By definition, a vaccine is a biological preparation that provides active, innate, and adaptive immunity to a particular infectious disease (e.g., measles, flu, SARS-CoV-2) by stimulating antibodies or manipulating messenger RNA (mRNA) to attack the source of the infection. The traditional approach has been to develop an agent that resembles the disease-causing microorganism made from fragments of the offending microbe (attenuated, a weakened or inactivated form or a viral vector, genetic copy of a virus), its toxins, or one of its surface proteins. This process induces a subclinical antigen stimulus that is recognized by the immune system that produces corresponding immune cells and antibodies but without inducing clinical disease. In the novel coronavirus, the spike protein was targeted for most of the vaccine human clinical trials. The greatest success (as of early 2022) against the RNA novel coronavirus used genetic instructions in the form of messenger RNA (mRNA) to prompt a subclinical immune response from the virus.
The science of the mRNA vaccine is an elegant model of immunology and genetics technology (Fig. 7.2). An RNA virus (e.g., novel coronavirus) means its genetic material is encoded in RNA rather than DNA. Once the virus is inside our cells, it releases its RNA and makes long viral proteins to compromise the immune system (see Fig. 7.1). genomic transcription and translation (see Blog #10) produce copies of the virus’ surface receptors (spike proteins, in the case of novel coronavirus). Then, as the patient’s immune system recognizes a “foreign invader,” it initiates an APC/Th and TC response (remember those from Blog #5?) that release Th cells that generate cytotoxic TC and B cells. The TC cells go to work doing their job of phagocytizing the virus while the B cells generate antibodies that bind and block the virus from infecting healthy cells. Goodbye virus, at least for 6 to 12 months they are projecting at which time booster shots are indicated.
One of the weapons in our cells is an RNA surveillance mechanism called nonsense-mediated mRNA decay (NMD) that protects us from many genetic mutations that could cause disease. The genome of COVID-19 is a positive-strand single-stranded RNA that can evade NMD and prevent it from degrading RNA by producing proteins that interact with certain proteins that modify the chemical structure of RNA. With the progression of new viral strains, the mRNA vaccines can be easily genetically reprogrammed to recognize mutant viral strains (called variants) and allow for the rapid development (within weeks) of second-generation vaccines that directly target processes critical to a virus’s life cycle.
CRISPR-Cas13 (see Blog #26 for CRISPR description) offers the potential for a broad-spectrum antiviral (BSA) RNA screening to inhibit many SARS-CoV-2 variants. Cas13d-mediated coronavirus inhibition is dependent on the crRNA cellular spatial colocalization with Cas13d and target viral RNA. It can significantly enhance the therapeutic effects of diverse small molecule drugs against coronaviruses for prophylaxis or treatment purposes and reduce viral titer by over four orders of magnitude. Using lipid nanoparticle-mediated RNA delivery, it has been demonstrated that the Cas13d system can effectively treat infection from multiple variants of coronavirus, including Omicron SARS-CoV-2, in human primary airway epithelium air-liquid interface (ALI) cultures. Recent studies establish CRISPR-Cas13 as a BSA which is highly complementary to existing vaccination and antiviral treatment strategies.
Discussion Questions:
The mRNA vaccine is an elegant model of immunology and genetics technology. Can you give a brief summary of the intracellular immunologic and genetic elements in the life cycle of the virus?
Nonsense-mediated mRNA decay (NMD) protects us from many genetic mutations that could cause disease and yet, the SARS-CoV-2 can evade it. What is the mechanism which enables the virus to do this?
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