Single-dose combination nanovaccine induces both rapid and durable humoral immunity and toxin neutralizing antibody responses against Bacillus anthracis

Safe and effective coronavirus disease–19 (COVID-19) vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged nonhuman primates (NHPs). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared with a single dose. In one-dose regimens, neutralizing antibody responses were stable for at least 14 wk, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and T helper cell (Th cell) 1–skewed cellular responses in aged NHPs that were comparable to those in adult animals. Aged Ad26.COV2.S-vaccinated animals challenged 3 mo after dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. Neutralization of variants of concern by NHP sera was reduced for B.1.351 lineages while maintained for the B.1.1.7 lineage independent of Ad26.COV2.S vaccine regimen.

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A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice

10.1101/2020.08.28.272518 ◽

2020 ◽

Cited By ~ 2

Author(s):

Abigail E. Powell ◽

Kaiming Zhang ◽

Mrinmoy Sanyal ◽

Shaogeng Tang ◽

Payton A. Weidenbacher ◽

...

Keyword(s):

Single Dose ◽

Neutralizing Antibodies ◽

Subunit Vaccine ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Receptor Binding Domain ◽

Amino Acid Deletion ◽

Vaccine Candidates ◽

Self Assembling ◽

Antibody Titers

AbstractDevelopment of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.

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Immunogenicity Studies of Bivalent Inactivated Virions of EV71/CVA16 Formulated with Submicron Emulsion Systems

BioMed Research International ◽

10.1155/2014/670506 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Chih-Wei Lin ◽

Chia-Chyi Liu ◽

Tsung-Chun Lu ◽

Shih-Jen Liu ◽

Yen-Hung Chow ◽

...

Keyword(s):

Single Dose ◽

Vaccine Candidate ◽

Emerging Infectious Diseases ◽

Foot And Mouth Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Submicron Particles ◽

Emulsion Systems ◽

Submicron Emulsion ◽

Immunogenicity Study

We assessed two strategies for preparing candidate vaccines against hand, foot, and mouth disease (HFMD) caused mainly by infections of enterovirus (EV) 71 and coxsackievirus (CV) A16. We firstly design and optimize the potency of adjuvant combinations of emulsion-based delivery systems, using EV71 candidate vaccine as a model. We then perform immunogenicity studies in mice of EV71/CVA16 antigen combinations formulated with PELC/CpG. A single dose of inactivated EV71 virion (0.2 μg) emulsified in submicron particles was found (i) to induce potent antigen-specific neutralizing antibody responses and (ii) consistently to elicit broad antibody responses against EV71 neutralization epitopes. A single dose immunogenicity study of bivalent activated EV71/CVA16 virion formulated with either Alum or PELC/CpG adjuvant showed that CVA16 antigen failed to elicit CVA16 neutralizing antibody responses and did not affect EV71-specific neutralizing antibody responses. A boosting dose of emulsified EV71/CVA16 bivalent vaccine candidate was found to be necessary to achieve high seroconversion of CVA16-specific neutralizing antibody responses. The current results are important for the design and development of prophylactic vaccines against HFMD and other emerging infectious diseases.

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Durability of antibody responses elicited by a single dose of Ad26.COV2.S and substantial increase following late boosting

10.1101/2021.08.25.21262569 ◽

2021 ◽

Cited By ~ 4

Author(s):

Jerald Sadoff ◽

Mathieu Le Gars ◽

Vicky Cardenas ◽

Georgi Shukarev ◽

Nathalie Vaissiere ◽

...

Keyword(s):

Clinical Trial ◽

Single Dose ◽

Booster Dose ◽

Age Groups ◽

Neutralizing Antibody ◽

Primary Vaccination ◽

Antibody Responses ◽

Binding Antibody ◽

Antibody Levels ◽

The Impact

AbstractBackgroundWe evaluated the durability of SARS-CoV-2 antibody levels elicited by the single dose Janssen COVID-19 vaccine, Ad26.COV2.S, and the impact on antibody responses of boosting with Ad26.COV2.S after 6 months in clinical trial participants.MethodsSpike-binding antibody and SARS-CoV-2 neutralizing antibody levels elicited by a single-dose Ad26.COV2.S (5×1010 viral particles [vp]) primary regimen and booster doses (5×1010 vp and 1.25×1010 vp) were assessed by ELISA and wild-type VNA in sera from participants in a Phase 1/2a clinical trial (Cohort 1a, 18–55 years old, N=25; Cohort 2a, 18–55 years old boosted at 6 months, N=17; Cohort 3, ≥65 years old, N=22) and a Phase 2 clinical trial (18–55 and ≥65-year old participants boosted at 6 months, total N=73). Neutralizing antibody levels were determined approximately 8 months after the primary vaccination in participants aged 18–55 years and approximately 9 months in participants aged ≥65 years. Binding antibody levels were evaluated 6 months after primary vaccination and 7- and 28-days after booster doses in both age groups.ResultsA single dose of Ad26.COV2.S elicited neutralizing antibodies that remained largely stable for approximately 8–9 months and binding antibodies that remained stable for at least 6 months irrespective of age group. A 5×1010 vp booster dose at 6 months post prime vaccination in 18–55-year-old adults elicited a steep and robust 9-fold increase at Day 7 post boost compared to Day 29 levels following the initial immunization. A lower booster dose of 1.25×1010 vp at 6 months in adults 18–55 and ≥65 years of age also elicited a rapid and high increase of 6–7.7 fold at Day 28 post boost compared to Day 29 levels following the initial immunization, with similar magnitude of post-boost responses in both age groups.ConclusionsA single dose of Ad26.COV2.S, which demonstrated protection in a Phase 3 efficacy trial, elicited durable neutralizing and binding antibodies for at least 8 and 6 months, respectively, in adults >18 years of age at levels similar to Day 29 responses. A 5×1010 vp or 1.25×1010 vp booster dose at 6 months elicited rapid and robust increases in spike binding antibody levels. The anamnestic responses after booster immunization imply robust immune memory elicited by single-dose Ad26.COV2.S.

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Immunogenicity of Bacillus anthracis Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

Clinical and Vaccine Immunology ◽

10.1128/cvi.00015-08 ◽

2008 ◽

Vol 15 (7) ◽

pp. 1115-1123 ◽

Cited By ~ 32

Author(s):

Nareen Abboud ◽

Arturo Casadevall

Keyword(s):

Bacillus Anthracis ◽

Antibody Titer ◽

Genetic Background ◽

Protective Antigen ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Full Length ◽

Mouse Strains ◽

Neutralizing Capacity ◽

Antibody Titers

ABSTRACT Neutralizing antibodies to Bacillus anthracis protective antigen (PA), a component of anthrax toxin, mediate protection against anthrax. PA is antigenically complex and can elicit protective and nonprotective antibodies. Furthermore, vaccinated individuals demonstrate considerable variability in their antibody responses to PA. To explore the relationship between PA structure and antigenicity, we produced Escherichia coli strains expressing full-length PA (PA1-4), domains 2 to 4 (PA2-4), domain 1, (PA1), and domain 4 (PA4) and evaluated the immunogenicities and protective efficacies of the protein fractions in four mouse strains (strains A/J, BALB/c, C57BL/6, and Swiss Webster). Immunization with PA1-4 resulted in significantly higher lethal toxin-neutralizing antibody titers than immunization with any recombinant protein (rPA) fraction of PA. The magnitude and neutralizing capacity of the antibody response to full-length PA and its fragments varied depending on the mouse strain. We found no correlation between the antibody titer and the neutralizing antibody titer for A/J and Swiss Webster mice. In C57BL/6 mice, antibody titers and neutralization capacity correlated for two of four rPA domain proteins tested, while BALB/c mice displayed a similar correlation with only one rPA. By correlating the reactivity of immune sera with solvent-exposed linear peptide segments of PA, we tentatively assign the presence of four new linear B-cell epitopes in PA amino acids 121 to 150, 143 to 158, 339 to 359, and 421 to 440. We conclude that the genetic background of the host determines the relative efficacy of the antitoxin response. The results suggest that the variability observed in vaccination studies with PA-derived vaccines is a result of host heterogeneity and implies a need to develop other antigens as vaccine candidates.

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SARS-CoV-2 Omicron Neutralization After Heterologous Vaccine Boosting

10.1101/2022.01.13.22268861 ◽

2022 ◽

Author(s):

Kirsten E Lyke ◽

Robert L Atmar ◽

Clara P. Dominguez Islas ◽

Christine M. Posavad ◽

Daniel Szydlo ◽

...

Keyword(s):

Single Dose ◽

Humoral Immunity ◽

Booster Dose ◽

Geometric Mean ◽

Age Groups ◽

Neutralizing Antibody ◽

Ongoing Study ◽

Subset Analysis ◽

Heterologous Boost

As part of an ongoing study assessing homologous and heterologous booster vaccines, following primary EUA series, we assessed neutralization of D614G and Omicron variants prior to and 28 days after boost. Subset analysis was done in six combinations (N = 10/group): four homologous primary-booster combinations included mRNA-1273 two-dose priming followed by boosting with 100-μg or 50-μg mRNA-1273, Ad26.COV2.S single-dose priming followed by Ad26.COV2.S booster and BNT162b2 two-dose priming followed by BNT162b2 boosting; and two heterologous primary-booster combinations: BNT162b2 followed by Ad26.COV2.S and Ad26.COV2.S followed by BNT162b2. Neutralizing antibody (Nab) titers to D614G on the day of boost (baseline) were detected in 85-100% of participants, with geometric mean titers (GMT) of 71-343 in participants who received an mRNA vaccine series versus GMTs of 35-41 in participants primed with Ad26.OV2.S. Baseline NAb titers to Omicron were detected in 50-90% of participants who received an mRNA vaccine series (GMT range 12.8-24.5) versus 20-25% among participants primed with Ad26.COV2.S. The booster dose increased the neutralizing GMT in most combinations to above 1000 for D614G and above 250 for Omicron by Day 29. Homologous prime-boost Ad26.COV2.S had the lowest NAb on Day 29 (D614G GMT 128 and Omicron GMT 45). Results were similar between age groups. Most homologous and heterologous boost combinations examined will increase humoral immunity to the Omicron variant.

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Antibody dynamics to SARS-CoV-2 in asymptomatic COVID-19 infections

10.1101/2020.07.09.20149633 ◽

2020 ◽

Cited By ~ 1

Author(s):

Qing Lei ◽

Yang Li ◽

Hongyan Hou ◽

Feng Wang ◽

Yandi Zhang ◽

...

Keyword(s):

Humoral Immunity ◽

Exposure Time ◽

Disease Transmission ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Pseudotyped Virus ◽

Serological Tests ◽

Asymptomatic Individuals ◽

Antibody Dynamics

Abstract Importance Asymptomatic COVID-19 infections have a long duration of viral shedding and contribute substantially to disease transmission. However, the missing asymptomatic cases have been significantly overlooked because of imperfect sensitivity of nucleic acid testing. We aimed to investigate the humoral immunity in asymptomatics, which will help us develop serological tests and improve early identification, understand the humoral immunity to COVID-19, and provide more rational control strategies for the pandemic. Objective To better control the pandemic of COVID-19, dynamics of IgM and IgG responses to 23 proteins of SARS-CoV-2 and neutralizing antibody in asymptomatic COVID-19 infections after exposure time were investigated. Design, setting, and participants 63 asymptomatic individuals were screened by RT-qPCR and ELISA for IgM and IgG from 11,776 personnel returning to work, and close contacts with the confirmed cases in different communities of Wuhan by investigation of clusters and tracing infectious sources. 63 healthy contacts with both negative results for NAT and antibodies were selected as negative controls. 51 mild patients without any preexisting conditions were also screened as controls from 1056 patients during hospitalization in Tongji Hospital. A total of 177 participants were enrolled in this study and serial serum samples (n=213) were collected. The research was conducted between 17 February 2020 and 28 April 2020. Serum IgM and IgG profiles of 177 participants were further probed using a SARS-CoV-2 proteome microarray. Neutralizing antibody responses in different population were detected by a pseudotyped virus neutralization assay system. The dynamics of IgM and IgG antibodies and neutralizing antibodies were analyzed with exposure time or symptoms onset. Results Asymptomatics were classified into four subgroups based on NAT and serological tests. In particular, only 19% had positive NAT results while approximately 81% detected positive IgM/IgG responses. Comparative SARS-CoV-2 proteome microarray further demonstrated that there was a significantly difference of antibody dynamics responding to S1 or N proteins among three populations, although IgM and IgG profiles could not be used to differentiate them. S1 specific IgM responses were elicited in asymptomatic individuals as early to the seventh day after exposure and peaked on days from 17d to 25d, which might be used as an early diagnostic biomarker and give an additional 36.5% seropositivity. Mild patients produced stronger both S1 specific IgM and neutralizing antibody responses than asymptomatic individuals. Most importantly, S1 specific IgM/IgG responses and the titers of neutralizing antibody in asymptomatic individuals gradually vanished in two months. Conclusions and relevance Our findings might have important implications for the definition of asymptomatic COVID-19 infections, diagnosis, serological survey, public health and immunization strategies.

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Immunogenicity and protective efficacy of one- and two-dose regimens of the Ad26.COV2.S COVID-19 vaccine candidate in adult and aged rhesus macaques

10.1101/2020.11.17.368258 ◽

2020 ◽

Author(s):

Laura Solforosi ◽

Harmjan Kuipers ◽

Sietske K. Rosendahl Huber ◽

Joan E.M. van der Lubbe ◽

Liesbeth Dekking ◽

...

Keyword(s):

Single Dose ◽

Vaccine Candidate ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Vaccine Dose ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Upper Respiratory Tract ◽

Post Dose ◽

Early Indication

AbstractSafe and effective coronavirus disease (COVID)-19 vaccines are urgently needed to control the ongoing pandemic. While single-dose vaccine regimens would provide multiple advantages, two doses may improve the magnitude and durability of immunity and protective efficacy. We assessed one- and two-dose regimens of the Ad26.COV2.S vaccine candidate in adult and aged non-human primates (NHP). A two-dose Ad26.COV2.S regimen induced higher peak binding and neutralizing antibody responses compared to a single dose. In one-dose regimens neutralizing antibody responses were stable for at least 14 weeks, providing an early indication of durability. Ad26.COV2.S induced humoral immunity and Th1 skewed cellular responses in aged NHP that were comparable to adult animals. Importantly, aged Ad26.COV2.S-vaccinated animals challenged 3 months post -dose 1 with a SARS-CoV-2 spike G614 variant showed near complete lower and substantial upper respiratory tract protection for both regimens. These are the first NHP data showing COVID-19 vaccine protection against the SARS-CoV-2 spike G614 variant and support ongoing clinical Ad26.COV2.S development.SummaryCOVID-19 vaccines are urgently needed and while single-dose vaccines are preferred, two-dose regimens may improve efficacy. We show improved Ad26.COV2.S immunogenicity in non-human primates after a second vaccine dose, while both regimens protected aged animals against SARS-CoV-2 disease.

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Impact of Low-Dose Methotrexate–Adalimumab Combination Therapy on the Antibody Response Induced by the mRNA-1273 SARS-CoV-2 Vaccine: Case of an Elderly Patient with Rheumatoid Arthritis

Vaccines ◽

10.3390/vaccines9080883 ◽

2021 ◽

Vol 9 (8) ◽

pp. 883

Author(s):

Yves Michiels ◽

Nadhira Houhou-Fidouh ◽

Gilles Collin ◽

Jérôme Berger ◽

Evelyne Kohli

Keyword(s):

Rheumatoid Arthritis ◽

Combination Therapy ◽

Immune Responses ◽

Low Dose ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Dose Methotrexate ◽

Adalimumab Therapy ◽

Dose Combination ◽

Weak Immune Response

Patients with rheumatoid arthritis (RA) are treated with drugs that may impact their immune responses to SARS-CoV-2 vaccines. We describe here the anti-Spike (anti-S) IgG and neutralizing antibody responses induced by the mRNA-1273 SARS-CoV-2 vaccine in a 78-years-old patient with RA, who received a low-dose combination therapy of methotrexate and adalimumab, shortly before vaccine administration. Both near-normal and impaired immune responses to vaccines have been reported previously in patients treated with these drugs. Our case report shows that, even at low doses, combined methotrexate-adalimumab therapy can be associated with a weak immune response to the mRNA1273 vaccine in elderly patients.

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mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant

10.1101/2021.12.14.21267755 ◽

2021 ◽

Author(s):

Wilfredo F Garcia-Beltran ◽

Kerri J. St Denis ◽

Angelique Hoelzemer ◽

Evan C. Lam ◽

Adam D. Nitido ◽

...

Keyword(s):

Humoral Immunity ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Cross Reactivity ◽

Antibody Responses ◽

Spike Protein ◽

Wild Type ◽

The Cross ◽

Potent Neutralization

Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody responses. In addition, we find Omicron pseudovirus is significantly more infectious than any other variant tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.

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