“Theyyyy’re Here!” SARS-CoV-2 Mutants: What Does This Mean?
“The bottom line is that we need to suppress transmission of all SARS-CoV-2 viruses as quickly as we can. The more we allow it to spread, the more opportunity it has to change.” - Tedros Adhanon Ghebreyesus, Director-General, WHO
“All this means that the speed of the vaccine rollout is of enormous importance . . . We should put every bit of energy, funding, and relentlessness into vaccinating as many people as possible as quickly as possible.” - Zeynep Tufekci, sociologist and writer
Thirty years ago scientists embarked on one of the most ambitious research projects ever—sequencing the entire human genome. Since its completion in 2003, the Human Genome Project has provided the groundwork for thousands of scientific studies associating genes with human diseases. Last January, Chinese researchers at Fudan University, Shanghai used genetic sequencing and made a landmark scientific discovery—the composition of the genome of a novel coronavirus, which we all know by now as SARS-CoV-2, namely, the virus that led to the pandemic we are continuing to battle. By the end of 2020, SARS-CoV-2 had infected more than 70 million people worldwide and killed more than 1.8 million.
Deciphering the SARS-CoV-2 genome quickly led to diagnostic tests, and, in record time, it fueled the development of vaccines. (As discussed in the December 23 Germ Gem post, two mRNA vaccines were approved by the U.S. Food and Drug Administration and rolled out in America in December.) Knowing the composition of the viral genome also allowed global monitoring for mutations that could alter the pace and severity of the COVID-19 pandemic. The goal of this Germ Gem post is to describe the impact of two genetic variants of SARS-CoV-2, one of which has unleashed global anxiety, including in the U.S. where it was recently detected.
Brief description of SARS-CoV-2’s genome. The human genome is composed of DNA and contains roughly 21,000 genes that code for RNA. RNA molecules in turn generate more than 80,000 different proteins that serve as the building blocks of the cells in the human body. By comparison to Homo sapiens, SARS-CoV-2 is a simple creature. Its genome is composed of RNA that codes for a small number of proteins: the spike (S) protein, envelope protein, membrane protein, and nucleocapsid protein. The S protein has received the most attention because researchers discovered early on that the S protein acts like a key fitting into a lock (ACE2 receptors) on the door of cells thus allowing viral entry. (See the April 1st Germ Gem post for more on how the S protein operates as a “key”.) The S protein also serves as the main target of most vaccines, meaning that vaccines that generate neutralizing antibodies or T cell responses against the S protein can block viral entry into cells.
As a rule, RNA genomes are less stable than are DNA genomes, that is, they are more prone to alterations (mutations). Coronaviruses evolve more slowly than viruses like influenza virus, but they continuously pick up mutations as they spread. SARS-CoV-2 has been adding one or two changes a month to its RNA genome since it emerged in China, and different versions of the virus have been circulating throughout the course of the pandemic.
Such mutations can increase viral fitness, meaning that they can increase the ability of the virus to infect or damage cells, as well as to evade the host’s immune system. (Two particularly notorious RNA viruses that thrive because of their ability to mutate are influenza viruses and HIV. The mutations of the hemagglutinin [HA] protein of flu viruses make it necessary to concoct new flu vaccines every year that target the new [mutated] HA protein. And the rapid development of mutations of HIV enzymes—the targets of many antiviral drugs—result in resistance to drugs that suppress HIV replication.)
Emergence of the SARS-CoV-2 variant D614G. Since the beginning of global monitoring of its viral genome, many genetic variants of SARS-CoV-2 have been detected. The D614G variant, however, was the first to capture great interest. In a December 31, 2020 New England Journal of Medicine article entitled “Emergence of a Highly Fit SARS-CoV-2 Variant,” epidemiologist Ralph Baric reported that genetic investigations conducted as early as February 2020 identified an emerging D614G mutation in Southern Europe that affects the S protein. Since then this variant has spread rapidly and is currently the most prevalent genotype worldwide.
Patients infected with the D614G variant are more likely to have higher viral loads in the upper respiratory tract than are those infected with the virus lacking the mutation. Also, laboratory studies of the virus with the altered S protein were found to have increased infectivity of cultured cells, implying an improved ability to bind to the ACE2 receptor. This appears to explain why it’s more infectious. In addition, studies of hamsters infected with the D614G variant showed higher levels of virus in nasal wash samples, suggesting increased fitness in a major upper airway compartment associated with enhanced transmission.
As bad as that sounds, there is some good news, namely, that the SARS-CoV-2 variant did not cause more severe disease than the non-mutated virus. Equally important, studies with a panel of serum specimens from COVID-19 patients showed that the variant is as sensitive to neutralization by anti-SARS-CoV-2 antibodies as the non-mutated virus. This finding allayed fears that D614G could escape vaccine-elicited immunity. Put another way, scientists believe that the vaccines will still be effective against the mutated virus D614G.
Emergence of the SARS-CoV-2 variant B.1.1.7. In December, the U.K. reported the emergence of another SARS-CoV-2 variant, named B.1.1.7. This variant has an unusually large number of genetic changes, particularly in the S protein. Like the D614G variant, B1.1.7 does not appear to cause more severe disease. Because it spread so rapidly throughout the U.K., on December 14, the U.K. Health Secretary reported that this variant might be linked to greater transmissibility. (It also appears that young people are more susceptible to infection by this variant.) Thus, officials immediately established stricter public health measures to curb new infections, doubling down on preventative strategies, such as wearing a mask, social distancing, and avoiding large gatherings. Travel restrictions of U.K. citizens to Europe and elsewhere were also imposed. And on January 4, 2021, Prime Minister Boris Johnson imposed a strict new national lockdown due to the escalation of COVID-19 case numbers.
Over the Christmas holiday weekend, more than a dozen other countries reported COVID-19 cases caused by the SARS-CoV-2 B.1.1.7 variant. On New Year’s Day 2021, Turkey became the 33rd country to find the variant. In North America, the Public Health Agency of Canada reported two cases in Ontario on December 26, both occurring in people who hadn’t traveled outside Canada. And on December 29, the first reported U.S. case was found in a young man living in Simla, Colorado, a small town thought to be isolated from the spread of new SARS-CoV-2 variants. Subsequently, two cases in males in their 20s were reported in California and Florida.
Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, commented that he expected that the new variant is likely present in many other states. It is this increased contagiousness that has many U.S. officials worried given our already overburdened health care system.
Are there other variants? In addition to the SARS-CoV-2 B.1.1.7 variant, the Center for Disease and Control and Prevention (CDC) is on the watch for a variant first identified in Nelson Mandela Bay, South Africa in October. This variant, named B.1.351, has been found in other countries, including in travelers from South Africa to the U.K. The good news is that this variant too, like the others mentioned above, doesn’t cause more severe disease nor does it have the potential for hindering the efficacy of SARS-CoV-2 vaccines.
Why surveillance for genetic variants is important for public health. Like other major public health institutions around the world, the CDC is monitoring SARS-CoV-2 mutations because new variants have the potential ability to: (1) spread or be transmitted more quickly in people, as is the case with both the D614G and B1.1.7 mutants; (2) cause either milder or more severe disease; (3) elude detection by diagnostic tests; (4) be less susceptible to therapeutic agents such as monoclonal antibodies; and (5) evade natural or vaccine-induced immunity. The B.1.1.7 variant, for example, has mutations that increase its binding affinity to ACE2 receptors which allows it to enter cells more readily. Whether it hasthe ability to evade the human immune response is unclear, but it appears that none of the variants isolated so far can circumvent the efficacy of vaccines.
What do you need to do now? There are various estimates of what the increased transmission of variants like B.1.1.7 means, but some researchers say the new variant could be 50 to 70% more transmissible than non-mutated SARS-CoV-2. Another way to look at it is that this variant has increased the reproduction number—a figure known as R-naught, which is the average of how many people one person will infect—from 1.1 to 1.5. This is a big difference. With the former, 10 infected people on average would lead to 11 new infections, but with the latter, those 10 people would cause 15 new infections. It is important to know, however, that R-naught can be lowered with interventions like masking and physical distancing. (Epidemics will grow if the figure is above 1, and shrink if it is brought below 1.) Therefore it is critical that we continue to practice the same mitigation measures recommended earlier by the CDC to prevent new COVID-19 infections:
· Avoid touching your eyes, nose and mouth
· Avoid close contact with people who are sick
· Stay at home when you are sick
· Wash your hands frequently and rigorously
· Cover your cough or sneeze with a tissue, then dispose of it properly
· Use a face covering when in public
· Practice physical distancing from others (at least 6 feet).
Vaccine rollout. As more contagious SARS-CoV-2 variants are spreading with exponential growth, the swift and efficient rollout of vaccines becomes even more important. In an article in the December 31, 2020 issue of The Atlantic, “The Mutated Virus Is a Ticking Time Bomb,” Zeynep Tufekci underscores that fact and states: “Each one of us [needs] to speak up now and to speak up loudly. We must insist on swift and aggressive action, along with more resources, in order to get this right. It is not too late. Many lives depend on what we do next.”
The CDC has provided a tracker (click here), which tracks distribution of the vaccines as well as the total number of people who have received their vaccine (at this point, a total of around 5 million people nationwide have received their first dose; nearly 18 million doses have been distributed.) It is increasingly clear that it’s time for our federal and state governments to work more closely together in presenting a unified plan for our nation for the swift and efficient delivery of vaccines to all parts of the country. And then it is up to us, you and me, to get vaccinated. Our lives, and those of others, depend on it.