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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330115

ABSTRACT

Summary The spike protein of SARS-CoV-2 is a critical antigen present in all approved SARS-CoV-2 vaccines. This surface viral protein is also the target for all monoclonal antibody therapies, but it is unclear whether antibodies targeting other viral proteins can also improve protection against COVID-19. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice. On the next day, the recipient mice were challenged intranasally with SARS-CoV-2 to evaluate whether nucleocapsid-specific humoral responses affect viral control. Interestingly, mice that received nucleocapsid-specific sera exhibited enhanced control of a SARS-CoV-2 infection. These findings provide the first demonstration that humoral responses specific to an internal coronavirus protein can help clear infection, warranting the inclusion of other viral antigens in next-generation SARS-CoV-2 vaccines and providing a rationale for the clinical evaluation of nucleocapsid-specific monoclonals to treat COVID-19. Highlights A SARS-CoV-2 nucleocapsid vaccine elicits robust nucleocapsid-specific antibody responses. This nucleocapsid vaccine generates memory B cells (MBC). Nucleocapsid-specific humoral responses do not prevent SARS-CoV-2 infection. Nucleocapsid-specific humoral responses help control a SARS-CoV-2 infection.

2.
Adv Sci (Weinh) ; 9(2): e2103240, 2022 01.
Article in English | MEDLINE | ID: covidwho-1508603

ABSTRACT

The outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research, the current treatment options show limited curative efficacies. Here the authors report a strategy incorporating neutralizing antibodies conjugated to the surface of a photothermal nanoparticle (NP) to capture and inactivate SARS-CoV-2. The NP is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with high-affinity neutralizing antibodies. The multifunctional NP efficiently captures SARS-CoV-2 pseudovirions and completely blocks viral infection to host cells in vitro through the surface neutralizing antibodies. In addition to virus capture and blocking function, the NP also possesses photothermal function to generate heat following irradiation for inactivation of virus. Importantly, the NPs described herein significantly outperform neutralizing antibodies at treating authentic SARS-CoV-2 infection in vivo. This multifunctional NP provides a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus it is expected to provide a broad range of protection against original SARS-CoV-2 and its variants.


Subject(s)
Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , COVID-19/therapy , Immunoconjugates/administration & dosage , Nanoparticles , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/physiology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/immunology , Antigen-Antibody Reactions , COVID-19/immunology , COVID-19/virology , Drug Evaluation, Preclinical , Hot Temperature , Humans , Immunoconjugates/immunology , Immunoconjugates/therapeutic use , Light , Mice , Nanoparticles/therapeutic use , Phosphatidylethanolamines , Polyethylene Glycols , Polymers , Receptors, Virus/physiology , Semiconductors , Spike Glycoprotein, Coronavirus/immunology , Thiadiazoles , Virus Inactivation
3.
Sci Immunol ; 6(66): eabi8635, 2021 Dec 03.
Article in English | MEDLINE | ID: covidwho-1467663

ABSTRACT

SARS-CoV-2 has caused a global pandemic that has infected more than 250 million people worldwide. Although several vaccine candidates have received emergency use authorization, there is still limited knowledge on how vaccine dosing affects immune responses. We performed mechanistic studies in mice to understand how the priming dose of an adenovirus-based SARS-CoV-2 vaccine affects long-term immunity to SARS-CoV-2. We first primed C57BL/6 mice with an adenovirus serotype 5 vaccine encoding the SARS-CoV-2 spike protein, similar to that used in the CanSino and Sputnik V vaccines. The vaccine prime was administered at either a standard dose or 1000-fold lower dose, followed by a boost with the standard dose 4 weeks later. Initially, the low dose prime induced lower immune responses relative to the standard dose prime. However, the low dose prime elicited immune responses that were qualitatively superior and, upon boosting, exhibited substantially more potent recall and functional capacity. We also report similar effects with a simian immunodeficiency virus (SIV) vaccine. These findings show an unexpected advantage of fractionating vaccine prime doses, warranting a reevaluation of vaccine trial protocols for SARS-CoV-2 and other pathogens.


Subject(s)
COVID-19 Vaccines/immunology , Immunogenicity, Vaccine , Adenoviridae/genetics , Adenoviridae/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , COVID-19 Vaccines/chemistry , Dose-Response Relationship, Immunologic , Female , Genetic Vectors , Male , Mice , Mice, Inbred C57BL
4.
J Clin Invest ; 131(24)2021 12 15.
Article in English | MEDLINE | ID: covidwho-1463085

ABSTRACT

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Animals , CD8-Positive T-Lymphocytes/cytology , Cross Reactions , Epitope Mapping , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , SARS-CoV-2 , Vaccination
5.
Cell Rep ; 36(10): 109664, 2021 09 07.
Article in English | MEDLINE | ID: covidwho-1375910

ABSTRACT

SARS-CoV-2 infection causes respiratory insufficiency and neurological manifestations, including loss of smell and psychiatric disorders, and can be fatal. Most vaccines are based on the spike antigen alone, and although they have shown efficacy at preventing severe disease and death, they do not always confer sterilizing immunity. Here, we interrogate whether SARS-CoV-2 vaccines could be improved by incorporating nucleocapsid as an antigen. We show that, after 72 h of challenge, a spike-based vaccine confers acute protection in the lung, but not in the brain. However, combining a spike-based vaccine with a nucleocapsid-based vaccine confers acute protection in both the lung and brain. These findings suggest that nucleocapsid-specific immunity can improve the distal control of SARS-CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines.


Subject(s)
COVID-19 Vaccines/immunology , Coronavirus Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Brain/drug effects , Brain/virology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Humans , Immunogenicity, Vaccine , Lung/drug effects , Lung/virology , Mice , Phosphoproteins/immunology , Viral Load/drug effects
6.
Matter ; 4(6): 2059-2082, 2021 Jun 02.
Article in English | MEDLINE | ID: covidwho-1198960

ABSTRACT

SARS-CoV-2 enters host cells through its viral spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors on the host cells. Here, we show that functionalized nanoparticles, termed "Nanotraps," completely inhibited SARS-CoV-2 infection by blocking the interaction between the spike protein of SARS-CoV-2 and the ACE2 of host cells. The liposomal-based Nanotrap surfaces were functionalized with either recombinant ACE2 proteins or anti-SARS-CoV-2 neutralizing antibodies and phagocytosis-specific phosphatidylserines. The Nanotraps effectively captured SARS-CoV-2 and completely blocked SARS-CoV-2 infection to ACE2-expressing human cell lines and primary lung cells; the phosphatidylserine triggered subsequent phagocytosis of the virus-bound, biodegradable Nanotraps by macrophages, leading to the clearance of pseudotyped and authentic virus in vitro. Furthermore, the Nanotraps demonstrated an excellent biosafety profile in vitro and in vivo. Finally, the Nanotraps inhibited pseudotyped SARS-CoV-2 infection in live human lungs in an ex vivo lung perfusion system. In summary, Nanotraps represent a new nanomedicine for the inhibition of SARS-CoV-2 infection.

7.
bioRxiv ; 2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-955698

ABSTRACT

The outbreak of 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic. Despite intensive research including several clinical trials, currently there are no completely safe or effective therapeutics to cure the disease. Here we report a strategy incorporating neutralizing antibodies conjugated on the surface of a photothermal nanoparticle to actively capture and inactivate SARS-CoV-2. The photothermal nanoparticle is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with neutralizing antibodies. Such nanoparticles displayed efficient capture of SARS-CoV-2 pseudoviruses, excellent photothermal effect, and complete inhibition of viral entry into ACE2-expressing host cells via simultaneous blocking and inactivating of the virus. This photothermal nanoparticle is a flexible platform that can be readily adapted to other SARS-CoV-2 antibodies and extended to novel therapeutic proteins, thus providing a broad range of protection against multiple strains of SARS-CoV-2.

8.
J Exp Med ; 217(12)2020 12 07.
Article in English | MEDLINE | ID: covidwho-726090

ABSTRACT

Type I interferons (IFN-I) are a major antiviral defense and are critical for the activation of the adaptive immune system. However, early viral clearance by IFN-I could limit antigen availability, which could in turn impinge upon the priming of the adaptive immune system. In this study, we hypothesized that transient IFN-I blockade could increase antigen presentation after acute viral infection. To test this hypothesis, we infected mice with viruses coadministered with a single dose of IFN-I receptor-blocking antibody to induce a short-term blockade of the IFN-I pathway. This resulted in a transient "spike" in antigen levels, followed by rapid antigen clearance. Interestingly, short-term IFN-I blockade after coronavirus, flavivirus, rhabdovirus, or arenavirus infection induced a long-lasting enhancement of immunological memory that conferred improved protection upon subsequent reinfections. Short-term IFN-I blockade also improved the efficacy of viral vaccines. These findings demonstrate a novel mechanism by which IFN-I regulate immunological memory and provide insights for rational vaccine design.


Subject(s)
Immunogenicity, Vaccine/immunology , Interferon Type I/antagonists & inhibitors , Interferon-alpha/immunology , Receptor, Interferon alpha-beta/immunology , Viral Vaccines/immunology , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Blocking/immunology , Antibodies, Blocking/pharmacology , Antibodies, Viral/immunology , Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/immunology , Disease Models, Animal , Gene Expression/immunology , HEK293 Cells , Humans , Immunologic Memory , Interferon-alpha/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptor, Interferon alpha-beta/genetics , Transfection , Zika Virus Infection/virology
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