Inactivated rabies virus vectored SARS-CoV-2 vaccine prevents disease in a Syrian hamster model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials

Passive and active antibody studies in primates to inform HIV vaccines

Introduction: Prevention of infection remains the ultimate goal for HIV vaccination, and there is compelling evidence that antibodies directed to Envelope are necessary to block infection. Generating antibodies that are sufficiently broad, potent, and sustained to block infection by the diverse HIV-1 strains circulating worldwide remains an area of intense study. Areas covered: In this review, we have summarized progress from publications listed as PubMed citations in 2016–17 in the areas of passive antibody studies using human neutralizing monoclonal antibodies in nonhuman primates, HIV Envelope vaccine development and active vaccination studies to generate potent neutralizing antibodies. Expert commentary: Passive transfer studies in nonhuman primates using human neutralizing monoclonal antibodies have informed the potency, specificity, and cooperativity of antibodies needed to prevent infection, leading to clinical studies now testing potent antibodies for prevention of HIV. Progress in understanding the structure of Envelope has led to novel vaccine constructs, including mimetics, scaffolds and native-like proteins. As yet, no single approach ensures protection against the circulating global HIV-1 strains, but there is progress in understanding why, and intense research continues in these and other areas for a solution. We offer perspectives on how this knowledge may shape the design of future HIV vaccines

SARS-Cov-2 Infection and Seroconversion Rates in Healthcare Providers Prior to COVID-19 Vaccine Rollout

ObjectiveA 6-month longitudinal surveillance study of asymptomatic healthcare providers (HCP) was carried out at a large urban academic medical center in the United States to assess whether their job occupation with higher exposure risks to SARS-CoV-2 would equate with higher risk of contracting COVID-19 at the beginning of the pandemic before COVID-19 vaccines were available.MethodsA longitudinal cohort study design was used to collect and analyze immunological and virological monitoring data and self-report survey assessments of personal protective equipment (PPE) availability, adherence to infection control guidelines, and time spent on COVID-19 wards.ResultsAmong 289 eligible participants, SARS-CoV-2 exposure risk was high with 48-69% participants working in COVID-19 units and more than 30% of them caring for COVID-19 patients. However, the seroconversion rate was low with only 2.1% of participants developing humoral or cellular immunity against SARS-CoV-2.ConclusionOur study findings suggest that, for this HCP cohort working at a large urban academic medical center, a low incidence of SARS-CoV-2 infection could be maintained under conditions of strict infection prevention protocols and reliable PPE availability

Inactivated rabies virus vectored SARS-CoV-2 vaccine prevents disease in a Syrian hamster model

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emergent coronavirus that has caused a worldwide pandemic. Although human disease is often asymptomatic, some develop severe illnesses such as pneumonia, respiratory failure, and death. There is an urgent need for a vaccine to prevent its rapid spread as asymptomatic infections accounting for up to 40% of transmission events. Here we further evaluated an inactivated rabies vectored SARS-CoV-2 S1 vaccine CORAVAX in a Syrian hamster model. CORAVAX adjuvanted with MPLA-AddaVax, a TRL4 agonist, induced high levels of neutralizing antibodies and generated a strong Th1-biased immune response. Vaccinated hamsters were protected from weight loss and viral replication in the lungs and nasal turbinates three days after challenge with SARS-CoV-2. CORAVAX also prevented lung disease, as indicated by the significant reduction in lung pathology. This study highlights CORAVAX as a safe, immunogenic, and efficacious vaccine that warrants further assessment in human trials. AUTHOR SUMMARY: We have developed an inactivated rabies virus vectored vaccine platform that has been used to develop a vaccine against SARS-CoV-2 (CORAVAX). CORAVAX induced high levels of neutralizing antibodies against SARS-CoV-2. Here we show that vaccinated hamsters, the best animal model for COVID-19, were protected against viral replication, indicating that this vaccine can stop transmission. CORAVAX also prevented lung disease. Rabies virus vaccines have been used in more than 100 million people worldwide, are safe and used in children and pregnant women. Therefore, it is anticipated that CORAVAX will generate robust immune responses against SARS-CoV-2 in humans that may also mimic the long-term protection seen in rabies vaccines

A single dose of replication-competent VSV-vectored vaccine expressing SARS-CoV-2 S1 protects against virus replication in a hamster model of severe COVID-19.

The development of effective countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal models of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine

Single-dose VSV-based vaccine protects cynomolgus macaques from disease after Taï Forest virus infection

ABSTRACTTaï Forest virus (TAFV) is a lesser-known ebolavirus that causes lethal infections in chimpanzees and is responsible for a single human case. Limited research has been done on this human pathogen; however, with the recent emergence of filoviruses in West Africa, further investigation and countermeasure development against this virus is warranted. We developed a vesicular stomatitis virus (VSV)-based vaccine expressing the TAFV glycoprotein as the viral antigen and assessed it for protective efficacy in nonhuman primates (NHPs). Following a single high-dose vaccination, NHPs developed antigen-specific binding and neutralizing antibodies as well as modest T cell responses. Importantly, all vaccinated NHPs were uniformly protected from disease after lethal TAFV challenge while the naïve control group succumbed to the disease. Histopathologic lesions consistent with filovirus disease were present in control NHPs but were not observed in vaccinated NHPs. Transcriptional analysis of whole blood samples obtained after vaccination and challenge was performed to gain insight into molecular underpinnings conferring protection. Differentially expressed genes (DEG) detected 7 days post-vaccination were enriched to processes associated with innate immunity and antiviral responses. Only a small number of DEG was detected in vaccinated NHPs post-challenge while over 1,000 DEG were detected in control NHPs at end-stage disease which mapped to gene ontology terms indicative of defense responses and inflammation. Taken together, this data demonstrates the effective single-dose protection of the VSV-TAFV vaccine, and its potential for use in outbreaks

3D model of PNGS of interest for 2G12 recognition.

<p>The three-dimensional model of SF162 gp120 monomer (light grey) shows the location of the four PNGS of interest (red spheres) and the N-glycans (blue spheres) important for 2G12 binding. The model was built by homology modeling using the SWISS- MODEL server (<u><a href="http://swissmodel.expasy.org/" target="_blank">http://swissmodel.expasy.org/</a></u>) based on the structure of the HIV-1 JRFL gp120 core protein complexed with CD4 and the X5 antibody (PDB code 2B4C) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075277#B27" target="_blank">27</a>]. The figure was generated with PyMOL Molecular Graphics System.</p

Early A141 variants are more sensitive to monoclonal antibodies than late variants.

<p>Serially diluted MAbs (b12, 2G12, 4E10 and 2F5) were tested for the neutralization of the pseudovirus of interest (d56 B3, d417 D15, d487 A6-1 and d670 A8-9) in a TZM-bl cell assay. The MAb concentration (µg/mL) required to reach 50% neutralization of each pseudovirus is reported as IC₅₀ (µg/mL). Data shown are mean +/- SD from three independent assays. Compared to d670 A8-9: *<i>P</i> < 0.005, **<i>P</i> < 0.0005, ^#<i>P</i> < 0.02, ^{# #}<i>P</i> < 0.003.</p

Specific PNGS affect heterologous neutralization.

<p>(<b>A</b>) Cartoon depicting PNGS profiles of A141 Env mutants. The mutants are indicated on the left and the corresponding PNG equivalent A141 clones are indicated on the right. Vertical bars indicate the presence of a PNGS at the amino acid positions (130, 139, 160 or 397) shown. (<b>B</b>) Serially diluted monoclonal antibodies (b12, 2G12, 4E10 and 2F5) were tested for the neutralization of the pseudovirus of interest [d56 B3, d417 D15, d487 A6-1 and d670 A8-9] or of the PNG mutant of interest [Δ(N130/397), Δ(N139/397) and Δ(N130/139/160/397)] in a TZM-bl cell assay. The MAb concentration (µg/mL) required to reach 50% neutralization of each pseudovirus is reported as IC₅₀ (µg/mL). Data shown are mean +/- SD from three independent assays. <i>P</i> < 0.02 compared to d670 A8-9. ^#<i>P</i> = 0.0003 compared to d487 A6-1. ^$<i>P</i> ≤ 0.0006 compared to d417 D15. ^¶<i>P</i> = 0.0042 compared to d56 B3.</p