SEE HOW
IT WORKS
SEE HOW
IT WORKS
In these vaccines, a harmless virus (the vector) is built to deliver genes from a harmful virus (the target) to your cells. Like with a real infection, your own cells make the viral proteins. Since they are more like a real infection, viral vector vaccines can cause a stronger immune response than protein-based vaccines.This approach can work for viruses where it’s not possible to develop a safe weakened form, or where protein-based vaccines don’t work.
These traditional approaches were used to make the first vaccines, many decades ago. Some of these vaccines are still in use today.EndFragment
Protein-Based
Traditional
Viral Vector
Whole Virus
Newer approaches build on what we have learned from genetic engineering. These approaches have already led to vaccines against viruses where older approaches didn’t work. And there are more coming. Some vaccines made with these newer approaches can also be developed more quickly. That’s very important during an outbreak of a novel virus.
These vaccines deliver viral genes to your cells—but they include no virus. The genes code for one or a few proteins from the virus’s surface. Like with a real infection, your own cells read the genes to build the viral proteins. But your cells make just part of the virus, which can’t come together to make whole viruses that can cause an infection.Nucleic acid vaccines are among the quickest and least costly to make while also leading to a strong immune response. This may make them very useful for fighting outbreaks of novel viruses.
Traditionally, vaccines were made from either whole viruses or pieces of viruses. But these older approaches don’t work for every virus. Plus they can take many years to develop.
Modern
Protein-based vaccines include just the parts of the virus that cause the strongest immune reaction. This is usually the proteins from the outer surface. They’re safe and can be fast to make. And it’s an approach that works and has stood the test of time. The biggest challenge is getting them to cause a strong immune reaction—though scientists are getting better at this all the time.
Nucleic Acid
2. Grow in huge numbers of fertilized chicken eggs (or sometimes in cells)
Whole Virus: Weakened
Weakened virus
3. Purify the virus to make the vaccine
Weakened (or attenuated) vaccines use a lab-grown version of the virus that is less dangerous than the wild virus.The weakened virus can get into the host’s cells, where it’s copied. Since it is a real infection, the immune response is strong. But since the infection is mild, the immune system can easily fight it. Often 1 or 2 doses give life-long immunity.
It’s great when it works. But not every virus can be weakened enough to make a safe vaccine.
Examples: MMR (measles, mumps, rubella), rotavirus, chickenpox (varicella), Flu (nasal vaccine), yellow fever. The oral polio vaccine, approved in 1961, used a weakened virus. Though no longer used in the US, it’s still used in other countries.
Genetic information
1. Infection: virus puts its genetic information into cells
1. Grow virus in non-human cells and/or under non-ideal conditions (e.g., low temperature) Virus accumulates mutations that make it less harmful
Viral proteins
2. Amplification: cell makes copies of genetic information & reads it to build viral proteins
3. Release: Genetic information & proteins come together into new virus particles, which can infect other cells
New virus copies
Measles
4. Immune cells attack infected cells & virus particles
HOW IT WORKS
HOW IT’S MADE
Inactivated virus
1. Viruses can’t cause an infection, so they stay in the spaces between cells
2. Immune cells attack viral particles
1. Grow virus in a large volume of cells (usually in a bioreactor)
Whole Virus: Inactivated
2. Collect & concentrate large amounts of ‘live’ virus
3. Inactivate: treat with chemicals or heat so virus can no longer infect cells
Inactivated vaccines use a virus that has been treated with heat or chemicals to “kill” or inactivate it. Inactivated viruses cannot infect cells—so this type of vaccine tends to be very safe. But that means it also causes a weaker immune response. It may take more doses or regular boosters (follow-up doses) to be protected.This approach doesn’t always work. For example, inactivated Ebola doesn’t cause enough of a reaction to protect someone.
Examples: Hepatitis A, Influenza A (flu), polio, rabies. The first inactivated rabies vaccine was developed in 1885, making it one of the first of its type. Most inactivated flu vaccines are grown in fertilized chicken eggs.
Polio
4. Purify the inactivated virus to make the vaccine
1. Viral proteins stay in the spaces between cells (they can’t cause an infection on their own)
2. Immune cells attack the viral proteins
Influenza A
1. Isolate genes that code for viral surface proteins
2. Genetic engineering: Put viral genes into cells that can grow in the lab
Protein-Based: Subunit
Subunit vaccines are made of just one or a few types of viral proteins. When the immune system learns to detect viral proteins, it’s ready to fight the real virus. And because much of the virus is left out of the vaccine—like the genetic information and internal proteins—the immune response tends to be very specific.Early subunit vaccines were made by growing whole viruses, breaking them apart, and purifying their proteins. Today, most subunit vaccines are made from cells that are genetically engineered to make viral proteins.
A subunit vaccine can have proteins from multiple strains of virus, or even multiple viruses, giving you broad protection.
Examples: Influenza A (recombinant flu vaccines), influenza B (Hib), shingles (varicella).
3. Cells read viral genes & build viral proteins
4. Purify proteins to make vaccine
SEE HOW IT’S MADE
4. Attach viral proteins to particles (e.g., engineered proteins or synthetic beads)
5. Purify particles to make vaccine
1. Nanoparticles stay in the spaces between cells (they can’t cause an infection on their own)
2. Immune cells attack the nanoparticles
Nanoparticles
Protein-Based: Nanoparticle
Nanoparticle vaccines are designed to look like real viruses in their size and shape. In this approach, lab-grown viral proteins are put onto or into tiny carrier particles. The carrier particles can be made from larger proteins, organic or inorganic polymers, metals, or other materials.Nanoparticles tend to stay in the body longer than individual protein subunits, so they cause a stronger immune response. To cause an even stronger response, they can be built to carry molecules that activate the immune system.
Examples: Experimental nanoparticle vaccines are in development for many viruses, including HIV, influenza, respiratory syncytial virus (RSV), Epstein Barr virus, and SARS.
Similar types of nanoparticles have been used for time-released and targeted drug delivery.
Several nanoparticle vaccines are being developed for animals, for example against foot and mouth disease.
Whole Virus: Heterologous
A heterologous vaccine works like a weakened vaccine, only it uses a virus that is found naturally.The first widely used vaccine of any kind was against smallpox. It was first given in 1796, and it was used to eradicate (completely get rid of) smallpox worldwide. It used live vaccinia virus, a naturally occurring virus that infects cows. Vaccinia is closely related to smallpox but causes a much milder reaction.
Factoid: The word vaccine is derived from vaccinia.
3. Release: Genetic information & proteins come together into new virus particles, which can infect other cells
Target virus (harmful)
1a. Isolate gene that codes for surface protein
These vaccines use a virus that can infect your cells, get copied, and spread to other cells. It works like a ‘live’ weakened virus vaccine. In fact, the viral vectors are based on a harmless or weakened virus (e.g., VSV or weakened measles). The difference is that the vector is built to carry genes from a different target virus.Once infected, your own cells read the genetic information to make more viruses—including the target protein. The immune system gets rid of the infection, learning to detect the target protein. Since the vaccine causes a real (but very mild) infection, the immune response is strong.
Examples: In December of 2019, an Ebola vaccine became the first of this type to be approved for human use. It’s based on an unrelated virus (VSV, which infects livestock) that’s built to make proteins from the Ebola virus.
Other vaccines of this type are being developed for HIV, influenza, dengue, and MERS. This approach is also being tested for treating certain types of cancer.
Vaccines approved for use in animals include oral rabies, avian influenza, equine influenza, feline leukemia virus, canine distemper, and several viruses in poultry.
1b. Discard gene that codes for surface protein
2. Place gene from target virus into viral vector
3. Grow virus in a large volume of cells (usually in a bioreactor)
4. Purify the virus to make the vaccine
Viral Vector: Replicating
1. Infection: viral vector puts its genetic information into cells
Viral vector (harmless)
3. Target proteins move to cell surface
4. Immune cells attack protein on cells
Like replicating vaccines, these vaccines also use a viral vector (e.g., adenovirus) that is built to carry genes from an unrelated target virus. But while non-replicating vaccines can infect your cells, they cannot be copied or spread.Once infected, your own cells read the target virus gene to make viral proteins. The proteins move to the cell surface, where the immune system learns to detect them. Since this process is like what happens during a real infection, the immune response tends to be stronger than with proteins made outside the body.
Examples: Several experimental vaccines are in development, including for rabies and HIV.
Viral vectors used in vaccines are similar to ones that are used in gene therapy.
Non-replicating vaccines have also been tested in animals, including for Rift Valley fever, a virus that infects livestock.
1. Isolate gene that codes for surface protein
Viral Vector: Non-Replicating
2. Cell reads genetic information to build target viral proteins
Viral genes (RNA)
These vaccines deliver viral genes in the form of RNA—a molecule that’s made as an intermediate between DNA and proteins. To get the RNA into cells, it can be packaged into tiny membrane-wrapped spheres. The spheres fuse with the cell membrane, delivering the RNA inside. RNA molecules can also be stuck onto nanoparticles, which cells will take up. Once inside, cellular machinery reads the RNA instructions to build viral proteins.This is one of the newest approaches to vaccine development.
Examples: Several experimental RNA vaccines have been tested, including for HIV, influenza, Ebola, Zika, Chikungunya, and rabies. The first two RNA vaccines ever to be widely used in people were against SARS-CoV-2.
The first two RNA vaccines ever to be widely used in people were against SARS-CoV-2.
2. Synthesize many RNA copies of the viral gene
3. Package RNA into membrane spheres
4. Make the vaccine
1. Sphere fuses with cell, releasing RNA inside
2. Cell reads viral RNA to make viral proteins
Nucleic Acid: RNA
3. Viral proteins move to cell surface
1a. (optional) Insert piece of a gene from another virus
2. Put viral genes into cells that can grow in the lab
3a. Cells build hybrid proteins
HPV
4a. Particles have protein from other virus on the surface
From the outside, virus like particles (VLPs) look like a real virus. But they are empty protein shells with no genetic information. Because they have lots of copies of viral proteins packed closely together, they’re better than individual proteins at causing the immune system to respond. And since they pose no risk of infection, they’re very safe.VLPs are made like subunit vaccines: scientists engineer cells in the lab to make viral proteins. The first VLP vaccine was against hepatitis B. The proteins that form the outer shell around hepatitis B have a slightly unusual and useful feature: they self-assemble. This means they piece themselves together to make whole, empty virus particles.
Scientists have used genetic engineering to take VLPs one step further. In one approach, they start with proteins from a virus that can self-assemble, like hepatitis B. Then they add pieces of proteins from a virus that cannot self-assemble. The new proteins can still self-assemble. And they display the bits from the other virus on the outside, where the immune system can learn to detect them.
Another approach is to make enveloped VLPs, which look like enveloped viruses. These are empty spheres of cell membrane with embedded viral proteins.
Examples: Hepatitis B, HPV (human papillomavirus), hepatitis E. An enveloped VLP vaccine for viral meningitis has been approved for use in some countries.
Many experimental VLP vaccines are in development, including for norovirus, rotavirus, respiratory syncytial virus influenza strain H5N1, chikungunya, and CMV (cytomegalovirus).
3. Cells read viral genes & build viral proteins
2. Immune cells attack the VLPs
4. Proteins self-assemble into empty particles
1. VLPs stay in the spaces between cells (they can’t cause an infection on their own)
Virus-like particles
Protein-Based: VLP
4. Viral proteins move to cell surface
5. Immune cells attack protein on cells
1. Isolate gene that codes for surface protein & put into a circular carrier DNA molecule
Viral gene (DNA)
2. Grow DNA in cells to make many copies
Nucleic Acid: DNA
3. Purify DNA & make the vaccine
1. Use electricity to make temporary holes in cell membranes
2. DNA enters cell nucleus
These vaccines deliver viral genes in the form of DNA—the same molecule your own cells use to encode genetic information. One of the hardest things with these vaccines is getting the DNA into the cell nucleus, where DNA is stored and read. It has to get through two membranes: one around the cell, and one around the nucleus. One approach is to use electricity to make temporary pores through the membrane.Even though research on DNA vaccines began in the 1990s, it’s still considered a new approach.
Examples: Several experimental DNA vaccines have been tested, including for Ebola, influenza, Zika virus, and SARS-CoV.
A few DNA vaccines have been approved for use in animals. The first was for salmon (against hematopoietic necrosis virus disease). Others include a vaccine for West Nile in horses, and for dogs a vaccine for the skin cancer melanoma. A candidate poultry vaccine has been developed against H5N1 influenza.
3. Cell copies viral gene as RNA & reads it to make viral proteins