Experts Warn That Once Vaccines And Antibodies Are Used Frequently In A Population, More Antibody Resistant SARS-CoV-2 Virus Strains Would Emerge

Antibody Resistant SARS-CoV-2: A new study and modeling platform created by researchers and scientist from Harvard Medical School, Dana-Farber Cancer Institute, Boston Children’s Hospital, University of Washington, Fractal Therapeutics,-Cambridge, Massachusetts Institute of Technology, Microsoft Research, Mark S. Hixon Consulting and  Boston University alarmingly indicates that due to the nature of coronaviruses, the SARS-CoV-2 will easily and effortlessly  undergo evolution and result in mutations that can escape the neutralizing antibodies targeting the spike protein and could replace the predominantly  circulating wildtype strains very easily and fast once vaccines and monoclonal or cocktail antibodies are introduced and used extensively in a population.


 
As many prophylactics such as vaccines and antibody protocols targeting SARS-CoV-2 are aimed at the spike protein receptor-binding domain (RBD), the stuy team examined the risk of immune evasion from previously published RBD targeting neutralizing antibodies (nAbs).  Epitopes for RBD-targeting nAbs overlap one another substantially and can give rise to escape mutants with ACE2 affinities comparable to wild type that still infect cells in vitro.
 
Based on this demonstrated mutational tolerance of the RBD, the study team used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs raised by vaccines, administered as prophylactics, or produced through natural immunity.
 
Their modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and likewise resistance to single or double antibody combinations will develop quickly under positive selection
 
The study team warned, “SARS-CoV-2 will evolve quickly to evade widely deployed spike RBD-targeting monoclonal antibodies, requiring combinations with at least three antibodies to suppress viral immune evasion.”
 
The study findings were published on a preprint server and are currently being peer-reviewed. https://www.medrxiv.org/content/10.1101/2020.11.17.20233726v1
 
The SARS-CoV-2 mutation burden and evolutionary rate (1x10-3 substitutions per base per year) have only been estimated under conditions that favor neutral genetic drift (not to be confused with antigenic drift), in the absence of strong positive selection pressure (provided by population-level immunity or other interventions that select for resistance mutations).
https://europepmc.org/article/MED/32387564
 
https://www.cdc.gov/flu/about/viruses/change.htm
 
In immunologically naïve COVID-19 patients, viral load and transmission peak near the time of symptom onset, while the host antibody response peaks approximately 10 days later. https://www.nature.com/articles/s41591-020-0869-5
 
rnals/laninf/PIIS1473-3099(20)30196-1.pdf">https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(20)30196-1.pdf
 
Hence most transmission occurs well in advance of the appearance of a robust humoral response, suggesting limited within-host immune evasion prior to transmission, consistent with direct genetic evidence from deep sequencing showing little to no positive selection. https://peerj.com/articles/10234/
 
Thus, the current evolutionary rate (based primarily on neutral genetic drift) may underestimate the evolutionary potential of the virus to evade nAbs deployed as prophylactics. Under the selective pressure of widely deployed nAb prophylactics, population-level selection for antibody-evading, infection-competent viral mutants could result in a rapid resurgence of SARS-CoV-2 infections.
 
Basically two key factors influence the rate of evolution under natural selection: mutation rate and mutational tolerance. Mutation rates alone offer a limited picture of the ability of viruses to generate successful escape mutations because even if escape mutations arise quickly, they will not persist in the population if they significantly reduce viral infectivity. While some vaccine preventable viruses have very low mutation rates (such as smallpox, ~1 x 10-6 sub/nuc/yr), others have high mutation rates (such as poliovirus, 1 x 10-2 sub/nuc/yr). The interplay between the mutation rate and the fitness costs imposed by the mutation offers powerful clues as to the potential for evolutionary escape. Additionally, there is a sharp contrast between the high antigenic evolvability of viruses like influenza, notable for their evolutionary capacity for immune evasion, and the low antigenic evolvability of viruses like poliovirus, which have proven highly tractable to antibody-mediated prophylaxis via vaccines despite a high evolutionary rate. Studies of other infectious diseases support the concept that natural selection promotes antigenic evolvability. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379562/
 
https://pubmed.ncbi.nlm.nih.gov/25006036/
 
https://www.nature.com/articles/s41467-019-14174-2
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828179/
 
The spread of SARS-CoV-2 through its newfound human hosts has occurred rapidly, and thus far, in the absence of medical countermeasures. Numerous COVID-19 prophylactics (and some therapies) are explicitly focused on the spike protein, and the immunodominance of the spike RBD in the natural immune response implies that even vaccines that use liveattenuated or inactivated SARS-CoV-2 will target this moiety to some extent.
 
As the next phase of this evolutionary chess game between SARS-CoV-2 and humans unfolds, anticipating the virus’ counter-move to the widespread deployment of spike RBD-targeting nAbs has significant implications for our ability to prevent spread of the disease via an antibody based prophylactic strategy. The evolvability of SARS-CoV-2 spike protein RBD in the presence of nAbs depends on two things: the mutation rate in the presence of selection pressure and the mutational tolerance of the spike protein. The mutation rate of SARS-CoV-2 is in line with that of other single-strand RNA viruses, ranging between two and four fold lower than that of influenza and HIV. https://pubmed.ncbi.nlm.nih.gov/29720522/
 
https://pubmed.ncbi.nlm.nih.gov/32901123/
 
In general mutation rates for RNA viruses are among the highest known (on the order of 10-6 per base per viral replication cycle). When compared against many other RNA viruses, such as Hepatitis C,for which evolution has practical clinical consequences, SARS-CoV-2 has a relatively high evolutionary rate.
https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=59932
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292934/
 
As mentioned earlier, the currently estimated mutation rate for SARS-CoV-2 is in the context of neutral genetic drift. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307108/
 
Mutation rates themselves are evolvable and increase over time due to natural selection, a SARS-CoV-2 RNA dependent RNA polymerase (RdRp) variant that increases the mutation rate by two to five times (eliminating the mutation rate differential with respect to HIV and influenza) has already been identified in clinical isolates. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107253/
 
https://pubmed.ncbi.nlm.nih.gov/32321524/
 
At the same time, the tolerance of spike protein RBD to immune-evading mutations appears to be relatively high. The study team’s analyses demonstrate that experimentally determined immune escape mutations are capable of binding host ACE2, in many cases with little to no loss of affinity relative to wild-type.  In fact, one prevalent RBD immune escape mutation (N439K) has been shown experimentally to enhance ACE2 binding and have similar in vitro replication fitness to wild-type virus. https://www.biorxiv.org/content/10.1101/2020.11.04.355842v1
 
The team’s analyses also demonstrate that compromising spike RBD function (either through loss of ACE2-binding or expression levels) has a weak impact on in vitro infectivity. The baseline mutation rate of SARS-CoV-2 has likely already produced a substantial population of viruses with single and double nucleotide changes that confer nAb resistance due to standing genetic variation. These variants will establish quickly in the population under selection pressure. In fact, there is already precedent for this type of selective sweep, as one such sweep occurred early on in the SARS-CoV-2 pandemic, as the D614G mutation rose to nearly 80% frequency in under 6 months. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332439/
 
This mutation confers increased infectivity on the virus  and was readily generated in sufficient numbers to ensure its expansion. As of this writing, a second selective sweep appears to be underway in Europe, with the 2A.EU1 variant .
 
Additionally, the recent outbreak in minks of a variant with a combination of mutations that reduce antibody binding suggests that even variants with multiple mutations can be generated and are viable. https://www.who.int/csr/don/06-november-2020-mink-associated-sars-cov2-denmark/en/
 
Currently, most of the SARS-CoV-2 genome is not under positive selection, but if nAbs are widely deployed as prophylactics, mutations that confer resistance via immune evasion will experience positive selection pressure and will have the opportunity to expand and render the prophylactic useless.
 
The current consensus in the scientific literature is that SARS-CoV-2 mutations and evolution are not likely to change the course of this pandemic.
 
One line of reasoning is that generating viral mutants with higher fitness is difficult because very few individual nucleotide changes are likely to increase viral replication, transmission, or infectivity. However, this argument confuses the rate of evolution in the absence of selection pressure (neutral genetic drift) with the rate of evolution under natural selection.
 
To this end, the team’s analysis suggests that mutations capable of evading nAbs with limited impact on viral fitness are already broadly present in the population. The N439K immune-evading spike mutant was reported to maintain replicative fitness in patients, supporting this idea.
 
A second line of reasoning is that because the SARS-CoV-2 mutation rate is relatively low, evolution will be too slow to be consequential. However, the reported mutation rate under drift is not particularly low, is likely to increase under selection pressure, and is high enough at present to generate single and double immune-evading mutants at a concerning frequency.
 
The questions addressed here are relevant to the prophylactic viability of any modality, including vaccines that rely on humoral immunity, which can be evaded by a series of single-nucleotide mutations. Similar questions can and should be asked of the viral capacity to evade the cellular adaptive immune response and the ability of other viral proteins to escape nAbs. Additionally, reports that SARS-CoV-2 mutates sufficiently rapidly within each patient to form a quasispecies suggests that genetic diversity within hosts may be sufficient to lead to acquired resistance to therapeutic nAbs. https://www.biorxiv.org/content/10.1101/2020.08.10.241414v1

The world is at the beginning of a protracted existential conflict with SARS-CoV-2, and it is the virus’ ability to evolve around selection pressures that will determine the ultimate tractability of our efforts at disease control.

Thailand Medical News would further like to add that the whole approach to the COVID-19 pandemic has been wrong and instead of focussing on vaccines and antibody treatments, a greater emphasis should have been on  finding effective drugs or therapeutics  including herbs, supplements and repurposed drugs that can halt the replication of the virus and also treat the various aspects of the COVID-19 disease or focus on the human host genes that can be affected by the viral proteins. The over emphasis on vaccines and antibody protocols will eventually backfire very badly and will keep the pandemic going but at a different level.

The rest of the world should also slow down and not follow everything that is being done in the United States. Let the U.S  embrace the vaccines and antibody treatments first and then wait for about 4 to 6 months to watch the 'fun' before embracing anything that they do. Focus on alternatives like repursposed drugs, herbs and supplements etc.They should also close their borders to Americans in the meanwhile as well to safeguard their local populations.
 
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