Single-dose therapeutic interfering particles reduce SARS-CoV-2 pathogenesis and shedding in hamsters

In a recent study posted on Bio Rxiv*Preprint server, researchers report that a single dose of therapeutic interfering particles (TIPs) reduces the pathogenesis and shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hamsters. did.

Background

The significant infectivity of SARS-CoV-2 is one of the main causes of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Current interventions, such as the COVID-19 vaccine, prevent severe illness and mortality, but to varying degrees Effectiveness This is probably due to the insufficient antiviral effect on respiratory mucosa.Previous reports have shown that parenteral vaccination of other viruses does not successfully shut down mucous membranes viral shedding or transmission.

Similarly, despite their success in reducing the etiology of viral disease, small-molecule antivirals have shown varying efficacy in blocking respiratory viral infection, even against SARS-CoV-2. seems to be Therefore, therapies that address viral replication sites may be more effective for limiting transmission of respiratory viruses.

The authors of the current study recently discovered a messenger ribonucleic acid (mRNA)-based, intranasally delivered TIP that reduced SARS-CoV-2 replication in a single dose. These TIPs displayed a substantial resistance barrier and prevented the hamster from severe her COVID-19.

About research

Since the respiratory tissue with the highest viral replication load for SARS-CoV-2 is the tissue that the previously developed TIPs inherently target, in the current study researchers hope to reduce SARS-CoV-2 We investigated the feasibility of TIP intervention to reduce This limits viral transmission between hamsters.

The team used the Syrian golden hamster model of COVID-19 based on previously described strategies to investigate whether TIP reduces transmission of SARS-CoV-2. They validated the infection results obtained with the SARS-CoV-2 Delta (B.1.617.2) variant in a similar hamster infection assessment using the conserved SARS-CoV-2 WA-1 strain. .

Additionally, the scientists added TIP to existing mathematical models of viral dynamics to investigate whether interactions in TIP-treated animals also show reduced viral shedding. Data were then extrapolated from nasal wash information of contact animals to predict the length of infectious viral shedding.

Notably, all live virus studies were performed at Gladstone Laboratories or Scripps Laboratories in containment facilities that met the requirements of Biosafety Level 3 (BSL3) or Animal Biosafety Level 3 (ABSL3), respectively.

result

The study results showed that source hamsters treated with TIP shed much less SARS-CoV-2 with daily nasal washes, as determined by infectious virus or viral RNA. , their nasal viral load declined more rapidly. Strikingly, infectious virus shed from 4 of his 5 animals treated with TIP decayed below the limit of detection (LOD) at 5 days post-infection. On the other hand, all control-treated source animals shed high virus titers by day 5. Similarly, contact of TIP-treated animals showed lower nasal viral shedding than control-treated animals.

In addition, TIP therapy reduced lung SARS-CoV-2 ribonucleic acid (RNA) levels by more than 2 Logs and reduced SARS-CoV-2 infectious burden by more than 3 Logs. In line with previous studies, contact hamsters had higher viral loads than source hamsters, possibly related to the inoculation method.

Study results show that a single dose of intranasally delivered TIP lipid nanoparticles (LNPs) reduces SARS-CoV-2 shedding and transmission, and protects contact animals. The team found that cell-to-cell spread of SARS-CoV-2 was efficient, but her TIP transfer between hosts experienced many bottlenecks, leading to basal reproductive rates (R₀) << 1.

Researchers found that TIP therapy reduced SARS-CoV-2 pathogenesis, shedding, and spread of various viral strains, including the WA-1 sequence and the Delta variant of concern (VOC). Furthermore, we noted that post-exposure TIP therapy of infected hamsters reduced infection by reducing the duration and level of viral shedding in both contact and source animals.

Conclusion

The authors reported that a single dose of TIP after exposure reduced nasal shedding of SARS-CoV-2. Furthermore, infectious virus was below the detection threshold in 4 of 5 infected animals by 5 days post-infection.

Furthermore, TIP reduces transmission of SARS-CoV-2 WA-1 strain or delta variant from infected hamsters to uninfected hamsters. Compared to animals housed with infected untreated animals, contact hamsters housed with infected TIP-treated animals had significantly lower viral loads, no severe lung injury, reduced inflammatory cytokines, and a longer molting duration. was short.

The findings of this study suggest TIP as a potential countermeasure to reduce SARS-CoV-2 transmission. This study demonstrated that a single delivery of mRNA-based TIP LNPs after viral exposure reduced the duration and amount of SARS-CoV-2 shedding. The data showed that TIP works against different archival SARS-CoV-2 variants, namely WA-1, and recent highly pathogenic VOCs like the Delta variant.

*Important Notices

bioRxiv publishes non-peer-reviewed, preliminary scientific reports and should not be considered conclusive, to guide clinical practice/health-related actions, or to be treated as established information .