Laboratory studies suggest that G614G is the more infectious SARS-CoV-2 genotype for humans

If variants encoding the Spike G614 protein are more transmissible or more infectious in several human populations, the dominant variant in this pandemic may not only spread faster, but also produce higher viral loads during infection

Recent research shows that a Sars-CoV-2 strain has been causing more serious diseases, but scientists claim that there is no significant mutation to suggest changes in viral behavior. In the article titled Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2, researchers at Los Alamos National Laboratory, Duke University and the University of Sheffield (UK) suggest that the Sars-CoV-2 strain called D614G, presents a small but significant change in the protein protruding off the surface of the virus, which it uses to invade and infect human cells. The study analyzed the initial 183 sequences and found that seven D614G strains were from Brazil, Europe, Mexico and Wuhan.

The initial results of the research were criticized for not proving that the mutation itself caused this dominance, and other factors or chance could be responsible. The team conducted additional experiments, analyzing data from 999 British patients hospitalized with COVID-19, and found that those who contracted the newest strain had more viral particles, but without affecting the severity of the disease.

Virologist Nathan Grubaugh of the Yale School of Public Health (YSPH), not involved in the research, said in a commentary that he did not believe the results will have a major impact on the general public. To learn more about the subject, the Communication Department of the Brazilian Society of Tropical Medicine (BSTM), interviewed Dr. Anderson Brito of Grubaugh Lab, Yale University, Department of Microbial Disease Epidemiology (EMD), member of Dr. Grubaughs team.

Find the full interview below.

BSTM: Could you tell us about the discovery?

Dr. Anderson Brito: To attach and invade the cells it infects, the coronavirus SARS-CoV-2 relies on a protein found in its surface. This protein, called Spike is made of 1273 amino acids. One of these amino acids, found at the position 614 of the protein is found in variants that now are the dominant form in circulation. At the beginning of the pandemic, most viruses had an aspartic acid (represented by the letter D) in that position, but since March, a variant showing a Glycine (G) became the most common variant found in virus circulating in most continents (https://nextstrain.org/ncov/global?branchLabel=aa&c=gt-S_614).

BSTM: Clinical and in vitro data suggest that D614G changes the virus phenotype. Can you talk about it?

Dr. Anderson Brito: Not all mutations that SARS-CoV-2 genomes accumulate over time cause changes of amino acids. The few mutations that do lead to almost neutral changes in protein structure, that is, they do not provide any advantage or disadvantage to the virus. As exceptions, a small number of mutations may provide new chemical properties to viral proteins, which in turn may result in observable changes in the way how the virus behaves during infections. This is what likely happened to the Spike protein when its amino acid D switched to a G: a new phenotype, with a different molecular functioning arose.

BSTM: What impact does the mutation have on transmission, disease and vaccine?

Dr. Anderson Brito: Transmission – It is important to distinguish three concepts: infectivity (the ability to produce infection); transmissibility (ability to pass to one host to another); and virulence (the degree of damage caused to the host). Concerning the variant G614, in vitro experiments and clinical observation revealed it may cause higher infectivity, but its impact on transmission in human populations remains to be determined.

Disease – Similar to impacts on transmission, it is not clear if the amino acid change D614G boosts the virulence of SARS-CoV-2. The same study describing the impact of G614 on levels of infectivity has shown no association with increased disease severity.

Vaccine – The Spike protein shows many functional regions (domains). The region most commonly targeted by antibodies is called RBD (Receptor Binding Domain), which, as its name suggests, is responsible by binding cell receptors, more specifically the receptor ACE2. The RBD is found from position 326 to 531, and the amino acid change at position 614 is found in another domain, called CTD, not commonly targeted by antibodies. It is still unknown if both variants can be equally neutralized by antibodies.

BSTM: Why is D614G more infectious in humans?

Dr. Anderson Brito: We still dont know if the variant G614 is more infectious in human populations. The evidences obtained so far revealed higher levels of infectivity in cell cultures. Also, indirect evidence suggest that patients infected with the G variants had higher concentrations of viral RNA in their collected samples, factor that may indicate higher viral load during the infection.

BSTM: Did the G614 variant really spread faster than the D614 variant? What explains that?

Dr. Anderson Brito: Viruses with the Spike protein G614 are the dominant pandemic variant, but the reason of such dominance remains to be determined. Evidences from in vitro experiments and clinical data suggest that the chemical change in the spike protein may account for the rapid spread of the virus, however, other factors probably also played a role, such as: founders’ effect; the diversity of the human populations that got infected with that variant early in the pandemic, and; its mode of dissemination in highly connected populations since March, in Europe and North America.

BSTM: What is the effect of D614G on pandemic control?

Dr. Anderson Brito: As mentioned above, it is not clear yet if the variants encoding the Spike protein G614 are indeed more transmissible or more infectious in natural, diverse human populations. If that proves to be true, it would mean that the dominant variant in this pandemic can not only spread faster, but also produce higher viral loads during infection. Both factors would represent challenges to pandemic control. However, based only on the evidence available as of today, socioeconomic and demographic factors are likely much bigger challenges for epidemic control, especially in low income countries.

BSTM: Can we say that it is better to have a more infectious and less deadly virus? Why?

Dr. Anderson Brito: A disease caused by a virus that often leads to visible symptoms can quickly be diagnosed, and the infected person can be isolated to prevent further spread. This fact alone could be seen as a positive aspect, however, if this same virus also causes lethal hemorrhagic fever, killing 50% of those infected, such human losses would place us in an undesirable scenario. This is what Ebola virus can cause: visible symptoms, but high case fatality rates. On the other hand, a virus that frequently causes mild or asymptomatic infections may not even be detected, and it will freely spread in the population. Even if the case fatality rate is lower than 1%, the large number of people that get infected and end up hospitalized will pose a large pressure on health care systems, and as a consequence, an increased disease burden. This is the case of SARS-CoV-2, a virus of difficult containment, which although not as virulent as other viruses, has been acting as a silent killer, and caused nearly a million deaths (as of September 19^th, 2020). In a few words: the better choice is to invest in pathogen surveillance, to detect and prevent the emergence of new viral outbreaks in the first place.

BSTM: Can the emergence of variants affect the development of vaccines and treatment of COVID-19 antibodies?

Dr. Anderson Brito: The genome of the virus SARS-CoV-2 is composed by nearly 30,000 nucleotides, which encode 10 proteins. Along the protein sequences, just like in the Spike protein, distinct regions of the proteins have specific functions. Not all regions are able to stimulate immune responses, like the production of antibodies and T cells. Only a small proportion of mutations in the viral genome may result in changes in the proteins, and among the few amino acid changing mutations, only those that eventually affect immunogenic protein regions will have some impact on vaccine development. Therefore, although SARS-CoV-2 accumulate an average of 2 or 3 mutations per month, these mutations rarely lead to relevant functional changes.

BSTM: How does in vitro infectivity, prevalence and phylogenetic data prove that this mutation makes Sars-CoV-2 more transmissible?

Dr. Anderson Brito: These evidences may only elicit hypotheses to be tested. The strongest evidences of changes in viral transmissibility will come from experiments of natural infection, in animal models. In vitro assays and computational models are useful methods to narrow down the space of hypotheses to be tested, and are essential for scientific discovery, but in isolation they cannot generate all the necessary evidence to explain complex natural phenomena.