Vaccines

Active Immunization or Vaccination

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.

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]

Kinds of Vaccines

1. Killed whole organisms

2. Attenuated organisms

3. Toxoids

4. Surface molecules

• Influenza vaccine contains purified hemagglutinins from the viruses currently in circulation around the world. [More]
• The gene encoding a protein expressed on the surface of the hepatitis B virus, called hepatitis B surface antigen or HBsAg, can now be expressed in E. coli cells and provides the material for an effective vaccine. Hepatitis B infection is strongly associated with the development of liver cancer. Here then is a vaccine against a cancer.
• The genes encoding the capsid proteins of 9 strains of human papilloma virus (HPV) can be expressed in yeast and the resulting recombinant proteins are incorporated in a vaccine (Gardasil 9®). Because infection with some of these strains of HPV can lead to cervical cancer [Link], here is another vaccine against cancer.
• Some 80 different strains of Streptococcus pneumoniae cause pneumonia in humans. They differ in the chemistry of the polysaccharide capsule that surrounds them (and makes it difficult for phagocytes to engulf them by endocytosis [View]). One current vaccine consists of tiny amounts of the purified capsular polysaccharides of the 23 most common and/or dangerous strains.

5. Inactivated virus

6. Attenuated virus

• it is given by mouth rather than by injection;
• the viruses it contains can spread to the other members of the vaccinee's family thus immunizing them as well.

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.

7. DNA Vaccines

With DNA vaccines, the subject is not injected with the antigen but with DNA encoding the antigen.

• DNA sequences encoding one or more protein antigens or, often, simply epitopes of the complete antigen(s);
• DNA sequences incorporating a promoter that will enable the DNA to be efficiently transcribed in the human cells.
• Sometimes DNA sequences encoding
  • costimulatory molecules
  • sequences that target the expressed protein to specific intracellular locations (e.g., endoplasmic reticulum)
  are included as well.

In contrast to conventional vaccines, DNA vaccines elicit cell-mediated — as well as antibody-mediated — immune responses.

The cell-mediated response

• The plasmid is taken up by an antigen-presenting cell (APC) like a dendritic cell.
• The gene(s) encoding the various components are transcribed and translated.
• The protein products are degraded into peptides.
• These are exposed at the cell surface nestled in class I histocompatibility molecules where
• they serve as a powerful stimulant for the development of cell-mediated immunity.

  How antigens are presented to cytotoxic T cells

  Dendritic-cell vaccines in cancer immunotherapy

The antibody-mediated response

• If the plasmid is taken up by other cells (e.g. muscle cells),
• the proteins synthesized are released and can be engulfed by antigen-presenting cells (including B cells).
• In this case, the proteins are degraded in the class II pathway and presented to helper T cells.
• These secrete lymphokines that aid B cells to produce antibodies [View].

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.

8. RNA Vaccines

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.

Summary Table

Some of the Triumphs of Vaccination

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.

Problems of vaccine development

With so many triumphs, why haven't vaccines eliminated other common diseases such as malaria and HIV-1 infection (the cause of AIDS)?

• toxins (diphtheria, tetanus)
• extracellular bacteria (pneumococci)
• even viruses that must pass through the blood to reach the tissues where they do their damage (polio, rabies)

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).

Example:

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.)