It is time to pay more attention to the Lambda variant of SARS-CoV-2. As the Delta variant ravages communities in Asia, Europe, and the United States, another variant of interest, Lambda, is spreading rapidly throughout South America.

The Lambda variant, or C.37, was first identified in Peru as early as August 2020. Initially, Lambda infections were relatively rare. However, in recent months Lambda has become the dominant variant in Argentina, Brazil, Chile, and Colombia. Lambda has been identified in most US States, though the strain has yet to gain traction. Lambda now accounts for less than one percent of all infections but given its trajectory in Latin America, it is well watching closely.

Understanding the Lambda variant’s mutations and how they correspond to virological features like transmissibility, virulence, immune escape, and pathogenesis may help us prepare for its eventual spread. We have previously described the mutations of the Lambda variant in some detail outlining the reasons for our concern.  A recent study by Kimura et al. examines the Lambda Spike (S) protein, commenting on certain mutations’ virological effects, specifically T76I, L452Q, and a 7-amino-acid deletion from positions 246 to 253.

To assess the contribution of each mutation in the S protein to infectivity, Kimura et al. introduced the mutations singularly and in combination.  One of the amino acid changes, G75V, in reduced infectivity. On the contrary, they found that when paining G75V with T76I, the latter compensates for the decrease attributable to  G75V alone. (Figure 1). 

FIGURE 1: Percentages of infectivity compared to the virus pseudotyped with parental S D614G. KIMURA ET AL

A similar effect was noted for the combination of L452Q and F490S. While F490S posted a slight decrease in infectivity, combination with L452Q enhanced infectivity. The researchers conclude that the T76I and L452Q mutations are largely responsible for the significantly higher infectivity of the Lambda variant. While direct comparisons of Lambda and Delta are yet to be widely available, epidemiology suggests that Lambda is far more transmissible than the D614G variant which drove the second wave, and potentially the Alpha variant which drove the third.

Next, the researchers tested mutations against the Pfizer mRNA vaccine. As shown in the figure below, the seven-amino-acid deletion from positions 246-253, L452Q, and F490S all convey contribute to neutralization escape (Figure 2). Notably, L452Q and F490S individually escape neutralization between 1.22 and 1.38 times more effectively, whereas in tandem, the combination escapes 1.62 times more effectively. The only Lambda mutation the abrogates neutralization by a monoclonal antibody (4A8) here specific to the N terminal domain is the 246-253 mutation that lies entirely within that domain (Figure 3).

FIGURE 2: Neutralization assay performed using the pseudoviruses featuring individual and … [+] KIMURA ET AL
FIGURE 3: Antiviral effect of an NTD-targeting 603 NAb clone 4A8. KIMURA ET AL

Figure 4 below is an elegant summary of the contribution of each of the Lambda spike protein mutations to infectivity and neutralization by Pfizer vaccine-derived antibodies and NAb clone 4A8. 

FIGURE 4: Graphical abstract of the findings in Kimura et al. Projected on the S protein are the … [+] KIMURA ET AL

Kimura et a valuable contribution to understanding some of the dangers posed by Lambda. Exclusive analysis of the S protein is unlikely to discuss the full potential of the Lambda variant. Lambda differs by 23 nucleotide changes and 18 amino acid changes from the original Wuhan strain. 16 nucleotide mutations and 11 amino acid mutations lie outside the S gene that encodes the spike protein (Figure 5). The effect of any of these changes may be mitigated by changes in the ability of Lambda to enhance replication and improve down-regulation of the innate and adaptive immune response early in infection. Such changes are unlikely to be apparent in tissue culture.

FIGURE 5: Common mutations external to the S protein in the lambda variant genome. Color code: … [+] ACCESS HEALTH INTERNATIONAL

Dr. Gregory Poland of the Vaccine Research Group at the Mayo Clinic notes that “any time a variant is identified and demonstrates the capacity to rapidly spread in a population, you have to be concerned.” The epidemiology of Covid-19 in South America tells us what we can expect if Lambda, in addition to Delta, gains wide circulation in the US. We are forewarned to prepare for a double onslaught.