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mRNA Vaccine Applications in Global Health: Promise and Challenges

The global COVID-19 pandemic has focused intense attention on the potential benefits and continuing challenges of vaccine development. In the twentieth century, a large number of important vaccines were developed empirically, without a clear understanding of molecular immunology. Mass vaccination with these products successfully eliminated the scourge of smallpox, and greatly reduced and contained the global burden of other diseases such as measles, pertussis, chicken pox, and polio. Nevertheless, many important global challenges remain unresolved, and there is a tremendous unmet need for safe and effective vaccines against diseases such as AIDS (Acquired Immune Deficiency Syndrome), parasitic infections, and tuberculosis (TB).

2020 was the year when many people first became aware of mRNA vaccine technology and its potential benefits to public health. The promise of this technology is clear. Importantly, the success of those COVID-19 vaccines was only possible because of decades of foundational work by industry and academic scientists. Some of that work was specifically envisioned as the basis for a response to future pandemics. Other foundational work comes from longstanding efforts in AIDS vaccine development.

Notably, there are important similarities and differences in the nature of the public health need represented by acute COVID-19 infection compared to that pertaining to AIDS and TB, for example. The SARS-CoV-2 infection causes an acute symptomatic infection typically followed by natural clearance of the SARS-CoV-2 virus from an infected person. In contrast, the causative agents of AIDS and TB produce long, slow latent infections. For diseases in this category, effective vaccines will probably need to provide stronger, broader, and more durable responses. In addition, the complex lifecycles and immune evasive properties of these pathogens make successful vaccine design significantly more difficult. Ongoing work is investigating the promise of mRNA in vaccine development for HIV and other infections of global importance. New RNA technologies under development, in combination with complementary vaccine approaches, will also add to the toolbox of approaches to meet the challenges of these global infectious diseases.

In infectious disease medicine, a prophylactic vaccine is a medicinal product intended to prime immunological memory and protect against infectious diseases caused by specific viruses, bacteria, or other pathogens. An antigen is the molecular target of an immune response – for example, a viral protein. A vaccine always includes one or more antigens or genetic material encoding such antigens. Each vaccine also needs a vehicle or vector to make sure the antigens are delivered to the correct cellular and anatomical locations. Vaccines also often include a drug substance intended to activate the immune response to the antigen, called an adjuvant.

Historically, many vaccines were developed using preparations of the target infectious agent that had been killed by heat or chemical exposure. Other vaccines incorporated live pathogen strains that were attenuated (unable to cause disease in healthy people). The Salkand Sabin-type polio vaccines respectively are examples of killed and live-attenuated type vaccines, both still in clinical use. More recently, vaccines have been developed that incorporate artificial recombinant protein antigens plus chemically designed adjuvant compounds; examples of recombinant protein vaccines in clinical use include hepatitis B and herpes zoster or shingles vaccines.

Within the past few years, we have seen FDA approval of vaccines incorporating modern synthetic biology and gene transfer technology. This includes vaccines based on viral vectors – artificially engineered viruses that deliver and express a target antigen in a manner designed to provoke a protective immune response. This category also includes vaccines using messenger RNA (mRNA). In normal cell biology, mRNA plays the critical role of encoding genetic information transcribed from chromosomal DNA, and carrying that encoded “message” to ribosomes, which are the protein factories of the cell. Thus, any properly encoded mRNA sequence can be expressed as a protein. Using synthetic biology, artificial RNA messages can be manufactured to encode any protein sequence. This allows rapid production of an mRNA product encoding any desired viral antigen sequence.