Supplemental Lecture (98/05/24 update) by Stephen T. Abedon (abedon.1@osu.edu)

1. Chapter title: Vaccination
1. A list of vocabulary words is found toward the end of this document
2. Vaccines are the single most important application of immunology. Along with improved sanitation, prophylactic vaccines are also the most important contributor to avoidance of disease-induced premature mortality (beating antibiotics hands down). The human (per capita) birth rate has remained fairly constant for hundreds of years. Growth of human populations therefore is a consequence far more of delayed death than increased rates of births. Vaccines, by contributing so significantly to avoidance of premature death, have consequently been instrumental in the achievement of the global human population explosion. Vaccines therefore are a crucial contributor to our planet's ongoing ecological collapse.
3. Ignoring these potentially impersonal, long-term, global problems associated with vaccination, vaccines nevertheless play enormous roles in assuring our and our children's ongoing health (contribution to the salvation of the planet through avoidance of vaccination is simply the playing of a very literal, microbiological version of Russian roulette---you lose, you die). Vaccines achieve their results simply through a "priming" of acquired humoral and cell-mediated active immunity. That is, vaccines work by fooling the body into behaving as though it has had previous immunological experience with a pathogen, thus allowing faster and more powerful inhibition of pathogen growth should subsequent exposure occur.
4. The strengths of prophylactic vaccination are also its weaknesses:
1. vaccines prevent disease, not infection
2. vaccination against a disease which does not induce natural immunity, even given exposure to the wild pathogen, is difficult
3. vaccines against toxins for various reaons must be boosted from time to time
4. because vaccines are biological materials, they suffer from the inherent lability of such materials and therefore are difficult to deliver intact to geographically remote locals
5. etc.
5. We will discuss the various strengths and weaknesses of prophylactic vaccination in this lecture.
2. Vaccine [vaccination, immunization]
1. Pathogen mimicry:
1. A vaccine is a suspension of microorganisms or parts of microorganisms that will induce immunity.
2. Immunity is induced in a host either upon injection or via exposure to a more typical portal of entry.
2. Vaccination confers artificially acquired active immunity.
3. Prophylactic vaccine
1. Disease prevention:
1. A prophylactic vaccine is a vaccine designed to prevent disease.
2. A prophylactic vaccine may be adminstered prior to exposure to the pathogen, or after exposure to a pathogen but prior to the occurrence of disease.
3. In most cases, when one thinks of vaccine, one is doing so in the context of a prophylactic use (e.g., prevention of infection by the measles virus by employing a measles vaccine).
2. Not disease treatment:
3. Contrast prophylactic vaccine with the use of vaccination to treat disease such as the adminstration of tetanus toxoid in response to accute tetanus toxemia.
4. For example, Jonas Salk proposed an anti-HIV vaccine to be administered to the HIV-infected, while various anti-cancer schemes involve vaccinating individuals already afflicted by a cancer with antigens from that cancer. The idea in both cases is to present, to the body, antigens from the pathogen (or cancer) which for whatever reason the body has not been able to already recognize in situ. The Salk plan was probably founded on an incomplete understanding of HIV infection (i.e., that body isn't already doing a pretty darn good job containing the infection). Anti-cancer vaccines have been shown to work well in certain circumstances, though treatments require complex in vitro manipulations of patient cells.
4. Booster [booster dose, booster shot]
1. Multiple immune system exposure:
1. Because of the means in which prophylactive vaccines function, sufficient levels of acquired immunity in the majority of vaccine recipients often requires a second or more round of vaccination.
2. These subsequent vaccinations are called:
1. boosters
2. a booster dose
3. a booster shot^*
4. *when the vaccine is administered by syringe.
2. Reasons for boosting differ depending on the vaccine employed. For example, in the case of live vaccines, boosting is employed to insure that an infection has taken. For vaccines which do not consist of live pathogens, boosting is employed in the more traditional sense of the word, i.e., to further enhance the immune boosting effect of vaccination by repeatedly exposing the immune system to the vaccine. Successful infection with a live vaccine essentially accomplishes this repeated exposure to the immune system by virtue of its establishment of an infection.
5. Control of viral disease
1. Few antivirals:
1. Unlike many bacterial diseases, the majority of viral diseases are not susceptible to antibiotics therapy.
2. Consequently, the best policy with regard to viral diseases is prevention.
2. Vaccination as disease prevention:
1. Barring avoidance (which is not always easy, or even possible), the best defense medicine has against viruses is vaccination.
2. Fortunately, many viruses are capable of conferring lifetime immunity upon infection (e.g., chicken pox, measles, rubella, smallpox, influenza, etc.).
3. Note that just because vaccination may be a preferred way to prevent specific viral diseases, it is not necessarily easy to develop viral vaccines.
6. Immunization against exotoxins [toxoids]
1. Antitoxin immunity:
1. A second area in which antibacterial antibiotics play a less than satisfactory (or complete) role in disease prevention is with regard to diseases whose symptoms are due to the production of exotoxins.
2. A number of vaccines are in use that act to confer active immunity against bacterial exotoxins.
3. Particularly, this includes:
1. anti-diphtheria vaccination
2. anti-tetanus vaccination
2. Active immunity in this case is simply an in situ stimulation of the production of antitoxin.
3. Toxoids:
1. Anti-exotoxin vaccines consist of intravenously delivered toxoids and have the characteristic of not conferring lifelong immunity.
2. This is because toxins themselves tend to be present in such low quantities that they do not induce or do not strengthen the antitoxin immune response, even given disease.
4. No toxin priming of immunity:
1. The inability of toxins produced by pathogens to increase immunity contrasts with anti-pathogen vaccines whose priming is stimulated to higher levels given the occurrence of infection.
2. Antipathogen vaccination essentially gives the immunized individual a head start against an infection. Antitoxin, on the other hand, must succeed in neutralizing toxin entirely within the confines of the existing, vaccine induced, immune response.
3. In other words, your antitoxin immune response does not necessarily improve given exposure to toxin produced by a pathogen (because toxin is produced in such small quantities), while immunity against the pathogen itself will actually improve upon pathogen exposure.
7. Herd immunity
1. Vaccination as an altruistic act:
1. While the lay public does not necessarily consider vaccination to be an act of altruism, for many diseases it, in fact, is. This is particularly true for diseases which are not extremely contagious (measles by contrast is an example of an extremely contagious disease against which herd immunity is not terribly effective).
2. For most diseases, vaccination of individuals confers individual immunity and also something known as herd immunity.
2. Combating endemicism:
1. Herd immunity is the inability of a population to support the epidemic dissemination of a disease, simply because not enough of the population is sufficiently naive (i.e., lacks immunity) to the disease to support continued pathogen dissemination.
2. The fewer who are naive, the more contagious must be the disease to maintain endemicism.
3. Thus, a person who is immunized not only is protecting herself but is also assuring that they will not transmit that disease to a neighbor (or, at least, greatly lower the probability of transmission) regardless of whether that neighbor also displays active immunity.
3. Note that for extremely contagious diseases, e.g., measles, the fraction of a population which must be susceptible to sustain an epidemic is so small as to make herd immunity essentially impossible to attain.
8. Difficulties in developing vaccines
1. While from a public health point of view vaccines are wonderful things, in practice it is not necessarily easy to engineer effective vaccines against any given disease.
2. Reasons that vaccine development is not always an fruitful endeavor can include:
1. limited range: a given vaccine tends to be effective only against individual serovars of pathogen species (some species have hundreds of serovars)
2. disease isn't immunizing: for some pathogens even exposure to disease (the ultimate form of immunization) does not confer active immunity
3. rapid evolution: development of vaccines against particularly rapidly evolving pathogens (such as HIV) is also difficult because they, essentially, are moving targets---at best such vaccines are rapidly made obsolete by pathogen evolution (e.g., anti-influenza vaccines)
4. exacerbation of disease: vaccines of certain types, against certain pathogens can actually exacerbate disease when it occurs
1. cause of disease: live vaccines retain at least some potential for causing the disease they are charged with preventing. This is especially true with regard to immunodepressed individuals (e.g., live polio vaccine)
2. cost-benefit problems: successful vaccine delivery is not always economically or politically justifiable
9. Types of vaccines
1. There are two general categories of vaccines:
1. whole-agent vaccines
2. subunit vaccines
10. Whole-agent vaccines
1. Whole organism:
1. Whole-agent vaccines consist of entire organisms that have been modified in some manner so that they are unable (or drastically less able) to cause disease.
2. The vast majority of vaccines in use today are whole-agent vaccines.
3. Whole-agent vaccines consist of two general categories:
1. inactivated^* (while killed)
2. genetically attenuated (live-attenuated)
3. *Inactivated physically or chemically.
2. Whole-agent vaccines are far easier to develop than subunit vaccines since they require much less knowledge of pathogen biology than do subunit vaccines.
3. The down side of whole-agent vaccines is that they retain at least some potential to cause disease.
11. Whole-killed vaccines
1. Physically inactivated pathogens:
1. Whole-killed vaccines are vaccines consisting of the entire microorganism (often a virus) that has been inactivated in some manner (chemically or physically).
2. Whole-killed vaccines tend to be administered intravenously.
2. Potential to cause disease:
1. Whole-killed vaccines are considered safe to the degree that one can be certain that all of the microorganisms present have been killed.
2. Since these microorganism, if not killed, are as virulent as those which normally cause disease, use of "whole-killed" vaccines which are not actually dead can lead to the very disease the vaccine was designed to prevent.
3. The other down side of whole-killed vaccines is that they typically are not able to confer immunity to the degree live attenuated vaccines are capable.
12. Live-attenuated vaccines
1. Genetically attenuated pathogens:
1. The advantage of live-attenuated vaccines is that they mimic pathogen infection to a large extent, but without causing disease.
2. That is, live attenuated vaccines actually cause infection, though ideally only a mild infection, of essentially the same type (only, of course, milder) as that caused by the wild pathogen.
2. Live-attenuated vaccines tend to be second in efficacy only to exposure to the unattenuated pathogen.
3. The down side of live-attenuated vaccines are:
1. they can both cause disease in immunocompromised individuals
2. they can reverse their genetic attenuation
3. they can cause disease in otherwise healthy individuals
13. Subunit vaccines
1. Vaccines made from well defined components of microorganisms are called subunit vaccines.
2. Minimal genes:
1. Particularly what must be absent from the vaccine are a sufficiently large number of genes so that there is no possible way that disease (or even replication) could result from vaccination.
2. In practice, subunit vaccines consist of either:
1. isolated proteins (or other immunogenic cellular components)
2. a limited number of genes from the microorganism that are introduced into the host in some manner and expressed within host cells
3. Safety bias:
1. In general, a subunit vaccine would be employed for reasons of safety rather than any bias toward long-term efficacy.
2. If efficacy is your only goal then a live-attenuated vaccine might be a better choice.
14. Recombinant vaccines
1. A subunit vaccine that is produced using recombinant techniques is called a recombinant vaccine.
15. Specific common vaccines (see overview, below)
1. Overview:
1. DTP vaccine
2. hepatitis B vaccine
3. influenza vaccine (flu shot)
4. MMR vaccine
5. Sabin vaccine
6. Salk vaccine
7. smallpox vaccine
2. DTP vaccine:
1. DTP vaccine is a trivalent vaccine that confers immunity against:
1. diphtheria (a toxoid)
2. tetanus (a toxoid)
3. pertussis (a whole killed vaccine)
3. Hepatitis B vaccine:
1. Hepatitis B vaccine is a recombinant vaccine that confers immunity against hepatitis B.
2. ". . . the formulation of a safe, effective, and inexpensive vaccine against hepatitis B. This virus, carried by about 300 million people worldwide, is transmitted through blood and sexual contact. Because chronic infections can ultimately lead to cirrhosis of the liver and liver cancer, millions of those infected die (worldwide). In the late 1970s, the only vaccine available was derived from human serum; it was in short supply, and those treated risked infection with other blood-borne viruses carried by the vaccine. Using our new technique, William Rutter of the School of Medicine at the University of California, San Fransisco, and Benjamin Hall of the University of Washington introduced the gene for the hepatitis B protein into yeast. The resulting genetically engineered yeast produced vast quantities of highly immunogenic but noninfectious virus particles, which were developed into a commercial vaccine by Merck in 1986. This vaccine is effective against hepatitis B, carries no blood-borne viruses, and is available in unlimited quantitites." (Fink, 1996)
3. All individuals and workers exposed to human body fluids who have not already been vaccinated against hepatitis B should do so prior to interaction with such materials.
4. The influenza vaccine (flu shot) is a whole killed vaccine that is reformulated each year and must be retaken annually.
5. MMR vaccine is a trivalent vaccine that confers immunity against:
1. measles (a live attenuated vaccine)
2. mumps (a live attenuated vaccine)
3. rubella (a live attenuated vaccine)
6. Sabin vaccine:
1. The Sabin vaccine is the oral polio vaccine.
2. It is a live attenuated vaccine.
3. Contrast with Salk vaccine.
7. Salk vaccine:
1. The Salk vaccine is an intravenous polio vaccine.
2. It is a whole killed vaccine.
3. Contrast with Sabin vaccine.
8. Smallpox vaccine:
9. The smallpox vaccine consists of vaccinia virus, a live attenuated vaccine delivered to the skin.
10. Targeted administration of the smallpox vaccine together with the effectiveness of herd immunity against smallpox has resulted in the successful eradication of smallpox in the wild.
16. Properties of an ideal vaccine
1. Overview:
1. An ideal vaccine would have the following properties:
1. 100% safe
2. won't cause disease in others
3. no residual pathogenicity
4. will prevent disease
5. effective against all strains
6. only one dose required
7. compatibility with other vaccines
8. deliverable without hypodermic syringe
9. indefinite room temperature storage
10. cheap to manufacture
11. capable of inducing effective herd immunity
2. Typically, as a consequence of the properties of the pathogen involved one or, in most cases, many of these ideals are not met.
3. Below we consider these ideals in greater detail.
2. 100% safe:
1. The vaccine would be 100% safe to the recipient.
2. An ideal vaccine should not retain any potential to cause the disease it is charged to protect against.
3. An ideal vaccine should not lead to any vaccine-associated disease, particularly ones which are not characteristics of the wild pathogen. These can include:
1. allergic responses in recipients
2. significant local inflammation
3. etc.
4. An ideal vaccine should not exacerbate symptoms given exposure to the wild pathogen.
3. Won’t cause disease in others:
1. An ideal vaccine should not be capable of causing disease in others.
2. Particularly, a major problem with some vaccines (particularly live-attenuated vaccines) is that the vaccine is both infectious and capable of producing progeny which can infect others.
3. In some cases, these progeny may even be wild-type revertants capable of causing full disease in unvaccinated (naive) secondary recipients.
4. This is especially a problem given the exposure of the immunodepressed to recently vaccinated individuals.
4. No residual pathogenicity:
1. The vaccine would automatically (and rapidly) clear itself from the recipients system over time so as not to retain residual pathogenicity.
2. Pathogens capable of causing latent infections could also cause latent infections when infecting in the guise of a live vaccine. In such a situation the vaccinee could become their own secondary recipient should they become immunologically depressed later in life and should further vaccine replication be induced.
3. HIV is one example of just such a latently infecting pathogen.
5. Will prevent disease:
1. The vaccine would prevent disease in all those successfully vaccinated.
2. A major, ongoing problem in vaccine development is coming up with a vaccine which is highly effective in inducing sufficient immunity.
3. Assuming that recovery from disease corresponds with inducement of immunity then, for a vaccine, being "more wild pathogen-like" and being a more effective vaccine often go hand in hand.
4. When efficacy is pursued at all costs, dangers associated with naive exposure to the pathogen can become important. Consequently, there can exist a perverse correlation in some vaccines between effectiveness and danger to the health of the recipient.
6. Effective against all strains:
1. The vaccine would be effective against all current and future strains of the pathogen.
2. Pathogens have a tendency to evolve, within infected individuals, away from immune system control. This ability to essentially escape immune system recognition impacts on the achievement of immunological control via vaccination as well.
3. Effectively, a vaccine itself induces an immune response and the successful pathogen is the one which escapes recognition by the vaccine-induced immune response. The less robust (i.e., less broadly acting) the vaccine, the faster this evolution away from immune system recognition and the sooner a vaccine become obsolete.
4. RNA viruses such as influenza and HIV are particularly good at escaping immune system control due to the inherent low fidelity RNA-dependent genomic-nucleic acid polymerases.
7. Only one dose required:
1. Only a single dose would be required to confer complete immunity in all recipients (i.e., boosting would be unnecessary).
2. Each dose of a vaccine requires a visit to a doctor or clinic. The cost and inconvenience associated with vaccination is therefore at least directly proportional to the degree of boosting necessary to induce sufficient coverage of a population (obviously this is not a problem if a vaccine is 100% effective with only a single delivery).
3. In addition to adding to the expense and inconvenience of a vaccine, successful completion of a full regimen for a given vaccine tends to decline as required boosts increase in number. People simply find it easier to do things all at once than in multiple steps occurring over long periods.
4. Additionally, the requirement for boosting creates another level of record keeping beyond a much simpler system of keeping track of whether an individual has or has not received a single delivery of the vaccine.
8. Compatibility with other vaccines:
1. Delivery of the vaccine simultaneously with other vaccines would be possible.
2. Many vaccines today are delivered simultaneous with other vaccines (e.g., DTP and MMR). This cuts down on the total number of deliveries, which must be made to achieve full vaccination.
9. Deliverable without hypodermic syringe:
1. The vaccine would be deliverable fast and easily without the use of a hypodermic syringe.
2. Syringes are expensive by third world standards thus making vaccine delivery by syringe inherently expensive.
3. Vaccination by syringe is also not appreciated by most recipients thus interfering psychologically with full compliance.
4. Unfortunately, except for live vaccines, which often have a portal of entry which does not require syringe and needle delivery, most vaccines must be delivered by syringe.
5. The smallpox vaccine, arguably the most successful vaccine implemented to date, had the advantage of achieving robust immunity without delivery by syringe.
10. Indefinite room temperature storage:
1. The vaccine itself could be stored indefinitely prior to delivery and without refrigeration.
2. This is especially a third world problem where refrigeration is expensive and rare.
3. People refer to maintaining cold chains which basically means that a vaccine which must be refrigerated must be kept cold from the point of manufacture to the point of delivery no matter how remote the local of delivery. Avoidence of breaking the cold chain is no easy task.
11. Cheap to manufacture:
1. The vaccine would be cheap to manufacture (ideally using third world technologies).
2. Obviously the less expensive the vaccine, the less of the total cost of the vaccine which is associated with its manufacture.
12. Capable of inducing effective herd immunity:
1. Herd immunity would be sufficient to protect a population.
2. Obviously a vaccine which effectively protects a population without total vaccination of the population would be expected to be more effective than one which does require total vaccination of the population.
3. Unfortunately, it is often a property of the pathogen rather than the vaccine which determines the ability of the a vaccine to achieve successful herd immunity in the absence of substantially less than 100% compliance.
17. Vocabulary
1. Booster
2. Booster dose
3. Booster shot
4. Control of viral disease
5. Difficulties in developing vaccines
6. DTP vaccine
7. Hepatitis B vaccine
8. Herd immunity
9. Immunization
10. Immunization against exotoxins
11. Influenza vaccine
12. Live attenuated vaccines
13. MMR vaccine
14. Properties of an ideal vaccine
15. Prophylactic vaccine
16. Recombinant vaccines
17. Sabin vaccine
18. Salk vaccine
19. Smallpox vaccine
20. Specific common vaccines
21. Subunit vaccines
22. Types of vaccines
23. Vaccination
24. Vaccine
25. Whole-agent vaccines
26. Whole killed vaccines
18. Practice questions
1. Whole agent vaccines are certainly simpler to develop than are subunit vaccines. However, even whole agent vaccines have their limitations. What property of various pathogens is the single greatest limitation on our ability to develop individual vaccines against all types of pathogens? [PEEK]
2. Name a common toxoid vaccine. (one word answer) [PEEK]
3. Name a difference between the Sabin and the Salk polio vaccines. [PEEK]
4. Name four diseases against which a live attenuated vaccine is commonly used. [PEEK]
5. Subunit vaccines tend to be lacking in efficacy when compared with whole vaccines, and also can be more difficult to develop. Nevertheless, name an advantage associated with the use of subunit vaccines. [PEEK]
6. Give two differences between the Salk and Sabin vaccines (other than who developed and named them) and make sure you tell me which property is associated with which vaccine. [PEEK]
7. Give an example of a whole-agent vaccine. [PEEK]
8. What is herd immunity? [PEEK]
9. What do the "D", the "T", and the "P" in "DTP" stand for? [PEEK]
10. What subunit vaccine is employed on humans? [PEEK]
11. Other than that both are against viruses and that both are taken intravenously, host does the Salk polio vaccine resemble the influenza vaccine? [PEEK]
12. Which of the following characteristics of an ideal vaccine are crucial for the vaccines success, particularly in third world countries? (circle three) [PEEK]
1. 100% safe
2. won't cause disease in others
3. no residual pathogenicity
4. will prevent disease
5. effective against all strains
6. only one dose required
7. compatibility with other vaccines
8. deliverable without hypodermic syringe
9. indefinite room temperature storage
10. cheap to manufacture
11. capable of inducing effective herd immunity
19. Practice question answers
1. not all infections confer immunity.
2. diphtheria or tetanus
3. Sabin's is an orally administered live-attenuated vaccine while Salk's is an intravenously administered whole killed vaccine. Salk's is also safer, more expensive, and not as long lasting. Both are trivalent.
4. measles, mumps, rubella, polio, plus smallpox.
5. safety.
6. Sabin vs. Salk: (i) live attenuated vs. whole killed, (ii) taken orally vs. injected.
7. mumps, measles, rubella, pertussis, influenza, either of the polio vaccines, smallpox vaccine; in other words, just about anything but the toxoid vaccines or the subunit vaccines, the latter limited mostly to the hepatitis B vaccine
8. the decreased tendency for a disease to be endemic within a population as the number of immune individuals within that population increases fractionally
9. Diphtheria, Tetanus, and Pertussis
10. the hepatitis B vaccine
11. both are whole-killed vaccines
12. vi through j are particularly relevant to third world success, with h through j are perhaps a particularly significant subset.
20. References
1. Black, J.G. (1996). Microbiology. Principles and Applications. Third Edition. Prentice Hall. Upper Saddle River, New Jersey. pp. 501-509.
2. Fink, G. R. (1996). Bureaucrats save lives. Science 271:1213.
3. Tortora, G.J., Funke, B.R., Case, C.L. (1995). Microbiology. An Introduction. Fifth Edition. The Benjamin/Cummings Publishing, Co., Inc., Redwood City, CA, pp. 448-452.