ANTIBODY RESPONSES TO NATURALLY OCCURRING POLIOMYELITIS INFECTIONS

The neutralizing antibody responses of 52 asymptomatic household contacts of patients with poliomyelitis were studied by the metabolic inhibition method. Half of these contacts were fecal carriers of poliomyelitis virus. For purposes of comparison the antibody responses of 25 patients with paralytic poliomyelitis, all fecal virus carriers, were studied. The errors of replication of the test procedure were determined by duplicate testing of 51 serums. Duplicate testing of serum specimens indicated disagreement regarding the presence or absence of antibody in 6.0 to 8.0 per cent of the serums. The second test gave antibody titers which disagreed with those from the first test by a factor of fourfold or more 37.0 per cent of the time; errors occurred equally in either direction. Half of all persons studied showed an increase of fourfold or more in the antibody titers of paired serums; this was 3 to 4 times as many as would be expected by chance. It was not possible to distinguish the antibody responses of paralyzed patients from asymptomatic household contacts; or the fecal virus carriers from the nonvirus carriers in the latter group. Four virus carriers who did not have homologous antibody in convalescent serums were found. By repeat testing homologous antibody was found in all but one of these. The limitations of the test procedure as a diagnostic tool are discussed.

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ANTIBODY RESPONSES TO NATURALLY OCCURRING POLIOMYELITIS INFECTIONS IN CHILDREN

PEDIATRICS ◽

10.1542/peds.14.6.573 ◽

1954 ◽

Vol 14 (6) ◽

pp. 573-586

Author(s):

C. ARDEN MILLER ◽

HERBERT A. WENNER

Keyword(s):

Neutralizing Antibody ◽

Clinical History ◽

Antibody Responses ◽

Naturally Occurring ◽

Erroneous Diagnosis ◽

Antibody Titers ◽

Stool Specimens ◽

Prototype Virus

Thirteen of fourteen children with a clinical diagnosis of poliomyelitis showed high neutralizing antibody titers in tissue culture tests aganst prototype viruses, as early as two days after the first symptom, and persisting for as long as 18 months without significant change in titer. A significant increase in titer from that during the first week was occasionally encountered, but the initial titer was usually in the same range as that of the subsequent 18 months. The 14th child had antibodies against none of the prototype poliomyelitis viruses, though his clinical history was quite compatible with a non-paralytic infection. In the third month this patient's Type 2 antibody rose after six negative serums to 1:5120, possibly indicating an inapparent poliomyelitis infection several months after an erroneous diagnosis of poliomyelitis. Stool specimens were available from seven of the 14 children. Six Type 1 poliomyelitis viruses and one Type 2 virus were recovered from these stools. Neutralizing antibody titers against the patient's own virus closely paralled those against the homologous prototype virus. When differences did occur, they were in favor of higher antibody titers against the patient's own virus. Serums from 10 patients had antibodies against more than one prototype virus. With the exception of only two patients, antibodies against one of the prototype viruses were present far in excess of the others. Possible explanations for the heterotypic antibodies are discussed. Neutralization tests, as performed, appear to be of value in ruling out a diagnosis of poliomyelitis, but not in establishing the diagnosis.

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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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Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals

10.1101/2021.02.01.21250493 ◽

2021 ◽

Author(s):

Alena J. Markmann ◽

Natasa Giallourou ◽

D. Ryan Bhowmik ◽

Yixuan J. Hou ◽

Aaron Lerner ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Human Antibody ◽

Antibody Titers ◽

Sex Disparities ◽

Binding Antibody ◽

Male Sex ◽

Antibody Levels ◽

First Time

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) has now caused over 2 million deaths worldwide and continues to expand. Currently, much is unknown about functionally neutralizing human antibody responses and durability to SARS-CoV-2. Using convalescent sera collected from 101 COVID-19 recovered individuals 21-212 days after symptom onset with forty-eight additional longitudinal samples, we measured functionality and durability of serum antibodies. We also evaluated associations between individual demographic and clinical parameters with functional neutralizing antibody responses to COVID-19. We found robust antibody durability out to six months, as well as significant positive associations with the magnitude of the neutralizing antibody response and male sex. We also show that SARS-CoV-2 convalescent neutralizing antibodies are higher in individuals with cardio-metabolic comorbidities.SignificanceIn this study we found that neutralizing antibody responses in COVID-19 convalescent individuals vary in magnitude but are durable and correlate well with RBD Ig binding antibody levels compared to other SARS-CoV-2 antigen responses. In our cohort, higher neutralizing antibody titers are independently and significantly associated with male sex compared to female sex. We also show for the first time, that higher convalescent antibody titers in male donors are associated with increased age and symptom grade. Furthermore, cardio-metabolic co-morbidities are associated with higher antibody titers independently of sex. Here, we present an in-depth evaluation of serologic, demographic, and clinical correlates of functional antibody responses and durability to SARS-CoV-2.

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Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron)

10.1101/2021.12.19.473354 ◽

2021 ◽

Author(s):

Daniel J. Sheward ◽

Changil Kim ◽

Roy A. Ehling ◽

Alec Pankow ◽

Xaquin Castro Dopico ◽

...

Keyword(s):

Healthcare Workers ◽

Blood Donors ◽

Neutralizing Antibody ◽

Neutralization Assay ◽

Antibody Responses ◽

Pseudotyped Virus ◽

Virus Neutralization Assay ◽

Form Part ◽

Antibody Titers ◽

Cross Neutralization

The recently-emerged SARS-CoV-2 B.1.1.529 variant (Omicron) is spreading rapidly in many countries, with a spike that is highly diverged from the pandemic founder, raising fears that it may evade neutralizing antibody responses. We cloned the Omicron spike from a diagnostic sample which allowed us to rapidly establish an Omicron pseudotyped virus neutralization assay, sharing initial neutralization results only 13 days after the variant was first reported to the WHO, 8 days after receiving the sample. Here we show that Omicron is substantially resistant to neutralization by several monoclonal antibodies that form part of clinical cocktails. Further, we find neutralizing antibody responses in pooled reference sera sampled shortly after infection or vaccination are substantially less potent against Omicron, with neutralizing antibody titers reduced by up to 45 fold compared to those for the pandemic founder. Similarly, in a cohort of convalescent sera prior to vaccination, neutralization of Omicron was low to undetectable. However, in recent samples from two cohorts from Stockholm, Sweden, antibody responses capable of cross-neutralizing Omicron were prevalent. Sera from infected-then-vaccinated healthcare workers exhibited robust cross-neutralization of Omicron, with an average potency reduction of only 5-fold relative to the pandemic founder variant, and some donors showing no loss at all. A similar pattern was observed in randomly sampled recent blood donors, with an average 7-fold loss of potency. Both cohorts showed substantial between-donor heterogeneity in their ability to neutralize Omicron. Together, these data highlight the extensive but incomplete evasion of neutralizing antibody responses by the Omicron variant, and suggest that increasing the magnitude of neutralizing antibody responses by boosting with unmodified vaccines may suffice to raise titers to levels that are protective.

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Glycosylation of Immunodominant Linear Epitopes in the Carboxy-Terminal Region of the Caprine Arthritis-Encephalitis Virus Surface Envelope Enhances Vaccine-Induced Type-Specific and Cross-Reactive Neutralizing Antibody Responses

Journal of Virology ◽

10.1128/jvi.78.17.9190-9202.2004 ◽

2004 ◽

Vol 78 (17) ◽

pp. 9190-9202 ◽

Cited By ~ 7

Author(s):

J. D. Trujillo ◽

N. M. Kumpula-McWhirter ◽

K. J. Hötzel ◽

M. Gonzalez ◽

W. P. Cheevers

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Fold Increase ◽

Antibody Responses ◽

Enzyme Linked Immunosorbent Assay ◽

Wild Type ◽

Virus Surface ◽

Antibody Titers ◽

Linear Epitopes ◽

Carboxy Terminal

ABSTRACT This study evaluated type-specific and cross-reactive neutralizing antibodies induced by immunization with modified surface glycoproteins (SU) of the 63 isolate of caprine arthritis-encephalitis lentivirus (CAEV-63). Epitope mapping of sera from CAEV-infected goats localized immunodominant linear epitopes in the carboxy terminus of SU. Two modified SU (SU-M and SU-T) and wild-type CAEV-63 SU (SU-W) were produced in vaccinia virus and utilized to evaluate the effects of glycosylation or the deletion of immunodominant linear epitopes on neutralizing antibody responses induced by immunization. SU-M contained two N-linked glycosylation sites inserted into the target epitopes by R539S and E542N mutations. SU-T was truncated at 518A, upstream from the target epitopes, by introduction of termination codons at 519Y and 521Y. Six yearling Saanen goats were immunized subcutaneously with 30 μg of SU-W, SU-M, or SU-T in Quil A adjuvant and boosted at 3, 7, and 16 weeks. SU antibody titers determined by indirect enzyme-linked immunosorbent assay demonstrated anamnestic responses after each boost. Wild-type and modified SU-induced type-specific CAEV-63 neutralizing antibodies and cross-reactive neutralizing antibodies against CAEV-Co, a virus isolate closely related to CAEV-63, and CAEV-1g5, an isolate geographically distinct from CAEV-63, were determined. Immunization with SU-T resulted in altered recognition of SU linear epitopes and a 2.8- to 4.6-fold decrease in neutralizing antibody titers against CAEV-63, CAEV-Co, and CAEV-1g5 compared to titers of SU-W-immunized goats. In contrast, immunization with SU-M resulted in reduced recognition of glycosylated epitopes and a 2.4- to 2.7-fold increase in neutralizing antibody titers compared to titers of SU-W-immunized goats. Thus, the glycosylation of linear immunodominant nonneutralization epitopes, but not epitope deletion, is an effective strategy to enhance neutralizing antibody responses by immunization.

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IMVAMUNE® and ACAM2000® Provide Different Protection against Disease When Administered Postexposure in an Intranasal Monkeypox Challenge Prairie Dog Model

Vaccines ◽

10.3390/vaccines8030396 ◽

2020 ◽

Vol 8 (3) ◽

pp. 396

Author(s):

M. Shannon Keckler ◽

Johanna S Salzer ◽

Nishi Patel ◽

Michael B Townsend ◽

Yoshinori J Nakazawa ◽

...

Keyword(s):

Animal Studies ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Prairie Dogs ◽

Smallpox Vaccination ◽

Prairie Dog ◽

Protein Targets ◽

Naturally Occurring ◽

Vaccination Time ◽

Time Point

The protection provided by smallpox vaccines when used after exposure to Orthopoxviruses is poorly understood. Postexposu re administration of 1st generation smallpox vaccines was effective during eradication. However, historical epidemiological reports and animal studies on postexposure vaccination are difficult to extrapolate to today’s populations, and 2nd and 3rd generation vaccines, developed after eradication, have not been widely tested in postexposure vaccination scenarios. In addition to concerns about preparedness for a potential malevolent reintroduction of variola virus, humans are becoming increasingly exposed to naturally occurring zoonotic orthopoxviruses and, following these exposures, disease severity is worse in individuals who never received smallpox vaccination. This study investigated whether postexposure vaccination of prairie dogs with 2nd and 3rd generation smallpox vaccines was protective against monkeypox disease in four exposure scenarios. We infected animals with monkeypox virus at doses of 104 pfu (2× LD50) or 106 pfu (170× LD50) and vaccinated the animals with IMVAMUNE® or ACAM2000® either 1 or 3 days after challenge. Our results indicated that postexposure vaccination protected the animals to some degree from the 2× LD50, but not the 170× LD5 challenge. In the 2× LD50 challenge, we also observed that administration of vaccine at 1 day was more effective than administration at 3 days postexposure for IMVAMUNE®, but ACAM2000® was similarly effective at either postexposure vaccination time-point. The effects of postexposure vaccination and correlations with survival of total and neutralizing antibody responses, protein targets, take formation, weight loss, rash burden, and viral DNA are also presented.

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Comparison of Human H3N2 Antibody Responses Elicited by Egg-Based, Cell-Based, and Recombinant Protein–Based Influenza Vaccines During the 2017–2018 Season

Clinical Infectious Diseases ◽

10.1093/cid/ciz996 ◽

2019 ◽

Vol 71 (6) ◽

pp. 1447-1453 ◽

Cited By ~ 1

Author(s):

Sigrid Gouma ◽

Seth J Zost ◽

Kaela Parkhouse ◽

Angela Branche ◽

David J Topham ◽

...

Keyword(s):

Recombinant Protein ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Influenza Vaccines ◽

Vaccine Antigen ◽

H3n2 Virus ◽

High Dose ◽

Wild Type ◽

H1n1 Vaccine ◽

Antibody Titers

Abstract Background The H3N2 component of egg-based 2017–2018 influenza vaccines possessed an adaptive substitution that alters antigenicity. Several influenza vaccines include antigens that are produced through alternative systems, but a systematic comparison of different vaccines used during the 2017–2018 season has not been completed. Methods We compared antibody responses in humans vaccinated with Fluzone (egg-based, n = 23), Fluzone High-Dose (egg-based, n = 16), Flublok (recombinant protein–based, n = 23), or Flucelvax (cell-based, n = 23) during the 2017–2018 season. We completed neutralization assays using an egg-adapted H3N2 virus, a cell-based H3N2 virus, wild-type 3c2.A and 3c2.A2 H3N2 viruses, and the H1N1 vaccine strain. We also performed enzyme-linked immunosorbent assays using a recombinant wild-type 3c2.A hemagglutinin. Antibody responses were compared in adjusted analysis. Results Postvaccination neutralizing antibody titers to 3c2.A and 3c2.A2 were higher in Flublok recipients compared with Flucelvax or Fluzone recipients (P < .01). Postvaccination titers to 3c2.A and 3c2.A2 were similar in Flublok and Fluzone High-Dose recipients, though seroconversion rates trended higher in Flublok recipients. Postvaccination titers in Flucelvax recipients were low to all H3N2 viruses tested, including the cell-based H3N2 strain. Postvaccination neutralizing antibody titers to H1N1 were similar among the different vaccine groups. Conclusions These data suggest that influenza vaccine antigen match and dose are both important for eliciting optimal H3N2 antibody responses in humans. Future studies should be designed to determine if our findings directly impact vaccine effectiveness. Clinical Trials Registration NCT03068949.

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Redundancy and Plasticity of Neutralizing Antibody Responses Are Cornerstone Attributes of the Human Immune Response to the Smallpox Vaccine

Journal of Virology ◽

10.1128/jvi.02244-07 ◽

2008 ◽

Vol 82 (7) ◽

pp. 3751-3768 ◽

Cited By ~ 61

Author(s):

Mohammed Rafii-El-Idrissi Benhnia ◽

Megan M. McCausland ◽

Hua-Poo Su ◽

Kavita Singh ◽

Julia Hoffmann ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Safety Net ◽

Antibody Responses ◽

Smallpox Vaccine ◽

Human Antibody ◽

Neutralization Activity ◽

Antibody Titers ◽

Human Immune Response ◽

Human Immune

ABSTRACT The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective humoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a “safety net” of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.

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Four SARS-CoV-2 vaccines induce quantitatively different antibody responses against SARS-CoV-2 variants

10.1101/2021.09.27.21264163 ◽

2021 ◽

Author(s):

Marit J. van Gils ◽

Ayesha H.A. Lavell ◽

Karlijn van der Straten ◽

Brent Appelman ◽

Ilja Bontjer ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Adenovirus Vector ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Wild Type ◽

Fold Reduction ◽

Antibody Titers ◽

Alpha Beta ◽

Vaccination Campaigns

Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. We performed a head-to-head comparison of the ability of sera from individuals vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S) to recognize and neutralize the four SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma and Delta). Four weeks after completing the vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (median titers of 1891 and 3061, respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (median titers of 241 and 119, respectively). VOCs neutralization was reduced in all vaccine groups, with the largest (5.8-fold) reduction in neutralization being observed against the Beta variant. Overall, the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after the final vaccination.

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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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