SARS-CoV2 variant-specific replicating RNA vaccines protect from disease and pathology and reduce viral shedding following challenge with heterologous SARS-CoV2 variants of concern

Despite mass public health efforts, the SARS-CoV2 pandemic continues as of late-2021 with resurgent case numbers in many parts of the world. The emergence of SARS-CoV2 variants of concern (VoC) and evidence that existing vaccines that were designed to protect from the original strains of SARS-CoV-2 may have reduced potency for protection from infection against these VoC is driving continued development of second generation vaccines that can protect against multiple VoC. In this report, we evaluated an alphavirus-based replicating RNA vaccine expressing Spike proteins from the original SARS-CoV-2 Alpha strain and recent VoCs delivered in vivo via a lipid inorganic nanoparticle. Vaccination of both mice and Syrian Golden hamsters showed that vaccination induced potent neutralizing titers against each homologous VoC but reduced neutralization against heterologous challenges. Vaccinated hamsters challenged with homologous SARS-CoV2 variants exhibited complete protection from infection. In addition, vaccinated hamsters challenged with heterologous SARS-CoV-2 variants exhibited significantly reduced shedding of infectious virus. Our data demonstrate that this vaccine platform elicits significant protective immunity against SARS-CoV2 variants and supports continued development of this platform.

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A Mini Review of the Covid-19, Vaccine Platform and Future Preparedness

International Journal of Scientific Research in Science and Technology ◽

10.32628/ijsrst1218420 ◽

2021 ◽

pp. 224-229

Author(s):

Md Ather Hussain Ansari ◽

Md Sadique Hussain ◽

Mohit

Keyword(s):

Protective Immunity ◽

Potential Role ◽

Recombinant Vaccines ◽

Passive Surveillance ◽

Vaccine Platform ◽

Search Terms ◽

The World ◽

Production And Distribution ◽

World Records

Many countries are engaged in making vaccine against COVID-19 as the world records more than 38 million SARS-CoV-2 infections and more than one million deaths. It has prompted nations to close the borders, halted companies, kept people inside their homes, and numerous other measures to prevent their spread. We systematically searched on Google scholar, PubMed, LitCovid, and MedRxiv using the certain search terms for published articles. The infection raging through communities is expected to have evoked some degree of immunity in many asymptomatic and recovered individuals. However, the level of protective immunity and duration of such immunity have not been studied in depth. At the same time, spanning from the conventional whole virus vaccine to recombinant vaccines using Adenovirus vectors and first-of-its kind mRNA vaccines are in human trials. Before the effectiveness and safety of such vaccines are established billions of doses have been produced and stockpiled to save time in production and distribution. Antigenic diversity and the potential role of passive surveillance in COVID-19 regulation are explored in this report.

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Multivalent nanoparticle-based vaccines protect hamsters against SARS-CoV-2 after a single immunization

Communications Biology ◽

10.1038/s42003-021-02128-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Shiho Chiba ◽

Steven J. Frey ◽

Peter J. Halfmann ◽

Makoto Kuroda ◽

Tadashi Maemura ◽

...

Keyword(s):

Coat Protein ◽

Infectious Virus ◽

Neutralizing Antibody ◽

Vaccine Platform ◽

Death Rates ◽

Widespread Distribution ◽

Syrian Hamsters ◽

Vaccine Trials ◽

Multiple Copies ◽

Antibody Titers

AbstractThe COVID-19 pandemic continues to wreak havoc as worldwide SARS-CoV-2 infection, hospitalization, and death rates climb unabated. Effective vaccines remain the most promising approach to counter SARS-CoV-2. Yet, while promising results are emerging from COVID-19 vaccine trials, the need for multiple doses and the challenges associated with the widespread distribution and administration of vaccines remain concerns. Here, we engineered the coat protein of the MS2 bacteriophage and generated nanoparticles displaying multiple copies of the SARS-CoV-2 spike (S) protein. The use of these nanoparticles as vaccines generated high neutralizing antibody titers and protected Syrian hamsters from a challenge with SARS-CoV-2 after a single immunization with no infectious virus detected in the lungs. This nanoparticle-based vaccine platform thus provides protection after a single immunization and may be broadly applicable for protecting against SARS-CoV-2 and future pathogens with pandemic potential.

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Borrelia burgdorferi P35 and P37 Proteins, Expressed In Vivo, Elicit Protective Immunity

Immunity ◽

10.1016/s1074-7613(00)80341-6 ◽

1997 ◽

Vol 6 (5) ◽

pp. 531-539 ◽

Cited By ~ 95

Author(s):

Erol Fikrig ◽

Stephen W Barthold ◽

Wei Sun ◽

Wen Feng ◽

Sam R Telford ◽

...

Keyword(s):

Borrelia Burgdorferi ◽

Protective Immunity

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MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

mBio ◽

10.1128/mbio.00665-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 55

Author(s):

Vineet D. Menachery ◽

Hugh D. Mitchell ◽

Adam S. Cockrell ◽

Lisa E. Gralinski ◽

Boyd L. Yount ◽

...

Keyword(s):

Public Health ◽

Viral Replication ◽

Rapid Response ◽

Mutant Virus ◽

Global Public Health ◽

Vaccine Platform ◽

Zoonotic Pathogens ◽

Related Group

ABSTRACT While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants. IMPORTANCE The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.

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Evaluation of Protection Afforded by Brucella abortus and Brucella melitensis Unmarked Deletion Mutants Exhibiting Different Rates of Clearance in BALB/c Mice

Infection and Immunity ◽

10.1128/iai.01787-05 ◽

2006 ◽

Vol 74 (7) ◽

pp. 4048-4057 ◽

Cited By ~ 59

Author(s):

M. M. Kahl-McDonagh ◽

T. A. Ficht

Keyword(s):

Mouse Model ◽

Brucella Abortus ◽

Protective Immunity ◽

Brucella Melitensis ◽

Deletion Mutants ◽

Heterologous Challenge ◽

Current Vaccine ◽

Protection Against Infection ◽

Ideal Vaccine

ABSTRACT Research for novel Brucella vaccines has focused upon the development of live vaccine strains, which have proven more efficacious than killed or subunit vaccines. In an effort to develop improved vaccines, signature-tagged mutant banks were screened to identify mutants attenuated for survival. Mutants selected from these screens exhibited various degrees of attenuation characterized by the rate of clearance, ranging from a failure to grow in macrophages after 24 h of infection to a failure to persist in the mouse model beyond 8 weeks. Ideal vaccine candidates should be safe to the host, while evoking protective immunity. In the present work, we constructed unmarked deletion mutants of three gene candidates, manBA, virB2, and asp24, in both Brucella abortus and Brucella melitensis. The Δasp24 mutants, which persist for extended periods in vivo, are superior to current vaccine strains and to other deletion strains tested in the mouse model against homologous challenge infection after 12, 16, and 20 weeks postvaccination. The Δasp24 mutants also display superior protection compared to ΔmanBA and ΔvirB2 mutants against heterologous challenge in mice. From this study, a direct association between protection against infection and cytokine response was not apparent between all vaccine groups and, therefore, correlates of protective immunity will need to be considered further. A distinct correlation between persistence of the vaccine strain and protection against infection was corroborated.

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Foodborne Transmission of Sars-Cov-2 Is More Evident Than It Has Been Before

10.20944/preprints202009.0361.v1 ◽

2020 ◽

Author(s):

Hamada Aboubakr ◽

Sagar Goyal

Keyword(s):

Infectious Virus ◽

Hepatitis A Virus ◽

Disease Outbreaks ◽

Foodborne Viruses ◽

Frozen Food ◽

Oral Transmission ◽

Viral Spread ◽

Food Packages ◽

Route Of Transmission ◽

The World

Background:Although highly strict social distancing and viral spread protection guidelines are in force, the reported numbers of COVID-19 cases across the world are still increasing. This indicates that we are still unable to completely understand the transmission routes of SARS-CoV-2. One of the possible routes that can play a significant role is the fecal-oral transmission since SARS-CoV-2 can replicate in the intestines as demonstrated by isolation of infectious virus from fecal samples of COVID-19 cases. Scope and approach:In this review, we compare the characteristics of SARS-CoV-2 with the distinctive characteristics of enteric foodborne viruses. We also discuss and respond to the arguments given in some reports that downplay the importance of foodborne transmission route of SARS-CoV-2. Key findings and conclusions:Enteric viruses such as human noroviruses (HuNoVs) and hepatitis A virus (HAV) are known to transmit through foods such as fresh produce and berries, leading to frequent multistate foodborne disease outbreaks all over the world. SARS-CoV-2 was found to share four distinctive characteristics of foodborne viruses that allow them to transmit through foods. This similarity in characteristics, recent report of detecting SARS-CoV-2 particles from frozen food packages in China, and recent suspected foodborne COVID-19 case in New Zealand, indicate that foodborne transmission of SARS-CoV-2 is more evident than previously thought possible. To support or deny this route of transmission, urgent research needs to be undertaken to answer two primary questions and many secondary ones as described in this review.

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Lentiviral and AAV-mediated Expression of Palivizumab Offer protection against Respiratory Syncytial Virus infection

10.21203/rs.3.rs-558941/v1 ◽

2021 ◽

Author(s):

Agata Antepowicz ◽

Omar Habib ◽

Freja Kirsebom ◽

Cecilia Johansson ◽

Deborah R. Gill ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Vulnerable Populations ◽

The Elderly ◽

Complete Protection ◽

Adeno Associated Virus ◽

Common Cause ◽

Immunodeficiency Virus ◽

Rsv Infection ◽

Syncytial Virus

Abstract Respiratory syncytial virus (RSV) infection is a common cause of hospitalisation in infants and the elderly. Palivizumab prophylaxis is the only approved treatment modality but is costly and only offered to select vulnerable populations. Here, we investigated gene delivery approaches via recombinant adeno-associated virus (rAAV2/8) and simian immunodeficiency virus (rSIV.F/HN) vectors to achieve sustained in vivo production of palivizumab in a murine model. Delivery of palivizumab-expressing vectors 28 days prior to RSV challenge resulted in complete protection from RSV-induced weight loss. This approach offers prophylaxis against RSV infection, allowing for wider use and reduction in treatment costs in vulnerable populations.

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Novel Antiviral Activities of Obatoclax, Emetine, Niclosamide, Brequinar, and Homoharringtonine

10.20944/preprints201909.0128.v1 ◽

2019 ◽

Author(s):

Petter I. Andersen ◽

Klara Krpina ◽

Aleksandr Ianevski ◽

Nastassia Shtaida ◽

Eunji Jo ◽

...

Keyword(s):

Influenza A ◽

Rift Valley Fever Virus ◽

Antiviral Agents ◽

Viral Disease ◽

World Health ◽

Valley Fever ◽

The World ◽

Health Organization ◽

Hiv 1

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Re-purposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), human immunodeficiency virus 1 (HIV-1), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FluAV), niclosamide against HSV-2, brequinar against HIV-1, and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vivo tests.

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Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

Journal of Molecular Medicine ◽

10.1007/s00109-021-02137-4 ◽

2021 ◽

Author(s):

Filiz Dermicik ◽

Susanna Lopez Kostka ◽

Stefan Tenzer ◽

Ari Waisman ◽

Esther Von Stebut

Keyword(s):

Dendritic Cells ◽

B Cell ◽

Protective Immunity ◽

Normal Mouse ◽

Leishmania Major ◽

Mouse Serum ◽

List Type ◽

Susceptibility To Infection ◽

Large Numbers

Abstract In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that “natural” cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM.

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Combination of a Sindbis-SARS-CoV-2 spike vaccine and αOX40 antibody elicits protective immunity against SARS-CoV-2 induced disease and potentiates long-term SARS-CoV-2-specific humoral and T-cell immunity

10.1101/2021.05.28.446009 ◽

2021 ◽

Author(s):

Antonella Scaglione ◽

Silvana Opp ◽

Alicia Hurtado ◽

Christine Pampeno ◽

Ziyan Lin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protective Immunity ◽

T Cell Response ◽

Spike Protein ◽

Effector Memory ◽

World Population ◽

Vaccine Platform ◽

Vaccine Approach

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world population at record speeds. However, there is still demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (OX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T cell response in mice. Protein binding, immunohistochemical and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response that can be used as a new candidate to combat SARS-CoV-2. Given the strong T cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as, serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.

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