As new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, fueling the continued spread of the coronavirus disease 2019 (COVID-19) pandemic, a new study offers encouragement. Released as a preprint on the bioRxiv* server, the study reports the protection offered by antibodies elicited by natural infection against the newer variants of the virus that are currently showing increased transmissibility and virulence.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Variants of concern
The UK variant is one of three variants of concern (VOCs) that abruptly emerged towards the end of 2020 in the UK, South Africa and Brazil, thus spanning three continents. These are showing extraordinary transmissibility, often becoming the dominant lineage in these areas over a period of weeks by displacing the older strains.
This has led to mounting concern as to whether their spread can be blocked by the presence of neutralizing antibodies against the virus, induced by natural immunity or vaccines. The current study aims to provide some answers to this question.
All three VOCs mentioned above have an N501Y substitution at the receptor-binding domain (RBD) of the spike glycoprotein. This mutation is associated with an increased binding affinity of the spike for the human host cell receptor, the angiotensin-converting enzyme 2 (ACE2).
The UK (B.1.1.7 lineage) variant first came to light in September 2020 and has additional mutations, including a deletion of amino acids 69/70, six other mutations in the spike gene, a premature stop codon in the open reading frame (ORF) 8 gene, a pair of nucleoprotein gene substitutions, and four changes in the ORF1 gene.
The South African (B.1.351) variant has additional K417N and E484K mutations in the RBD. The first is thought to break up a salt bridge between the spike and the ACE2 receptor, while the second may disrupt another ACE2-RBD binding to enhance spike-ACE2 binding.
Effect of mutations in the VOCs
Some research indicates that these variants enable immune evasion by avoiding neutralization by antibodies directed against ACE2-binding class 1 and class 2 epitopes. However, the class 3 and 4 epitope-binding antibodies retain their neutralizing capacity. These epitopes are generally on the periphery of the RBD, and are not substituted in the VOCs mentioned here.
Immunological protection
The mechanism of protection against reinfection, following natural infection or vaccination, involves anti-spike antibodies, both neutralizing and non-neutralizing, as well as cellular immunity mediated by CD4 and CD8 T cells specific to multiple viral proteins. Natural immunity, including spike- and N-specific antibodies, is associated with protection against symptomatic infection for at least six months, as observed in the first wave in the UK.
The question of reinfection remains unanswered, and if immunity fails to prevent this, this could be a prime factor behind the emergence of novel strains.
Hamster studies
Animal models of COVID-19 are useful in providing insights into how the disease manifests in humans and the effects of various treatments or preventive measures. Among small animals, the hamster is preferred as it develops both upper and lower respiratory infections, with clinical features that reflect those found in humans.
Hamster studies also throw light on the pathogenesis of the disease. In addition, these animals allow the effects of vaccines and therapeutics to be evaluated, as they shed and transmit the virus readily between themselves.
Study results
The researchers infected four groups of hamsters with the earlier Liverpool (LIV) strain of the virus, and after three weeks, reinfected them with the same strain, the UK variant, the South African variant, or with PBS control solution.
These animals first lost weight for six days post-infection (dpi) but regained normal weight by 10 dpi.
Following rechallenge with any viral strain, all animals in this group gained weight over a week, with a final gain of 10% to 17%. Those rechallenged with the VOCs showed no other signs of infection.
A control set of four groups were inoculated with PBS and then with the same four inocula after three weeks. These animals first gained 10% of their weight by 10 dpi. Those that received PBS in both rounds increased their weight over a week. However, those that received any viral strain in the rechallenge lost weight.
The hamsters first treated with PBS, and rechallenged with the LIV strain, began to regain weight by day 7 dpi. This was not the case with hamsters rechallenged with the other two VOCs, indicating that these may increase the disease's severity. This is being explored with the study samples at present.
What are the implications?
These findings indicate that prior infection with an earlier strain of SARS-CoV-2 circulating in the UK is protective against clinical disease caused by the same strain or two VOCs now in circulation.
Overall, the study demonstrates that though some neutralizing antibodies appear to lose their efficacy, the diversity of the immune response ensures adequate protection from reinfection. This is a reassuring finding in view of the limited protection offered by neutralizing antibodies in vitro and implies the feasibility of achieving herd immunity by natural infection combined with large-scale vaccination.
*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
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