MUST READ! SARS-CoV-2 Variants Display Unique Humoral Response And Transcriptional Profiles According To U.S. NIAID Study On Hamster Models

Finally a study that goes along the lines of what Thailand Medical News has been saying for a long time: every SARS-CoV-2 variant exhibits a unique pathogenesis pattern and also affects the human immune system differently! COVID-19 is not a homogenous diseases caused by a common pathogen! Every variant is unique and hence ultimately the only way to better treat COVID-19 is through a personalized medicine approach as even existing human gene profiles and existing comorbidities all play a distinct role in the infection outcome. The situation is expected to be aggravated and made more complicated soon as co-infections with two or more variants is going to be the norm! The same goes for medical conditions that will arise in Long COVID. Though the study was done on hamster models, it’s a starting point and hopefully more researchers will start focusing on this path.

The study conducted by researchers from the U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health and the University of California-Irvine found that SARS-CoV-2 variants display unique humoral response and transcriptional profiles on hamster models.

Since the debut of the SARS-CoV-2 coronavirus in Wuhan –China and the resulting rapid spread throughout the world, new viral variants of concern (VOC) have emerged. There is a critical need to understand the impact of the emerging variants on host response and disease dynamics to facilitate the development of vaccines and therapeutics. 

Syrian golden hamsters are the leading small animal model that recapitulates key aspects of severe coronavirus disease 2019 (COVID-19). 

The study team demonstrated that although intranasal inoculation of SARS-CoV-2 into hamsters with the ancestral virus (nCoV-WA1-2020) or VOC first identified in the United Kingdom (B.1.1.7) and South Africa (B.1.351) led to similar gross and histopathologic pulmonary lesions, there were differences in viral genomic copy numbers noted in the lung and oral swabs of the challenged animals.

Though infectious titers in the lungs were comparable, antibody neutralization capacities varied, dependent on the original challenge virus and cross-variant protective capacity. Transcriptional profiling indicated significant induction of antiviral pathways in response to all three challenges with a more robust inflammatory signature in response to B.1.1.7.

Furthermore, no additional mutations in the spike protein were detected at peak disease. In conclusion, the emerging VOC showed distinct humoral responses and 37 transcriptional profiles in the hamster model compared to the ancestral virus.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.07.11.451964v1
 
It has been observed that high levels of transmission in regions with low rates of vaccination encourage mutations that boost viral fitness. SARS-CoV-2 variants of concern (VOCs) are variants with one or more mutations having adverse epidemiologic, immunologic, or pathogenic properties.

To date, it is known that the B.1.1.7 (Alpha) variant has over 20 mutations, including N501Y within the spike (S) protein, and is associated with increased transmissibility co mpared to the original virus. It also has increased binding affinity to the angiotensin-converting enzyme 2 (ACE2) receptor in host cells that plays a role in viral entry.

We also have the B.1.351 (Beta) variant, originally reported in South Africa, that has similar mutations in the spike as well as the K417N and E484K substitutions that could decrease the efficacy of currently available vaccines.

Considering the possibility of potential vaccine resistance of the VOCs, it is crucial to understand the impact of the newly emerging variants on host immune response and disease dynamics to guide the development of COVID-19 vaccines and therapeutics.

The study focused on analyzing the pathogenic and transcriptomic differences of emerging SARS-CoV-2 VOCs in the Syrian golden hamster model.

Currently Syrian golden hamsters are one of the most popular small animal models used in COVID-19 research globally. Syrian golden hamsters were chosen for this study as they are highly susceptible to infection and were found to have high viral replication in the lungs.

The study found that the ancestral virus (nCoV-WA1-2020), the B.1.1.7 variant first identified in the UK and the B.1.351 variant first identified in South Africa caused similar gross and histopathologic pulmonary lesions.

However differences in viral genomic copy numbers were observed in the lungs and oral swabs of infected animals.

Also antibody neutralization capacities varied based on the original virus and cross-variant protective capacity. 

Transcriptional profiling showed significant induction of antiviral pathways in response to all three viral variants with a more robust inflammatory signature in response to the B.1.1.7 variant

No additional spike protein mutations were detected at peak disease.

Alarmingly the study team also detected many differentially expressed genes (DEGs) related to tissue morphogenesis and angiogenesis in all three infection challenges. This warrants further detailed studies.

Microvascular injury can further aggravate inflammation-driven lung fibrosis. It was found that genes that have a role in tissue repair were downregulated after infection with the B.1.35 and ancestral variants.

The study found that the neutralization cross-protection depended on the variant the hamster was initially exposed to.

To summarize, this study describes the pathogenesis of SARS-CoV-2 variants and the development of cross-reactive neutralizing antibodies.

The study team said that this is the first study that performed a comparative and longitudinal analysis of the immune response after infection with SARS-CoV-2 VOCs.

The team found that infection with the B.1.1.7 VOC results in a better response compared to infection with the B.1.35 VOC.

This broader response to B.1.1.7 may be partly mediated by the more robust transcriptional response induced by this variant, including a more significant induction of antiviral and inflammatory pathways. The authors believe that additional studies must investigate the mechanisms through which the mutations detected in the B.1.35 VOC result in reduced neutralization potential.

The study team said that future experiments should assess transcriptional changes beyond 4 DPC to determine the kinetics of the host response at this critical site. 

It is importan to realize that whatever we discovered through studies in the first 12 months of the COVID-19 pandemic might be absolute  as the emerging variants  are all unique themselves. The same goes for treatment protocols, therapeutics etc to a certain degree!

For more on SARS-CoV-2 Variants, keep on logging to Thailand Medical News.