564. SARS-CoV-2 Ferritin Nanoparticle Vaccines Elicit Broad SARS Coronavirus Immunogenicity

Abstract Background The zoonotic emergence of SARS-CoV-2 quickly developed into a global pandemic. Multiple vaccine platforms have been advanced to clinical trials and emergency use authorization. The recent emergence of SARS-CoV-2 virus variants with Spike receptor-binding domain (RBD) and N-terminal domain (NTD) mutations, highlights the need for next-generation vaccines that can elicit immune responses that are resilient against Spike mutations. Methods Using a structure-based vaccine design approach, we developed multiple optimized SARS-CoV-2 nanoparticle immunogens that recapitulate the structural and antigenic profile of the SARS-CoV-2 prefusion spike. We assessed these immunogens in murine immunogenicity studies and in a K18-hACE2 transgenic mouse model with a SARS-CoV-2 challenge. Immune sera from vaccinated mice were assessed for SARS-CoV-2 binding, and neutralization against SARS-CoV-2, variants of concern, and the heterologous SARS-CoV-1 virus. Results In combination with a liposomal-saponin based adjuvant (ALFQ), these immunogens induced robust binding, ACE2-inhibition, and authentic virus and pseudovirus neutralization. A Spike-Ferritin nanoparticle (SpFN) vaccine elicited neutralizing ID50 titers >10,000 after a single immunization, while RBD-Ferritin (RFN) nanoparticle immunogens elicited ID50 titer values >10,000 values after two immunizations. Purified antibody from SpFN- or RFN-immunized mice was transfused into K18-ACE2 transgenic mice and challenged with a high-dose SARS-CoV-2 virus stock. In order to understand the breadth of vaccine-elicited antibody responses, we analyzed SpFN- and RBD-FN-immunized animal sera against a set of heterologous SARS-CoV-2 RBD variants and SARS-CoV RBD. High binding titers with ACE2-blocking activity were observed against SARS-CoV-2 variants and the heterologous SARS-CoV-1 RBD. Furthermore, both SpFN- and RFN-immunized animal sera showed SARS-CoV-1 neutralizing ID50 titers of >2000. Conclusion These observations highlight the importance of SARS-CoV-2 neutralizing antibody levels in providing protection against emerging SARS-like coronaviruses and provide a robust platform for pandemic preparedness. Structure-based design enables development of a SARS-CoV-2 nanoparticle immunogen. Disclosures All Authors: No reported disclosures

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Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant

10.1101/2021.05.09.443299 ◽

2021 ◽

Author(s):

Venkata-Viswanadh Edara ◽

Lilin Lai ◽

Malaya Sahoo ◽

Katharine Floyd ◽

Mamdouh Sibai ◽

...

Keyword(s):

Protective Immunity ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Live Virus ◽

Global Pandemic ◽

Virus Assay ◽

Recent Emergence ◽

The World ◽

Antibody Resistance ◽

Second Wave

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.

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Choosing the right tool for the job: A comprehensive assessment of serological assays for SARS-CoV-2 as surrogates for authentic virus neutralization

10.1101/2021.04.14.21255399 ◽

2021 ◽

Author(s):

Nicholas Wohlgemuth ◽

Kendall Whitt ◽

Sean Cherry ◽

Ericka Kirkpatrick Roubidoux ◽

Chun-Yang Lin ◽

...

Keyword(s):

Neutralizing Antibody ◽

Virus Neutralization ◽

Diagnostic Tools ◽

Pseudotyped Virus ◽

Global Pandemic ◽

Level 3 ◽

The Right ◽

Antibody Levels ◽

Reliable Methods ◽

Biosafety Level

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and has since caused a global pandemic resulting in millions of cases and deaths. Diagnostic tools and serological assays are critical for controlling the outbreak, especially assays designed to quantitate neutralizing antibody levels, considered the best correlate of protection. As vaccines become increasingly available, it is important to identify reliable methods for measuring neutralizing antibody responses that correlate with authentic virus neutralization but can be performed outside of biosafety level 3 (BSL3) laboratories. While many neutralizing assays using pseudotyped virus have been developed, there have been few studies comparing the different assays to each other as surrogates for authentic virus neutralization. Here we characterized three enzyme-linked immunosorbent assays (ELISAs) and three pseudotyped VSV virus neutralization assays and assessed their concordance with authentic virus neutralization. The most accurate assays for predicting authentic virus neutralization were luciferase and secreted embryonic alkaline phosphatase (SEAP) expressing pseudotyped virus neutralizations, followed by GFP expressing pseudotyped virus neutralization, and then the ELISAs.

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Longitudinal dynamics of the neutralizing antibody response to SARS-CoV-2 infection

10.1101/2020.07.14.20151159 ◽

2020 ◽

Cited By ~ 5

Author(s):

Kai Wang ◽

Quan-Xin Long ◽

Hai-Jun Deng ◽

Jie Hu ◽

Qing-Zhu Gao ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Symptom Onset ◽

Neutralizing Antibodies ◽

Antiviral Agents ◽

Neutralizing Antibody ◽

Peak Time ◽

Igg Antibody ◽

Longitudinal Dynamics ◽

Global Pandemic ◽

Antibody Levels

Background Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of SARS-CoV-2-specific neutralizing antibodies (NAbs) in COVID-19 patients. Methods Blood samples (n=173) were collected from 30 COVID-19 patients over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs, using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. Results SARS-CoV-2-specific NAb titers were low for the first 7-10 d after symtom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 d (IQR 24-59 d) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR 19.6-42.4%). NAb titers increased over time in parallel with the rise in IgG antibody levels, correlating well at week 3 (r = 0.41, p < 0.05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including SCF, TRAIL, and M-CSF. Conclusions These data provide useful information regarding dynamic changes in NAbs in COVID-19 patients during the acute and convalescent phases.

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Immune responses of mice to inactivated rabies vaccine administered orally: potentiation by Quillaja saponin

Canadian Journal of Microbiology ◽

10.1139/m86-078 ◽

1986 ◽

Vol 32 (5) ◽

pp. 414-420 ◽

Cited By ~ 46

Author(s):

I. Maharaj ◽

K. J. Froh ◽

J. B. Campbell

Keyword(s):

Immune Responses ◽

Oral Vaccine ◽

Neutralizing Antibody ◽

Rabies Vaccine ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Antibody Titres ◽

The Many ◽

Antibody Levels ◽

Quillaja Saponin

Administered orally, Quillaja saponin markedly potentiated the humoral immune responses of mice fed inactivated rabies vaccine, and significantly increased their resistance to subsequent intracerebral challenge with live rabies virus. Although mean serum neutralizing antibody titres were generally 8- to 16-fold higher when vaccine was given intraperitoneally, orally administered vaccine, with saponin, stimulated production of high protective antibody levels that were maintained for at least 6 months. The potentiating effect of saponin appeared to be mediated through several mechanisms, one of which was by increasing the permeability of the intestinal mucosa, allowing increased uptake of viral antigen. The potentiating effect was enhanced when saponin was administered in advance (up to at least 16 h) of the oral vaccine. Mice tolerated the effective saponin doses without any visible signs of distress or injury. In view of the many favourable physiological activities and low toxicity of orally delivered saponins, it is suggested that they may find more general applications in the immunopotentiation of oral vaccines.

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Are COVID-19 Vaccine Boosters Needed? The Science behind Boosters

Journal of Virology ◽

10.1128/jvi.01973-21 ◽

2021 ◽

Author(s):

Rachel M. Burckhardt ◽

John J. Dennehy ◽

Leo L. M. Poon ◽

Linda J. Saif ◽

Lynn W. Enquist

Keyword(s):

Herd Immunity ◽

Neutralizing Antibody ◽

Global Pandemic ◽

Vaccine Booster ◽

Vaccine Distribution ◽

Antibody Levels ◽

Induced Immunity

Waning vaccine-induced immunity coupled with the emergence of SARS-CoV-2 variants has led to increases in breakthrough infections, prompting consideration for vaccine booster doses. Boosters have been reported to be safe and increase SARS-CoV-2-specific neutralizing antibody levels, but how these doses impact the trajectory of the global pandemic and herd immunity is unknown. Information on immunology, epidemiology and equitable vaccine distribution should be considered when deciding the timing and eligibility for COVID-19 vaccine boosters.

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Transcutaneous Immunization with Cross-Reacting Material CRM197 of Diphtheria Toxin Boosts Functional Antibody Levels in Mice Primed Parenterally with Adsorbed Diphtheria Toxoid Vaccine

Infection and Immunity ◽

10.1128/iai.00797-07 ◽

2008 ◽

Vol 76 (4) ◽

pp. 1766-1773 ◽

Cited By ~ 12

Author(s):

Paul Stickings ◽

Marisa Peyre ◽

Laura Coombes ◽

Sylviane Muller ◽

Rino Rappuoli ◽

...

Keyword(s):

Immune Responses ◽

Diphtheria Toxin ◽

Neutralizing Antibodies ◽

Time Course ◽

Herd Immunity ◽

Neutralizing Antibody ◽

Diphtheria Toxoid ◽

Booster Immunization ◽

Transcutaneous Immunization ◽

Antibody Levels

ABSTRACT Transcutaneous immunization (TCI) capitalizes on the accessibility and immunocompetence of the skin, elicits protective immunity, simplifies vaccine delivery, and may be particularly advantageous when frequent boosting is required. In this study we examined the potential of TCI to boost preexisting immune responses to diphtheria in mice. The cross-reacting material (CRM197) of diphtheria toxin was used as the boosting antigen and was administered alone or together with either one of two commonly used mucosal adjuvants, cholera toxin (CT) and a partially detoxified mutant of heat-labile enterotoxin of Escherichia coli (LTR72). We report that TCI with CRM197 significantly boosted preexisting immune responses elicited after parenteral priming with aluminum hydroxide-adsorbed diphtheria toxoid (DTxd) vaccine. In the presence of LTR72 as an adjuvant, toxin-neutralizing antibody titers were significantly higher than those elicited by CRM197 alone and were comparable to the functional antibody levels induced after parenteral booster immunization with the adsorbed DTxd vaccine. Time course study showed that high levels of toxin-neutralizing antibodies persisted for at least 14 weeks after the transcutaneous boost. In addition, TCI resulted in a vigorous antigen-specific proliferative response in all groups of mice boosted with the CRM197 protein. These findings highlight the promising prospect of using booster administrations of CRM197 via the transcutaneous route to establish good herd immunity against diphtheria.

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Long-term course of humoral and cellular immune responses in outpatients after SARS-CoV-2 infection

10.1101/2021.06.24.21259218 ◽

2021 ◽

Author(s):

Julia Schiffner ◽

Insa Backhaus ◽

Jens Rimmele ◽

Soeren Schulz ◽

Till Moehlenkamp ◽

...

Keyword(s):

Immune Responses ◽

Peripheral Blood ◽

Natural Infection ◽

Neutralizing Antibody ◽

Igg Antibodies ◽

Igg Antibody ◽

Antibody Titres ◽

Ifn Γ ◽

Antibody Levels ◽

Prospective Longitudinal

Characterisation of the naturally acquired B and T cell immune responses to SARS-CoV-2 is important for the development of public health and vaccination strategies to manage the burden of COVID-19 disease. We conducted a prospective, longitudinal analysis in COVID-19 recovered patients at various time points over a 10-month period in order to determine how circulating antibody levels and interferon-gamma (IFN-γ) release by peripheral blood cells change over time following natural infection. From March 2020 till January 2021, we enrolled 412 adults mostly with mild or moderate disease course. At each study visit, subjects donated peripheral blood for testing of anti-SARS-CoV-2 IgG antibodies and IFN-γ release after SARS-CoV-2 S-protein stimulation. Anti-SARS-CoV-2 IgG antibodies were identified in 316/412 (76.7%) of the patients and 215/412 (52.2%) had positive neutralizing antibody levels. Likewise, in 274/412 (66.5 %) positive IFN-γ release and IgG antibodies were detected. With respect to time after infection, both IgG antibody levels and IFN-γ concentrations decreased by about half within three hundred days. Statistically, IgG and IFN-γ production were closely associated, but on an individual basis we observed patients with high antibody titres but low IFN-γ levels and vice versa. Our data suggest that immunological reaction is acquired in most individuals after infection with SARS-CoV-2 and is sustained in the majority of patients for at least 10 months after infection. Since no robust marker for protection against COVID-19 exists so far, we recommend utilizing both, IgG and IFN-γ release for an individual assessment of immunity status.

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Intersection of Sex and Frailty in Humoral Immune Responses to Influenza Vaccine in Community-Dwelling Older Adults

Innovation in Aging ◽

10.1093/geroni/igaa057.869 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 271-272

Author(s):

Janna Shapiro ◽

Helen Kuo ◽

Rosemary Morgan ◽

Huifen Li ◽

Sabra Klein ◽

...

Keyword(s):

Older Adults ◽

Immune Responses ◽

Influenza A ◽

Community Dwelling ◽

Influenza Vaccines ◽

Health Study ◽

Cardiovascular Health Study ◽

High Dose ◽

Humoral Immune ◽

Humoral Immune Responses

Abstract Older adults bear the highest burden of severe disease and complications associated with seasonal influenza, with annual vaccination serving as the best option for protection. Variability in vaccine efficacy exists, yet the host factors that affect immune responses to inactivated influenza vaccines (IIV) are incompletely understood. We hypothesized that sex and frailty interact to affect vaccine-induced humoral responses among older adults. To test this hypothesis, community-dwelling adults above 75 years of age were recruited yearly, assessed for frailty (as defined by the Cardiovascular Health Study criteria), and vaccinated with the high-dose trivalent IIV. Humoral immune responses were evaluated via hemagglutination inhibition titers. The study began during the 2014-2015 influenza season, with yearly cohorts ranging from 76-163 individuals. A total of 617 vaccinations were delivered from 2014-2019. In preliminary analyses, the outcome of interest was seroconversion, defined as ≥ 4-fold rise in titers. Crude odds ratios suggest that females are more likely to seroconvert to influenza A strains (H1N1: OR = 1.39, (0.98-1.96) ; H3N2: 1.17 (0.85 – 1.62)), while males are more likely to seroconvert to the B strain (OR = 0.85 (0.60 – 1.22)). Furthermore, this sex difference was modified by frailty – for example, the odds of seroconversion to H1N1 were 65% higher for females than males among those who were nonfrail, and only 30% higher among females who were frail. Together, these results suggest that sex and frailty interact to impact immune responses to influenza vaccines. These findings may be leveraged to better protect vulnerable populations.

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Immunization with RBD-P2 and N protects against SARS-CoV-2 in nonhuman primates

Science Advances ◽

10.1126/sciadv.abg7156 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabg7156

Author(s):

So-Hee Hong ◽

Hanseul Oh ◽

Yong Wook Park ◽

Hye Won Kwak ◽

Eun Young Oh ◽

...

Keyword(s):

Nucleocapsid Protein ◽

Nonhuman Primates ◽

Vaccine Candidate ◽

Statistical Significance ◽

Neutralizing Antibody ◽

Spike Protein ◽

Vaccine Candidates ◽

Cell Responses ◽

Antibody Levels ◽

Further Development

Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), various vaccines are being developed, with most vaccine candidates focusing on the viral spike protein. Here, we developed a previously unknown subunit vaccine comprising the receptor binding domain (RBD) of the spike protein fused with the tetanus toxoid epitope P2 (RBD-P2) and tested its efficacy in rodents and nonhuman primates (NHPs). We also investigated whether the SARS-CoV-2 nucleocapsid protein (N) could increase vaccine efficacy. Immunization with N and RBD-P2 (RBDP2/N) + alum increased T cell responses in mice and neutralizing antibody levels in rats compared with those obtained using RBD-P2 + alum. Furthermore, in NHPs, RBD-P2/N + alum induced slightly faster SARS-CoV-2 clearance than that induced by RBD-P2 + alum, albeit without statistical significance. Our study supports further development of RBD-P2 as a vaccine candidate against SARS-CoV-2. Also, it provides insights regarding the use of N in protein-based vaccines against SARS-CoV-2.

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Influenza vaccination and the risk of COVID-19 infection and severe illness in older adults in the United States

Scientific Reports ◽

10.1038/s41598-021-90068-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kelly Huang ◽

Shu-Wen Lin ◽

Wang-Huei Sheng ◽

Chi-Chuan Wang

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

The United States ◽

Cross Sectional Study ◽

Severe Illness ◽

Cross Sectional ◽

Global Pandemic ◽

Study Population ◽

Health Database

AbstractThe coronavirus disease of 2019 (COVID-19) has caused a global pandemic and led to nearly three million deaths globally. As of April 2021, there are still many countries that do not have COVID-19 vaccines. Before the COVID-19 vaccines were developed, some evidence suggested that an influenza vaccine may stimulate nonspecific immune responses that reduce the risk of COVID-19 infection or the severity of COVID-19 illness after infection. This study evaluated the association between influenza vaccination and the risk of COVID-19 infection. We conducted a retrospective cross-sectional study with data from July 1, 2019, to June 30, 2020 with the Claims data from Symphony Health database. The study population was adults age 65 years old or older who received influenza vaccination between September 1 and December 31 of 2019. The main outcomes and measures were odds of COVID-19 infection and severe COVID-19 illness after January 15, 2020. We found the adjusted odds ratio (aOR) of COVID-19 infection risk between the influenza-vaccination group and no-influenza-vaccination group was 0.76 (95% confidence interval (CI), 0.75–0.77). Among COVID-19 patients, the aOR of developing severe COVID-19 illness was 0.72 (95% CI, 0.68–0.76) between the influenza-vaccination group and the no-influenza-vaccination group. When the influenza-vaccination group and the other-vaccination group were compared, the aOR of COVID-19 infection was 0.95 (95% CI, 0.93–0.97), and the aOR of developing a severe COVID-19 illness was 0.95 (95% CI, 0.80–1.13). The influenza vaccine may marginally protect people from COVID-19 infection.

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