Active immunity can be conferred artificially by vaccination— exposing a person to material that is immunogenic but not pathogenic. The discovery of vaccination was one of the furthest-reaching and most important developments in medical science. The basic principle behind vaccination is to stimulate a primary response that primes the immune system for future exposure to a pathogen. If this pathogen enters the body, the secondary immune response will be immediate, powerful, and sustained. Second or additional doses of vaccines can also stimulate the anamnestic response.
Vaccines have profoundly reduced the prevalence and impact of many infectious diseases that were once common and often deadly. In this section, we survey the principles of vaccine preparation and important considerations surrounding vaccine indication and safety. Vaccines are also given specific consideration in later chapters on infectious diseases and organ systems.
Principles of Vaccine Preparation
A vaccine must be considered from the standpoints of immunogen selection, effectiveness, ease in administration, safety, and cost. In natural immunity, an infectious agent stimulates a relatively long-term protective response. In artificial active immunity, the objective is to obtain this same response with a modified version of the microbe or its components. Most vaccine preparations are based on one of the following antigen preparations:
1. killed whole cells or inactivated viruses;
2. live, attenuated bacterial cells or viruses;
3. antigenic molecules derived from bacterial cells or viruses; or
4. genetically engineered microbes or microbial antigens.
The main qualities of an effective vaccine are listed in table 1.
Table1. Checklist of Requirements for an Effective Vaccine
Large, complex antigens such as whole cells or viruses are very effective immunogens. Depending on the vaccine, these are either killed or attenuated. Killed or inactivated vaccines are pre pared by cultivating the desired strain or strains of a bacterium or virus and treating them with formalin, radiation, heat, or some other agent that kills the microbe but does not change its antigenic structure (figure 1a). One type of vaccine for the bacterial disease cholera is of this type. The IPV (injected) polio vaccine and some forms of influenza vaccine contain inactivated viruses. Because the microbe does not multiply, killed vaccines often re quire a larger dose and more boosters to be effective.
Fig1. Whole pathogen vaccines. (a) Whole pathogens are killed (or inactivated in the case of viruses) using methods that retain their antigenicity. The microbe will stimulate immunity but cannot cause disease. Because the microbe cannot multiply, larger doses and more boosters are usually needed. (b) Attenuated vaccines have been treated to reduce or eliminate virulence. The pathogen can multiply but cannot cause disease. Smaller doses and fewer boosters are generally needed.
A number of vaccines are prepared from attenuated microbes. Attenuation is any process that substantially lessens the virulence of viruses or bacteria. It is usually achieved by modifying the growth conditions or manipulating microbial genes in a way that eliminates virulence factors. Attenuation methods include long-term cultivation, selection of mutant strains that grow at colder temperatures (cold mutants), passage of the microbe through unnatural hosts or tissue culture, and removal of virulence genes. The vaccine for tuberculosis (BCG) was obtained after 13 years of subculturing the agent of bovine tuberculosis. Vaccines for measles, mumps, polio (oral vaccine), and rubella contain active, nonvirulent viruses (figure1b). The primary advantages of these preparations are that (1) viable microorganisms can multiply and produce infection (but not dis ease) like the natural organism, (2) they confer long-lasting protection, and (3) they usually require fewer doses and boosters than other types of vaccines.
Disadvantages of using live microbes in vaccines are that they require special storage facilities, can be transmitted to other people, and can conceivably mutate back to a virulent strain.
If the exact antigenic determinants that stimulate immunity are known, these substances can be isolated from microorganisms and serve as the basis for a vaccine (figure 2). Vaccines made from bacterial cell parts are called acellular or subcellular vac cines. If isolated from viruses, they are called subunit vaccines. The antigen used in these vaccines may be extracted from cultures of the microbes, produced by genetic engineering, or synthesized chemically.
Fig2. Acellular and subunit vaccines Acellular and subunit vaccines rely on just a portion of the cell or virus as an antigen. Cell structures including capsules, cell wall, or flagellar proteins generally make excellent antigens. Toxoid vaccines use a denatured exotoxin as the antigen, providing immunological protection against the toxin but not the bacterial cell. Tetanus and diphtheria vaccines use this approach because the toxin is far more dangerous than the bacteria that produce it.
Examples of extracted antigens currently in use are the capsules of the pneumococcus and meningococcus, the protein surface antigen of anthrax, and the surface proteins of hepatitis B virus. A special type of vac cine is the toxoid, which consists of a purified fragment of bacterial exotoxin that has been inactivated. By eliciting the production of antitoxins that can neutralize the natural toxin, toxoid vaccines provide protection against toxinoses such as diphtheria and tetanus.
Genetically Engineered Vaccines
Some of the genetic engineering concepts introduced in chapter 10 offer novel approaches to vaccine development, and as genetic manipulation simultaneously becomes cheaper and more powerful, genetic methods of vaccine development may supplant more traditional methods. For instance, a cloning host can be stimulated to synthesize and secrete a protein product (antigen), which is then harvested and purified for use as a vaccine (figure 3). Vaccines for hepatitis and human papillomavirus are currently being prepared in this way. Antigens from the agents of syphilis, Schistosoma, and influenza have been similarly isolated and cloned and are currently being considered as potential vaccine material.
Fig3. Purified antigen vaccine. Vaccines reliant on surface antigens can be produced by engineering a plasmid that contains the gene for the antigen and then inserting the plasmid into a yeast cell. The yeast cell will synthesize the antigen, which can be purified for use as a vaccine.
Viral vector vaccines use a modified virus to deliver the genetic code of the antigen to human cells, mimicking what happens during a viral infection. The Johnson & Johnson COVID-19 vaccine is based on this strategy. A strain of adenovirus called Ad26, which has been modified so it cannot replicate or cause illness, served as the vector. A small stretch of DNA that codes for one of the viral spikes of SARS-CoV-2 was then inserted into the genome of the virus. When the vaccine—the modified viral vector containing the SARS-CoV-2 DNA insert—is injected, the virus enters cells of the host, and the viral DNA enters the nucleus. From there, the host produces mRNA, which in turn produces spike proteins, which are exported from the cell. The protein spikes act to stimulate an immune response (process figure 4). This same strategy was used to create a vaccine for Ebola in 2019, and trials of adenovirus-based vaccines to protect against HIV and Zika are currently ongoing.
Fig4. Viral vector vaccines. (1) The gene for a viral antigen (a spike protein in this case) is isolated from a virus, converted from RNA to DNA (in the case of RNA viruses), and inserted into the genome of a modified adenovirus. (2) The adenovirus vaccine is injected into the body and the virus invades the host cell. (3) The viral DNA enters the nucleus. (4) The gene for the viral antigen is transcribed into mRNA. (5) The mRNA is translated to produce viral proteins, which are inserted into the host cell membrane or exported from the cell. Spike proteins are also released when a vaccinated cell dies. (6) The viral proteins, or fragments of them, serve as antigens to stimulate the immune system. Barry Chess/McGraw Hill
RNA vaccines have become well-known as the primary means of protecting against COVID-19. The technique used to produce these vaccines is very similar to gene therapy, except in this case, viral RNA (rather than human DNA) is inoculated into a recipient. The first step in construction of such a vaccine is to isolate the mRNA of a gene unique to the virus. For SARS-CoV-2, for example, a viral spike protein was used. The mRNA is then enclosed in a layer of lipid nanoparticles to insulate it from the host cell’s protective enzymes that would otherwise destroy a piece of foreign RNA. When injected into the body, the lipid nanoparticles fuse with host cells, allowing the mRNA to enter the cytoplasm, where it is translated by cellular ribosomes. The proteins produced—once again, spike proteins in the case of SARS CoV-2—act as antigens, causing B and T cells to be sensitized and forming memory cells (process figure 5). The mRNA from the vaccine is eventually destroyed by enzymes in the cell, leaving no permanent trace.
Fig5. mRNA vaccines. (1) The gene for a viral antigen (a spike protein in this case) is isolated from a virus. (2) To prevent degradation of the mRNA, it is enclosed in a lipid coating. (3) The vaccine is injected into the body, and the lipid nanoparticle fuses with the host cell membrane, releasing the mRNA into the cell. (4) The mRNA is translated to produce viral proteins, which are inserted into the host cell membrane or exported from the cell. (5) The viral proteins, or fragments of them, serve as antigens to stimulate the immune system. Barry Chess/McGraw Hill
Prior to COVID-19, mRNA vaccine research was focused on fighting cancer. The thought was that a gene unique to cells in a cancerous tumor could be used to make a highly personalized vaccine that would attack the specific cancer cells of a single individual. The fact that this research could pivot so quickly points to an inherent quality of mRNA vaccines—by changing the mRNA used, it should be possible to rapidly create vaccines against nearly any pathogen. Vaccines targeted against a variety of pathogens, including influenza, are currently in clinical trials.
