Studies on mutations show SARS-CoV-2 has become more transmissible but less deadly

Researchers have been mapping the genetic diversity of SARS-CoV-2 ever since its emergence, in order to identify variants with a selective advantage, and also to study the impact of this genetic variability on transmissibility, virulence, the accuracy of diagnostic tests and of course, the success of vaccines.

In this article we talk about two genetic variants & their impact:

1. G614: A variant from D614G mutation
2. Δ382: A variant with a 382-nucleotide deletion

1. G614: A variant from D614G mutation

This mutation in SARS-CoV-2 has changed the amino acid at position 614, from D (aspartic acid) to G (glycine). Initially, the pandemic started with D614, but now G614 is the dominant variant worldwide.

Let's go through three studies, all published in Cell in July 2020.

Dr Bette Korber's study published in Cell in July 2020, which analyzed SARS-CoV-2 sequences from 999 patients in the UK, showed that patients infected with the G614 variant had a higher viral load compared to the other variant, namely D614. Through their lab experiment in human cell cultures, the authors showed that the G614 variant demonstrated higher infectivity than D614.

The second study (Chinese) published in Cell, July 2020 also demonstrated the same. The authors stated that the dominant strain G614 could be 10-fold more infectious than the original Wuhan strain.

The third article published in Cell, July 2020 was a research review from the Yale School of Public Health, where the authors stated that - 'although the current studies suggest increased viral transmissibility, they do not prove it.'

The review highlighted two limitations in this regard:

1. Increased viral shedding or RNA does not reflect viral transmission capacity.
2. Cell culture work done in the lab does not necessarily translate to living human conditions.

We have to look at this from an evolution point of view. A variant like G614 variant that is spreading faster can only be more infectious. It can't be any deadlier than its first variant D614, because a deadlier variant would only kill the hosts faster, and a dead host makes it a dead-end for the virus as well, which would automatically stop its spread. So the virus has to choose between transmission (infectivity) vs virulence. A rise in infectivity means a drop in virulence. In other words, G -614 is less deadly as opposed to a sensational headline that said G614 could be 10 times deadlier than D614.

Coming to its relevance to the development of vaccines, since D614G is not in the Receptor Binding Domain (RBD) of Spike Protein but in the interface area, it's unlikely to come in the way of antibodies or have a major impact on the vaccines.

Coming to the most important question, whether there is any confirmatory evidence that the D614G mutation (G614 variant) has enhanced the viral spread? The answer is: 'not yet, we have to wait for more evidence.'

2. Δ382: A variant with a 382-nucleotide deletion

SARS-CoV-2 variants with a 382-nucleotide deletion (∆382) in the open reading frame 8 (ORF8) region of the genome have been detected in many countries.

Here we summarize the findings of a study published in The Lancet, 18 Aug 2020, which shows that the ∆382 variant of SARS-CoV-2 seems to be associated with a milder infection.

The repeated emergence of SARS-CoV-2 viruses with a deletion in ORF8 suggests this region is important for viral adaptation to humans. ORF8 is a hotspot for coronavirus mutation. The clinical effect of deletions in this region appears to be a milder infection with a lesser likelihood of a cytokine storm and a more effective immune response to SARS-CoV-2. ∆382 variants might also be less effective at establishing infection in a new host because of the loss of the immune evasion functions of ORF8.

1. Clinical outcomes were considerably better in patients infected with the ∆382-variant than with the wild-type virus.
2. Immunological findings in patients with mild symptoms revealed that patients infected with ∆382 variants had more effective T-cell responses.
3. Genomic data indicate that the ∆382 variants are not related to the D614G clade, which might or might not exhibit altered virus transmissibility.

The analysis of serial respiratory samples from patients with wild-type and ∆382 variant co-infection suggested that the ∆382 variant could have out-competed the wild-type virus. The authors state that the disappearance of ∆382 variants in Singapore, Taiwan, and presumably China could be attributed to infection control measures.

A similar thing happened in the SARS-CoV epidemic in 2002-03 as well. The one that caused the epidemic, a characteristic 29-nucleotide deletion (Δ29) in ORF8 occurred soon after its zoonotic transmission from civets to humans in 2002, and studies reported larger deletions of 82 nucleotides and 415 nucleotides in the same genomic region. Although the effects of these deletions on the course of the SARS epidemic is unknown, in-vitro studies have indicated that the Δ29 variant of SARS-CoV replicates less efficiently than the wild-type virus. As a result, Δ29 variant has been hypothesised to result in a milder clinical illness than that caused by the wild-type virus.

In conclusion, we can say that we still need answers to many complex, unanswered questions wrt mutations and the impact of multiple SARS-CoV-2 variants. We will wait for the results from the currently ongoing studies. But one thing is sure that the mutations are not making the virus any deadlier.

Tags: