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Herd immunity is no longer possible, the virus is mutating and likely has animal hosts. We must raise the bar on public health outcomes, not only focusing on deaths but also morbidity and long-hauler syndrome which can be all too common, even occurring with vaccine breakthrough infections.
One could never have predicted how much difference a year would make in our understanding of COVID-19. Currently, it is almost impossible to have a conversation without bringing up the subject of variants. For most of last year, we were in almost total denial of the dangers of COVID-19 variants and the ability of COVID-19 to mutate.
SARS-CoV-2, the virus which causes COVID-19, is an RNA virus. RNA viruses are known to mutate, and mutations can cause variants. A variant is created when a meaningful change occurs in the infectivity or lethality of the virus. Mutations which modify the virus’s spike protein can cause meaningful changes in both transmissibility and disease severity. Spike proteins are numerous projections which surround the virus’s capsule and are used to attach the virus to the host cell’s ACE2 receptor.
The original SARS-CoV-2 virus was first detected in Wuhan, China in the Fall of 2019. Within just a few months, it had rapidly spread around the world, causing severe disease and hundreds of thousands of deaths. By spring it was evident that the virus had changed and mutated, the spike protein mutation was denoted as D614G. (This nomenclature means Aspartate was replaced with Glycine at position 614).
A study by Korber B, et al., from the Los Alamos National Laboratory and Sheffield COVID-19 Genomics Group reported in a preprint that the virus was increasing at an “alarming rate” and the virus had a “fitness” advantage. They reported detection of D614G was associated with fewer PCR cycles, indicating higher viral loads. The authors also presented evidence of recombination between strains producing hybrid viruses.
This report should have sounded an alarm, but instead the findings were downplayed as was the evidence of increased transmissibility. The final publication in Cell, dropped the word “alarming.” The term “fitness” was spun by policy makers as not an important change.
The narrative that SARS-CoV-2 did not have a high mutation rate and, thus, would not quickly form variants was bolstered by the finding that SARS-CoV-2 had a mutation rate about half that of the seasonal flu. This is because SARS-CoV-2 has a reparative enzyme designed to correct replication mistakes. With the seasonal flu, we encounter one new strain per year and have a vaccine ready for its emergence. Thus, it was hoped that a SARS-CoV-2 vaccine could be produced and administered yearly, possibly less frequently, to control the pandemic.
Korber, et al., was an example of the data not fitting the hypothesis and the response by all too many was to try to discount the data. However, there is now a plethora of research documenting increased transmissibility of D614G. But an even larger problem was looming.
When the virus replicates, it can mutate. If replication and transmission increase so does mutations. The wild type of SARS-CoV-2 is at least 3 times as infectious as the seasonal flu4 and the D614G strain increases infectivity further by generating 4 to 5 times the number of spike proteins on its capsule, increasing its transmissibility. This set the stage for rampant mutations. It may be true that each virus mutates half as much as the seasonal flu but with increased transmissibility, SARS-CoV-2 rapidly mutated and outpaced the seasonal flu with the emergence of new variants.
There are 2 ways which the virus can evolve and adapt to its environment. One is a point mutation or substitution of a specific amino acid due to an error in the replication. The other is by recombination when the virus swaps large portions of its genetic code with another virus. Kober, et al., found evidence of recombination with SARS-CoV-2. Recombination is promoted by high rates of community infections and sets the stage for the creation of super-variants.
By November of 2020, it became evident that the virus was mutating and at a fast rate. The website nextstrain.org vividly illustrates the myriad of lineages and mutations of SARS-CoV-2. There should be no question that SARS-COV-2 has a high rate of mutation.
It was also hoped that any meaningful change in the spike protein would also decrease SARS-CoV-2’s ability to attach to the cell. This of course did not happen. By the end of 2020, a variant arose in South Africa (B.1.351) with an immune escape mutation, E484K, sometimes referred to as the “EeK” mutation. By April 2021, a number of other SARS-CoV-2 viruses of different lineages had independently developed the E484K mutation including the Brazilian variant (P.1), and some strains of the New York variant (B.1.536) and the United Kingdom variant (B.1.1.7). This was an example of convergent evolution, and some felt the virus possibly had reached an evolutionary plateau, since so many different lineages were acquiring the same solution to partially escape immunity.
By this time the number of variants was becoming so numerous, and the corresponding numbers and letters used to denote names were so complex, that a new system of nomenclature was needed. The use of the country or region of origin is usually not used since it can politicize a pandemic. The best example is of the Spanish flu, a pandemic whose first known case was in Kansas. The United States and Europe did not want to acknowledge the infection or the massive impact it was having on our WWI troops, since it might embolden the German army. Spain, on the other hand, was neutral in the war and fully transparent regarding the pandemic. Its monarch, King Alfonso XIII, became severely sick with the flu and the country was then blamed for the pandemic.
Hence, the World Health Organization decided to name the major variants with Greek Letters as shown in the table below.
The United States government SARS-CoV-2 Interagency Group (SIG) also prioritized variants classifying them into three categories based upon their impact on civilization.
Variant of Interest: The virus has specific genetic markers which may affect transmission, diagnosis, therapeutics, or immune escape. There is evidence that the variant is the cause of an increased proportion of cases, or it can cause unique outbreaks. But it has limited prevalence in the US or other countries.
Variant of Concern: Has a significant impact on diagnostics, treatments or vaccines, Increased transmissibility and/or Increased disease severity.
Variant of High Consequence: High impact on countermeasures, including failure of diagnostic tests, low vaccine protection against severe illness along with more severe clinical disease and increased hospitalizations.
SARS-CoV-2 has continued to evolve. It has now become evident that with each emerging variant, the virus has appeared to progressively become more infective. Variants which increase viral load may also increase transmissibility and the opportunity to mutate, along with overwhelming a host’s immune system and becoming more virulent. To make matters worse, SARS-CoV-2 is infecting a number of animals, including cats, large cats, dogs and gorillas. Most recently, concern has been raised that it may have found an animal host in white tail deer, with SARS-CoV-2 antibodies identified in 40% of surveyed animals.
A mutation in India, the delta variant, acquired several important mutations (including L452R, P681R, D614G, T478K) and by the summer of 2021, became the dominate strain in the US and in the UK. This variant acquired another important mutation, K417N, becoming the delta plus.
Many of these variants appear to be effective in evading immunity. Anthony Fauci, MD, the director of the National Institute of Allergy and Infectious Diseases and President Biden’s chief medical advisor, testified during a senate hearing:
“In the South African study conducted by Johnson & Johnson, they found that [unvaccinated] people who were infected with wild type were exposed to the variant in South Africa, the 351. It was as if they had never been infected before. They had no protection.”
In early autumn 2020, the city of Manaus, Brazil was assumed to have reached herd immunity with two thirds of its population found to have antibodies to SARS-CoV-2 (and others without antibodies may have had memory B cells) and then it was hit with another even larger wave caused by the gamma variant which devastated its population. In Delhi, India, it was assumed in January 2021 that herd immunity to SARS-CoV-2 may have been achieved after antibody testing revealing 60% of its population carried antibodies to SARS-CoV-2. Similar to Brazil, India was subsequently devastated with an adapted virus, this time the delta variant.
An emerging pattern is that each new wave which envelops a nation is caused by different variants of the virus. The US has had 4 major waves of SARS-CoV-2, each caused by a different variant. We had the wild-type virus, the D614G variant, the alpha variant and the delta variant (see figure below).
It also is apparent that each major wave is caused by a variant which possesses immune escape properties. These waves are coming frequently, at least several a year, and are outpacing our ability to produce and administer highly effective vaccines. Unfortunately, future variants are also waiting in the wings including the kappa and lambda variants which may also cause large waves of infections in the future. The lambda variant is of utmost concern since it has immune escape properties and has significantly different mutations (G75V, T76I, L452Q, F490S, D614G, T859N and a deletion Δ246-252) compared to other variants.
Herd immunity is no longer possible, the virus is mutating and likely has animal hosts. We must raise the bar on public health outcomes, not only focusing on deaths but also morbidity and long-hauler syndrome which can be all too common, even occurring with vaccine breakthrough infections. SARS-CoV-2 is not the flu, it does not disappear with seasons, and it affects every organ of the body. The emergence of a Variant of High Consequence is all but certain with evasion of protection of the vaccine and our ability to detect it with tests. Slowing down the replication and mutation of this virus is of utmost importance. To do this we must take the following steps:
The above steps are also necessary to restore consumer confidence and to maintain our economy. We must plan and invest in long-term solutions. This virus might disappear, similar to the 1918 flu, or it could be present for decades, similar to polio, measles and smallpox. Consistent messaging and widespread embracement of vaccines along with public health measures are key to providing our pharmaceutical industry the necessary time to formulate new vaccines and therapeutics which can effectively treat and prevent infections.