Last updated 18 April 2022
The first human vaccines against viruses were based on using weaker or attenuated viruses to generate immunity, while not giving the recipient of the vaccine the full-blown illness or, preferably, any symptoms at all. For example, the smallpox vaccine used cowpox, a poxvirus similar enough to smallpox to protect against it, but usually didn’t cause serious illness. Rabies was the first virus attenuated in a lab to create a vaccine for humans.
Vaccines are made using several processes. They may contain live viruses that have been attenuated (weakened or altered to not 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 major type.
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 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 can be grown through—“passaged” through—upwards of 200 different embryos or cell cultures. Eventually, the attenuated virus will not replicate well (or at all) in human cells, and can be used in a vaccine. All 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 not 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 lead to a more virulent strain. This is unlikely, as the vaccine virus’s ability to replicate is limited. However, possible mutations are considered 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 lead to 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 the protection 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 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 shorter 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 (injectable).
Some bacterial diseases are not directly caused by a bacterium, but by a toxin produced by the bacterium. One example is tetanus: the Clostridium tetani bacterium does not cause its symptoms, a neurotoxin it produces (tetanospasmin) does. 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 that they contain an inactivated toxin, not an inactivated form of bacteria.
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 can 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 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 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 used for children against pneumococcal bacterial infections are made using this technique.
In 2020, as the COVID-19 pandemic was well underway, the United States and other countries around the world raced to create a vaccine against the SARS CoV-2 virus, the virus causing the pandemic. In the United States, “Operation Warpspeed” provided billions of dollars in funding to numerous pharmaceutical companies to develop a successful vaccine and take it to market. Under normal circumstances, the vaccine trials would have happened subsequently (i.e. phase I, phase II, phase III, etc.). Because of the public health emergency, vaccine trials occurred consecutively (phases I, II and III simultaneously).
Two vaccines were authorized for emergency use by the end of 2020 in the United States, both based on mRNA technology. (A third vaccine would be authorized early in 2021, based on viral vectors, which will be discussed in the next section.) This technology uses mRNA enveloped in a lipid (fat) sphere. The vaccine is then introduced into the body, where the body’s immune cells take up the vaccine particles and reveal the mRNA. The mRNA gives the cell “code” to create a protein similar to the “spike” protein on the coronavirus’ surface. The immune cell then releases that protein to other immune cells, triggering an immune response that includes antibody production and activation of specialized cells to find and kill coronaviruses bearing that spike protein and any host cells infected.
In early 2021, a third vaccine for the COVID-19 pandemic was authorized for use in the United States. That vaccine used a simian adenovirus that was basically hollowed out and the mRNA for coding a coronavirus spike protein was put inside. Like the mRNA vaccines, the mRNA in the viral vector is introduced into immune cells after those immune cells take up the simian adenovirus after recognizing it as a pathogen. The immune cell then creates the spike protein and triggers the ensuing immune response.
Researchers continue to develop new vaccine types and improve current approaches. For more information about experimental vaccines and delivery techniques, see our article .
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- Plotkin, S.A., Orenstein, W.A., Offit, P.A., eds. Vaccines. 6th. ed. Philadelphia: Elsevier; 2013.
- Understanding mRNA COVID-19 Vaccines. Centers for Disease Control and Prevention. Available at: