Take a Stand Now to Stop COVID-19 Variants

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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 infection, is a ribonucleic acid (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 that modify the virus’ spike protein can cause meaningful changes in both transmissibility and disease severity. Spike proteins are numerous projections that surround the capsule of the virus and attach the virus to the host cell’s angiotensin-converting enzyme 2 receptor.

The original SARS-CoV-2 virus was first detected in Wuhan, China, in the fall of 2019. Within a few months, it had rapidly spread around the world, causing severe disease and hundreds of thousands of deaths. By spring 2020 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). Bette Korber and colleagues reported in a preprint study that the virus was increasing at an “alarming rate” and had a “fitness” advantage.¹ According to the authors, the detection of D614G was associated with fewer polymerase chain reaction cycles, indicating higher viral loads. They also presented evidence of recombination between strains that produce hybrid viruses.

Downplayed

This study should have sounded an alarm, but instead the findings were downplayed, as was the evidence of increased transmissibility. In its final publication in Cell the word alarming was dropped.² The term fitness was spun by policymakers as an unimportant 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 seasonal influenza.³ This is because SARS-CoV-2 has a reparative enzyme designed to correct replication mistakes. With the seasonal flu, we encounter 1 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 and colleagues’ study 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 too do mutations. The wild type of SARS-CoV-2 is at least 3 times as infectious as the seasonal flu,⁴ and the D614G strain increases infectivity further by generating 4 to 5 times the number of spike proteins on its capsule, increasing its transmissibility.⁵ 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 flu with the emergence of new variants.

The virus can evolve and adapt to its environment in 2 ways. One way is by 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. Korber and colleagues 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 supervariants.

By November 2020, it had become evident that the virus was mutating and at a fast rate.⁶ The website nextstrain.org vividly illustrates the myriad of lineages and mutations of SARS-CoV-2. There should be no question that this virus has a high rate of mutation.

In addition, investigators had 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 (B.1.351) had arisen in South Africa with an immune escape mutation, E484K, sometimes referred to as “EeK.” By April 2021, a number of other SARS-CoV-2 viruses of different lineages had independently developed the E484K mutation, including the Brazil variant (P.1) and some strains of the New York (B.1.526) and United Kingdom (B.1.1.7) variants. This was an example of convergent evolution, and some believed that the virus had possibly reached an evolutionary plateau because so many different lineages were acquiring the same solution to partially escape immunity.

Nomenclature

By this time the variants were becoming so numerous, and the corresponding numbers and letters used to denote names so complex, that a new system of nomenclature was needed. Typically, the name of the country or region of origin is not used as it can politicize a pandemic. The best example is the Spanish flu, a 1918-1919 pandemic for which the first known case occurred in Kansas. The United States and Europe did not want to acknowledge the infection or the massive impact it was having on their World War I troops, as it might have emboldened the German army. Spain, on the other hand, which had remained neutral in the war, was fully transparent regarding the pandemic. The Spanish monarch, Alfonso XIII, became severely sick with the disease and the country was then blamed for the pandemic.⁷

Hence the World Health Organization decided to name the major variants of SARS-CoV-2 with Greek letters, as shown in the Table below.⁸

The US government’s SARS-CoV-2 Interagency Group (SIG) has also prioritized variants, classifying them into 3 categories based upon their impact.⁹

Variant of interest: has specific genetic markers that may affect transmission, diagnosis, therapeutics, or immune escape. There is evidence that the variant is the cause of an increased proportion of cases or can cause unique outbreaks, but it has limited prevalence in the US and other countries.

Variant of concern: has a significant impact on diagnostics, treatments, or vaccines, and has 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, and with each emerging variant, it appears to have become progressively more infective. Variants that increase viral load may also increase transmissibility and the ability 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.¹⁰ Most recently, concern has been raised that the virus may have found an animal host in white-tailed deer, with SARS-CoV-2 antibodies identified in 40% of surveyed animals.¹¹

A mutation in India, the Delta variant, acquired several important mutations (including L452R, P681R, D614G, and T478K), and by the summer of 2021, it had become the dominant strain in the US and United Kingdom. This variant acquired another important mutation, K417N, also known as Delta plus.

Many of these variants appear to be effective at evading immunity. Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases and President Joe Biden’s chief medical advisor, testified to that effect in March 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 [B.1.]351,” he said. “It was as if they had never been infected before. They had no protection.”¹²

In early fall 2020, the city of Manaus, Brazil, was assumed to have reached herd immunity with two-thirds of its population having antibodies to SARS-CoV-2 (and others without antibodies potentially having memory B cells). Then it was hit with another even larger wave caused by the Gamma variant, which devastated its population.¹³

In Delhi, India, officials assumed in January 2021 that herd immunity to SARS-CoV-2 may have been achieved after antibody testing revealed that 60% of the country’s population carried antibodies to SARS-CoV-2. Like Brazil, India was subsequently devastated with an adapted virus, this time the Delta variant.¹⁴

An emerging pattern is that each new wave that 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: the wild-type virus, the D614G variant, the Alpha variant, and the Delta variant.

It also is apparent that each major wave is caused by a variant that possesses immune escape properties. These waves are coming frequently, at least several times 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. Lambda is of particular concern because it has immune escape properties and significantly different mutations (G75V, T76I, L452Q, F490S, D614G, T859N, and a deletion Δ246-252) compared with other variants.¹⁵

Herd immunity is no longer possible; the virus is mutating and likely has animal hosts. We must raise the bar on public health outcomes, focusing not only on deaths but also on morbidity and long-hauler syndrome, which can be all too common and even occur with vaccine breakthrough infections.¹⁶

SARS-CoV-2 is not influenza. 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 vaccine protection and our ability to detect it with tests. Slowing down the replication and mutation of this virus is of the utmost importance.

To do so, we must take the following steps:

• Upgrade recommendations for mask usage, including the use of N95 or KN95 masks whenever possible.
• Everyone who can do so must get vaccinated. Like Israel, we should fast-track approval for mRNA boosters for individuals at higher risk, including those who are immunosuppressed, over the age of 60 years, and at least 5 months out from vaccination.
• Upgrade building ventilation systems to increase air exchanges and air
  sanitization.
• Expand testing capabilities to be able to test frontline workers and schoolchildren at least twice a week and other workers at least once a week.
• Limit sizes of gatherings, including learning pods in schools, and plan for permanent hybrid instruction to limit class sizes.
• Businesses, including restaurants, need to offer online ordering along with curbside pickup and, when possible, home delivery.
• Mandatory vaccines should be required in many settings, including health care. Vaccine passports or green cards are being implemented in Israel and France and should be implemented in the United States.

The above steps are also necessary to restore consumer confidence and maintain our economy. We must plan and invest in long-term solutions. This virus may disappear, like the 1918 influenza, or it may be present for decades, like polio, measles, and smallpox. Consistent messaging and the widespread embrace of vaccines and other public health measures are key to providing our pharmaceutical industry with the necessary time to formulate new vaccines and therapeutics that can effectively treat and prevent infections.

KEVIN KAVANAGH, MD, is founder of the patient advocacy group Health Watch USA and a frequent contributor to Infection Control Today®. He is a member of Infection Control Today®’s Editorial Advisory Board.

References:

1. Korber B, Fischer WM, Gnanakaran S, et al. Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. bioRxiv. Preprint posted online April 30, 2020. doi:10.1101/2020.04.29.069054
2. Korber B, Fischer WM, Gnanakaran S, et al. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020;182(4):812-827.e19. doi:10.1016/j.cell.2020.06.043
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8. Tracking SARS-CoV-2 variants. World Health Organization. Updated August 25, 2021. Accessed August 16, 2021.
   https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/
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11. Kavanagh K. Lambda variant, COVID-19 animal hosts present deadly mix. Infection Control Today®. August 5, 2021.Accessed August 12, 2021. https://www.infectioncontroltoday.com/view/lambda-variant-covid-19-animal-hosts-present-deadly-mix
12. Examining our COVID-19 response: an update from federal officials. US Senate Committee on Health, Education, Labor and Pensions. March 18, 2021. Accessed July 20, 2021. https://www.help.senate.gov/hearings/examining-our-covid-19-response-an-update-from-federal-officials
13. Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science. 2021;372(6544):815-821. doi:10.1126/science.abh2644
14. Kamat P. Herd immunity in sight for India’s capital? WebMD. January 29, 2021. Accessed July 27, 2021. https://www.webmd.com/lung/news/20210129/herd-immunity-in-sight-for-indias-capital
15. Robertson S. Lambda lineage of SARS-CoV-2 has potential to become variant of concern. News Medical. June 27, 2021. Accessed July 15, 2021. https://www.news-medical.net/news/20210627/Lambda-lineage-of-SARS-CoV-2-has-potential-to-become-variant-of-concern.aspx
16. Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 breakthrough infections in vaccinated health care workers. New Engl J Med. Published online July 28, 2021. doi:10.1056/NEJMoa2109072