Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans

Basu, Madhubanti; Piepenbrink, Michael S.; Francois, Czestochowa; Roche, Fritzlaine C.; Zheng, Bo; Spencer, David A.; Hessell, Ann J.; Fucile, Christopher; Rosenberg, Alexander F.; Bunce, Catherine A.; Liesveld, Jane L.; Keefer, Michael C.; Kobie, James J.

doi:10.1016/j.xcrm.2020.100015

Cited by 11 publications

(28 citation statements)

References 80 publications

(97 reference statements)

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“…Removal of any residual genomic DNA was performed using the Turbo DNA-Free kit (Invitrogen) and cDNA was generated using the qScript cDNA synthesis kit (QuantaBio). Two rounds of PCRs were performed to generate the libraries with either global (VH1 -VH6) or individual VH targeted forward primers as previously described (27,39) with the modifications adapted for Illumina Nextera approach. The final PCR products were gel extracted (QIAQuick, Qiagen, Hilden, Germany) and further purified using the ProNex sizeselective purification system (Promega) to select products between 500-700 bp range.…”

Section: Molecular Features and Clonal Dynamics The Most Potent Hmabmentioning

confidence: 99%

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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Piepenbrink¹,

Park

Oladunni

et al. 2020

Preprint

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SARS-CoV-2 infection results in viral burden in the upper and lower respiratory tract, enabling transmission and often leading to substantial lung pathology. Delivering the antiviral treatment directly to the lungs has the potential to improve lung bioavailability and dosing efficiency. As the SARS-CoV-2 Receptor Binding Domain (RBD) of the Spike (S) is increasingly deemed to be a clinically validated target, RBD-specific B cells were isolated from patients following SARS-CoV-2 infection to derive a panel of fully human monoclonal antibodies (hmAbs) that potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, has high affinity for SARS-CoV-2 RBD which enables its direct inhibition of RBD binding to ACE2. The 1212C2 hmAb exhibits in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhale treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration. Taken together, these results warrant an accelerated clinical development of 1212C2 hmAb formulated and delivered via inhalation for the prevention and treatment of SARS-CoV-2 infection.

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Section: Molecular Features and Clonal Dynamics The Most Potent Hmabmentioning

confidence: 99%

“…Monoclonal antibody production. Single B cells were sorted using a FACSMelody (BD Biosciences) into 96-well PCR plates and immediately frozen at −80 °C until thawed for reverse transcription and nested PCR performed for IgH, Igλ, and Igκ variable gene transcripts as previously described(27,39). 0075% P20, and 100μg/mL BSA.…”

mentioning

confidence: 99%

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Piepenbrink¹,

Park

Oladunni

et al. 2020

Preprint

Self Cite

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“…The CDR3 is the most variable region of the antibody molecule and a major determinant for antigen recognition and binding. Among various known characteristics, the presence of long HCDR3, as defined as > 22 aa, is a common feature for some well-characterized bnmAbs against HIV-1, and several Env-reactive mAbs isolated from HIV vaccine trials also possess this feature (Basu et al ., 2020; Easterhoff et al, 2017). We searched for this trait in the pre-immune peripheral blood B cells and found significant (p<0.0001) enrichment of lineages with long HCDR3 in the gp120pos over gp120neg fraction in 17 of the 21 (∼81%) participants ( Figure 1D ).…”

Section: Resultsmentioning

confidence: 99%

“…The pre-immune HIV Env-reactive B cell fraction is assumed to not have had any prior exposure to HIV Env and is anticipated to have a certain degree of representation in the resulting HIV Env vaccine-induced B cell repertoire. Previously, for the HIV Env vaccine phase 1 trial HVTN 105, BCR repertoires from day 7 post-vaccination peripheral blood (D7), expected to be dominated by vaccine-induced IgG plasmablasts, were sequenced (Basu et al ., 2020). We sought to understand the degree of overlap between the gp120pos pre-vaccination and the vaccine-induced BCR repertoire.…”

Section: Resultsmentioning

confidence: 99%

“…Observing shared lineage members in the pre and post vaccination samples, we next sought to definitively characterize the dynamics of the gp120 pre-immune lineages that respond to vaccination. Previously we isolated 66 gp120 specific mAbs from HVTN 105 participants after their last vaccination (Basu et al ., 2020). We sought to determine whether the precursor B cells for these mAbs were present in the pre-immune B cell compartment and subsequently participated in the Env-reactive B cell response to the vaccination.…”

Section: Resultsmentioning

confidence: 99%

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Mixed Origins: HIV gp120-specific memory develops from pre-existing memory and naïve B cells following vaccination in humans

Basu

Piepenbrink

Fucile

et al. 2021

Preprint

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The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naive B cell receptor, fail to bind Env suggesting that the initial responding B cell population is not exclusively comprised of a naive population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated gp120-reactive monoclonal antibodies (mAbs) from participants in HVTN 105, an HIV vaccine trial. Using deep sequencing VH-lineage tracking we identified several of these mAb lineages in pre-immune peripheral blood. Several of these pre-immune lineages also persisted in the bone marrow, including CD138+ long-lived plasma cell compartment, ~7 months after the final vaccination. The majority of the pre-immune lineage members included IgM, however IgG and IgA members were also prevalent and exhibited somatic hypermutation. These results suggest that vaccine-induced gp120-specific antibody lineages originate from both naive and cross-reactive memory B cells.

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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Piepenbrink

Park

Oladunni

et al. 2021

Cell Reports Medicine

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SARS-CoV-2 infection results in viral burden in the respiratory tract, enabling transmission and leading to substantial lung pathology. The 1212C2 fully human monoclonal antibody was derived from an IgM memory B cell of a COVID-19 patient, has high affinity for the Spike protein Receptor Binding Domain, neutralizes SARS-CoV-2 and exhibits in vivo prophylactic and therapeutic activity in hamsters when delivered intraperitoneally, reducing upper and lower respiratory viral burden and lung pathology. Inhalation of nebulized 1212C2 at levels as low as 0.6mg/kg, corresponding to 0.03mg/kg of lung deposited dose, reduced viral burden below the detection limit, and mitigated lung pathology. The therapeutic efficacy of an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery for dose-sparing benefits as compared to the conventional parenteral route of administration. These results suggest clinical development of 1212C2 formulated and delivered via inhalation for the treatment of SARS-CoV-2 infection should be considered.

show abstract

Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans

Cited by 11 publications

References 80 publications

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Mixed Origins: HIV gp120-specific memory develops from pre-existing memory and naïve B cells following vaccination in humans

Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

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