SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease

SUMMARYRift Valley fever virus (RVFV) is a mosquito-transmitted bunyavirus (genusPhlebovirus) associated with severe disease in livestock and fatal encephalitis or haemorrhagic fever in a proportion of infected humans. Although live attenuated and inactivated vaccines have been used in livestock, and on a limited scale in humans, there is a need for improved anti-RVFV vaccines. Towards this goal, Sindbis virus replicon vectors expressing the RVFV Gn and Gc glycoproteins, as well as the non-structural nsM protein, were constructed and evaluated for their ability to induce protective immune responses against RVFV. These replicon vectors were shown to produce the RVFV glycoproteins to high levelsin vitroand to induce systemic anti-RVFV antibody responses in immunized mice, as determined by RVFV-specific ELISA, fluorescent antibody tests, and demonstration of a neutralizing antibody response. Replicon vaccination also provided 100% protection against lethal RVFV challenge by either the intraperitoneal or intranasal route. Furthermore, preliminary results indicate that the replicon vectors elicit RVFV-specific neutralizing antibody responses in vaccinated sheep. These results suggest that alphavirus-based replicon vectors can induce protective immunity against RVFV, and that this approach merits further investigation into its potential utility as a RVFV vaccine.

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Neutralizing antibody titres in SARS-CoV-2 infections

Nature Communications ◽

10.1038/s41467-020-20247-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eric H. Y. Lau ◽

Owen T. Y. Tsang ◽

David S. C. Hui ◽

Mike Y. W. Kwan ◽

Wai-hung Chan ◽

...

Keyword(s):

Severe Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Global Public Health ◽

Rt Pcr ◽

Asymptomatic Patients ◽

Antibody Titres ◽

Observational Cohort ◽

Public Health Challenge ◽

Asymptomatic Infections

AbstractThe SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT90) and 50% (PRNT50) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT50 titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT50 antibody titres to decrease by half (T1/2) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT90 and PRNT50 antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.

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Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates

10.1101/2021.08.11.456015 ◽

2021 ◽

Author(s):

Kizzmekia S. Corbett ◽

Matthew Gagne ◽

Danielle Wagner ◽

Sarah O'Connell ◽

Sandeep R. Narpala ◽

...

Keyword(s):

Nonhuman Primates ◽

Geometric Mean ◽

Severe Disease ◽

Neutralizing Antibody ◽

Fold Increase ◽

Primary Response ◽

Antibody Responses ◽

Lower Airway ◽

Memory Time ◽

High Level

Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 μg of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.β (heterologous), which encompasses the spike sequence of the B.1.351 (beta or β) variant. Reciprocal ID50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the β variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost β-specific reciprocal ID50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the β variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations.

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CoV-RBD121-NP Vaccine Candidate Protects against Symptomatic Disease Following SARS-CoV-2 Challenge in K18-hACE2 Mice and Induces Protective Responses That Prevent COVID-19-Associated Immunopathology

Vaccines ◽

10.3390/vaccines9111346 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1346

Author(s):

Jennifer K. DeMarco ◽

Joshua M. Royal ◽

William E. Severson ◽

Jon D. Gabbard ◽

Steve Hume ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibodies ◽

Potential Role ◽

Vaccine Candidate ◽

Severe Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Receptor Binding Domain ◽

Symptomatic Disease ◽

Human Igg1

We developed a SARS-CoV-2 vaccine candidate (CoV-RBD121-NP) comprised of a tobacco mosaic virus-like nanoparticle conjugated to the receptor-binding domain of the spike glycoprotein of SARS-CoV-2 fused to a human IgG1 Fc domain. CoV-RBD121-NP elicits strong antibody responses in C57BL/6 mice and is stable for up to 12 months at 2–8 or 22–28 °C. Here, we showed that this vaccine induces a strong neutralizing antibody response in K18-hACE2 mice. Furthermore, we demonstrated that immunization protects mice from virus-associated mortality and symptomatic disease. Our data indicated that a sufficient pre-existing pool of neutralizing antibodies is required to restrict SARS-CoV-2 replication upon exposure and prevent induction of inflammatory mediators associated with severe disease. Finally, we identified a potential role for CXCL5 as a protective cytokine in SARS-CoV-2 infection. Our results suggested that disruption of the CXCL5 and CXCL1/2 axis may be important early components of the inflammatory dysregulation that is characteristic of severe cases of COVID-19.

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Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters

10.1101/2021.09.30.462514 ◽

2021 ◽

Author(s):

Malika Aid ◽

Samuel Vidal ◽

Cesar Piedra-Mora ◽

Sarah Ducat ◽

Chi Chan ◽

...

Keyword(s):

Immune Responses ◽

Expression Profiles ◽

Severe Disease ◽

Gene Expression Profiles ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Type I ◽

Adaptive Immune ◽

Syrian Golden Hamsters ◽

The Impact

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates antiviral, myeloid, and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.

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Vaccines Elicit Highly Cross-Reactive Cellular Immunity to the SARS-CoV-2 Omicron Variant

10.1101/2022.01.02.22268634 ◽

2022 ◽

Author(s):

Jinyan Liu ◽

Abishek Chandrashekar ◽

Daniel Sellers ◽

Julia Barrett ◽

Michelle Lifton ◽

...

Keyword(s):

T Cell ◽

Cellular Immunity ◽

Severe Disease ◽

Substantial Reduction ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cd8 T Cell ◽

Antibody Responses ◽

Effector Memory ◽

Cell Responses

The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 Spike immunogen, resulting in increased breakthrough infections and reduced vaccine efficacy. Cellular immune responses, particularly CD8+ T cell responses, are likely critical for protection against severe SARS-CoV-2 disease. Here we show that cellular immunity induced by current SARS-CoV-2 vaccines is highly cross-reactive against the SARS-CoV-2 Omicron variant. Individuals who received Ad26.COV2.S or BNT162b2 vaccines demonstrated durable CD8+ and CD4+ T cell responses that showed extensive cross-reactivity against both the Delta and Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron-specific CD8+ T cell responses were 82-84% of WA1/2020-specific CD8+ T cell responses. These data suggest that current vaccines may provide considerable protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantial reduction of neutralizing antibody responses.

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Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19

10.1101/2020.07.29.20164285 ◽

2020 ◽

Author(s):

Xiangyu Chen ◽

Zhiwei Pan ◽

Shuai Yue ◽

Fei Yu ◽

Junsong Zhang ◽

...

Keyword(s):

Disease Severity ◽

Severe Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Positive Correlation ◽

Asymptomatic Patients ◽

Neutralizing Capacity

COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection. It is currently unknown as to the correlation between the magnitude of neutralizing antibody (NAb) responses and the disease severity in COVID-19 patients. In a cohort of 59 recovered patients with disease severity including severe, moderate, mild and asymptomatic, we observed the positive correlation between serum neutralizing capacity and disease severity, in particular, the highest NAb capacity in sera from the patients with severe disease, while a lack of ability of asymptomatic patients to mount competent NAbs. Furthermore, the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-to-moderate symptoms. These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity, highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.

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