Role of Genomics in Vaccine Development

Dr Hima Challa MD, Dr Kalyan Uppaluri MD, K&H Personalized Medicine Clinic & Dr Ramesh Byrapaneni MD, Endiya Partners

SARS- CoV-2, the virus causing the COVID- 19 pandemic, originated in Wuhan, China in the late 2019 and has since caused close to 1,75,000 deaths worldwide till date. Almost all countries across the world have faced the burden of this pandemic, leading to significant social and economic breakdown. The genomic sequence of the virus was identified and was found to be closely related to the SARS-CoV-1, a group of beta coronaviruses. The fatality rate was found to be higher in the elderly and the immunocompromised. Since it is also becoming apparent that more pandemics are on the horizon and several other pathogenic strains waiting to be discovered, it is imperative that we develop a fast and effective way of coping from these situations. Vaccination is one such modality as it leads to mass immunization and is very effective in keeping infections at bay.

PREGENOMIC ERA VACCINE DEVELOPMENT

Vaccination to produce active immunity traditionally is achieved in 4 different ways. Basic principle of vaccination remains the same, host (in this case human) should develop immunity to fight the pathogen(virus/bacteria) when exposed.

1.    Whole inactivated pathogen is injected after series of steps where the basic structure of pathogen is preserved but cannot cause disease because of inactivation Eg: Pertussis, influenza vaccines

2.    Immunity producing fraction of the pathogen is injected to host to develop immunity. Eg: pneumococcal, meningococcal, hepatitis B vaccines

3.    Toxins of the pathogens are separated and are treated by physical or chemical means until they no longer produce disease but retain the capacity to induce immunity. They are called toxoids. Eg: Diphtheria and Tetanus toxoids

4.    Attenuated infectious vaccines are derived from offending organism after it has undergone repeated passages in laboratory so that it remains infectious but loses ability to induce disease. Eg: polio, measles, mumps, rubella, yellow fever vaccines.

As you can imagine this is a laborious process and must go through rigorous testing to establish safety. Usual timeline from concept to product is 5 to 8 years.

GENOME-BASED VACCINE DEVELOPMENT

Since the advent of the “Genomics Era” the process of developing drugs and vaccines has picked up pace. We have now been able to catalog the genomic sequence of almost every pathogen known to infect humans. With the advancements in genomic sequencing technologies and the bioinformatics tools, this catalog is growing at a rapid pace. Once the entire genome sequence of the pathogen is available, it becomes easy to identify potential targets for vaccines. The identification of these targets can be done in silico, saving a lot of time and effort. Also, the genome-based vaccine development projects provide clear insights into the pathogen’s (Bacterial or viral) epidemiology, pathogenesis and the functioning of its proteins.

CORONAVIRUSES IN A NUTSHELL

SARS-CoV-2 belongs to the coronaviridae family. They are named so, due to the crown like appearance of the surface glycoproteins of the viruses as seen under electron microscopy. The virulent ones are the beta coronaviruses, which include SARS-CoV-1, MERS and the current pandemic of SARS-CoV-2. These viruses have large RNA genome. The genes encode for 4 main proteins- Spike(S) protein, Membrane(M) protein, Envelope(E) protein and Nucleocapsid(N) protein. The S protein was found to be a potential target for vaccine development during the pandemics of SARS-CoV-1 and MERS. Since, SARS-CoV-2 is similar to the other beta coronaviruses, it could be possible in this case too.

VACCINE DEVELOPMENT FOR SARS-CoV-2

Genomic sequence of SARS-CoV-2 was rapidly made available by high throughput sequencing techniques. It was also possible, by applying advanced bioinformatics, to identify the structure of the proteins encoded by the viral genome. This is a very important step as it helps locate potential targets for vaccine development.

Early institution of the vaccine is very crucial in order to prevent a second pandemic wave. Several pharmaceutical companies are taking advantage of genomic technology and trying to come up with a vaccine as soon as possible. Coalition for Epidemic Preparedness Innovation (CEPI) is funding and encouraging several innovative players in the field.

There are 3 major types of candidate vaccines in clinical evaluation phase according to most recent WHO report (April 20,2020)

1.    A mRNA-based vaccine, which expresses target antigen after injection of mRNA encapsulated in lipid nanoparticles, is co-developed by Moderna and the Vaccine Research Center at the National Institutes of Health and has already started phase I studies.

2.     A viral vector vaccine like adenovirus type 5 vector by CanSino Biologics/Beijing institute of biotechnology, which is into phase 2 studies

3.    DNA vaccine is another method where a small piece of DNA (plasmid) is introduced into human cell. Inovio Pharmaceuticals, South Korea, started phase 1 studies in developing this type of vaccine for SARS-CoV-2.

There are also 71 more studies in progress, working on a recombinant S protein vaccine, viral vector-based vaccines, live attenuated vaccines and inactivated vaccines. It is estimated that a vaccine will probably be made available by early 2021. This shows the significant reduction in time taken to develop vaccines, using genomics.

KNOWLEDGE OF HUMAN GENOME

Vaccine development has stringent screening guidelines for choosing the target for the vaccine. The targets should be expressed and accessible to the host immune system, or to a therapeutic agent, during human disease.

Another major challenge is that the chosen target should not have any similarity to the host (human) tissue. Immune responses against a pathogen can cross-react with host antigens if homologies exist in the primary amino acid sequence, potentially leading to damage to the host tissue. In other words, there is chance of inducing significant autoimmunity if there is similarity between the proteins of the pathogen and the host.

Knowledge of the human genome can help prevent these complications. It will help in screening for any protein molecules which might be homologous to the viral proteins. It also helps in predicting the immunogenicity in the host and understand the immune response against the pathogen.

Comparing human genome to the viral genome and the proteins encoded will effectively screen the probable targets for the vaccine.

THE FUTURE

We believe that genomics is going to cause a paradigm shift in practicing medicine. Its uses are going to be multifaceted, being used in both delivering care and as well as developing new therapeutics. For example, if mRNA/DNA/Viral vector vaccinations are successful in providing immunity against SARS-CoV-2 and get us over the immediate pandemic effect, the scope can be extended to cancers as well using the same principle. These would be particularly helpful as it is easy to scale the genomic based vaccines. At the same time, we cannot ignore the time tested, traditional, inactivated vaccines, as these would provide large scale herd immunity.

Furthermore, as novel technologies emerge in the field of genomics, sequencing is going to be more accessible and affordable. As we see pandemics taking over the world, causing significant damage to human health, more resources need to be allocated to genomics in order to provide efficient preventive measures.

There is a pressing need to develop infrastructure, which can help deliver vaccines and therapeutics quickly and efficiently for the entire world population. A healthy balance between traditional methods of vaccine development and genomic based vaccines needs to exist. This way, the world will be better prepared to handle any future pandemic and hopefully nip it in the bud.