VIRAL STRAINS AND IMMUNITY

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Fig. 1.  Types of Mutations

Types of
Mutations

A mutation is a change in the genome. A few examples of the changes are in Figure 1. By themselves, the mutations do not affect an organism. It is the proteins created by the mutated DNA/RNA that cause problems. A sample unmutated DNA sequence is shown in green in the figure. We know that it is a DNA fragment because it has the A, C, G and T nucleotides. RNAs have U instead of T. As discussed in the Section Biochemistry of Viruses, triplets of nucleotides code for amino acids and that the amino acids combine end-to-end to form a protein. The triplets are called codons. Please click on Figure 1 to view a codon table. The original sequence shown in the first line of the figure has been separated into codons in the second line. The corresponding coded amino acids are in the third line. In the example, CTC codes for L (leucine), CCC for P (proline), and so on. In Substitution A, the third C in the second codon has been replaced with A. It has no effect because both CCC and CCA code for P. However when the second C in the same codon is replaced with A (Substitution B), the coded amino acid changes from P to H (histidine). In other types of mutations, a nucleotide gets inserted into or deleted from the genome. The insertion of A into the unmutated sequence is shown with a green arrowhead. That changes the coded protein from LPSR TO LHQS. Once again we know from the codon table that CAC, CAG and TCG code for H (histidine), Q (glutamine) and S (serine), respectively. Similarly, the deletion of a nucleotide in the second codon (yellow arrowhead) changes the protein from LPSR to LPVD. Once again, the change of second codon from CCC to CCA has no material effect because both code for P.

Mutations are
a Fact of Life

Mutations happen for so many reasons. The nucleotides and peptides float around in the dense chemical milieu inside the cell. That causes constant destabilization due to the chemical forces. Genome replication is a complex process. Polymerases have inbuilt error correction mechanism while they are creating mRNA copies of the genome. However, they are not perfect and introduce errors. RNA polymerases have an error rate of 1 in 10^4 operations while DNA polymerases are far more reliable with an error rate of 1 in 10^10. That is a factor of one million. The open ends of segmented genome, as in flu and coronaviruses, further contributes to mutations because the nucleotides are exposed to the surrounding chemicals. The number of strands is also a factor. In a double-stranded genome, the second strain is used as a backup. Therefore, the segmented single-strand RNA (ssRNA) viruses are the most mutation prone because they do not have a backup copy, RNA replication is unreliable and segments are not secure. Both flu and coronavirus fall in that category. On the other end, the double-strand DNA (dsDNA) human genome is the best. Our DNA is further protected by tightly packing into chromosomes. The packing ratio is amazing. The chromosomes are contained inside the nucleus that has a diameter of ~10 micrometers. If the chromosomes were unpacked and their nucleotides laid end to end, the resulting string would stretch out to an unbelievable length of ~11 meters!

Viral Strains

Viruses are constantly mutating to avoid destruction by the immune system. The mutations also occur naturally due to the aforementioned error-prone replication process. As the mutations accumulate, groups of viruses start diverging. For example, consider starting with a colony of identical viruses. Over a period, three groups develop, each with a different mutation A, B or C. Later, the group A further subdivides with mutations 1 and 2. Now there are four groups A1, A2, B and C. These groups are called strains or clades. Therefore, viral strains are all about accumulated mutations. Naturally, there are generational relationships among strains, similar to human families. A virus strain is a descendant of some strains and ancestor to others.

Immune
System

Immune system is a vast and complex system that involves dozens of types of cells and chemicals. We will discuss just enough details necessary for our discussion. The immune system operates in the environment outside the cells, i.e. in the blood and lymph. There are two types of immunity - innate and adaptive. Innate immunity is the first line of defense. It is quick and preprogrammed to kill indiscriminately anything that seems foreign. Therefore, viruses and bacteria in the blood are a fair target for it. In comparison, the adaptive immunity destroys the foreign material in an elaborate, slow and precise process and builds a memory bank of what it has destroyed. Innate immunity can identify and kill only a small subset of foreign material while almost nothing can escape the adaptive immunity. Only vertebrates have adaptive immunity. B cells and T cells are the two key components of adaptive immunity that are relevant for our discussion. The B cells produce antibodies and T cells kill the infected cells and foreign material. When B cells recognize a foreign body such as a virus or bacterium it creates antibodies specific to the microbe. The antibodies get stuck to the microbe and travel with it in the blood and lymph. The T cells patrolling the blood and lymph are on the constant lookout for the antibodies that are tagging microbes. Once found, the antibody-microbe complex is destroyed by T cells and other killer cells of the immune system. The antibodies and the B cells producing them dissipate when the infection is over. However, a small quantity of those B cells are retained in the blood. They are called memory B cells. We will investigate the role of memory B cells in the next paragraph.

Vaccines

A vaccine is a part of a microbe that induces our immune system to produce antibodies and memory B cells. The parts of the microbe that elicit immune response are called antigenic targets or parts. We can also inject the whole live virus to develop immunity. However, that will be like an infection and could make the recipient sick. Using the whole live virus worked for Edward Jenner and smallpox because live cowpox is a milder form of smallpox. Instead, inactivated microbes or antigenic parts of the microbes are used nowadays. In case of flu and coronavirus, our immune system responds most strongly to the hemagglutinin and spike proteins, respectively. Therefore, the vaccines contain only those proteins. Since the remaining parts the virus are missing, the person receiving the vaccine cannot get sick. The body develops adaptive immunity, i.e. antibodies and memory B cells against the injected antigenic parts. Only a handful of memory cells are retained in the blood, rest are recycled. Later when the immunized person is infect with the real microbe, the memory B cells recognize the microbe, get into hyperactive mode and produce an army of antibodies. The antibodies look for and tag the microbes so that other cells of the immune system can destroy them.

Effectiveness
of Vaccines

So, why are vaccines only partially effective or why do we need booster shots? As stated earlier, the viruses are constantly mutating. Most mutations are not relevant for vaccines. Consider the case of coronavirus. The vaccines target spike protein of the virus. A mutation in any part of the viral RNA other than the one that produces spike protein will not affect the vaccine. However, different viral strains have accumulated different mutations in their spike protein. A particular vaccine will recognize most flavors of spike protein, but to different extent. The degree of recognition will depend upon how far away the spike protein has mutated from the vaccine. That makes any vaccine partially effective. Therefore, the one-size-fits-all vaccines has a limited efficiency. A new formulation of the vaccine is needed when the prevalent strains drift too far from the current vaccine. That happens within a year for flu virus. We need a flu vaccine annually. The new vaccine enables our immune system to target the viral mutations that have accumulated since the last vaccine. It must be noted that our immune system naturally catches up with the new strains, thanks to the never-ending war between microbes and immunity. However, vaccines expedite the process. Further, the antibodies and memory B cells die over time. Therefore, we need to get vaccinated again with a booster shot.

References
  • Peck, K et al. (2018). Complexities of Viral Mutation Rates. Journal of Virology. 82(14) e01031-17. DOI: 10.1128/JVI.01031-17.

  • Murray, T. (2015). Repeated flu shots may blunt effectiveness. Canadian Medical Association Journal. (187(6). E180. doi: 10.1503/cmaj.109-5000.

  • Isabel, S et al. (2020). Evolutionary and structural analyses of SARS-CoV-2 D614G spike protein mutation now documented worldwide. Nature Scientific Report. doi.org/10.1038/s41598-020-70827-z

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