Last week, we overviewed vaccine development and manufacture, focusing on those that use whole pathogens to protect us from a disease. This week, we examine subunit, polysaccharide, and DNA/RNA-based vaccines, which use different strategies to fight infection. We also take a brief look at the US Food and Drug Administration (FDA)’s vaccine approval process.


The structure of viral cells is much simpler than that of our own cells. Despite the damage they can do, viruses consist only of one or more strands of DNA or RNA, encased in a protein shell such as in the viruses you see below.

This simple structure means that sometimes only part, or subunit, of a virus is enough to stave off infection. Different subunit vaccines use different bits of a pathogen. Often, they consist of nothing more than one of a virus’s surface protein. Subunit vaccines work because our immune systems recognize and respond readily to these surface proteins.

For subunit vaccines, drug manufacturers alter yeast, bacteria, or Chinese hamster ovary (CHO) cells to produce a protein by transferring the gene encoding the virus into them. These host cells make the viral protein, which the manufacturer then isolates and formulates into the vaccine. Subunit vaccines include those for hepatitis B and human papillomavirus (HPV).

Sometimes a viral subunit or subunits form what’s called a virus-like particle (VLP)–a protein structure whose shape closely mimics a virus with none of its genetic material. In these cases, the body’s immune system responds very robustly.

A subunit vaccine can also derive from toxins produced by dangerous bacteria. For example, Clostridium tetani (tetanus) secretes tetanospasmin, a neurotoxin that causes severe muscle spasms, potentially leading to death. The vaccine contains inactivated toxin, which helps develop antibodies that prevent future illness.
Because subunit vaccines contain none of a pathogen’s genetic code, they are generally very safe.


In general, bacterial infections tend to be more difficult to protect against by vaccine than viral infections. That’s because the surface of some bacteria is covered in long chains of carbohydrate molecules. Called polysaccharides, they mask the bacteria’s proteins. This “cloaking device” means the body doesn’t recognize the threat and mount an immune response. But molecular biologists and other scientists have discovered that it’s possible to link polysaccharides to a harmless protein, thereby coaxing an immune response. These vaccines are known as conjugated polysaccharide vaccines because the carbohydrate is conjugated (connected) to a protein. The Haemophilus influenzae type B (or Hib) and some types of pneumococcal and meningococcal vaccines are made this way.

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The basics of immunization have been around over a century—use a disease-causing microbe, or just a part, against itself. However, the latest step in the evolution of vaccines takes a different tack, delving more deeply into the building blocks of life—DNA or RNA.

Instead of immunizing someone with a whole pathogen or fragment, a DNA vaccine injects only a small bit of a virus’s genetic code. Drug companies nestle the code in plasmids— small, circular DNA molecules within a pathogen. As you can see below, the “visiting” DNA prompts the host to produce the target viral protein and consequent immune response within their own cells, but without an infection. RNA vaccines consist of a single strand of RNA that encodes the instructions for making a viral protein, typically encased in a lipid nanoparticle.

The key challenge for DNA/RNA vaccines is getting patients’ cells to accept the introduced genetic material. So far, the most effective technique seems to be electroporation–delivering short pulses of electrical current to the patient with the vaccine. The electricity creates temporary pores in a patient’s cell membranes, enabling the DNA/RNA to enter.

The FDA has yet to approve any DNA or RNA vaccines for human use. The prospect of these types of vaccines, however, presents some important advantages, which includes producing a strong immune response and somewhat easier manufacturing. Producing large volumes of viral gene-containing plasmids still means growing lots of bacteria in which to reproduce the plasmids, but purifying and formulating these vaccines is more straightforward due to the relative simplicity of DNA/RNA’s structure. In addition, DNA vaccines don’t require refrigeration, extending their shelf life and transportation time.

Clinical trials of an RNA vaccine for COVID-19, developed by Moderna (Cambridge, MA), are currently underway in Seattle.


How does a new vaccine come to market? The FDA requires companies test vaccines for safety and effectiveness on human subjects. The process differs somewhat from clinical drug trials. Researchers test a new drug on sick volunteers to see if it makes them well; researchers administer an investigational vaccine to healthy volunteers to see if it prevents illness.

Clinical vaccine trials involve three distinct steps.

  • Phase 1 is typically a small study in which healthy volunteers get the vaccine. Doctors monitor them for side effects. If no unacceptable reactions occur, the vaccine advances to the next stage.
  • In Phase 2, more subjects, typically hundreds, get the vaccine. The same number of subjects participate in the study without receiving the vaccine. Scientists refer to this second group as the control. Both groups are at the same level of risk for contracting the target disease. Researchers observe the “vaccinatees” for two years or more to see if they contract the disease at lower rates than those in the control group. Researchers also monitor immune response by measuring levels of anti-pathogen antibodies in the participants’ blood.
  • For Phase 3, even more subjects—often thousands–at high risk for the disease receive the vaccine and are monitored as described in Phase 2, from three to five years. This trial also includes a control group.


Getting a shot won’t make you sick. Sometimes, people feel mild symptoms such as fatigue, headache, and low-grade fever after receiving a shot. These are signs that an immune response is being activated.

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