|Index to this page|
The terms vaccination and vaccine derive from the work of Edward Jenner who, over 200 years ago, showed that inoculating people with material from skin lesions caused by cowpox (L. vaccinus, of cows) protected them from the highly contagious and frequently fatal disease smallpox.
|Link to discussion of smallpox.|
Since Jenner's time, the term has been retained for any preparation of dead or weakened pathogens, or their products, that when introduced into the body, stimulates the production of protective antibodies or T cells without causing the disease. In molecular terms, the goal is to introduce harmless antigen(s) with epitopes that are also found on the pathogen.
Vaccination is also called active immunization because the immune system is stimulated to develop its own immunity against the pathogen. Passive immunity, in contrast, results from the injection of antibodies formed by another animal (e.g., horse, human) which provide immediate, but temporary, protection for the recipient. [Link to discussion of passive immunity]
It has the disadvantage that — on rare occasions — one of the strains in the vaccine regains full virulence and causes the disease. For this reason, the Salk vaccine has once again become the preferred vaccine worldwide.
|A new method of attenuation|
The various attenuated-virus vaccines in current use were developed by rather hit-or-miss methods. However, scientists have been working on a technology — exploiting the phenomenon of codon bias — that may make possible the rational development of safer vaccines.
One group, at Stony Brook University (see J.R. Coleman et al., Science, 27 June 2008), has engineered polio virus with hundreds of mutations in the genes encoding its capsid protein. However, every one of these is a "silent" mutation; that is, it simply changes the codon for the amino acid to a different codon for the same amino acid. When they created polio viruses in which pairs of new codons were ones that the wild polio virus avoids using (because its human host does), they found that the new viruses were far less infectious that the original. But note, that this procedure did not introduce any change in the amino acid sequence of the capsid protein. So one would expect that all the epitopes recognized by the immune system would be unchanged. And, indeed, they went on to show that mice immunized with the synthetic virus were protected from disease caused by the wild virus.
As mentioned above, one of problems associated with the attenuated live virus polio vaccine (Sabin) is the rare back mutation to full virulence. Such back mutation in these engineered viruses would be extremely unlikely considering the hundreds of silent mutations that would have to be reversed.
With DNA vaccines, the subject is not injected with the antigen but with DNA encoding the antigen.The DNA is incorporated in a plasmid containing
In contrast to conventional vaccines, DNA vaccines elicit cell-mediated — as well as antibody-mediated — immune responses.
|How antigens are presented to cytotoxic T cells|
|Dendritic-cell vaccines in cancer immunotherapy|
|Related link: The Immunological Synapse|
So far, most of the work on DNA vaccines has been done in mice where they have proved able to protect them against tuberculosis, SARS, smallpox, and other intracellular pathogens. In addition, DNA vaccines against SARS-CoV-2 — the cause of COVID-19 — are in clinical trials.
Another approach uses a harmless adenovirus as the vector to carry the gene (DNA) for the SARS-CoV-2 spike protein into the host cells. There the gene is transcribed and translated into the spike protein to which the host's immune system responds. One of these (distributed by Johnson&Johnson) has proven safe and effective and in March 2021 began to be used to combat COVID-19.
RNA vaccines operate on the same principal as DNA vaccines except that transcription of the gene encoding the desired antigen is done in vitro. The resulting messenger RNA (mRNA) is then subjected to several modifications to improve its stability after which it is injected into the host. Once within host cells, the mRNA is translated. Its protein product can then be displayed at the cell surface ready to interact with cells of the immune system.
Two RNA vaccines, both encoding the spike protein of the SARS-CoV-2 virus (the cause of the current COVID-19 pandemic), are now (2021) in widespread use.
|SARS-CoV-2 the agent of COVID-19||mRNA encoding the spike protein on the surface of the virus||The spike protein is essential for viral entry into the host cell. Once inside, the mRNA is translated into the spike protein which is then recognized by the immune system as an antigen.|
|Diphtheria||Toxoid||Often given in a single preparation
Tdap containing all 3 antigens or Td which does not contain acellular pertussis.
|Pertussis (whooping cough)||Purified components of the bacteria
(acellular pertussis = "ap")
||Inactivated polio vaccine: IPV (Salk)|
|Attenuated virus||Oral polio vaccine; OPV (Sabin)|
Both vaccines trivalent (types 1, 2, and 3)
|Hepatitis A||Inactivated virus||HAVRIX® and VAQTA®; also available in single shot with HBsAg (Twinrix®)|
|Hepatitis B||Protein (HBsAg) from the surface of the virus||Made by recombinant DNA technology|
|Rotavirus||Attenuated virus (Rotarix®) or 5 strains of the virus (RotaTeq®)||to prevent this serious diarrheal disease in infants|
|Human Papilloma Virus (HPV)||Protein from the capsid of 9 strains of the virus||Gardasil 9®; made by recombinant DNA technology|
|Diphtheria, tetanus, pertussis, polio, and hepatitis B||uses acellular pertussis and IPV (Salk)||Pediarix®; combination vaccine given in 3 doses to infants|
|Diphtheria, tetanus, pertussis, polio, and Hemophilus influenzae type b (Hib)||uses acellular pertussis and IPV (Salk)||Pentacel®; combination vaccine given in 4 doses to infants|
|Measles||Attenuated virus||Often given as a mixture (MMR)
Do not increase the risk of autism. (Nor do any vaccines containing thimerosal as a preservative.)
aka "German measles"
|Chickenpox (Varicella)||Attenuated varicella-zoster virus (VZV)||VARIVAX® Also available combined with MMR ("MMRV" or ProQuad®)|
|Shingles (reactivation later in life of a latent VZV infection)||(1) attenuated live virus (Zostavax®)
(2) single viral antigen (Shingrix®)
|The viral antigen in Shingrix® is made by recombinant DNA technology.|
|Cholera||Killed bacteria||Three oral vaccines available|
|Influenza||Hemagglutinins||Contains hemagglutinins from the type A
and type B viruses recently in circulation [Details]
|Attenuated virus||FluMist® — contains weakened viruses of the type B
and two type A strains recently in circulation
|Pneumococcal infections||Capsular polysaccharides||Pneumovax 23®. A mixture of the capsular polysaccharides of 23 common types. Works poorly in infants.|
|13 capsular polysaccharides conjugated to protein||Prevnar 13®. Mobilizes helper T cells; works well in infants.|
|Meningococcal disease||4 polysaccharides conjugated to protein||To prevent outbreaks among new groups of young adults, e.g., college freshmen, military recruits|
|Hemophilus influenzae, type b (Hib)||Capsular polysaccharide conjugated to protein||Prevents meningitis in children|
|Rabies||Inactivated virus||Vaccine prepared from human diploid cell cultures (HDCV)
or chick embryo cells (PCECV)
|Smallpox||Vaccinia virus||Despite the global eradication of smallpox, is used to protect against a possible bioterrorist attack|
|Anthrax||Extract of attenuated bacteria||Primarily for veterinarians and military personnel|
|Typhoid||Three available: 1. live, attenuated bacteria (oral) 2. a polysaccharide vaccine
3. the polysaccharide conjugated to protein
|Yellow fever||Attenuated virus|
|Tuberculosis||Attenuated bacteria (BCG)||Rarely used in the U.S.|
The greatest triumph is the eradication of smallpox from the planet, with no naturally-occurring cases having been found since 1977. "Naturally-occurring" because one case (fatal) occurred later following the accidental release of the virus in a laboratory. As far as the public knows, smallpox virus now exists only in laboratories in the U.S. and Russia. There is currently a vigorous debate as to whether these should be destroyed. If smallpox ever should get back out into the environment, the results could be devastating because smallpox vaccination is no longer given and so the population fully susceptible to the disease grows year by year. [More]
A program to try to eliminate polio from the world is now underway. Except for cases caused by OPV, the disease has now been eliminated from the Western hemisphere. Outbreaks of polio still occur in Africa, the Indian subcontinent, and parts of the Near East.
This table compares the number of cases of illness in the U.S. in a representative year (either before a vaccine was available or before it came into widespread use) with the number of cases reported in 1994.
|Disease||Total cases||Year||Cases in 1994||% Change|
With so many triumphs, why haven't vaccines eliminated other common diseases such as malaria and HIV-1 infection (the cause of AIDS)?One problem is that experimental vaccines often elicit an immune response that does not actually protect against the disease. Most vaccines preferentially induce the formation of antibodies rather than cell-mediated immunity. This is fine for those diseases caused by
But viruses are intracellular parasites, out of the reach of antibodies while they reside within their target cells. They must be attacked by the cell-mediated branch of the immune system, such as by cytotoxic T lymphocytes (CTLs). Most vaccines do a poor job of eliciting cell-mediated immunity (CMI).
Much of the early — and so far unsuccessful — work on anti-HIV-1 vaccines has focused on the antibody response of the test animal. Antibodies may have a role in preventing infection or minimizing its spread, but cell-mediated responses will probably turn out to be far more important. Patients die of AIDS despite having high levels of anti-HIV-1 antibodies. (The most widespread test for HIV-1 infection does not detect the presence of the virus but the presence of antibodies against the virus.)
|Discussion of cell-mediated immunity|
|How cytotoxic T lymphocytes (CTL) work|