COVID-19 and the vaccine renaissance

This pandemic is a historic use case for nucleic acid vaccines

Michael Trịnh


Quarantine has become so normal in most of our day-to-day lives now that my friends nostalgically remember early 2020 like it was decades ago. In a year defined by repetitive Zoom meetings, isolating remote work, and high demand for barbers, we’ve also seen huge changes to the future of how we are doing biomedical research.

A year where decades happened in Biomedical Research

We saw companies working on repurposing drugs for treating the virus present libraries of potential drug compounds to test against COVID-19, including notable failures like Remdesivir (1) and Hydroxychloroquine (2). We’ve seen multi-millionaire investors and CEOs outside of the life sciences set up emergency grant funding for COVID-19 research (3). We’ve seen stories of vaccine programmes wrapping up the kinds of clinical trials that we would not see had it not been for the pandemic. The current Pfizer vaccine that has been making headlines started with a Phase I/II trial that delivered its primary outcome after two months (4) and then jumped into a Phase II/III trial (5).

For biomedical research, this is what it looks like to have a decade’s worth of change happen in just one year.

It used to be that developing a vaccine, going through the clinical trial process, and performing all the due diligence would take upwards of 15 years (6). Add this timeline on top of a high chance that your vaccine could crash and fail at any point along this billion-dollar journey, and you can quickly see how the progress that we’re seeing now is anything but normal.

While headlines cover the waves of infection that continuously batter our communities, another wave is happening silently in the pursuit of a COVID-19 vaccine. However, this wave is one of the few things that may give you hope as 2020 wraps up. The pandemic has been a forced test case for a new vaccination approach that promises to be as effective, more affordable, and less timely to produce than anything we’ve seen before.

How viral infections work

When someone is exposed to SARS-COV-2, the virus that causes COVID-19, it proceeds to infect cells on the surface of the lower airway (7). The virus infects us through an interaction between our own cell surface receptor, hACE2, and the famed coronavirus “spike” protein. After this interaction between spike and hACE2, the virus is taken up into our cell. These airway cells and some of our immune cells can sense that there is an infection, process the threat, and signal that there is a specific virus causing the infection. These signals trigger the two facets of our immune system: the adaptive immune response with our T cells and B cells and the innate immune response with our macrophages and dendritic cells.

The adaptive immune system is the part of our immune response that can deal with threats from within our cells — cancer, viral infections, and certain bacteria. These adaptive immune cells are activated by a unique disease-specific signal called an antigen. When these cells are activated by a specific antigen, they rapidly clone themselves in a process called clonal expansion.

This expanded cell colony will maintain a small “memory cell” subpopulation to readily fend off the same disease should it re-emerge in the body.

Our activated B cells, known as Plasma cells, will secrete specific antibodies against the virus, acting as molecular bear traps against SARS-COV-2. Meanwhile, the activated T cells have diverse roles in killing infected cells and regulating the immune response.

One of the most important graphs in immunology, showing us how vaccine-generated memory plasma cells launch a stronger antibody response when we are infected with a pathogen (PC: Lumen Learning)

In viral infections, the innate immune system’s role is one of detection and flagging. Antigen-presenting cells called macrophages and dendritic cells both uniquely detect viral threats as they enter a tissue in the body. After detection, these innate immune cells will process and display the viral threat for our B and T cells to bind and become active.

How vaccines work

Vaccination is preparing a body’s adaptive and innate immune responses for an anticipated future threat. In the case of a COVID-19 vaccine, we want to trigger the adaptive cells with a “fake” SARS-COV-2 in order to generate readily-available memory cells for a possible future COVID-19 infection. If a vaccinated patient is exposed to the live virus for the first time but does not develop COVID-19, it is because this isn’t their adaptive immune system’s first exposure.

We also want to alert the innate immune system in this whole process. Although they do not have a memory cell component, our innate cells will be the first-responders of our immune system to an infection. Most of the vaccines below would include a vaccine adjuvant: a disease-signal that will prime the innate immune response. Everything is interconnected, this primed innate system will also help us ready the adaptive system.

Deciding how we are going to implement a vaccine is an art: we can choose between a menu of different strategies to trick our immune system into responding against a “phony” disease that won’t actually harm us. This arsenal of approaches has been evolving since vaccines were conceptualized. Today we commonly use one of a few unique strategies (8, 9), some of which are being used as COVID-19 vaccine candidates:

  1. Attenuated viruses: SARS-COV-2 that has been mutated to pose less of a health threat to humans (9, 10).
  2. Inactivated viruses: A version of SARS-COV-2 virus that cannot cause an infection (9).
  3. Recombinant proteins: A full protein of SARS-COV-2 that can be injected, triggering the adaptive immune response and establishing memory cells against the virus (9, 11).
  4. Recombinant viral vectors: A less virulent, separate viral species that expresses a part of SARS-COV-2 and mimics a COVID-19 infection (9, 12).
  5. Protein subunit vaccines: Introducing a part of a SARS-COV-2 protein to the immune system, triggering an immune response against a harmless protein subunit (9).
  6. Nucleic acid Vaccines: DNA or RNA transcripts of the virus genome that can be read and assembled into a SARS-COV-2 protein within our cells. This triggers an adaptive immune response and memory (9, 13).

This last option presents to us the newest and a long-rejected idea in the vaccine space since its origin in the 1990s: encoding a part of a virus into DNA/RNA and using that as a vaccine (14).

The status quo of vaccination

Until recently, our approach to vaccination against a viral threat has mostly consisted of either a weakened (attenuated) or dead version of the virus itself. Then emerged a new strategy of synthesizing a non-virulent protein part of the pathogenic virus and using that as a vaccine. This was a step in the right direction for minimizing the complexity and potential costs of vaccine production.

Nucleic acid vaccines offer a new, more scalable approach

Information flows in biology roughly by a model known as the “central dogma”. This model states that biological entities are encoded by a DNA or RNA genome, from which genes can then be transcribed into messenger RNA (mRNA), which are then translated into functional proteins.

The first step of the central dogma involves a genome, which can consist of DNA or RNA. (PC: Pinterest)

This is a huge simplification of life, but the central dogma is why nucleic acid vaccines are so exciting. When SARS-COV-2 was first identified for the world, its RNA genome was publicized right away (15). With this information, teams were able to quickly develop vaccine candidates that encoded SARS-COV-2 subunits in DNA or mimicked mRNAs that would be transcribed from the coronavirus genome itself.

DNA and RNA can be modified to be a vaccine, and then co-delivered in a specialized coat or nanoparticle in order to reach its target cell in a patient (16). While a viral genome encodes all its viral mRNAs and thus all its viral proteins, an mRNA vaccine will only encode one viral protein or subunit that cannot cause an infection like COVID-19 on its own.

(LNP = Lipid Nanoparticle) An mRNA strand that encodes a part of SARS-COV-2, aka. an exogenous antigen can be delivered to its target cell through an affordable, bubble-like LNP. (PC: Reichmuth et al. 2016)

This is a stark contrast to the dead or attenuated viruses that require viral isolation protocol, induced mutation, and incubation procedures (17). Recombinant protein approaches are more scalable in this sense, but they still require costly additional steps in manufacturing such as protein synthesis. DNA or RNA vaccines are unique from the crowd: they can be readily manufactured and iterated upon in a facility that can be used to produce other nucleic acid vaccines for different diseases (18).

This newly-gained ability to iteratively test different sequences of nucleic acid vaccines may provide the scalability that vaccines need for more equitable pricing going forward.

Conferring immunity with a nucleic acid vaccine

Once the nucleic acid vaccine is taken up by the cell it gets processed by the cell’s protein-assembling and RNA-processing machinery. After assembling the DNA/RNA-encoded viral protein, the host cell will identify it as a foreign threat and present it to the immune system as an antigen. When this newly-produced antigen is presented to the immune system, it triggers our adaptive immune response. Thinking that our body has COVID-19, B and T cells that match the antigen will undergo rapid cell division and set aside some memory cells against SARS-COV-2. These memory cells can then be quickly re-activated in case the vaccinated patient is exposed to SARS-COV-2 again, stopping any future COVID-19 infection in its tracks.

The COVID-19 vaccination strategy landscape. (PC: Jeyanathan et al. 2020)

Currently out of 150 vaccine clinical trials, 37 are nucleic acid vaccines (8). This includes the recently announced mRNA vaccine candidate from Pfizer that was described as “95% effective” and with “no significant side effects” by the company (19).

Stigma and unaddressed problems still need to be covered

Up until this pandemic, vaccines have primarily been developed the old way: with dead or attenuated viruses that would then trigger an adaptive immune response and develop memory cells. Previous accidents from these vaccines (20) and public skepticism on the speed of these vaccine clinical trials have led to many communities fearing the idea of COVID-19 vaccines (21). There may be hope in the sense that nucleic acid vaccines don’t change our DNA and don’t code for an entire virus.

The secret to regaining public approval may lie in communicating this key scientific fact to communities that have felt neglected by the biomedical and public health sectors. Going forward, our ability to rapidly develop affordable, effective, and scalable vaccines during this pandemic will hopefully be the trump card that biomedical research needs to win back the trust of the general public.

Biotechnology is progressively adopting frameworks that we have traditionally associated with engineering. These include concepts like scalability, rapid development, and iterative testing: the exact reasons why we will be seeing more nucleic acid vaccines in the future. The wave of nucleic acid vaccines presents us with a sneak peek into our future: a future where we will be quick and systematic in tackling biology’s toughest problems.

This will not come without issues, nucleic acid vaccines have plenty when it comes to logistical requirements (22). The big question then lies for a new conversation: what new lessons will this next wave of biomedical innovation bring and what can we help do to better inform our own communities along the way?


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Michael Trịnh

Undergraduate builder & researcher @UofT in the crossroads of bioinformatics, immunology, and genome engineering.