
Toxoid immunizations on the U.S. Recommended Childhood Immunization schedule include the tetanus and diphtheria immunizations, which are available in a combined form.
Subunit and Conjugate Vaccines
Both subunit and conjugate vaccines contain only pieces of the pathogens they protect against.
Subunit vaccines use only part of a target pathogen to provoke a response from the immune system. This may be done by isolating a specific protein from a pathogen and presenting it as an antigen on its own. The acellular pertussis vaccine and influenza vaccine (in shot form) are examples of subunit vaccines.
Another type of subunit vaccine can be created via genetic engineering. A gene coding for a vaccine protein is inserted into another virus, or into producer cells in culture. When the carrier virus reproduces, or when the producer cell metabolizes, the vaccine protein is also created. The end result of this approach is a recombinant vaccine: the immune system will recognize the expressed protein and provide future protection against the target virus. The Hepatitis B vaccine currently used in the United States is a recombinant vaccine.
Another vaccine made using genetic engineering is the human papillomavirus (HPV) vaccine. Two types of HPV vaccine are available—one provides protection against two strains of HPV, the other four—but both are made in the same way: for each strain, a single viral protein is isolated. When these proteins are expressed, virus-like particles (VLPs) are created. These VLPs contain no genetic material from the viruses and can’t cause illness, but prompt an immune response that provides future protection against HPV.
Conjugate vaccines are somewhat similar to recombinant vaccines: they’re made using a combination of two different components. Conjugate vaccines, however, are made using pieces from the coats of bacteria. These coats are chemically linked to a carrier protein, and the combination is used as a vaccine. Conjugate vaccines are used to create a more powerful, combined immune response: typically the “piece” of bacteria being presented would not generate a strong immune response on its own, while the carrier protein would. The piece of bacteria can’t cause illness, but combined with a carrier protein, it can generate immunity against future infection. The vaccines currently in use for children against pneumococcal bacterial infections are made using this technique.
More Information
Researchers continue to develop new vaccine types and improve current approaches. For more information about experimental vaccines and delivery techniques, see our article The Future of Immunization.
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