Coronavirus News: Frequent Reformulation Of COVID-19 Vaccines Will Be Required As Studies Shows Coronaviruses Display Constant Adaptive Evolution

Coronavirus News: Even if any of the current COVID-19 vaccines under development is able to offer only short-term protection against certain strains of the SARS-CoV-2 coronavirus without causing any long term adverse effects such as ADE (Antibody-dependent enhancement) or other issues, the vaccines will need to be constantly reformulated as emerging studies show that the coronaviruses are constantly in adaptive evolution.


 
Scientists from the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center-USA, have revealed that adaptive evolution in the antigenic regions facilitates seasonal coronaviruses to escape the host immune responses and to cause recurrent infections.
 
The seasonal human coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. This study addresses the influence of antigenic drift on immune evasion of seasonal coronaviruses. The study team provides evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively-selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.
 
The findings also has direct implications on the current COVID-19 vaccines that are expected to be to be used on the masses soon despite no long term studies and trial results are in reality vague and non-conclusive. To make matters worse, the vaccine development teams have not been keeping up with the evolutionary changes in the SARS-CoV-2 coronaviruses as of date, tons of new variants and many new mutations have arose in just the last few weeks alone.
 
Their study findings were published on preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.10.30.352914v1
 
The new research highlights that vaccines developed against these coronaviruses may need to be reformulated continuously to better manage viral infections. This also means that COVID-19 vaccines currently in their final stages of investigations may need to be frequently reformulated in the future to effectively eliminate circulating viral variants of SARS-CoV-2.    
 
Ever since their identification in the 1960s, human coronaviruses  including OC43, 229E, HKU1, and NL63 are known to be responsible for at least 15% of common colds. Seasonal infections caused by these viruses generally peak in January – March in the Northern Hemisphere. In the general human population, these viruses cause mild respiratory infections; however, in aged people or in people with weakened immune systems, severe infections may occur.
 
So far three new human coronaviruses have been identified in recent years, which are known to cause severe respiratory infections i n humans. These viruses include severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle-East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 (the causative pathogen for coronavirus disease 2019; COVID-19).
 
In order to cause repeated infections in humans, a virus must acquire genetic mutations that cause adaptive alteration in the antigenic viral region. This allows the virus to escape the humoral immune responses of the host. Some seasonal human respiratory viruses, such as the influenza virus, are known to undergo antigenic evolution. Vaccines developed against such viruses thus need to be reformulated frequently to tackle viral spread.
 
Importantly in the case of human coronaviruses, the most antigenic protein is the spike protein, which is a viral surface protein responsible for viral entry into host cells. Studies have shown that the predominance of certain genetic variants of human coronaviruses is associated with positive selection in the viral spike protein.
 
The study team used computational methods to analyze adaptive evolution in the spike protein and RNA-dependent RNA polymerase of four seasonal coronaviruses (OC43, 229E, HKU1, and NL63) that are known to cause repeated infections in humans. Specifically, they analyzed the mutations that change the amino acid sequence of a protein (nonsynonymous substitution). Additionally, they estimated the rate of adaptive substitutions and the Time to Most Recent Ancestor (TMRCA). TMRCA is the timescale of population turnover used to quantify the positive selection.
 
The team used publicly available genetic sequences of human coronaviruses to create a phylogenetic tree. Through phylogenetic analysis - the study of the evolutionary development of a species or a group of organisms or a particular characteristic of an organism they observed that several co-evolving lineages are present for OC43. In OC43 and 229E lineages, the average number of mutations at each position was found to be higher in S1 subunit of the spike protein compared to that in S2 subunit.
 
Pertaining to the rate of mutations, they observed a significantly higher rate of nonsynonymous mutation in the spike protein of OC43 and 229E compared to that in the RNA-dependent RNA polymerase. Moreover, the nonsynonymous divergence increased progressively in the spike protein; whereas in RNA-dependent RNA polymerase, it remained constant. These findings indicate positive selection on the spike protein and purifying selection on the RNA-dependent RNA polymerase.
 
With regards to the rate of adaptive substitution, they observed that the S1 subunit of the OC43 gathers 0.45 – 0.56 adaptive substitutions each year. Similarly, the S1 subunit of 229E spike protein gathers 0.26 adaptive substitutions each year.
 
The study team further observed that the rate of accumulation of adaptive substitutions in the influenza virus's receptor-binding domain is 3 times faster than that in OC43 and 229E. Taken together, these findings indicate that the S1 subunit of the OC43 and 229E spike protein is under positive selection, which can give rise to new genetic variants.
 
Simply by estimating and analyzing the TMRCA values, the study team observed robust directional selection in the S1 subunit of both OC43 and 229E, which may be driven by pressures to escape host immune responses.
The take-home message
 
Significantly the S1 subunit of the spike protein of human coronaviruses (OC43 and 229E) is under adaptive evolution. The rate of accumulation of adaptive mutations is about one-third of the influenza virus rate. The antigenic evolution observed in S1 may be selectively favoring viruses to escape host immune responses. However, no evidence of adaptive evolution is observed for other seasonal coronaviruses, such as NL63 or HKU1. 
 
Importantly given the genetic similarity between OC43 and SARS-CoV-2, it might be expected that SARS-CoV-2 also evolves selectively in S1; and in that case, COVID-19 vaccines that are presently under final stages of investigations may need to be frequently reformulated to effectively eliminate circulating viral variants.   
 
This is important because many of the SARS-CoV-2 vaccines that are in production exclusively include spike proteins. https://www.nature.com/articles/s41586-020-2798-3
 
If SARS-CoV-2 evolves adaptively in S1 as the closely-related HCoV OC43 does, it is possible that the SARS-CoV-2 vaccine would need to be frequently reformulated to match the circulating strains, as is done for seasonal influenza vaccines.
 
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