As the COVID-19 pandemic continues to spread, governments, citizens, and healthcare workers everywhere turn their hopes to a new vaccine that will stop transmission. This WEEKLY takes a look at different types of vaccines and their manufacture, as well as what kind of vaccines are in development for COVID-19.
JENNER’S NEEDLE IN THE HAYSTACK
Vaccines have been around a long time—dating from the late 19th century during the smallpox pandemic. This deadly disease killed or disabled hundreds of thousands of people just in England! In 1796, an English doctor, Edward Jenner, noticed that local milkmaids were immune to smallpox. Jenner observed that these women had all suffered from cowpox, a related but harmless virus. Jenner hypothesized that the cowpox imparted some type of immunity, so to test his theory Jenner took pus from a cowpox blister and inoculated his gardener’s small son, James, with the virus through shallow scratches. James developed a slight fever afterward, but when intentionally exposed to smallpox later, the little boy never became ill.
Jenner’s methods were a little rough (not to mention unethical by today’s standards), but his thinking was spot on. The idea behind vaccines is simple. First expose someone to a harmless version of a disease-causing microorganism, or pathogen. Amazingly, this “trains” their immune system to recognize and fight the germ. Exposure to the disease forces the body to create special white blood cells, known as memory cells, which combat any further exposure to the disease.
TYPES OF VACCINES
Vaccines come in different varieties including: inactivated whole, live attenuated, and subunit vaccines. Each necessitates different manufacturing requirements.
Inactivated whole vaccine. Made with dead microorganisms (viruses or bacteria), these stimulate an immune response. Among the most famous is Dr. Jonas Salk’s polio vaccine, developed in 1955. Sinovac (Beijing, China) is working on an inactivated vaccine for COVID-19.
Live, attenuated (weakened) vaccine. These are created by reducing a pathogen’s strength so that they become harmless. Live vaccines tend to produce the strongest immune reaction. Codagenix (Farmingdale, NY) is working on a live attenuated vaccine for COVID-19.
Subunit vaccine. These vaccines use only one part of a pathogen, an antigen. The antigen provokes an immune response. One method of making subunit vaccines involves isolating a specific protein from a virus and administering only this protein. Many companies are pursuing subunit vaccines for COVID-19, including CanSino Biologics (Tianjin, China), ExpresS2ion (Horsholm, Denmark), United States Army Medical Research Institute of Infectious Diseases (Frederick, MD), Clover Biopharmaceuticals/GlaskoSmithKline (Chengdu, China/Brentford, U.K.), Vaxil Bio (Ontario, Canada), AJ Vaccines (Copenhagen, Denmark), Generex/EpiVax (Miramar, FL/Providence, RI), Sanofi Pasteur (Paris, France), Novavax (Gaithersburg, MD), Heat Biologics (Morrisville, NC), and iBio/CC-Pharming (Newark, DE/Beijing, China).
Scientists are also currently developing DNA- and RNA-based vaccines. These consist of a gene encoding a pathogenic protein as opposed to the protein itself. When delivered to a patient, the patient will temporarily make the viral protein, inducing an immune response. Companies working on DNA-based vaccines for COVID-19 vaccines include Inovio (Plymouth Meeting, PA), Takis/Applied DNA Sciences/Evvivax (Rome, Italy/Stonybrook, NY/Rome, Italy), and Zydus Cadila (Ahmedabad, India). Companies working on RNA-based vaccines include Moderna (Cambridge, MA), BioNTech/Pfizer (Mainz, Germany/New York, NY), Arcturus (San Diego, CA), and CureVac (Tubingen, Germany). (Article continues below)
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Most whole pathogen vaccines protect against viruses, such as rabies, not bacteria. But making any vaccine means first growing lots of virus. This “virus-farming” involves selecting and obtaining a strain of a particular virus, the seed strain, and choosing what to grow it in (the medium).
Where do manufacturers buy a pathogen in the first place? They come from one of two sources. Viruses (and other microorganisms and biological materials) are produced and housed in well established “culture collections,” such as the American Type Culture Collection (Manassas, VA.) Some companies or academic institutions also develop strains of particular viruses “in-house.” For COVID-19 vaccine development, the Center for Disease Control (CDC; Atlanta, Georgia) has grown the virus in cell culture and sent it to the National Institute of Health’s Biodefense and Emerging Infections Resources Repository (Bethesda, MD) for use by the broad scientific community to develop preventive and therapeutic vaccines.
Choosing the seed strain is only the first step of vaccine manufacture. Although dangerous and often deadly, viruses are powerless without a host—someone or something to grow on. Two of the most common “host-cell platforms” are chicken eggs and animal cell culture.
Chicken eggs? Yes, the incredible edible egg provides a fantastic growth medium for influenza and other viruses. (Side note: The CDC recommends that most people with egg allergies be vaccinated. However, it also suggests that those with severe, life-threatening allergies receive only certain vaccines.) Some viruses thrive in certain types of animal cells. Two of the most commonly used in vaccine production include one from the kidney of the African green monkey—known as Vero cells, and one derived from the kidney cells of a cocker spaniel (MDCK cells). Sars-Cov-2, the virus that causes COVID-19, can be grown in Vero cells. Though it is easier and quicker to scale up animal cell culture vaccine production, it is much more expensive than egg-based vaccine growth.
Regardless of medium, once there’s enough virus, the manufacturer needs to separate or isolate it from the host material. Isolation involves centrifuging and filtering to divide virus particles from the host cells.
Production of whole pathogen or inactivated vaccines involves the critical step of inactivation. This means disabling a virus’s ability to infect without eliminating the parts of the virus that trigger an immune response. Inactivation involves a variety of strategies, including detergent treatment, heat treatment, or exposure to UV light.
- Detergent-treated:Specific for envelope viruses, detergents break the chemical bonds that hold the virus’s envelop (outside surface) together disabling its ability to invade a host.
- Heat, chemical, and pH-treated:Viruses use proteins on their surface to infect host cells. Altering their shape destroys their ability to recognize and infect cells.
- Ultraviolet light-treated:A virus’s basic building blocks—their DNA or RNA—are destroyed by UV light. With no genetic code, viruses cannot make more of themselves.The last step in making vaccines is formulation. The inactivated virus gets mixed into a sterile water or salt solution along with stabilizers and preservatives. Some vaccines also contain adjuvants at this point. An adjuvant is a substance that boosts the immune response to a vaccine. Vials are then filled, inspected, labeled, and shipped. Most vaccines require refrigerated storage and shipping.
ALIVE, NOT KICKING
Producing a live, attenuated vaccine follows similar steps, without inactivation. In addition, it starts with a seed strain that has been rendered harmless. The new organism continues to grow but produces immunity without causing illness. Attenuated vaccines produce stronger, usually longer-lasting, immune responses than inactivated vaccines because they more closely mimic actual infection. Attenuated vaccines should not be given to people with weakened immune systems, such as cancer patients or the elderly.
Safe, attenuated vaccine strains are produced in a few different ways. Sometimes, it may simply be a related, but harmless virus that kicks in the immune response. Jenner’s vaccine, which was essentially the cowpox virus, is a classic example. Today’s smallpox vaccine uses a related virus, vaccinia. Another common method to produce vaccines is raising several generations of a clinical isolate, or a laboratory-pure version of a pathogen. Growing in non-human cells, it adapts to its new host, becoming less infectious over time. Examples include the measles, yellow fever, and poliovirus vaccine strains. Scientists can also use recombinant DNA technology to delete the portions of a virus’s genome that cause infection.
Vaccines have a simple premise, but the science and manufacturing that make them possible is complex. Different microorganisms require individual approaches. Through trial and error, microbiologists, virologists, and other scientists determine the best formulation.
In part two of this series, we’ll discuss other kinds of vaccines, including virus-like particle (VLP), polysaccharide, and further discuss subunit vaccines. We’ll also give an overview of how vaccines are tested and approved.
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Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.