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Lambda after Delta? Scientists find molecular reasons behind what and why could happen

Owing to rapid mutations, the continual emergence of several SARS-CoV-2 variants have been reported, among which some are regarded to be variants of concern (VOC), e.g., Alpha, Beta, and Delta. Other variants are known as variants of interests (VOI), e.g., Eta, Kappa, Lambda, and Iota. As a result, researchers keep an eye on the prevalence of these variants since they may pose a global threat. Multiple mutations are present in the Spike (S) protein of VOCs and VOIs, and these variants have been reported to be resistant to the neutralizing antibodies (NAbs) that were elicited post-vaccination or post-natural COVID-19 infection. Since the receptor-binding domain (RBD) of the S protein is immunodominant, a mutation in this site causes immune evasion. Also, mutations in the N-terminal domain (NTD) aid viruses in escaping neutralization. Therefore, to date, all the vaccines that received emergency use authorization (EUA) from various regulatory bodies are targeted towards the Spike protein.

Do all mutations have a negative impact on vaccine effectiveness? Not indeed, all mutations do not disrupt the effectiveness of the vaccine-induced immune responses. For example, previous research has shown HV69-70 deletion does not have any effect on the sensitivity of neutralizing antibodies sensitivity, however, it increases viral infectivity. Similarly, deletion of the LAL242-244 in the Beta variant does not affect the sensitivity to the vaccine-induced neutralization. However, it has shown little resistance to NTD-targeting neutralizing antibodies. The Lambda variant belongs to the C.37 lineage, which has been newly designated as a VOI last June 14 by WHO. This variant is predominantly spreading in South American countries that include Chile, Peru, Argentina and Ecuador. Recently, during the spring of 2021, a rapid surge in COVID-19 cases was observed in Chile.  This is because the Lambda variant is capable of escaping the immune responses induced via vaccination.

A new study published on the bioRxiv* preprint server used molecular phylogenetic analysis to study the evolutionary trait of the Lambda variant. In this study, the researchers have revealed that insertion of 246-RSYLTPGD-253 mutation in the NTD of the Lambda S protein is associated with the increased virulence. This mutation is responsible for the rapid spread of the Lambda variant in the Southern American countries. The authors of this study have indicated two of the critical virological features of the Lambda variant, namely, a) resistance to viral-induced immune responses due to the RSYLTPGD246- 253N, L452Q, and F490S mutations and b) enhancement in the rate of transmission due to the T76I and L452Q mutations. This study revealed that the Lambda S is more resistant to the vaccine-induced antisera compared to the Lambda + N246-253 Spike derivative. Another important aspect of this is that 246-253 mutation overlaps with a component of the NTD “supersite” indicating that it is the immunodominant site.

Hence, mutation of this site has enabled the Lambda variant to escape immune responses elicited by the COVID-19 vaccine. The findings of this study are in line with previous studies that had revealed that higher infectivity of the Lambda, Delta and Epsilon variants is due to the L452Q/R mutation. Scientists have explained that only increased viral infectivity does not attribute to a large-scale infection. Such an instance was observed for the Epsilon variant, where even after possessing high infectivity, it failed to spread in the human population. Thereby, WHO excluded it from the VOC/VOI classification on July 6, 2021. In order to understand if a variant would infect a large number of people, it is essential to determine two characteristic virological features of the variant, i.e., increased viral infectivity and evasion from the immune response. This study revealed that the Lambda variant possesses both these virological features.

WHO virologist Jairo Mendez-Rico did not spread any alarming information, yet commented worrisomly on this topic: “So far we have seen no indication that the lambda variant is more aggressive. It is possible that it may exhibit higher infection rates, but we don’t yet have enough reliable data to compare it to gamma or delta. Although it is possible, currently there is no indication that variants are more dangerous and lead to increased mortality. It is likely that SARS-CoV-2 will become more transmissible throughout the course of its evolution but not necessarily more damaging. Many scientists believe that the coronavirus pandemic won’t be over until at least 80% of the world’s population has been vaccinated. Variants like lambda could continue to emerge until that is achieved. This is why inoculation presented the most effective defense. “All of the vaccines we have approved worldwide have been generally effective against circulatin coronavirus variants, and there is no reason to suspect them to be less so against lambda”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Kimura I et al. bioRxiv 2021 Jul 28:454085.

McCallum M et al. Science. 2021 Jul 1:eabi7994. 

Shen X et al. New Engl J Med 2021; 384:2352-54.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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