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Vaccine Development II: Strategies

In the first part of this series on vaccine development, I went over how our immune system responds to pathogens like viruses or bacteria. Briefly, when our body encounters a novel pathogen, specialized cells from our immune system create antibodies that bind to specific molecular signatures called antigens found on that pathogen. The blueprints for effective antibodies are retained as memory so that we can quickly produce large quantities of those antibodies when needed.  To develop a vaccine that can protect us from a particular pathogen, hence, we need to somehow elicit these responses without getting sick from that disease. In this essay, I will describe how researchers try to achieve that.1

Let’s come up with some strategies with the information we already have from the first part of this essay. Assuming the antigens are present, can’t we use dead pathogens to elicit the same immune response? Indeed, in the 19th century, scientists discovered that inactivated or killed microbes could induce immunity. And that discovery led to the development of inactivated vaccines where pathogens are killed by chemicals (usually formalin), heat, or radiation. Harvix, a hepatitis A vaccine, is an example of these vaccines. 

But how do we know if we have inactivated a pathogen? Though the risk is very low, it’s a risk scientists have to always consider in vaccine development. Furthermore, inactivated vaccines don’t elicit strong immune responses, and hence, multiple doses of these vaccines are always required. The strength of immunization induced by these vaccines also diminishes over time. To elicit a strong immune reaction, hence, these vaccines are usually given with some chemical compounds such as aluminum salts. These compounds boost the immune response and are called adjuvants.

Live attenuated vaccines, on the other hand, generate a strong immune response because these are very similar to actual pathogens. These vaccines can provide life-long immunity after only one or two doses. As the name suggests, these vaccines do contain live, whole bacterial cells or viral particles but are too weak to cause disease. 

Attenuation is often achieved by growing a pathogen in less than suboptimal conditions for an extended period. The organisms that can grow well in these suboptimal conditions but are no longer capable of causing disease are then selected for vaccines. Often, an attenuated virus can be created by introducing a virus into a species where the virus doesn’t replicate well or by extensive passaging where the replicated viral particles are repeatedly transferred from one cell culture to another.  To prepare the influenza vaccine, for example, the virus is passaged in chick embryos for an extended period. Similarly, measles, rubella, mumps, and yellow fever vaccines are created by passaging the disease-causing viruses through non-human hosts or cells.

However, in patients with immunodeficiency, such as in patients with leukemia or AIDS, live attenuated vaccine could cause severe or fatal reactions due to the pathogen’s uncontrolled growth. A live attenuated vaccine could also revert to its original disease-causing form, which only happened with the oral polio vaccine. Finally, it’s not always possible to identify sufficiently attenuated pathogens.

Since there are some drawbacks with inactivated or live attenuated vaccines, can we use either the antigen or part of a pathogen to elicit an immune response? And that’s the idea behind subunit vaccines. For example, inactivated bacteria (Bordetella pertussis) were originally used in the vaccine for whooping cough. While the vaccine was effective, the side effects associated with that vaccine led researchers to develop another vaccine that only contained some purified components of the organism instead of the whole organism. 

These vaccines can also be produced easily. For example, using recombinant DNA technology to combine DNA from different sources, scientists can produce antigen for the hepatitis B vaccine in yeast cells. These yeast cells contain the genetic code for the viral protein.  

Since our immune system can also detect polysaccharides—a string of connected sugar molecules—that are found on the cell walls of some bacteria, polysaccharide vaccines have also been developed. Disease-causing proteins or toxins that are secreted by some bacteria can also elicit an immune response, and toxoid vaccines use chemically inactivated toxins as antigens. Diphtheria and tetanus vaccines are examples of toxoid vaccines. 

While these vaccines are safer and can be produced easily, these vaccines often need to be supplemented with adjuvants to induce strong, long-term immunization.

1918 H1 influenza VLP. Left: Cryo-electron microscopy; Right: 3D rendition (Coursey: NIH)

To circumvent that drawback, vaccines containing virus-like particles (VLPs) have been developed against human papillomavirus (HPV). Using recombinant DNA technology, scientists managed to create an outer shell that closely resembles the actual virus and can induce a strong immune response. Furthermore, since these VLPs lack the viral genetic material, this vaccine can't cause disease. 

Instead of generating the antigens in the laboratory, how about we insert a piece of DNA or RNA and let our body produce those antigens using its own molecular machinery? Many human vaccines that are in the pipeline are based on this idea. 

Plasmids in E. Coli (Courtesy:

DNA plasmid vaccines contain small circular pieces of DNA called plasmids. Though plasmids are mostly found in bacteria, they can easily be inserted into other hosts. The genetic code for a protein or antigen can be inserted into these plasmids to induce protein production in the host (to know more about genetic code, DNA or RNA go here). Since these plasmids can be quickly produced in large quantities, these experimental vaccines could be developed to address emerging diseases like COVID-19 (you can find out what vaccines are currently being tested on this COVID-19 tracker. To get more information on a particular vaccine, click on the green plus sign on the left of a listed vaccine. As you will see, several experimental listed there are DNA plasmid vaccines).

Instead of using plasmids, mRNA vaccines use mRNA, the intermediary between DNA and protein, to induce antigen production. While mRNA is unstable and is difficult to deliver into the cells, recent technological advances have largely overcome those problems. An experimental mRNA vaccine protected mice and monkeys against Zika virus infection after a single dose.

Instead of directly delivering DNA or RNA into the cells, recombinant vector vaccines use a harmless virus or bacterium as a vector or carrier to introduce genetic material into the cells. Once inside the cells, these vectors will then augment the necessary antigen or protein production. Adenovirus, vesicular stomatitis virus (VSV), and cytomegalovirus (CMV) are the most commonly used vectors.

As you can see, like a writer who always is trying to write one perfect short story or novel, the quest for finding the perfect vaccine never ends. As we gain deeper insights into our immune system and newer tools become available, we can expect better and safer vaccines (I will come back to safety and efficacy in the third essay of this series).

1. This is was based mostly on the following three sources:

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