mRNA Vaccines Against Infectious Diseases
Yan Zhi, PHD

mRNA Vaccines Against Infectious Diseases

Magic bullet to control pandemic?

The total confirmed COVID-19 cases have passed 7 million, with over 404,000 fatal cases globally. WHO and world-wide infectious diseases experts believe an effective vaccine against COVID-19 will be needed to ultimately control this pandemic.

One of the more promising strategies are messenger RNA vaccines, or mRNA vaccines. Currently there are about seventeen mRNA vaccine candidates in various development stages against COVID-19 by companies and universities globally. If any of these candidates make it through, they would likely be the first ever mRNA vaccine to be approved for any human disease.

In contrast to conventional vaccine platforms such as live attenuated or inactivated virus, mRNA vaccines are a promising alternative technology with characteristics that make them promising for SARS-CoV-2.

First, mRNA vaccines are potentially much safer than live attenuated virus, without any potential risk of infection. In vivo half-life as well as the inherent immunogenicity of mRNA vaccines can be modulated by nucleotide modification, formulation, and the delivery route to further increase their safety margins.

Second, mRNA vaccines can be appropriately engineered and sufficiently purified to efficiently express the desired antigen in the cytoplasm as well as to further boost antigen levels by repeated administrations.

Finally, mRNA vaccines can be rapidly manufactured at a large scale by in vitro transcription in a cell-free system with all required components available at the GMP grade.

Even though DNA vaccines can also be safely and rapidly manufactured, experts believe mRNA vaccines can potentially elicit stronger antigen-specific immune responses than DNA vaccines. By design, mRNA vaccines can express antigens in the cytosol, while DNA vaccines need to reach nucleus in order to express antigens. In addition, mRNA vaccines are perceived to be safer than DNA vaccines without any potential integration into the human genome.

Because of the speedy process from DNA sequences of a selected antigen to cGMP manufacturing, mRNA vaccines have become the front runners in the race for a vaccine against COVID-19. Nevertheless, so far no mRNA vaccine has been licensed or even tested in a large clinical trial against any infectious disease.  

Two major types of mRNA vaccines are currently under development: non-replicating (aka conventional) mRNA vaccines, which encode the desirable antigen plus 5’ and 3’ untranslated regions; and self-amplifying mRNA vaccines derived from engineered Alphavirus genomes, such as Sindbis virus and Semliki Forest virus. Both types of mRNA vaccines can be cGMP manufactured by in vitro transcription from DNA templates in a cell-free system at a large scale.

Self-amplifying mRNA vaccines are capable of inducing strong immune responses at lower dose than non-replicating mRNA vaccines, most likely due to amplification in vivo and additional adjuvants from encoded replicon genes. As a result, the immunogenicity of the replication proteins may limit repeated administration.

The mechanism of immunogenicity invoked by mRNA vaccines needs to be better understood. It is generally believed that efficient uptake of mRNA vaccines, high level of antigen expression in the cytosol to mimic viral pathogen infection, and strong adjuvants are required to elicit antigen-specific humoral and cellular immune responses for protection from infectious diseases.

mRNA vaccines have been formulated and complexed with lipids, peptides, polymers and nanoparticles to prevent degradation by ubiquitous extracellular RNases and to be efficiently internalized for antigen expression in cytosol.

Sequence and codon optimization during constructs design coupled with the further improvements of cGMP manufacturing process for mRNA vaccines are able to achieve higher expression level of antigens. Additional purification step(s) by chromatography methods can effectively remove double-stranded RNA (dsRNA) impurity in mRNA vaccines. dsRNA is a potent pathogen-associated molecular pattern (PAMP) activating innate immune responses, which will in turn reduce expression of antigens from mRNA vaccines.

Ideally any vaccine should also possess a strong adjuvant effect by providing a danger signal to prime the adaptive immune responses in addition to the desired antigen. However, the inherent immunostimulatory properties of mRNA vaccines can be a double-edge sword. It is the delicate balance between eliciting strong innate immunity through toll-like receptors (TRLs) and/or non-TRLs and invoking antigen-specific B and T cell immune responses through sufficient expression level of antigens by formulated and complexed mRNA vaccines.

Most countries and regions around the world have been devastated by COVID-19 pandemic. Experts have already warned about the second wave of COVID-19 infection. The unprecedented speed of mRNA vaccines development to fight COVID-19 could finally prove the worth of this new technology platform. The whole world is watching and waiting.


Note: More information about mRNA vaccine can be found in “mRNA vaccines – a new era in vaccinology” and “Advanced in mRNA Vaccines for Infectious Diseases”.