LESSON 5.5 WORKBOOK - wikis.uit.tufts.edu

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W o r k b o o kLesson 5.5

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DEFINITIONS OF TERMS

Vaccination — the administration of a vaccine. The

word is derived from the Latin word vaccinus, meaning from

the cow, and was first used by Edward Jenner.

Immunity — the state of being not susceptible (immune) to a

certain pathogen.

For a complete list of defined terms, see the Glossary.

LESSON 5.5 WORKBOOKWhat makes a good vaccine?

What is a vaccine?

A vaccine is a substance that has the ability to trick your immune system into thinking it has met a pathogen, so that it mounts an adaptive immune response. A vaccine is usually made of the parts of a pathogen we want the immune system to build immunity to. However, that vaccine does not contain the normal pathogen, instead, it is a weakened or killed pathogen, or only antigens from the pathogen. In this way, vaccines trick the immune system into responding to antigens that are not dangerous, as if they were diseases causing pathogens.

But why do we want to trick the immune system and how would this protect us from a potent pathogen? These questions are the focus of this lesson.

Figure 1: Vaccines build immunity to pathogens without causing an infection.

In the last few lessons, we have covered the central parts of the immune response. In this lesson, we will apply them to understanding how vaccines work. Then we will use this knowledge to investigate the pros and cons of vaccination. At the end of this course, during the vaccine debate, we will use this information to discuss an ethical dilemma: should certain vaccines be mandatory?

http://sites.tufts.edu/greatdiseases/student/glossary/

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1. Pathogens and toxins can be manipulated to generate an immune response and memory even if a damaging infection is absent.

.a True

.b False______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How do vaccines work?In essence, a vaccine stimulates immune responses (B and T cells) in the absence of a disease. But how?

1. Vaccines contain molecules from a select pathogen that stimulate innate cells. The purple cell in Fig. 2, is an innate cell and the yellow halo shows that it has been activated. This innate cell has 'seen' molecules in the vaccine that lead to activation as a pathogen would; the innate cells present parts of the vaccine they phagocytosed to T cells and secrete cytokines (not shown on figure) to stimulate innate and adaptive responses. The innate cells then search for a helper T cell that recognizes the antigen, and when they meet one that is specific for the antigen it becomes activated (the red cell with the halo). This leads to clonal expansion and the development of effector T cells, just like a response to a normal infection.

2. The activated T cells then release cytokines (in green) that give antigen specific B cells (shown in pink) permission to activate and make antibodies. As with any pathogen, when B cells respond to antigens from a vaccine they need T cell help to fully activate and undergo clonal expansion, to become an effector B cell that makes antibodies. Some of the effector B and T cells will then become memory cells that patrol the body for decades. So, if we are exposed to the intact and active pathogen the immune response will be swift and powerful. In addition, a vaccine can generate neutralizing antibodies that prevent future infections or the actions of a toxin (review lesson 5.3 on how antibody neutralization works).

Figure 2: The immune system recognizes pathogen molecules, e.g., PAMPs and antigens, in a vaccine, and responds to them. See text for description.

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2. Which of the following statements about vaccines is false?

.a It allows a person to develop immunity to a disease without contracting the disease.

.b It contains an antigen from a select pathogen that stimulates innate cells.

.c It pretends to be pathogens and active innate cells through PAMPs.

.d none of the above ________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________


Sterilizing — complete clear-ance of an infection.


So what’s the trick? Most of the processes that are described above occur normally during an infection. However, a vaccine is able to simulate innate cells in the absence of an intact active pathogen. Remember, an innate cell needs to recognize a pathogen before it responds. This is why vaccines have to look enough like pathogens to trick the innate cells; the vaccine needs to be recognized as non-self to generate a response.

If you remember from the previous lessons, mounting an immune response to a pathogen for the first time takes about 8–12 days (this is called a primary response). Is this fast enough? Usually it is, but some pathogens can cause irreversible damage to the host before an adaptive response is made, for example tetanus can lead to severe diseases within days of exposure. However, if the immune system already has a memory of the pathogen from a vaccine, it will mount a strong and fast adaptive immune response (this is called a secondary response).

What makes a good vaccine?

A good vaccine needs to: provide protection, be safe, generate long-term memory, be practical, and be economical.

Effective protectionA vaccine should provide effective protection against a pathogen. This immunity can be sterilizing, which means that it will enable the body to clear the infection completely. And most vaccines have this property. However, sometimes designing such a vaccine can be very challenging. Instead, it may be more feasible to design a vaccine that provides non-sterilizing immunity. This means that the vaccine will not prevent infection, but will lessen the severity of the disease. For example, some of the current efforts to design an HIV vaccine are working to create one that is non-sterilizing.

Figure 3: The first time the immune system meets a pathogen, it will need more time to respond compared to subsequent encounters.

Figure 4: A CDC poster that also outlines some key properties of a good vaccine.


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3. Because vaccines stimulate B and/or T cell responses to establish memory in the absence of a dangerous infection, the person will have a/the _____ adaptive immune response when he/she comes into contact with the real pathogen.

.a same

.b slower

.c faster

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SafetyA vaccine should be safe and should have limited side effects. The challenge is creating a vaccine that looks enough like a pathogen to generate a good immune response without causing disease. For example, innate cells need to be tricked into making cytokines to prime adaptive responses. But as we have learned, the cytokines themselves cause the symptoms of inflammation (pain, redness, swelling, heat, and even fever). These are the main side effects of most vaccines, however they are really the outcome of a good immune response.

Immunological memoryA good vaccine should provide immunological memory that will last for years or a lifetime. Sometimes, this is very difficult to achieve, as is the case with the current flu vaccine. The flu virus changes so much via antigenic shifts and drifts that we need a new vaccine for every new flu season. But other vaccines, such as the hepatitis B vaccine, can provide good immunity for decades.

PracticalityThe best vaccines provide immunity after one dose, don't need cold storage, and can be given in a way that is not invasive. In general, most vaccines require a few doses to provide immunity. But if a vaccine needs too many doses to provide protection, very few people will get the full regimen, especially in impoverished countries. Vaccines that need constant refrigeration from production to administration are hard to deliver in many countries with hot climates. This is why scientists are constantly working to create vaccines that don't need the so-called 'cold chain'. In addition, some vaccines can be delivered orally, as a nasal spray or even a skin patch, and can be administered by people who do not have formal training. In

contrast, injectable vaccines require properly trained staff to administer them safely, as well as easy and affordable access to clean needles.

EconomicalIs a vaccine affordable? This is extremely important since vaccines that are too expensive may never

Figure 5: US Army laboratory working on a HIV vaccine.

Figure 6: A cooler used to maintain the cold chain for vaccine storage during transportation in hot climates.

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Cowpox — a disease caused by the cowpox virus, similar to smallpox. It causes disease in

rodents and bovine animals.

Smallpox — was a viral disease with very high mortality rate of

about 30–35%, characterized by skin lesions.

Inoculation — the introduction of a microbe into a suitable situation for growth, such as into a human

host.


become widely used. For example, in the 1970s Jerome Vanderberg developed a vaccine for malaria that provides 90% protection from the disease. However, the cost of production and administration is astronomical and this vaccine has never been manufactured and used on a large scale.

How were vaccines invented?

The person who is known as the inventor of vaccines is Edward Jenner. He lived in England from 1749–1823. At the age of 13, he was apprenticed to Dr. Ludlow in Sodbury, in the English countryside. At that time smallpox was a scourge. Young Edward saw that dairymaids never caught smallpox, even though they often caught cowpox. He wondered if there might be a connection, but Dr. Ludlow wasn’t interested and Jenner soon left for medical school. After he graduated, a smallpox epidemic struck Jenner’s hometown. The farmers in the area insisted that cowpox could prevent smallpox infections, reenforcing his youthful suspicion.

A few years later, Sarah Nelmes, a local milk-maid, contracted cowpox and went to Jenner for treatment. Jenner took the opportunity to test his theory. He inoculated James Phipps, his gardener’s eight-year-old son, with cowpox taken from one of Sarah’s pustules. After an extremely weak bout of cowpox, James recovered. Jenner then tried to infect James with smallpox but (fortunately) nothing happened — the boy was immune to smallpox.

Jenner reported his observations to a skeptical Royal Society in London, who advised him to repeat his unexpected observations. Jenner soon accumulated a further 23 cases, including his son Edward, who were successfully protected from smallpox with an inoculation of cowpox. However, this was a new and revolutionary approach that had its opponents from the beginning. Some people feared the unknown, others refused to be subjected to mass treatments recommended or mandated by an authority.

By 1800, Jenner’s work had been published in all of the major European languages and his ‘vaccination process’ was being performed all over Europe and the United States. While the death rate from smallpox was previously close to 30–35%, it became close to zero. Smallpox vaccination was continued until around 1974 in the UK. At that time, the typical death rate from the vaccination itself was roughly one per

Figure 7: Jenner's methods were controversial at the time. People feared they would grow cow's appendages after getting inoculated with cowpox.


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Attenuate — to weaken.


million, making it the most dangerous immunization that was widely provided in modern times. Thanks to the development of the smallpox vaccine, the disease became the first human infectious disease to be officially eradicated in 1979.

How vaccines are made in the 21st century?

Long gone are the days when a biological sample from one infected person is obtained and administered to another. Currently, there are four main types of vaccines. Each one of them has pros and cons. In addi-tion, new or improved types of vaccines are constantly being researched by scientists.

1. Killed (inactivated) pathogen. Pathogens can be killed by heating or by treating with chemicals. In this case, the virus remains relatively intact but is unable to replicate. The inactivated pathogen still has many of its PAMPs and its antigens, so the immune response recognizes them and responds. However, since the pathogen will sustain some damage during inactivation, it will lose some antigens. In addition, during manufacturing there is always a chance, although very small, that the microbe will not be completely killed. This can be especially dangerous for people who are immunocompromised.Pros: Generates strong immune response because it contains many PAMPs and antigens from the microbe.Cons: Potential for manufacturing errors which can result in insufficient inactivation of the pathogen. Examples: The injectable flu shot.

2. Live but attenuated (weakened) pathogen. These vaccines contains the live microbe that will replicate a little bit in your body. But because the microbe is weakened, it cannot cause disease like the

normal pathogen. This type of vaccine is generally safe for healthy people but can be dangerous in immunocompromised people. Live microbes can be weakened (attenuated) by removing a dangerous gene, such as a gene coding for a toxin or for infectivity, while keeping the other antigens intact. This can be done through targeted selection of mutants or by growing the pathogen in another host so that is de-evolves for humans. However, if inactivation is incomplete this could result in microbes that are alive and capable of causing a full-blown disease. In addition, even when properly attenuated, once the microbe is administered and starts replicat-ing in the host, there is a small chance that it will mutate which can lead to a more dangerous form of the pathogen. Is it worth the risks? Since the

Figure 8: A killed pathogen has many of its antigens.

Figure 9: A weak-ened pathogen can replicate in the host.


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Adjuvant — a chemical added to a vaccine. The adjuvant mimics a

PAMP and stimulates the innate immune response.


microbe is replicating its live intact self inside the host, its PAMPs and antigens will be presented to the immune system, and the immune response will be very strong.Pros: Generates very strong immune response.Cons: Not suitable for immunocompromised people; small chance of mutation to a more dangerous form.Examples: Flu shot, nasal spray form.

3. Pathogen's antigens. In some cases, the antigen that most readily stimulates the immune system can be isolated and used in the vaccine. This is great approach in terms of preventing unwanted infection, but single antigens often don’t stimulate the innate immune system very well because they lack PAMPs to activate and stimulate innate cells, as well as other antigens from the pathogen. To get around this problem, a stimulant called an adjuvant is used. An adjuvant can take the place of PAMPs and can stimulate the innate cells in a non-specific way. Then once they are stimulated, they have a better likelihood of mounting a response to the single antigen. But this is still often not very effective. The tetanus vaccine is made like this. It uses a part of the toxin that is not dangerous but allows B cells to make antibodies, and also includes an adjuvant.Pros: Very safe.Cons: They often don’t activate the innate immune system sufficiently.Examples: Tetanus vaccine.

4. Recombinant pathogen. Perhaps the best approach, in terms of safety and effectiveness, is to genetically engineer a pathogen that contains all of the important antigens (usually proteins) to stimulate both innate and adaptive immunity. At the same time, it lacks the dangerous features such as genetic material which is needed for infectivity. Such a vaccine is very safe and in addition, there is full control over the manufacturing process. But designing this type of vaccines is a major engineering project. Currently, there are a few such vaccines on the market, composed of artificially produced and assembled viral capsids but without the genome. The immune system ‘sees’ the viral capsid with all of its antigens and mounts a complete immune response.

Pros: Very safe, complete control over the final product, great immune response.Cons: Hard to make, needs lots of engineering and research.Examples: Hepatitis B and HPV vaccines.

Figure 10: A vaccine can contain only some antigens.

Figure 11: Recombinant pathogen looks much like the live one to the immune system.


STUDENT RESPONSES

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Remember to identify your sources

What are the characteristics of a good vaccine?

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Explain how the body reacts to a vaccine, identifying the various immune cells involved and specific interactions between immune cells and the resulting responses.

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What are challenges of creating an effective new vaccine?

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TERMS

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TERM DEFINITION

Adjuvant A chemical added to a vaccine. The adjuvant mimics a PAMP and stimulates the innate immune response.

Attenuate To weaken.

Cowpox A disease caused by the cowpox virus, similar to smallpox. It causes disease in rodents and bovine animals.

Immunity The state of being not susceptible (immune) to a certain pathogen.

Inoculation The introduction of a microbe into a suitable situation for growth, such as into a human host.

Smallpox Was a viral disease with very high mortality rate of about 30–35%, characterized by skin lesions.

Sterilizing In this case, to provide a state free of a pathogen.

Vaccination The administration of a vaccine. The word is derived from the Latin word vaccinus, meaning 'from the cow', and was first used by Edward Jenner.

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LESSON 5.5 WORKBOOK - wikis.uit.tufts.edu