Complexity of Human Antibody Response to Dengue Virus: Implication for Vaccine Development

Dengue virus (DENV) is a mosquito-borne virus that causes severe health problems. An effective tetravalent dengue vaccine candidate that can provide life-long protection simultaneously against all four DENV serotypes is highly anticipated. A better understanding of the antibody response to DENV envelope protein domain III (EDIII) may offer insights into vaccine development. Here, we identified 25 DENV cross-reactive mAbs from immunization with Pichia pastoris-expressed EDIII of a single or all four serotype(s) using a prime–boost protocol, and through pepscan analysis found that 60 % of them (15/25) specifically recognized the same highly conserved linear epitope aa 309–320 of EDIII. All 15 complex-reactive mAbs exhibited significant cross-reactivity with recombinant EDIII from all DENV serotypes and also with C6/36 cells infected with DENV-1, -2, -3 and -4. However, neutralization assays indicated that the majority of these 15 mAbs were either moderately or weakly neutralizing. Through further epitope mapping by yeast surface display, two residues in the AB loop, Q316 and H317, were discovered to be critical. Three-dimensional modelling analysis suggests that this epitope is surface exposed on EDIII but less accessible on the surface of the E protein dimer and trimer, especially on the surface of the mature virion. It is concluded that EDIII as an immunogen may elicit cross-reactive mAbs toward an epitope that is not exposed on the virion surface, therefore contributing inefficiently to the mAbs neutralization potency. Therefore, the prime–boost strategy of EDIII from a single serotype or four serotypes mainly elicited a poorly neutralizing, cross-reactive antibody response to the conserved AB loop of EDIII.

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The Human Antibody Response to Dengue Virus Infection

Viruses ◽

10.3390/v3122374 ◽

2011 ◽

Vol 3 (12) ◽

pp. 2374-2395 ◽

Cited By ~ 199

Author(s):

Wahala M. P. B. Wahala ◽

Aravinda M. de Silva

Keyword(s):

Virus Infection ◽

Antibody Response ◽

Dengue Virus ◽

Human Antibody ◽

Dengue Virus Infection

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Analysis of Individuals from a Dengue-Endemic Region Helps Define the Footprint and Repertoire of Antibodies Targeting Dengue Virus 3 Type-Specific Epitopes

mBio ◽

10.1128/mbio.01205-17 ◽

2017 ◽

Vol 8 (5) ◽

Cited By ~ 9

Author(s):

Daniela V. Andrade ◽

Leah C. Katzelnick ◽

Doug G. Widman ◽

Angel Balmaseda ◽

Aravinda M. de Silva ◽

...

Keyword(s):

Public Health ◽

Monoclonal Antibody ◽

Antibody Response ◽

Dengue Virus ◽

Vaccine Development ◽

Human Monoclonal Antibody ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Kinetics Of

ABSTRACT The four dengue virus serotypes (DENV1 to 4) cause dengue, a major public health problem worldwide. Individuals exposed to primary DENV infections develop serotype-specific neutralizing antibodies, including strongly neutralizing antibodies targeting quaternary epitopes. To date, no studies have measured the levels and kinetics of serum antibodies directed to such epitopes among populations in regions where dengue is endemic. Here, we use a recombinant DENV4 (rDENV4/3-M14) displaying a major DENV3 type-specific quaternary epitope recognized by human monoclonal antibody 5J7 to measure the proportion, magnitude, and kinetics of DENV3 type-specific neutralizing antibody responses targeting this epitope. Primary DENV3 sera from 30 individuals in a dengue hospital-based study in Nicaragua were studied 3, 6, 12, and 18 months post-infection, alongside samples collected annually 1 to 4 years post-primary DENV3 infection from 10 individuals in a cohort study in Nicaragua. We found substantial individual variation in the proportion of DENV3 type-specific neutralizing antibody titers attributed to the 5J7 epitope (range, 0 to 100%), with the mean significantly increasing from 22.6% to 41.4% from 3 to 18 months. We extended the transplanted DENV3 5J7 epitope on the virion (rDENV4/3-M16), resulting in increased recognition in several individuals, helping define the footprint of the epitope. However, 37% and 13% of the subjects still showed little to no recognition of the 5J7 epitope at 3 and 18 months, respectively, indicating that one or more additional DENV3 type-specific epitopes exist. Overall, this study demonstrates how DENV-immune plasma from populations from areas of endemicity, when coupled with structurally guided recombinant viruses, can help characterize the epitope-specific neutralizing antibody response in natural DENV infections, with direct implications for design and evaluation of dengue vaccines. IMPORTANCE The four serotypes of dengue virus cause dengue, a major public health burden worldwide, yet it has been challenging to develop a vaccine that is safe and equally effective against all four serotypes. More in-depth characterization of natural human neutralizing antibody responses is needed to identify determinants of protective antibody responses to all DENV serotypes. Here, we use hospital and cohort studies in a region where dengue is endemic to assess the proportion and kinetics of the DENV3 neutralizing antibody response directed to a quaternary epitope on DENV3 recognized by strongly neutralizing human monoclonal antibody 5J7, which was transplanted into a DENV4 backbone. We show that many individuals recognized the 5J7 epitope, but to various degrees over time, suggesting that additional DENV3-specific epitopes likely exist. Thus, characterization of epitope-specific neutralizing antibody responses in natural DENV infections can help define the footprint and repertoire of antibodies directed to DENV3 type-specific epitopes, with implications for dengue vaccine development. IMPORTANCE The four serotypes of dengue virus cause dengue, a major public health burden worldwide, yet it has been challenging to develop a vaccine that is safe and equally effective against all four serotypes. More in-depth characterization of natural human neutralizing antibody responses is needed to identify determinants of protective antibody responses to all DENV serotypes. Here, we use hospital and cohort studies in a region where dengue is endemic to assess the proportion and kinetics of the DENV3 neutralizing antibody response directed to a quaternary epitope on DENV3 recognized by strongly neutralizing human monoclonal antibody 5J7, which was transplanted into a DENV4 backbone. We show that many individuals recognized the 5J7 epitope, but to various degrees over time, suggesting that additional DENV3-specific epitopes likely exist. Thus, characterization of epitope-specific neutralizing antibody responses in natural DENV infections can help define the footprint and repertoire of antibodies directed to DENV3 type-specific epitopes, with implications for dengue vaccine development.

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Somatic hypermutations and isotype switches in the progeny of a single virgin B cell predominating the human antibody response to the capsular polysaccharide of Haemophilus influenzae type b

Immunology Letters ◽

10.1016/s0165-2478(97)87211-2 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 95

Author(s):

T Barington

Keyword(s):

Antibody Response ◽

Haemophilus Influenzae ◽

B Cell ◽

Capsular Polysaccharide ◽

Haemophilus Influenzae Type ◽

Human Antibody ◽

Haemophilus Influenzae Type B ◽

Type B

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Faculty Opinions recommendation of The structural basis for serotype-specific neutralization of dengue virus by a human antibody.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.720388292.793513024 ◽

2016 ◽

Author(s):

Gavin Screaton ◽

Sophie Yacoub

Keyword(s):

Dengue Virus ◽

Structural Basis ◽

Human Antibody

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COVID-19 Vaccine mRNABNT162b2 Elicits Human Antibody Response in Milk of Breastfeeding Women

Vaccines ◽

10.3390/vaccines9070785 ◽

2021 ◽

Vol 9 (7) ◽

pp. 785

Author(s):

Maurizio Guida ◽

Daniela Terracciano ◽

Michele Cennamo ◽

Federica Aiello ◽

Evelina La Civita ◽

...

Keyword(s):

Breast Milk ◽

Antibody Response ◽

Human Milk ◽

Human Antibody ◽

Serum Antibodies ◽

Serum Samples ◽

Low Concentration ◽

Milk Samples ◽

Milk Antibodies ◽

Roche Diagnostics

Objective: The objective of this research is to demonstrate the release of SARS-CoV-2 Spike (S) antibodies in human milk samples obtained by patients who have been vaccinated with mRNABNT162b2 vaccine. Methods: Milk and serum samples were collected in 10 volunteers 20 days after the first dose and 7 seven days after the second dose of the mRNABNT162b2 vaccine. Anti-SARS-CoV-2 S antibodies were measured by the Elecsys® Anti-SARS-CoV-2 S ECLIA assay (Roche Diagnostics AG, Rotkreuz, Switzerland), a quantitative electrochemiluminescence immunometric method. Results: At first sample, anti-SARS-CoV-2 S antibodies were detected in all serum samples (103.9 ± 54.9 U/mL) and only in two (40%) milk samples with a low concentration (1.2 ± 0.3 U/mL). At the second sample, collected 7 days after the second dose, anti-SARS-CoV-2 S antibodies were detected in all serum samples (3875.7 ± 3504.6 UI/mL) and in all milk samples (41.5 ± 47.5 UI/mL). No correlation was found between the level of serum and milk antibodies; the milk antibodies/serum antibodies ratio was on average 2% (range: 0.2–8.4%). Conclusion: We demonstrated a release of anti-SARS-CoV-2 S antibodies in the breast milk of women vaccinated with mRNABNT162b2. Vaccinating breastfeeding women could be a strategy to protect their infants from COVID-19 infection.

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