J&J vaccine prevents SARS-CoV-2-induced thrombosis and inflammation in hamsters

The coronavirus disease 2019 (COVID-19) pandemic has resulted in an intense focus on the development of vaccines. Animal models have been utilized to evaluate the efficacy of newly developed vaccines and to define molecular and immunologic correlates of protection.

Study: Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters. Image Credit: pcruciatti / Shutterstock.com

The utility of animal models

Hamsters and rhesus macaques are primary models used to study the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and vaccine effectiveness. The utility of these models is due to their ability to exhibit robust viral replication in the upper and lower respiratory tracts when infected with SARS-CoV-2.

Proteomic and transcriptomic reports from SARS-CoV-2 infected hamster lung tissues and blood have demonstrated complement activation, upregulation of interferon (IFN) and pro-inflammatory pathways, and recruitment of macrophages and neutrophils to lungs of infected hamsters. Taken together, these responses correlate with the presence of SARS-CoV-2 viral RNA, which supports the roles of pro-inflammatory responses in the severity of COVID-19.

Thus, it is essential that COVID-19 vaccinations are tested in these models to determine whether they influence host immune and transcriptional responses. Additionally, these studies can also determine whether protection is provided against excessive pro-inflammatory responses.

In a recent study published on the preprint server bioRxiv*, researchers performed bulk ribonucleic acid (RNA)-Seq transcriptomic profiling of lung tissue from vaccinated and unvaccinated hamsters four days post-challenge with SARS-CoV-2. The vaccinations utilized for this study was the Ad26.COV2.S (Ad26) and the S.dTM.PP.

AD26 vaccine eradicates detection of SARS-CoV-2

Analysis via RNA-Seq and transcriptomic profiling revealed that within each group of hamsters, the transcriptomic profiles were homogenous. Furthermore, no significant difference between groups of animals who received differing doses of vaccine was observed.

In unvaccinated hamsters, RNA-Seq reads were mapped to the SARS-CoV-2 genome. A significant number of reads mapped to SARS-CoV-2 transcripts were observed, ranging from 300-315,000.

However, within S.dTM.PP vaccinated hamsters, a lower number of reads were found to have mapped to SARS-CoV2 transcripts, ranging from 10 to 16,000 reads. With Ad26 vaccinated hamsters, SARS-CoV-2 reads were undetectable, with only 0 to 12 reads mapping SARS-CoV-2 transcripts.

Compared to naïve animals, differences were observed in gene upregulation and downregulation in vaccinated and unvaccinated animals by differential expression gene analysis (DEGs). Significant differences in the transcriptomic profile of hamsters who were administered the AD26 vaccine were observed as compared to unvaccinated hamsters, with 3,401 genes differentially expressed between the two groups. Comparatively, only 87 differentially expressed genes were detected between SdTM.PP vaccinated hamsters as compared to unvaccinated hamsters.

Vaccinated hamsters were found to express downregulation of pro-inflammatory markers and increased expression of IFN receptors when compared to unvaccinated animals. These results are consistent with previous work conducted by the authors, where they found that hamsters were vaccinated with the S.dMT.PP vaccine experienced more adverse side effects when compared to hamsters who received the Ad26 vaccine.

Ad26 vaccine attenuates IFN and inflammatory signaling pathways

A major contributing factor to the severity of disease and death is an excessive inflammatory response to SARS-CoV-2. Previously reported in the lung tissue and blood of both COVID-19 patients and SARS-CoV-2 infected hamsters were the activation of pro-inflammatory cytokines and chemokines, and type I and II IFN responses.

The authors integrated their transcriptomic data in hamsters who had been vaccinated and compared levels of certain pro-inflammatory pathways to naïve and unvaccinated groups.

Gene set enrichment analysis of DEGs displayed pathways of the inflammasome, IFN signaling, and pro-inflammatory cytokine signaling, such as tumor necrosis factor (TNF), IFN-α, interleukin-1 (IL-1), and IL-6 signaling, were increased significantly in unvaccinated hamsters when compared to naïve hamsters. At four days post-infection, a direct comparison between the vaccinated and unvaccinated hamsters showed a significant decrease in the activation of pro-inflammatory pathways in the S.dMT.PP vaccinated as compared to the unvaccinated hamsters.

Pro-inflammatory cytokines and chemokines such as IL-6, IL-1α, and IL-1β have been shown to contribute to the pathogenesis of COVID-19. IL-6, IL-1α, and IL-1β were all found to be highly expressed in unvaccinated hamsters as compared to naïve hamsters. The levels of expression of these pro-inflammatory cytokines and chemokines were comparable between vaccinated and naïve hamsters.

Implications

The author found that Ad26.COV2.S vaccination in hamsters prevented the upregulation of the pathological pathways that are induced by SARS-CoV-2. Furthermore, the researchers demonstrated how the transcriptomic profile of vaccinated hamsters was comparable to sham uninfected hamsters.

Humoral and cellular immune responses were also induced as a consequence of the Ad26 vaccine. Taken together, the findings of the current study provided insights into the potential methods of protection in lungs against SARS-CoV-2.

*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.

Written by

Colin Lightfoot

Colin graduated from the University of Chester with a B.Sc. in Biomedical Science in 2020. Since completing his undergraduate degree, he worked for NHS England as an Associate Practitioner, responsible for testing inpatients for COVID-19 on admission.