• Vaccines are an important tool for protecting people from diseases caused by viruses or bacteria.
• They train the body’s immune system to respond to an invading microbe, even one that it’s never encountered before.
• The immune system’s job is to prevent viruses and bacteria from invading the body and to eliminate them once an infection has started.

Vaccines have been protecting people from diseases such as polio, smallpox, and measles for decades, but scientists are now developing vaccines that might work against the viruses that cause HIV, Zika, and most recently COVID-19.

Vaccines are an important tool for protecting people from diseases caused by viruses or bacteria. They train the body’s immune system to respond to an invading microbe, even one that it’s never encountered before.

Many vaccines are designed to prevent disease rather than treat an active infection. However, scientists are working on therapeutic vaccines that could be used to treat an illness after you have it.

With all eyes focused on a potential vaccine for COVID-19, here is an overview of how vaccines work and the different types of vaccines that are currently used or under development.

How the immune system fights infection

When a microbe such as a virus or bacteria enters the body and multiplies, it causes an infection. The immune system’s job is to prevent microbes from invading the body in the first place and to eliminate them once an infection has started.

The immune system uses several tools to fight microbes, including different types of white blood cells (WBCs), or leukocytes:

• B lymphocytes, or B cells, release Y-shaped proteins (antibodies) that bind to markers (antigens) found on invading microbes. Each B cell makes a specific antibody. The binding of an antibody to its antigen triggers an immune response aimed at weakening or killing the microbe.
• T lymphocytes, or T cells, target cells in the body that have already been infected. T cells have a variety of functions, including stimulating nearby B cells to produce antibodies, activating other T cells, or attacking cells with abnormal or foreign molecules on their surface.
• Macrophages. These cells engulf and digest microbes that have entered the body, and also clear away debris left behind by dead cells. After digesting a microbe, a macrophage presents antigens from that microbe to nearby T cells. Macrophages also release chemicals called cytokines that are involved in initiating inflammation.

The first time the immune system encounters a virus or bacteria, it can take several days to activate a full immune response.

However, some B cells and T cells can become memory cells, which help the immune system respond more quickly the next time it encounters the same microbe. This long-term protection against disease is called immunity.

How vaccines help the immune system

A vaccine helps your body fight infection more quickly and effectively. It does this by priming your immune system to recognize a virus or bacteria, even if it hasn’t encountered that microbe before.

Vaccines consist of weakened or killed microbes, pieces of microbes, or genetic material from a microbe.

Vaccines with dead virus particles or pieces of the virus aren’t capable of causing an infection, but they make your immune system think that one has occurred.

When a vaccine is given, the immune system produces antibodies to the markers (antigens) on the microbe, and in some cases, also memory B or T cells. After vaccination, the body responds more quickly the next time it encounters that microbe.

Vaccines reduce the severity of an infection if it occurs. Some vaccines can even block a microbe before it causes an infection, while some vaccines also keep people from passing the virus or bacteria onto other people.

As a result of this reduced transmission between people, when you get vaccinated you are protecting not only yourself but also your community. This is known as community, or herd, immunity.

Community immunity protects:

• people too young to be vaccinated
• those who can’t be vaccinated because of weakened immune systems or other medical conditions
• people who choose not to get vaccinated for religious or other reasons

Herd immunity also protects people for whom the vaccine does not work.

In general, vaccines target a specific virus or bacteria. However, some scientists fighting SARS-CoV-2 — the coronavirus that causes COVID-19 — are trying to develop a vaccine that would work across multiple coronaviruses.

This group of viruses is responsible for causing not only COVID-19, but also severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the common cold.

While each coronavirus causes a different disease, some parts of their genetic material are the same, or “conserved.” This provides a potential way for one vaccine to target many of these viruses.

“What we’re trying to do is have the best of both worlds — vaccinate against things that are uniquely immunogenic in SARS-CoV-2, but also vaccinate against highly conserved regions across all the known coronaviruses,” said Dr. John M. Maris, a pediatric oncologist at Children’s Hospital of Philadelphia (CHOP).

Maris and his colleagues are using cancer immunotherapy tools to identify regions of SARS-CoV-2 to target with a vaccine. Their work was published recently in the journal Cell Reports Medicine.

Most of the other COVID-19 vaccines in development target just the “spike protein,” which the virus uses to bind with and enter human cells. Maris and his colleagues are casting a wider net.

“What’s different about this approach is that we’re pulling pieces from all of the genes in the virus, rather than just focusing on the spike protein,” said Mark Yarmarkovich, PhD, a postdoctoral scientist in Maris’ laboratory at CHOP.

The researchers are now testing potential vaccines in mice to see if they generate an immune response. They expect to have data from this within a few weeks. These kinds of animal studies — also known as preclinical studies — are needed before candidate vaccines can be tested in people.

Types of vaccines

Several types of vaccines exist. All of them train the immune system to fight off a virus or bacteria, even before it has encountered the microbe. This can prevent the disease or reduce the severity of symptoms.

Live, attenuated vaccines

Live, attenuated vaccines contain a form of the living virus or bacteria that has been weakened in the laboratory so it can’t cause serious illness in people with a healthy immune system.

One or two doses of the vaccine can elicit a strong immune response that provides lifelong immunity. People with weakened immune systems — such as children undergoing chemotherapy or people with HIV — can’t receive these vaccines.

Examples of live, attenuated vaccines include the measles, mumps, and rubella (MMR) vaccine and the chickenpox (varicella) vaccine.

Scientists have also used genetic engineering techniques to develop live, attenuated viruses that combine parts of different viruses. This is known as a chimeric vaccine. One vaccine like this consists of a dengue virus backbone and Zika virus surface proteins. It’s undergoing early stage clinical trials.

Inactivated vaccines

Inactivated vaccines contain a virus or bacteria that have been killed, or inactivated, using chemicals, heat, or radiation so it can’t cause disease.

Even though the microbes are inactive, these vaccines can still stimulate an effective immune response. However, multiple doses of the vaccine are needed to build up or maintain a person’s immunity.

The injectable vaccines for polio and the seasonal flu are both inactivated vaccines. Another example is Havrix, a vaccine that protects against the hepatitis A virus.

Subunit vaccines

Subunit vaccines contain only part of a virus or bacteria — unlike live, attenuated vaccines and inactivated vaccines that contain the entire microbe.

Scientists choose which parts, or antigens, to include in a vaccine based on how strong of an immune response they generate.

Because this type of vaccine doesn’t include the entire virus or bacteria, it can be safer and easier to produce. However, other compounds called adjuvants often need to be included in the vaccine in order to elicit a strong, long lasting immune response.

One example of a subunit vaccine is the pertussis (whooping cough) vaccine, which contains only parts of Bordetella pertussis, the bacteria responsible for this disease. This vaccine causes fewer side effects than an earlier inactivated vaccine. The pertussis vaccine is included in the DTaP (diphtheria, tetanus, and pertussis) vaccine.

Dr. Natasa Strbo, assistant professor of microbiology and immunology at the University of Miami Miller School of Medicine, and colleagues are working on a subunit vaccine for the coronavirus that causes COVID-19. This uses a chaperone protein called gp96 to deliver the virus’ spike protein to the immune system, which then generates an immune response.

Strbo says preclinical research in mice shows that this candidate vaccine causes the immune system to generate T cells that target the spike protein, including in the respiratory system, where the virus first takes hold.

“With this vaccine, we can induce T-cell-specific responses in the airways,” she said, “which is definitely the place where everybody wants the immune response to be when it comes to a respiratory infection.”

The results of the study were published on the preprint server bioRxiv. The work is being done in conjunction with biotech company Heat Biologics. This candidate vaccine will need to go through clinical studies before scientists will know if it works in people.

Toxoid vaccines

Toxoid vaccines are a type of subunit vaccine. They prevent diseases caused by bacteria that release toxins, a type of protein. The vaccine contains toxins that have been chemically inactivated.

This causes the immune system to attack these proteins when it encounters them. Diphtheria and tetanus components of the DTaP vaccine are both toxoid vaccines.

Conjugate vaccines

Conjugate vaccines are another type of subunit vaccine that targets the sugars (polysaccharides) that form the outer coating of certain bacteria.

This type of vaccine is used when the polysaccharides (antigen) cause only a weak immune response. To boost the immune response, the microbe’s antigen is attached, or conjugated, to an antigen that the immune system responds well to.

Conjugate vaccines are available to protect against Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal infections.

Nucleic acid vaccines

Nucleic acid vaccines are made from genetic material that contains the code for one or more proteins (antigens) from a virus. Once the vaccine is given, the body’s own cells convert the genetic material into the actual proteins, which then produces an immune response.

A DNA plasmid vaccine uses a small circular piece of DNA called a plasmid to carry the genes for the antigens into the cell. An mRNA vaccine uses messenger RNA, which is an intermediary between DNA and the antigen.

This technology has enabled scientists to produce candidate vaccines more quickly.

However, these types of vaccines are still being researched. Potential vaccines using this technology are currently being studied for protection against the Zika virus and the coronavirus that causes COVID-19.

Recombinant vector vaccines

Recombinant vector vaccines are a type of nucleic acid vaccine that uses a harmless virus or bacteria to carry the genetic material into the cells, instead of delivering the DNA or mRNA directly to the cells.

One of the vectors commonly used is an adenovirus, which causes the common cold in people, monkeys, and other animals. Vaccines using an adenovirus are being developed for HIV, Ebola, and COVID-19.

Virus vector vaccines are already used to protect animals from rabies and distemper.

Delivery methods for vaccines

Most vaccines are given as an injection in the muscle — intramuscular — but this isn’t the only option.

An oral polio vaccine helped health officials eliminate wild poliovirus in many countries in Africa. Also, a seasonal flu vaccine is available as a nasal spray.

Dr. Michael S. Diamond, a professor of medicine, molecular microbiology, pathology, and immunology at Washington University School of Medicine in St. Louis, thinks a nasal vaccine might provide stronger protection against the coronavirus that causes COVID-19.

The key to any vaccine lies in the immune response that it generates.

When a vaccine is injected into the muscle, the immune response occurs throughout the body. If the response is strong enough, it can protect a person from serious illness.

An intramuscular vaccine doesn’t always produce a strong immune response in the mucous membranes lining the nose and respiratory tract, which is the entry point for respiratory viruses like SARS-CoV-2.

If a respiratory virus is able to infect cells that line the airways and multiply, a person could still transmit the virus, even if a vaccine protected them from serious illness.

Diamond and his colleagues have developed a nasal vaccine for COVID-19, using a recombinant vector vaccine based on a chimp adenovirus.

So far, they have tested it in mice, comparing its effectiveness to an intramuscular version of the same candidate vaccine. The results suggest a stronger response via the nasal route.

“Even though you generate good systemic immunity with the intramuscular version,” said Diamond, “you generate better immunity with the intranasal one, and you also generate mucosal immunity. That mucosal immunity essentially stops the infection at its starting point.”

Their work was published recently in the journal Cell. Another group of researchers had similar findings with a different intranasal vaccine for COVID-19.

While this vaccine still needs to be tested in clinical trials in people, Diamond thinks the local immune response generated by a nasal vaccine might help prevent people from transmitting the virus to others.

This vaccine is also designed to produce a strong immune response with one dose, which reduces the need for people to come back to a clinic or pharmacy for their second dose.

Not every vaccine, though, can be given in just one dose. Several vaccines require more than one dose to provide more complete immunity. This includes the vaccines for Hib, human papillomavirus (HPV), and measles, mumps, and rubella (MMR).

For other vaccines, immunity wears off over time and a “booster” shot is needed to increase the level of immunity. For example, adults should receive a booster shot of the tetanus, diphtheria, and pertussis (Tdap) vaccine every 10 years.

In the case of the seasonal flu, people need to be vaccinated each year. This is because the flu viruses that are circulating may vary from season to season. Even if the same viruses return, the immunity generated by the flu vaccine wears off over time.

Vaccine testing and approval

Like medications used to treat illness, vaccines go through several stages of research and development before they’re approved for widespread use. These stages are needed in order to show whether candidate vaccines are safe and effective.

Exploratory stage

This stage involves early work done by scientists to understand how a virus or bacteria causes disease, and to identify potential candidate vaccines that might protect people from the disease.

Much of this work is done in the laboratory, although advances in genetic and other technologies have enabled scientists to do more of the work using computers.

Preclinical stage

During this stage, sometimes called the “proof-of-concept” stage, scientists test potential vaccines in mice, rats, rhesus macaques, or other animals to see if the vaccine generates a strong immune response and if there are any adverse side effects.

This stage has to happen before the vaccine can move onto human clinical trials.

Clinical trial and approval

Clinical trials in humans involve multiple stages, or phases.

• Phase 1 clinical trial. During this stage, a small group of healthy people receives the candidate vaccine to see if it generates an immune response and if there are any concerns about safety.
• Phase 2 clinical trial. This clinical study involves a larger number of people with similar characteristics as the intended population — such as similar age range, physical health, and ideally ethnic background.
• Phase 3 clinical trial. In this study, thousands of people are randomly assigned to receive either the candidate vaccine or an inactive placebo. Scientists then wait for people to be exposed to the virus or bacteria and compare the effectiveness of the vaccine to the placebo. This large-scale study is the only way to know if a vaccine is safe and effective.
• Regulatory review and approval. Once a vaccine has been shown safe and effective in a phase 3 clinical trial, the manufacturer can apply for approval from a country’s regulatory agency. In the United States, this review is carried out by the Food and Drug Administration (FDA). The FDA will look at data from the clinical studies and determine if the risks of the vaccine outweigh the potential benefits to the population.
• Phase 4 clinical trial. After a vaccine is approved and distributed to the general public, the FDA and the Centers for Disease Control and Prevention continue to monitor the safety and effectiveness of the vaccine. This is needed because some side effects are so rare that they only show up after hundreds of thousands or millions of people have received the vaccine. Also, mutations in a virus or bacteria can make a vaccine less effective.

Like all medications, vaccines carry some risks. However, most side effects of vaccines, such as redness or pain at the injection site, are mild and go away quickly.

Some people, such as those with weakened immune systems or allergies to ingredients used in vaccines, may be at higher risk of side effects.

If you have any concerns about the safety of a vaccine for you or your child, talk to your healthcare provider.

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