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1.
Nat Commun ; 13(1): 2263, 2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1815533

ABSTRACT

The emerging threat represented by SARS-CoV-2 variants, demands the development of therapies for better clinical management of COVID-19. MAD0004J08 is a potent Fc-engineered monoclonal antibody (mAb) able to neutralize in vitro all current SARS-CoV-2 variants of concern (VoCs) including the omicron variant even if with significantly reduced potency. Here we evaluated data obtained from the first 30 days of a phase 1 clinical study (EudraCT N.: 2020-005469-15 and ClinicalTrials.gov Identifier: NCT04932850). The primary endpoint evaluated the percentage of severe adverse events. Secondary endpoints evaluated pharmacokinetic and serum neutralization titers. A single dose administration of MAD0004J08 via intramuscular (i.m.) route is safe and well tolerated, resulting in rapid serum distribution and sera neutralizing titers higher than COVID-19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralize major SARS-CoV-2 variants of concern (alpha, beta, gamma and delta). MAD0004J08 can be a major advancement in the prophylaxis and clinical management of COVID-19.


Subject(s)
Antibodies, Monoclonal , SARS-CoV-2 , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/blood , Antibodies, Viral , COVID-19 , Humans , Injections, Intramuscular , Neutralization Tests , SARS-CoV-2/immunology
2.
Sci Transl Med ; 14(638): eabn4342, 2022 Mar 30.
Article in English | MEDLINE | ID: covidwho-1769820

ABSTRACT

New technologies and unprecedented public investment have transformed vaccine development and allowed fast delivery of safe and efficacious COVID-19 vaccines, mitigating the impact of the pandemic on health and the economy. A quantum change in public investment for vaccine development and widespread vaccine distribution are necessary to achieve global pandemic preparedness.


Subject(s)
COVID-19 , Influenza Vaccines , Influenza, Human , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Influenza, Human/epidemiology , Pandemics/prevention & control
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330741

ABSTRACT

Despite the remarkable efficacy of COVID-19 vaccines, waning immunity, and the emergence of SARS-CoV-2 variants such as Omicron represents a major global health challenge. Here we present data from a study in non-human primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine, consisting of RBD (receptor binding domain) on the I53-50 nanoparticle, adjuvanted with AS03, currently in Phase 3 clinical trial ( NCT05007951 ). Vaccination induced robust neutralizing antibody (nAb) titers that were maintained at high levels for at least one year after two doses (Pseudovirus nAb GMT: 2207, Live-virus nAb GMT: 1964) against the ancestral strain, but not against Omicron. However, a booster dose at 6-12 months with RBD-Wu or RBD-B (RBD from the Beta variant) displayed on I53-50 elicited equivalent and remarkably high neutralizing titers against the ancestral as well as the Omicron variant. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Importantly, vaccination resulted in protection against Omicron infection in the lung (no detectable virus in any animal) and profound suppression of viral burden in the nares (median peak viral load of 7567 as opposed to 1.3x107 copies in unvaccinated animals) at 6 weeks post final booster. Even at 6 months post vaccination, there was significant protection in the lung (with 7 out of 11 animals showing no viral load, 3 out of 11 animals showing ~20-fold lower viral load than unvaccinated controls) and rapid control of virus in the nares. These results highlight the durable cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine platform.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-306995

ABSTRACT

The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines which are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.

5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328827

ABSTRACT

SARS-CoV-2 vaccines, administered to billions of people worldwide, are mitigating the effects of the COVID-19 pandemic, however little is known about the molecular basis of antibody cross-protection to emerging variants, such as Omicron (B.1.1.529), and other coronaviruses. To answer this question, 276 neutralizing monoclonal antibodies (nAbs), previously isolated from seronegative and seropositive donors vaccinated with BNT162b2 mRNA vaccine1, were tested for neutralization against the Omicron variant and SARS-CoV-1 virus. Cross-neutralizing antibodies were isolated from 100% of seropositive and 20% of seronegative vaccinees. Only 14.2% and 4.0% of tested antibodies neutralized the Omicron variant and SARS-CoV-1 respectively. These nAbs recognized mainly the SARS-CoV-2 receptor binding domain (RBD) and targeted class 3 and class 4 epitope regions on the SARS-CoV-2 spike protein. Antibodies targeting class 1/2 epitope regions only rarely showed cross-neutralization activity. Cross-protective antibodies derived from a variety of germlines, the most frequents of which were the IGHV1-58;IGHJ3-1 and IGHV1-69;IGHV4-1. Only 15.6% and 7.8% of predominant gene-derived nAbs elicited against the original Wuhan virus cross-neutralized Omicron and SARS-CoV-1 respectively. Our data provide evidence of the presence of cross-neutralizing antibodies induced by vaccination and map conserved epitopes on the S protein that can inform vaccine design.

6.
Pharmacol Rev ; 74(1): 313-339, 2022 01.
Article in English | MEDLINE | ID: covidwho-1662299

ABSTRACT

We have experienced an enormous cohesive effort of the scientific community to understand how the immune system reacts to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and how to elicit protective immunity via vaccination. This effort resulted in the development of vaccines in record time with high levels of safety, efficacy, and real-life effectiveness. However, the rapid diffusion of viral variants that escape protective antibodies prompted new studies to understand SARS-CoV-2 vulnerabilities and strategies to guide follow-up actions to increase, and maintain, the protection offered by vaccines. In this review, we report the main findings on human immunity to SARS-CoV-2 after natural infection and vaccination; we dissect the immunogenicity and efficacy of the different vaccination strategies that resulted in products widely used in the population; and we describe the impact of viral variants on vaccine-elicited immunity, summarizing the main discoveries and challenges to stay ahead of SARS-CoV-2 evolution. SIGNIFICANCE STATEMENT: This study reviewed findings on human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), analyzed the immunogenicity and efficacy of the various vaccines currently used in large vaccination campaigns or candidates in advanced clinical development, and discussed the challenging task to ensure high protective efficacy against the rapidly evolving SARS-CoV-2 virus. This manuscript was completed prior to the emergence of the Omicron variant and to global vaccine boosting efforts.


Subject(s)
COVID-19 , Viral Vaccines , Humans , SARS-CoV-2 , Technology
7.
Nat Immunol ; 23(2): 275-286, 2022 02.
Article in English | MEDLINE | ID: covidwho-1661973

ABSTRACT

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.


Subject(s)
COVID-19/immunology , Immunity, Humoral , Receptors, Pattern Recognition/immunology , SARS-CoV-2/immunology , Animals , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/metabolism , COVID-19/virology , Case-Control Studies , Chlorocebus aethiops , Complement Activation , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/immunology , Coronavirus Nucleocapsid Proteins/metabolism , Female , Glycosylation , HEK293 Cells , Host-Pathogen Interactions , Humans , Male , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Mannose-Binding Lectin/metabolism , Phosphoproteins/genetics , Phosphoproteins/immunology , Phosphoproteins/metabolism , Polymorphism, Genetic , Protein Binding , Receptors, Pattern Recognition/genetics , Receptors, Pattern Recognition/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serum Amyloid P-Component/immunology , Serum Amyloid P-Component/metabolism , Signal Transduction , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
8.
Ann N Y Acad Sci ; 1511(1): 59-86, 2022 May.
Article in English | MEDLINE | ID: covidwho-1625044

ABSTRACT

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.


Subject(s)
COVID-19 , Influenza Vaccines , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Global Health , Humans , Pandemics/prevention & control , Vaccines/therapeutic use
9.
Sci Transl Med ; 13(624): eabm3249, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1583225

ABSTRACT

The SARS-CoV-2 pandemic has generated a renaissance in vaccinology, with COVID-19 mRNA vaccines delivering a "digital code" of the viral antigen with no need to purify proteins or inactivate pathogens.


Subject(s)
COVID-19 , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Pandemics/prevention & control , SARS-CoV-2
10.
Methods Mol Biol ; 2410: 3-25, 2022.
Article in English | MEDLINE | ID: covidwho-1575758

ABSTRACT

The COVID-19 pandemic of 2020-2021 has highlighted the importance of vaccines and vaccination in human health. The pandemic has resulted in social distancing, travel restrictions, decreased trade, high unemployment, commodity price decline, and financial stress that has impacted the global economy. Since December 2020, a massive vaccination campaign is undergoing in every country on the planet to protect against SARS-CoV-2. Vaccination is the cheapest health-care interventions that can save more lives than any other drugs or therapies. Some of the common diseases of the twentieth century including smallpox and polio are seldom reported due to intense vaccination programs that eradicated it. Smallpox is completely eradicated globally; whereas, polio is confined to only a couple of countries. Vaccination has not only improved the health of man but also improved food security by preventing diseases in farm animals and aquacultured fish. Awareness of the principles of immunology and novel vaccines has led to effective vaccination strategies. Climate change could lead to generation of new strains of infectious microorganisms that would require development of novel vaccines. Recent years have seen the increase in incidence of brain-eating amoeba and flesh-eating bacteria (necrotizing fasciitis). There are no vaccines for these diseases. Though vaccination programs have eradicated several diseases and increased the quality of life, there are several diseases that have no effective vaccines. Currently there are no vaccines for cancer, neurodegenerative diseases, autoimmune diseases, as well as infectious diseases like tuberculosis, AIDS, and parasitic diseases including malaria. Spontaneous evolution of pathogenic microorganisms may lead to pandemics that impact the health of not only humanity but also other animals. Hence, the challenge to vaccinologists is the development of novel vaccines and vaccination strategies within limited time period and using minimum resources. In addition, the vaccine developed should be administered globally within a short duration so as to prevent generation of pathogenic variants more lethal than the parent strain.


Subject(s)
Vaccination , Vaccines , Animals , COVID-19 , Humans , Pandemics , Quality of Life
11.
Nature ; 600(7889): 530-535, 2021 12.
Article in English | MEDLINE | ID: covidwho-1475311

ABSTRACT

The emergence of SARS-CoV-2 variants is jeopardizing the effectiveness of current vaccines and limiting the application of monoclonal antibody-based therapy for COVID-19 (refs. 1,2). Here we analysed the memory B cells of five naive and five convalescent people vaccinated with the BNT162b2 mRNA vaccine to investigate the nature of the B cell and antibody response at the single-cell level. Almost 6,000 cells were sorted, over 3,000 cells produced monoclonal antibodies against the spike protein and more than 400 cells neutralized the original SARS-CoV-2 virus first identified in Wuhan, China. The B.1.351 (Beta) and B.1.1.248 (Gamma) variants escaped almost 70% of these antibodies, while a much smaller portion was impacted by the B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants. The overall loss of neutralization was always significantly higher in the antibodies from naive people. In part, this was due to the IGHV2-5;IGHJ4-1 germline, which was found only in people who were convalescent and generated potent and broadly neutralizing antibodies. Our data suggest that people who are seropositive following infection or primary vaccination will produce antibodies with increased potency and breadth and will be able to better control emerging SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/genetics , Antibodies, Viral/isolation & purification , /immunology , Broadly Neutralizing Antibodies/genetics , Broadly Neutralizing Antibodies/isolation & purification , Convalescence , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Female , Humans , Male , Neutralization Tests , Seroconversion , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
12.
Cell ; 184(21): 5432-5447.e16, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1454060

ABSTRACT

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

14.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1366850

ABSTRACT

To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.


Subject(s)
Amino Acid Substitution , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Neutralizing/chemistry , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/chemistry , Antibodies, Viral/genetics , Antibodies, Viral/pharmacology , Binding Sites , COVID-19/genetics , COVID-19/virology , Chlorocebus aethiops , Convalescence , Gene Expression , Humans , Immune Evasion , Immune Sera/chemistry , Models, Molecular , Mutation , Neutralization Tests , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vero Cells
16.
Nature ; 594(7862): 253-258, 2021 06.
Article in English | MEDLINE | ID: covidwho-1192479

ABSTRACT

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).


Subject(s)
Adjuvants, Immunologic , Antibodies, Neutralizing/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccines, Subunit/immunology , Alum Compounds , Animals , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , COVID-19/virology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Models, Animal , Immunity, Cellular , Immunity, Humoral , Macaca mulatta/immunology , Male , Oligodeoxyribonucleotides , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Squalene
17.
Semin Immunol ; 50: 101439, 2020 08.
Article in English | MEDLINE | ID: covidwho-958912
18.
J Exp Med ; 218(5)2021 05 03.
Article in English | MEDLINE | ID: covidwho-1114805

ABSTRACT

The neutralizing antibody response to SARS-CoV-2 is dominated by antibodies deriving from germlines IGHV3-53/IGHV3-66, which are also associated with self-reacting antibodies. Could vaccines avoid the expansion of this immunodominant response, decrease the risk of autoimmunity, and still protect against emerging SARS-CoV-2 variants?


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Germ Cells/immunology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , Antigens, Viral/immunology , COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions/genetics , Humans
19.
Cell ; 184(7): 1821-1835.e16, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1095899

ABSTRACT

Human monoclonal antibodies are safe, preventive, and therapeutic tools that can be rapidly developed to help restore the massive health and economic disruption caused by the coronavirus disease 2019 (COVID-19) pandemic. By single-cell sorting 4,277 SARS-CoV-2 spike protein-specific memory B cells from 14 COVID-19 survivors, 453 neutralizing antibodies were identified. The most potent neutralizing antibodies recognized the spike protein receptor-binding domain, followed in potency by antibodies that recognize the S1 domain, the spike protein trimer, and the S2 subunit. Only 1.4% of them neutralized the authentic virus with a potency of 1-10 ng/mL. The most potent monoclonal antibody, engineered to reduce the risk of antibody-dependent enhancement and prolong half-life, neutralized the authentic wild-type virus and emerging variants containing D614G, E484K, and N501Y substitutions. Prophylactic and therapeutic efficacy in the hamster model was observed at 0.25 and 4 mg/kg respectively in absence of Fc functions.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , Antibodies, Viral/administration & dosage , B-Lymphocytes/immunology , COVID-19 , Convalescence , 3T3 Cells , Animals , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , B-Lymphocytes/cytology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/therapy , Chlorocebus aethiops , Disease Models, Animal , Female , HEK293 Cells , Humans , Immunoglobulin Fc Fragments/immunology , Male , Mice , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
20.
Nature ; 590(7844): 36, 2021 02.
Article in English | MEDLINE | ID: covidwho-1083550
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