A human antibody that broadly neutralizes betacoronaviruses protects against SARS-CoV-2 by blocking the fusion machinery

The repeated spillovers of {beta}-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent individuals and found to cross-react with multiple {beta}-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal {beta}-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry by inhibiting membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through direct viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-{beta}-coronavirus vaccines eliciting broad protection.

Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite a lack of an antiviral effect

In response to the ongoing COVID-19 pandemic, repurposing of drugs for the treatment of SARS-CoV-2 infections is being explored. The HIV protease inhibitor Nelfinavir, widely prescribed in combination with other HIV inhibitors, has been shown to inhibit in vitro SARS-CoV-2 replication. We here report on the effect of Nelfinavir in the Syrian hamster SARS-CoV-2 infection model. Although treatment of infected hamsters with either 15 or 50 mg/kg BID Nelfinavir [for four consecutive days, initiated on the day of infection] does not reduce viral RNA loads nor infectious virus titres in the lungs compared to the vehicle control, the drug reduced virus-induced lung pathology to nearly the baseline scores of healthy animals. A substantial interstitial infiltration of neutrophils is observed in the lungs of treated (both infected and uninfected) animals. The protective effect of Nelfinavir on SARS-CoV-2-induced lung pathology (at doses that are well tolerated and that result in exposures nearing those observed in HIV-infected patients) may lay the foundation for clinical studies with this widely used drug.

Molnupiravir (EIDD-2801) inhibits SARS-CoV2 replication in Syrian hamsters model

Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV2. In recent days preliminary efficacy data have been reported in COVID-19 patients. We here studied the combined antiviral effect of the drugs in the SARS-CoV2 hamster infection model. We first demonstrate that Molnupiravir can reduce infectious virus titers in lungs of infected animals in a dose-dependent manner by up to 3.5 log10 which is associated with a marked improvement of virus-induced lung pathology. When animals are treated with a combination of suboptimal doses of Molnupiravir and Favipiravir (that each alone result in respectively a 1.3 log10 and 1.1 log10 reduction of infectious virus titers in the lungs), a marked combined potency is observed. Infectious virus titers in the lungs of animals treated with the combo are on average reduced by 4.5 log10 and infectious virus are no longer detected in the lungs of 60% of treated infected animals. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs. In the combo-treated hamsters an increased frequency of C-to-T and G-to-A mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir and Favipiravir in the treatment of COVID-19.

A single-dose live-attenuated YF17D-vectored SARS-CoV2 vaccine candidate

The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines to quench the unrestrained spread of SARS-CoV-2. Several promising vaccine platforms, developed in recent years, are leveraged for a rapid emergency response to COVID-191. We employed the live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express the prefusion form of the SARS-CoV-2 Spike antigen. In mice, the vaccine candidate, tentatively named YF-S0, induces high levels of SARS-CoV-2 neutralizing antibodies and a favorable Th1 cell-mediated immune response. In a stringent hamster SARS-CoV-2 challenge model2, vaccine candidate YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose confers protection from lung disease in most vaccinated animals even within 10 days. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine candidate.

STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters

Introductory paragraphSince the emergence of SARS-CoV-2 causing COVID-19, the world is being shaken to its core with numerous hospitalizations and hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that productive SARS-CoV-2 infection in the lungs of mice is limited and restricted by early type I interferon responses. In contrast, we show that Syrian hamsters are highly permissive to SARS- CoV-2 and develop bronchopneumonia and a strong inflammatory response in the lungs with neutrophil infiltration and edema. Moreover, we identify an exuberant innate immune response as a key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Finally, we assess SARS-CoV- 2-induced lung pathology in hamsters by micro-CT alike used in clinical practice. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.