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Marit J. van Gils

Other affiliations: VU University Amsterdam
Bio: Marit J. van Gils is an academic researcher from University of Amsterdam. The author has contributed to research in topics: Epitope & Neutralizing antibody. The author has an hindex of 23, co-authored 78 publications receiving 2871 citations. Previous affiliations of Marit J. van Gils include VU University Amsterdam.

Papers published on a yearly basis

Papers
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Journal ArticleDOI
07 Aug 2020-Science
TL;DR: It is shown that the patients had strong immune responses against the viral spike protein, a complex that binds to receptors on the host cell, and monoclonal antibodies isolated here are promising candidates for COVID-19 treatment and prevention.
Abstract: The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3, and VH1-24 gene usage. A subset of the antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.

1,070 citations

Journal ArticleDOI
05 Feb 2021-Nature
TL;DR: In this paper, the authors report chronic SARS-CoV-2 with reduced sensitivity to neutralizing antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days.
Abstract: SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

651 citations

Journal ArticleDOI
10 Jul 2015-Science
TL;DR: A major goal of HIV-1 vaccine development is to identify immunogens capable of inducing protective titers of broadly neutralizing antibodies (bNAbs) against circulating, neutralization-resistant (tier 2) viruses, and soluble, recombinant trimers based on the BG505 clade A and B41 clade B tier 2 viruses are engineered.
Abstract: INTRODUCTION A major goal of HIV-1 vaccine development is to identify immunogens capable of inducing protective titers of broadly neutralizing antibodies (bNAbs) against circulating, neutralization-resistant (tier 2) viruses. The envelope glycoprotein (Env) trimer on the virus surface is the only bNAb target and accordingly serves as the basis for recombinant protein immunogens intended to induce bNAbs. We have engineered soluble, recombinant trimers based on the BG505 clade A and B41 clade B tier 2 viruses. These proteolytically cleaved and stabilized trimers, designated BG505 and B41 SOSIP.664 gp140, display multiple bNAb epitopes and have antigenic properties that mimic viral Env. High-resolution structures of the BG505 trimers reinforce this perspective. In contrast, other trimer designs (uncleaved gp140) that lack the SOSIP modifications and are based on eliminating the intersubunit proteolytic cleavage site adopt non-native configurations. RATIONALE To determine the NAb response elicited by native-like trimers, we immunized rabbits and macaques with BG505 SOSIP.664 gp140 proteins, and rabbits with their B41 counterparts. For comparison with the BG505 trimers, we also tested gp120 monomers and uncleaved gp140 proteins of the same genotype. We characterized the resulting antibody responses by quantifying their ability to neutralize the autologous tier 2 viruses and multiple heterologous tier 1 (neutralization-sensitive) and tier 2 viruses. We mapped the BG505 NAb responses using various techniques, including a large panel of Env-pseudotyped virus mutants. RESULTS BG505 SOSIP.664 trimers consistently induced potent NAbs against the autologous tier 2 virus in rabbits and similar but weaker responses in macaques. Cross-reactive NAbs against the more sensitive tier 1 viruses were also induced in all the immunized animals, but heterologous neutralization of tier 2 viruses was seen only weakly and sporadically. The rabbit responses to B41 SOSIP.664 trimers were qualitatively similar to those seen in the BG505 trimer recipients. The autologous tier 2 NAb titers to both SOSIP.664 trimers were greater than any such responses previously observed using various uncleaved gp140 proteins, including the BG505 version used in this study. The rabbit tier 2 and tier 1 NAb responses to the BG505 SOSIP.664 trimers were uncorrelated. Mapping studies showed the tier 2 NAbs recognized conformational epitopes that differed between animals. In some cases, these NAbs targeted components of the glycan shield previously associated with bNAb epitopes. In contrast, the tier 1 NAbs targeted linear epitopes in the gp120 V3 region. CONCLUSIONS Although an autologous tier 2 NAb response is not sufficient for vaccine protection against HIV-1, it may be a necessary step in various strategies intended to induce bNAbs. Thus, our findings indicate that native-like trimers represent a promising starting point for the further development of recombinant Env immunogens intended to broaden the NAb response. The high-resolution structures of SOSIP.664 trimers allow improvements to be rationally designed. Relevant strategies include the further stabilization of trimer-associated bNAb epitopes while reducing the antigenicity of V3 and other non-neutralizing epitopes that may be distractive; immunizing with longitudinal series of SOSIP.664 trimers from infected individuals who generate bNAbs; using trimer cocktails (e.g., from clades A, B, and C); and priming with trimer variants that trigger desirable germline responses before boosting with wild-type trimers.

476 citations

Journal ArticleDOI
TL;DR: In this article, the authors studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.7 and B.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers.
Abstract: The emergence of SARS-CoV-2 variants harboring mutations in the spike (S) protein has raised concern about potential immune escape. Here, we studied humoral and cellular immune responses to wild type SARS-CoV-2 and the B.1.1.7 and B.1.351 variants of concern in a cohort of 121 BNT162b2 mRNA-vaccinated health care workers (HCW). Twenty-three HCW recovered from mild COVID-19 disease and exhibited a recall response with high levels of SARS-CoV-2-specific functional antibodies and virus-specific T cells after a single vaccination. Specific immune responses were also detected in seronegative HCW after one vaccination, but a second dose was required to reach high levels of functional antibodies and cellular immune responses in all individuals. Vaccination-induced antibodies cross-neutralized the variants B.1.1.7 and B.1.351, but the neutralizing capacity and Fc-mediated functionality against B.1.351 was consistently 2- to 4-fold lower than to the homologous virus. In addition, peripheral blood mononuclear cells were stimulated with peptide pools spanning the mutated S regions of B.1.1.7 and B.1.351 to detect cross-reactivity of SARS-CoV-2-specific T cells with variants. Importantly, we observed no differences in CD4+ T-cell activation in response to variant antigens, indicating that the B.1.1.7 and B.1.351 S proteins do not escape T-cell-mediated immunity elicited by the wild type S protein. In conclusion, this study shows that some variants can partially escape humoral immunity induced by SARS-CoV-2 infection or BNT162b2 vaccination, but S-specific CD4+ T-cell activation is not affected by the mutations in the B.1.1.7 and B.1.351 variants.

370 citations

Journal ArticleDOI
26 Feb 2021-Science
TL;DR: In this paper, the authors reported that afucosylated IgG (~6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens.
Abstract: IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (~6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses, but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high levels of afucosylated IgG antibodies against SARS-CoV-2, amplifying pro-inflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.

210 citations


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Journal ArticleDOI
25 Aug 2020-JAMA
TL;DR: This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19, the novel severe acute respiratory syndrome coronavirus 2 pandemic that has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease.
Abstract: Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

3,371 citations

Journal ArticleDOI
TL;DR: A review of the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure is presented in this article.
Abstract: Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been characterized by the emergence of mutations and so-called variants of concern that impact virus characteristics, including transmissibility and antigenicity. In this Review, members of the COVID-19 Genomics UK (COG-UK) Consortium and colleagues summarize mutations of the SARS-CoV-2 spike protein, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

2,047 citations

Journal ArticleDOI
09 Apr 2021-Science
TL;DR: Using a variety of statistical and dynamic modeling approaches, the authors estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants, and a fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases.
Abstract: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in September 2020 and is rapidly spreading toward fixation. Using a variety of statistical and dynamic modeling approaches, we estimate that this variant has a 43 to 90% (range of 95% credible intervals, 38 to 130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine rollout, COVID-19 hospitalizations and deaths across England in the first 6 months of 2021 were projected to exceed those in 2020. VOC 202012/01 has spread globally and exhibits a similar transmission increase (59 to 74%) in Denmark, Switzerland, and the United States.

1,935 citations

Journal ArticleDOI
TL;DR: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death, in an international, randomized, double-blind, placebo-controlled, phase 3 trial.
Abstract: Background The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-...

1,760 citations

Journal ArticleDOI
08 Mar 2021-Nature
TL;DR: In this paper, the authors show that B.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclanal antibody against the receptor-binding domain.
Abstract: The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

1,641 citations