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Identification and characterization of neutralization epitopes at VP2 and VP1 of enterovirus A71

NikNadia N, Tan CW, Ong KC, Sam IC, Chan YF

J Med Virol, 2018 06;90(6):1164-1167.
PMID: 29457642 DOI: 10.1002/jmv.25061

Enterovirus A71 (EV-A71) neutralization escape mutants were generated with monoclonal antibody MAB979 (Millipore). The VP2-T141I and VP1-D14N substitutions were identified. Using reverse genetics, infectious clones with these substitutions were constructed and tested by neutralization assay with immune sera from mice and humans. The N-terminus VP1-14 is more important than EF loop VP2-141 in acute human infection, mainly because it recognised IgM present in acute infection. The N-terminus VP1 could be a useful target for diagnostics and therapeutic antibodies in acute infection.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext Advances in Antigenic Peptide-Based Vaccine and Neutralizing Antibodies against Viruses Causing Hand, Foot, and Mouth Disease

Anasir MI, Poh CL

Int J Mol Sci, 2019 Mar 13;20(6).
PMID: 30871133 DOI: 10.3390/ijms20061256

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext A broadly neutralizing germline-like human monoclonal antibody against dengue virus envelope domain III

Hu D, Zhu Z, Li S, Deng Y, Wu Y, Zhang N, et al.

PLoS Pathog, 2019 06;15(6):e1007836.
PMID: 31242272 DOI: 10.1371/journal.ppat.1007836

Dengue is the most widespread vector-borne viral disease caused by dengue virus (DENV) for which there are no safe, effective drugs approved for clinical use. Here, by using sequential antigen panning of a yeast antibody library derived from healthy donors against the DENV envelop protein domain III (DIII) combined with depletion by an entry defective DIII mutant, we identified a cross-reactive human monoclonal antibody (mAb), m366.6, which bound with high affinity to DENV DIII from all four DENV serotypes. Immunogenetic analysis indicated that m366.6 is a germline-like mAb with very few somatic mutations from the closest VH and Vλ germline genes. Importantly, we demonstrated that it potently neutralized DENV both in vitro and in the mouse models of DENV infection without detectable antibody-dependent enhancement (ADE) effect. The epitope of m366.6 was mapped to the highly conserved regions on DIII, which may guide the design of effective dengue vaccine immunogens. Furthermore, as the first germline-like mAb derived from a naïve antibody library that could neutralize all four DENV serotypes, the m366.6 can be a tool for exploring mechanisms of DENV infection, and is a promising therapeutic candidate.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext Yellow fever vaccination in Malaya by subcutaneous injection and multiple puncture. Neutralizing antibody responses in persons with and without pre-existing antibody to related viruses

Gordon Smith CE, Turner LH, Armitage P

Bull World Health Organ, 1962;27:717-27.
PMID: 13993152

Because of the risk of introduction of yellow fever to South-East Asia, comparative studies were made of yellow fever vaccination in Malayans who had a high prevalence of antibody to related viruses and in volunteers without related antibody. The proportions of positive neutralizing antibody responses to subcutaneous vaccination with 17D vaccine were not significantly different between volunteers with and without heterologous antibody but the degree of antibody response was greater in those without. The ID(50) of 17D in both groups was about 5 mouse intracerebral LD(50). Multiple puncture vaccination with 17D gave a much lower response rate than subcutaneous vaccination in volunteers with heterologous antibody. In both groups subcutaneous doses of about 50 mouse intracerebral LD(50) gave larger antibody responses than higher doses. The neutralizing indices and analysis of results were calculated by a method based on the survival time of the mice. This method, which has advantages over that of Reed & Muench, is fully described in an annex to this paper.

Matched MeSH terms: Antibodies, Neutralizing*
Fulltext The neutralizing role of IgM during early Chikungunya virus infection

Chua CL, Sam IC, Chiam CW, Chan YF

PLoS One, 2017;12(2):e0171989.
PMID: 28182795 DOI: 10.1371/journal.pone.0171989

The antibody isotype IgM appears earlier than IgG, within days of onset of symptoms, and is important during the early stages of the adaptive immune response. Little is known about the functional role of IgM during infection with chikungunya virus (CHIKV), a recently reemerging arbovirus that has caused large global outbreaks. In this study, we studied antibody responses in 102 serum samples collected during CHIKV outbreaks in Malaysia. We described the neutralizing role of IgM at different times post-infection and examined the independent contributions of IgM and IgG towards the neutralizing capacity of human immune sera during the early phase of infection, including the differences in targets of neutralizing epitopes. Neutralizing IgM starts to appear as early as day 4 of symptoms, and their appearance from day 6 is associated with a reduction in viremia. IgM acts in a complementary manner with the early IgG, but plays the main neutralizing role up to a point between days 4 and 10 which varies between individuals. After this point, total neutralizing capacity is attributable almost entirely to the robust neutralizing IgG response. IgM preferentially binds and targets epitopes on the CHIKV surface E1-E2 glycoproteins, rather than individual E1 or E2. These findings provide insight into the early antibody responses to CHIKV, and have implications for design of diagnostic serological assays.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext Structural Evaluation of the Spike Glycoprotein Variants on SARS-CoV-2 Transmission and Immune Evasion

Salleh MZ, Derrick JP, Deris ZZ

Int J Mol Sci, 2021 Jul 10;22(14).
PMID: 34299045 DOI: 10.3390/ijms22147425

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents significant social, economic and political challenges worldwide. SARS-CoV-2 has caused over 3.5 million deaths since late 2019. Mutations in the spike (S) glycoprotein are of particular concern because it harbours the domain which recognises the angiotensin-converting enzyme 2 (ACE2) receptor and is the target for neutralising antibodies. Mutations in the S protein may induce alterations in the surface spike structures, changing the conformational B-cell epitopes and leading to a potential reduction in vaccine efficacy. Here, we summarise how the more important variants of SARS-CoV-2, which include cluster 5, lineages B.1.1.7 (Alpha variant), B.1.351 (Beta), P.1 (B.1.1.28/Gamma), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota) and B.1.617.2 (Delta) confer mutations in their respective spike proteins which enhance viral fitness by improving binding affinity to the ACE2 receptor and lead to an increase in infectivity and transmission. We further discuss how these spike protein mutations provide resistance against immune responses, either acquired naturally or induced by vaccination. This information will be valuable in guiding the development of vaccines and other therapeutics for protection against the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Matched MeSH terms: Antibodies, Neutralizing/immunology
Fulltext Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes

Yeo AS, Azhar NA, Yeow W, Talbot CC, Khan MA, Shankar EM, et al.

PLoS One, 2014;9(4):e92240.
PMID: 24727912 DOI: 10.1371/journal.pone.0092240

Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.

Matched MeSH terms: Antibodies, Neutralizing/metabolism
Fulltext Formaldehyde-inactivated whole-virus vaccine protects a murine model of enterovirus 71 encephalomyelitis against disease

Ong KC, Devi S, Cardosa MJ, Wong KT

J Virol, 2010 Jan;84(1):661-5.
PMID: 19864378 DOI: 10.1128/JVI.00999-09

Enterovirus 71 (EV71) causes childhood hand, foot, and mouth disease and neurological complications, and no vaccines or therapeutic drugs are currently available. Formaldehyde-inactivated whole-virus vaccines derived from EV71 clinical isolates and a mouse-adapted virus (MAV) were tested in a mouse model of EV71 encephalomyelitis. After only two immunizations, given to mice at 1 and 7 days of age, the MAV vaccine protected mice at 14 days of age from disease. Tissues from immunized mice were negative for virus by viral culture, reverse transcriptase PCR, immunohistochemistry analysis, and in situ hybridization. Cross-neutralizing EV71 antibodies to strains with genotypes B3, B4, and C1 to C5 generated in immunized adult mice were able to passively protect 14-day-old mice from disease.

Matched MeSH terms: Antibodies, Neutralizing/immunology
Immunological cross-reactivity and neutralization of the principal toxins of Naja sumatrana and related cobra venoms by a Thai polyvalent antivenom (Neuro Polyvalent Snake Antivenom)

Leong PK, Fung SY, Tan CH, Sim SM, Tan NH

Acta Trop, 2015 Sep;149:86-93.
PMID: 26026717 DOI: 10.1016/j.actatropica.2015.05.020

The low potency of cobra antivenom has been an area of concern in immunotherapy for cobra envenomation. This study sought to investigate factors limiting the neutralizing potency of cobra antivenom, using a murine model. We examined the immunological reactivity and neutralizing potency of a Thai polyvalent antivenom against the principal toxins of Naja sumatrana (Equatorial spitting cobra) venom and two related Asiatic cobra venom α-neurotoxins. The antivenom possesses moderate neutralizing potency against phospholipases A2 (P, potency of 0.98mg/mL) and moderately weak neutralizing potency against long-chain α-neurotoxins (0.26-0.42mg/mL) but was only weakly effective in neutralizing the short-chain α-neurotoxins and cardiotoxins (0.05-0.08mg/mL). The poor neutralizing potency of the antivenom on the low molecular mass short-chain neurotoxins and cardiotoxins is presumably the main limiting factor of the efficacy of the cobra antivenom. Our results also showed that phospholipase A2, which exhibited the highest ELISA reactivity and avidity, was most effectively neutralized, whereas N. sumatrana short-chain neurotoxin, which exhibited the lowest ELISA reactivity and avidity, was least effectively neutralized by the antivenom. These observations suggest that low immunoreactivity (low ELISA reactivity and avidity) is one of the reasons for poor neutralization of the cobra venom low molecular mass toxins. Nevertheless, the overall results show that there is a lack of congruence between the immunological reactivity of the toxins toward antivenom and the effectiveness of toxin neutralization by the antivenom, indicating that there are other factors that also contribute to the weak neutralization capacity of the antivenom. Several suggestions have been put forward to overcome the low efficacy of the cobra antivenom. The use of a 'proper-mix' formulation of cobra venoms as immunogen, whereby the immunogen mixture used for hyperimmunization contains a mix of various types of α-neurotoxins and cardiotoxins in sufficient amount, may also help to improve the efficacy and broaden the neutralization spectrum of the antivenom.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Cross neutralization of common Southeast Asian viperid venoms by a Thai polyvalent snake antivenom (Hemato Polyvalent Snake Antivenom)

Leong PK, Tan CH, Sim SM, Fung SY, Sumana K, Sitprija V, et al.

Acta Trop, 2014 Apr;132:7-14.
PMID: 24384454 DOI: 10.1016/j.actatropica.2013.12.015

Snake envenomation is a serious public health threat in many rural areas of Asia and Africa. Antivenom has hitherto been the definite treatment for snake envenomation. Owing to a lack of local production of specific antivenom, most countries in these regions fully depend on foreign supplies of antivenoms. Often, the effectiveness of the imported antivenoms against local medically important species has not been validated. This study aimed to assess cross-neutralizing capacity of a recently developed polyvalent antivenom, Hemato Polyvalent Snake Antivenom (HPAV), against venoms of a common viper and some pit vipers from Southeast Asia. Neutralisation assays showed that HPAV was able to effectively neutralize lethality of the common Southeast Asian viperid venoms examined (Calloselasma, Crytelytrops, Popeia, and Daboia sp.) except for Tropidolaemus wagleri venom. HPAV also effectively neutralized the procoagulant and hemorrhagic activities of all the venoms examined, corroboratively supporting the capability of HPAV in neutralizing viperid venoms which are principally hematoxic. The study also indicated that HPAV fully prevented the occurrence of hematuria and proteinuria in mice envenomed with Thai Daboia siamensis venom but was only partially effective against venoms of Myanmar D. siamensis. Thus, HPAV appears to be useful against its homologous venoms and venoms from Southeast Asian viperids including several medically important pit vipers belonging to the Trimeresurus complex. Nevertheless, the effectiveness of HPAV as a paraspecific antivenom for treatment of viperid envenomation in Southeast Asian region requires further assessment from future clinical trials.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext Rational attenuation of RNA viruses with zinc finger antiviral protein

Gonçalves-Carneiro D, Mastrocola E, Lei X, DaSilva J, Chan YF, Bieniasz PD

Nat Microbiol, 2022 Oct;7(10):1558-1567.
PMID: 36075961 DOI: 10.1038/s41564-022-01223-8

Attenuation of a virulent virus is a proven approach for generating vaccines but can be unpredictable. For example, synonymous recoding of viral genomes can attenuate replication but sometimes results in pleiotropic effects that confound rational vaccine design. To enable specific, conditional attenuation of viruses, we examined target RNA features that enable zinc finger antiviral protein (ZAP) function. ZAP recognized CpG dinucleotides and targeted CpG-rich RNAs for depletion, but RNA features such as CpG numbers, spacing and surrounding nucleotide composition that enable specific modulation by ZAP were undefined. Using synonymously mutated HIV-1 genomes, we defined several sequence features that govern ZAP sensitivity and enable stable attenuation. We applied rules derived from experiments with HIV-1 to engineer a mutant enterovirus A71 genome whose attenuation was stable and strictly ZAP-dependent, both in cell culture and in mice. The conditionally attenuated enterovirus A71 mutant elicited neutralizing antibodies that were protective against wild-type enterovirus A71 infection and disease in mice. ZAP sensitivity can thus be readily applied for the rational design of conditionally attenuated viral vaccines.

Matched MeSH terms: Antibodies, Neutralizing/metabolism
Evaluation of neutralizing antibodies produced by papaya mosaic virus nanoparticles fused to the E2EP3 peptide epitope of Chikungunya envelope

Nor Rashid N, Teoh TC, Al-Harbi SJ, Yusof R, Rothan HA

Trop Biomed, 2021 Mar 01;38(1):36-41.
PMID: 33797522 DOI: 10.47665/tb.38.1.007

Chikungunya virus (CHIKV) infection is the cause of acute symptoms and chronic symmetrical polyarthritis associated with long-term morbidity and mortality. Currently, there is no available licensed vaccine or particularly useful drug for human use against CHIKV infection. This study was conducted to evaluate the efficacy of antibodies produced by papaya mosaic virus (PapMV) nanoparticles fused to E2EP3 peptide of CHIKV envelope as a recombinant CHIKV vaccine. PapMV, PapMV-C- E2EP3, and E2EP3-N-PapMV were produced in E. coli with an approximate size of 27 to 30 kDa. ICR mice (5 to 6 weeks of age) were injected subcutaneously with 25 micrograms of vaccine construct, and ELISA measured the titer of CHIKV specific IgG antibodies. The results showed that both recombinant proteins E2EP3-N-PapMV and PapMVC-E2EP3 were able to induce IgG antibodies production in immunized mice against CHIKV while immunization with recombinant PapMV showed no IgG antibodies induction. The neutralizing activity of the antibodies generated by either E2EP3-N-PapMV or PapMV-C-E2EP3 exhibited similar inhibition to CHIKV replication in Vero cells using the cells based antibody neutralizing assay and analyzed by plaque formation assay. This study showed the effectiveness of nanoparticles vaccine generated by fusing epitope peptide of CHIKV envelope to papaya mosaic virus envelope in inducing a robust immune response in mice against CHIKV. The data showed that levels of neutralizing antibodies correlate with a protective immune response CHIKV replication.

Matched MeSH terms: Antibodies, Neutralizing/immunology*
Fulltext Immunogenicity, reactogenicity, and safety of a second booster with BNT162b2 or full-dose mRNA-1273: A randomized VACCELERATE trial in adults aged ≥75 years (EU-COVAT-1-AGED Part B)

Stemler J, Yeghiazaryan L, Stephan C, Mohn KG, Carcas-Sansuan AJ, Rodriguez ER, et al.

Int J Infect Dis, 2024 Sep;146:107161.
PMID: 38992789 DOI: 10.1016/j.ijid.2024.107161

OBJECTIVES: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years.
METHODS: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days.
RESULTS: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%).
CONCLUSIONS: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age.

Matched MeSH terms: Antibodies, Neutralizing/blood
Association of total and dengue-specific IgE levels in the sera with dengue virus inhibition and antibody-dependent enhancement

Annsley DS, Chin KL, Tan KK, AbuBakar S, Zainal N

Trop Biomed, 2024 Dec 01;41(4):481-490.
PMID: 39876506 DOI: 10.47665/tb.41.4.009

Dengue, caused by the dengue virus (DENV), poses a significant global health challenge. Effective vaccines and treatments for dengue are lacking due to gaps in understanding its pathogenesis and mechanisms in severe cases. This study investigates the role of immunoglobulin E (IgE) in dengue, focusing on its potential association with virus neutralization and antibody-dependent enhancement (ADE) in DENV replication. Serum samples were obtained from dengue-positive (dengue-IgG positive), SLE (dengue-IgG negative), and control (dengue-IgG and SLE-negative) individuals. SLE sera were included as a control for their high total IgE levels. Total IgE and dengue-specific IgE levels were measured using ELISA. Neutralization assays in Vero and KU812 cells were conducted to assess virus neutralization and ADE, respectively. Dengue-positive and SLE sera showed higher total IgE levels than control sera, although there was no significance seen. Dengue-positive sera showed the presence of dengue-specific IgE, whereas SLE and control sera exhibited negligible levels. Neutralization assay in dengue-positive sera revealed no correlation between IgE levels and virus inhibition. SLE sera, however, demonstrated an inverse correlation between total IgE levels and DENV neutralization, suggesting a potential involvement of total IgE in DENV replication in the context of SLE. Seventy-eight percent of SLE sera, 65% of denguepositive and 54% of control sera exhibited enhanced virus replication in KU812 cells with serum compared to virus alone, indicating the highest occurrence of ADE in SLE, followed by dengue-positive and control sera. DENV expression in KU812 cells was notably higher in SLE sera, indicating increased ADE risk. However, no association was found between IgE levels and virus expression in KU812 cells across all groups. The inverse correlation between total IgE levels and DENV neutralization in SLE sera suggests that IgE may facilitate virus replication. Further comprehensive exploration is needed to fully understand the role of IgE in dengue pathogenesis.

Matched MeSH terms: Antibodies, Neutralizing/blood
Sera of patients with systemic lupus erythematosus cross-neutralizes dengue viruses

Zainal N, Tan KK, Johari J, Hussein H, Wan Musa WR, Hassan J, et al.

Microbiol. Immunol., 2018 Oct;62(10):659-672.
PMID: 30259549 DOI: 10.1111/1348-0421.12652

Dengue is the most prevalent mosquito-borne disease in Southeast Asia, where the incidence of systemic lupus erythematosus (SLE) is approximately 30 to 53 per 100,000. Severe dengue, however, is rarely reported among individuals with SLE. Here, whether sera of patients with SLE cross-neutralize dengue virus (DENV) was investigated. Serum samples were obtained from individuals with SLE who were dengue IgG and IgM serology negative. Neutralization assays were performed against the three major DENV serotypes. Of the dengue serology negative sera of individuals with SLE, 60%, 61% and 52% of the sera at 1/320 dilution showed more than 50% inhibition against dengue type-1 virus (DENV-1), DENV-2 and DENV-3, respectively. The neutralizing capacity of the sera was significantly greater against DENV-1 (P

Matched MeSH terms: Antibodies, Neutralizing/blood; Antibodies, Neutralizing/immunology*
A monoclonal antibody to ameliorate central nervous system infection and improve survival in a murine model of human Enterovirus-A71 encephalomyelitis

Tan SH, Ong KC, Perera D, Wong KT

Antiviral Res, 2016 Aug;132:196-203.
PMID: 27340013 DOI: 10.1016/j.antiviral.2016.04.015

BACKGROUND: Enterovirus A71 (EV-A71) encephalomyelitis is an often fatal disease for which there is no specific treatment available. Passive immunization with a specific monoclonal antibody to EV-A71 was used on a murine model of EV-A71 encephalomyelitis to evaluate its therapeutic effectiveness before and after established central nervous system (CNS) infection.
METHODS: Mice were intraperitoneally-infected with a mouse-adapted EV-A71 strain and treated with a dose of monoclonal antibody (MAb) daily for 3 days on day 1, 2 and 3 post-infection or for 3 days on 3, 4 and 5 post-infection. Treatment effectiveness was evaluated by signs of infection and survival rate. Histopathology and qPCR analyses were performed on mice sacrificed a day after completing treatment.
RESULTS: In mock-treated mice, CNS infection was established from day 3 post-infection. All mice treated before established CNS infection, survived and recovered completely without CNS infection. All mice treated after established CNS infection survived with mild paralysis, and viral load and antigens/RNA at day 6 post-infection were significantly reduced.
CONCLUSIONS: Passive immunization with our MAb could prevent CNS infection in mice if given early before the establishment of CNS infection. It could also ameliorate established CNS infection if optimal and repeated doses were given.

Matched MeSH terms: Antibodies, Neutralizing/immunology; Antibodies, Neutralizing/pharmacology*
Fulltext Development of enhanced antibody response toward dual delivery of nano-adjuvant adsorbed human Enterovirus-71 vaccine encapsulated carrier

Saeed MI, Omar AR, Hussein MZ, Elkhidir IM, Sekawi Z

Hum Vaccin Immunother, 2015;11(10):2414-24.
PMID: 26186664 DOI: 10.1080/21645515.2015.1052918

This study introduces a new approach for enhancing immunity toward mucosal vaccines. HEV71 killed vaccine that is formulated with nanosize calcium phosphate adjuvant and encapsulated onto chitosan and alginate delivery carriers was examined for eliciting antibody responses in serum and saliva collected at weeks 0, 1, 3, 5, 7 and 9 for viral-specific IgA & IgG levels and viral neutralizing antibody titers. The antibody responses induced in rabbits by the different formulations delivered by a single (buccal) route were compared to those of dual immunization (intradermal / mucosal) and un-immunized control. Chitosan-loaded vaccine adjuvant induced elevated IgA antibody, while Alginate-adjuvant irreversible bonding sequestered the vaccine and markedly reduced immunogenicity. The induced mucosal and parenteral antibody profiles appeared in an inverse manner of enhanced mucosal IgA antibody accompanied by lower systemic IgG following a single oral immunization route. The combined intradermal and oral dual-immunized group developed an elevated salivary IgA, systemic IgG, and virus neutralizing response. A reduced salivary neutralizing antibody titer was observed and attributed to the continual secretion exchanges in saliva. Designing a successful mucosal delivery formulation needs to take into account the vaccine delivery site, dosage, adjuvant and carrier particle size, charge, and the reversibility of component interactions. The dual immunization seems superior and is a important approach for modulating the antibody response and boosting mucosal protection against HEV71 and similar pathogens based on their transmission mode, tissue tropism and shedding sites. Finally, the study has highlighted the significant role of dual immunization for simultaneous inducing and modulating the systemic and mucosal immune responses to EV71.

Matched MeSH terms: Antibodies, Neutralizing/analysis*; Antibodies, Neutralizing/blood
Association of circulatory Tfh-like cells with neutralizing antibody responses among chronic HIV-1 subtype C infected long-term nonprogressors and progressors

Swathirajan CR, Nandagopal P, Vignesh R, Srikrishnan AK, Goyal R, Qureshi H, et al.

Pathog Dis, 2019 06 01;77(4).
PMID: 31505637 DOI: 10.1093/femspd/ftz044

HIV-1 vaccine functioning relies on successful induction of broadly neutralizing antibodies (bNAbs). CXCR3- circulatory T-follicular helper (cTfh) cells are necessary for inducing B-cells for generating bNAbs. Recent studies have suggested that CXCR3+ Tfh cells might also influence bNAb production. Plasma samples from 34 ART-Naïve HIV-1 infected individuals [long-term nonprogressors (LTNP)-19; Progressors-13] were tested against a heterologous virus panel (n = 11) from subtypes A, B, C, G, AC, BC and AE. Frequencies of CXCR3+ and CXCR3- cTfh-like cells in peripheral circulation were studied using flow cytometry. LTNP showed significantly lower CXCR3+ and higher CXCR3- cTfh-like cell frequencies, while neutralization breadth was observed to be broader in progressors. A positive correlation was observed between bNAb breadth and potency with CXCR3+PD-1+ cTfh-like cells in LTNP. Based on neutralization breadth, 9 HIV-1 infected individuals were classified as 'top neutralizers' and 23 as 'low neutralizers' and they did not show any correlations with CXCR3+ and CXCR3- cTfh-like cells. These preliminary data suggest that CXCR3+ similar to CXCR3- might possess significant functional properties for driving B-cells to produce bNAbs. Hence, an HIV vaccine which is capable of optimal induction of CXCR3+ cTfh cells at germinal centers might confer superior protection against HIV.

Matched MeSH terms: Antibodies, Neutralizing
[Epitope analysis of the hemagglutinin molecule of the Victoria lineage influenza B viruses]

Sorokin EV, Tsareva TR, Sominina AA, Pisareva MM, Komissarov AV, Kosheleva AA, et al.

Vopr. Virusol., 2014;59(6):27-31.
PMID: 25929033

A panel of five monoclonal antibodies (MAbs) to the HA1 molecule of the influenza B virus of the Victorian lineage with high virus-neutralizing activity was developed. For identification of the virus neutralizing epitopes in HA1 escape mutants (EM) of the influenza BIShandong/07/97 and B/Malaysia/2506/04 virus were selected using virus- neutralizing antibodies (MAbs). Three EMs had single, two--double and one--triple amino acid substitutions (AAS) in HA1 (H122N, A202E, K203T, K2031, K203N or A317V). In addition, AAS N197S was detected in three EMs. A correlation of AAS identified with peculiarities of interaction of EMs with Mabs was discussed.

Matched MeSH terms: Antibodies, Neutralizing/biosynthesis; Antibodies, Neutralizing/immunology*; Antibodies, Neutralizing/isolation & purification
Fulltext Microarray Profiling of Vaccination-Induced Antibody Responses to SARS-CoV-2 Variants of Interest and Concern

Svetlova J, Gustin D, Manuvera V, Shirokov D, Shokina V, Prusakov K, et al.

Int J Mol Sci, 2022 Oct 30;23(21).
PMID: 36362010 DOI: 10.3390/ijms232113220

Mutations in surface proteins enable emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to escape a substantial fraction of neutralizing antibodies and may thus weaken vaccine-driven immunity. To compare available vaccines and justify revaccination, rapid evaluation of antibody (Ab) responses to currently circulating SARS-CoV-2 variants of interest (VOI) and concern (VOC) is needed. Here, we developed a multiplex protein microarray-based system for rapid profiling of anti-SARS-CoV-2 Ab levels in human sera. The microarray system was validated using sera samples from SARS-CoV-2-free donors and those diagnosed with COVID-19 based on PCR and enzyme immunoassays. Microarray-based profiling of vaccinated donors revealed a substantial difference in anti-VOC Ab levels elicited by the replication-deficient adenovirus vector-base (Sputnik V) and whole-virion (CoviVac Russia COVID-19) vaccines. Whole-virion vaccine-induced Abs showed minor but statistically significant cross-reactivity with the human blood coagulation factor 1 (fibrinogen) and thrombin. However, their effects on blood clotting were negligible, according to thrombin time tests, providing evidence against the concept of pronounced cross-reactivity-related side effects of the vaccine. Importantly, all samples were collected in the pre-Omicron period but showed noticeable responses to the receptor-binding domain (RBD) of the Omicron spike protein. Thus, using the new express Ab-profiling system, we confirmed the inter-variant cross-reactivity of the anti-SARS-CoV-2 Abs and demonstrated the relative potency of the vaccines against new VOCs.

Matched MeSH terms: Antibodies, Neutralizing

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