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Sequencing Data to Develop Recombinant Vaccines

Child receiving vaccine

Sequencing Data to Develop Recombinant Vaccines


Disease prevention and eradication are possible through the use of vaccinations. Traditionally, vaccines have been created using live or inactive viruses, active poisons and toxins, and other material that can cause adverse reactions.

This article explores historical and current methods of vaccine development, including the limitations of existing methods. Then, we discuss the methodology behind developing recombinant vaccines and what their development means for the future of disease prevention. 

Development of Existing Vaccines

The first successful vaccine was developed in the late 1700s, when physician Edward Jenner realized that people who’d been exposed to cowpox were immune to smallpox. He successfully immunized an 8-year-old boy against smallpox using material collected from a cowpox sore. The next century saw developments in vaccine research for cholera, rabies, and diphtheria. 

Today, people in the United States have routine access to vaccinations for many diseases that were previously extremely infectious and dangerous. This is not limited to hepatitis, influenza, mumps, pertussis, and tetanus. 

Vaccine developments have saved countless lives. For example, an estimated 1.5 million childhood deaths have been prevented since 1988 thanks to the polio vaccine. Major disabilities and medical interventions are also prevented through routine vaccination. 

However, traditional vaccines have their limitations. With the advent of genetic research, recombinant vaccines have the potential to protect against classes of pathogens that were previously untouchable. 

Types of Traditional Vaccines

Inactivated and attenuated vaccines

Inactivated vaccines are typically developed using microbes, including viruses or bacteria. These materials are grown via culture and “killed” via chemical exposure or heat to prevent infectivity. These dead viruses and bacteria still have many of the identifying components necessary to alert the immune system, so an immune response is still stimulated. 

Live attenuated vaccines are traditionally made using a weakened version of live viruses (e.g. varicella/chicken pox). These viruses are usually modified in a laboratory to decrease their ability to cause illness. The virus is unable to replicate to the point of causing infection in the vaccine recipient. However, it still induces an immune response to protect the recipient from future infection. 

From the 1950s onward, vaccine development used viral tissue culture methods still used today. These vaccines are responsible for nearly eradicating Polio, mumps, Rubella, and other harmful diseases. While these vaccines have helped control, prevent, and eradicate disease, most still make use of live pathogens.

Limitations of existing vaccines

In inactivated vaccines, the immune response is weaker than it would be to a live vaccine. This means that some inactivated vaccines require booster injections for stronger, longer-lasting protection. In rural areas or developing countries, creating a schedule for booster vaccines can be difficult. Inactivated vaccines also don’t typically stimulate mucosal immune response, which is an important component of the body’s defenses. 

Live attenuated vaccines pose a risk to individuals with weakened immune systems, including pregnant people and people with HIV or AIDS. Many live vaccines also require storage and shipment in extremely cold conditions, and should be handled by trained healthcare professionals. This limits the accessibility of vaccines in some communities. 

The Rise of Recombinant Vaccines

The first recombinant vaccine for human use was the Recombivax HB, used as protection against hepatitis B. In recombinant vaccines, a few genes from a pathogen are inserted into a different host, like yeast. The inserted genes code for a desired product — in the case of the hepatitis vaccine, hepatitis surface antigen proteins. 

These proteins are purified away from the host and can be used to induce an immune response without the same risks associated with using the weakened/ inactivated pathogen. These proteins can then be used to induce a strong immune response against the disease. However, these often require one for more boosters for prolonged protection.

Genetic vaccines

DNA vaccines use the genetic code (deoxyribonucleic acid) that is the blueprint of life in all living cells. Researchers use small circular pieces of DNA to deliver the information to make one or more proteins from the pathogen inside the cells of the recipient. 

There was initially much excitement about DNA vaccination (late 1990s-early 2000s) due to its exceptional safety profile and ease of manufacturing. Unfortunately, DNA vaccines often don’t elicit the strong, durable immune responses required to protect the recipients.  

Thanks in part to the SARS-CoV-2 pandemic, mRNA (messenger ribonucleic acid) has become a standard tool used by scientists in the disease prevention space. In this approach, the mRNA is designed so that it stimulates a strong but balanced immune response. The antibodies generated after an mRNA vaccine have enhanced immunogenicity compared to other methods. Like other vaccine designs, mRNA-based approaches have limitations including storage and stability. 

The Role of Nucleic Acids Sequencing Data

Genomic data is an invaluable tool in vaccine development. From identifying the pathogen in question to monitoring and optimizing treatments, genomic technologies are changing the way vaccines are developed.

Identifying pathogens

The first step in recombinant vaccine development is identifying the pathogen responsible for the disease. Pathogenic sequencing helps researchers identify the bacterial and viral genes that encode antigens.

Antigens are the proteins or other substances on the pathogen's surface that create an immune response in the host. By understanding the genes that code antigens, researchers identify drug targets and can begin developing an appropriate disease defense.

The World Health Organization (WHO) has explored many ways to improve the development of yearly influenza vaccines. One major suggestion is the development of laboratory assays to better identify candidate flu viruses. That said, it is still not possible to create vaccines for strains that proliferate suddenly in the middle of flu season.

Vector selection

Recombinant vaccines often use a plasmid — a circular DNA backbone — to shepherd genetic material to desired cells. DNA sequencing helps select appropriate vectors that can efficiently carry and express the target genes in host cells.

Technologies like whole plasmid sequencing (WPS) are also used to verify that the inserted genetic material has not been altered. This ensures recombinant vaccines are actually delivering the desired product. WPS also allows scientists to confirm that the rest of the plasmid hasn't developed variations in the process of inserting novel genetic material.

Safety and quality assurance

With full-length sequencing, researchers can verify that recombinant DNA has no unintended mutations. This is an important step in demonstrating the safety and integrity of recombinant vaccines.

Variant monitoring

In fast-mutating pathogens, sequencing is a key tool in understanding how the disease is changing. Existing vaccines may not be as effective against new iterations of a virus or bacterium.

Take a look at our wastewater surveillance study with Integrated DNA Technologies to see SARS-CoV-2 variant monitoring in action.

Vaccination, whatever the design, has saved countless lives since its introduction in the 18th century. It will be interesting to see how new methods evolve now that the whole world is watching. 

Psomagen thanks Dr. Stacy Matthews Branch for her contributions to the research and writing of the original version of this article. Dr. Branch is a biomedical consultant, medical writer, and veterinary medical doctor. She owns Djehuty Biomed Consulting and has published research articles and book chapters in the areas of molecular, developmental, reproductive, forensic, and clinical toxicology. Dr. Matthews Branch received her DVM from Tuskegee University and her Ph.D. from North Carolina State University.

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