Madhubanti Basu

University of Alabama at Birmingham

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Michael S. Piepenbrink

University of Alabama at Birmingham

James J. Kobie

University of Alabama at Birmingham

Luis Martínez‐Sobrido

Texas Biomedical Research Institute

Sanghita Sarkar

University of Alabama at Birmingham

Michael C. Keefer

University of Rochester

Alexander F. Rosenberg

University of Alabama at Birmingham

Christopher Fucile

University of Alabama at Birmingham

Chengjin Ye

Texas Biomedical Research Institute

Mark R. Walter

University of Alabama at Birmingham

Ahmed Magdy Khalil

Texas Biomedical Research Institute

Cooperative Institutions

University of Rochester

University of Rochester Medical Center

University of Alabama at Birmingham

Aridis Pharmaceuticals (United States)

Texas Biomedical Research Institute

Oregon National Primate Research Center

Oregon Health & Science University

New York University

Office of Infectious Diseases

University of Alabama

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Highly Cross-Reactive and Protective Influenza A Virus H3N2 Hemagglutinin- and Neuraminidase-Specific Human Monoclonal Antibodies

Microbiology Spectrum (2023)

Michael S. Piepenbrink Fatai S. Oladunni Aitor Nogales Ahmed Magdy Khalil Theresa Fitzgerald

Influenza A virus (IAV) infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets within the influenza virus hemagglutinin and neuraminidase proteins.

H5N1 genetic structure

Pandemic

10.1128/spectrum.04728-22

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Citations (3)

Potent neutralization by a receptor binding domain monoclonal antibody with broad specificity for SARS-CoV-2 JN.1 and other variants

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Michael S. Piepenbrink Ahmed Magdy Khalil Ana C. Chang Ahmed Mostafa Madhubanti Basu

SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. While increasing herd immunity, current vaccines, and therapeutics have improved outcomes for some; prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) - ACE2 fusion protein and differential selection process with native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan and more recent Omicron JN.1 strain, as well as SARS-CoV. Structure determination of the SARS-CoV-2 EG5.1 Spike/1301B7 Fab complex by cryo-electron microscopy at 3.1Å resolution demonstrates 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain, making contacts using CDRs1-3, as well as framework region 3 (FR3). Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.

10.1101/2024.04.27.591446

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CD4+ T cells are dispensable for induction of heterologous tier 2 HIV neutralizing antibodies in rhesus macaques

The Journal of Immunology (2020)

James Kobie Philip Barnette Shilpi Pandey David C. Spencer Madhubanti Basu

Abstract Induction of a sustained and broad neutralizing antibody (Ab) response is a major goal in developing a protective HIV vaccine. Many HIV Envelope (Env)-specific broadly neutralizing antibodies isolated to date exhibit substantial somatic hypermutation, and their development in HIV infected individuals has been correlated with T follicular helper responses. This has bolstered the rational that a robust CD4+ T helper cell response will likely be required for the induction of such HIV broadly neutralizing antibody responses by vaccination. Using the VC10014 DNA-protein co-immunization vaccine platform consisting of gp160 envelope plasmids and gp140 trimeric envelope proteins derived from a clade B HIV-1 infected subject who developed broadly neutralizing serum Abs, and which has been previously shown to induce Tier 2 heterologous neutralizing Abs in rabbits and rhesus macaques, we determined the influence of CD4+ T cell depletion during the vaccination regimen on the characteristics of the Env-specific humoral response in rhesus macaques. Both CD4+ depleted and non-depleted animals developed Tier 2 heterologous neutralizing plasma antibodies, with no inferiority in titers among the CD4+ T cell depleted animals. Similarly, there was no diminishment of titers of HIV Env-specific cross-clade binding antibodies, antibody dependent cellular phagocytosis or antibody dependent complement deposition in the CD4+ depleted animals. These results suggest that HIV neutralizing antibodies can be induced in the absence of robust CD4+ T cell help, which may have implications for developing effective HIV vaccine strategies.

Heterologous

HIV vaccine

10.4049/jimmunol.204.supp.247.11

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Fc-Effector-Independent in vivo Activity of a Potent Influenza B Neuraminidase Broadly Neutralizing Antibody

Viruses (2023)

Ahmed Magdy Khalil Michael S. Piepenbrink Ian Markham Madhubanti Basu Luis Martínez‐Sobrido

Influenza B virus (IBV) contributes to substantial influenza-mediated morbidity and mortality, particularly among children. Similar to influenza A viruses (IAV), the hemagglutinin (HA) and neuraminidase (NA) of IBV undergo antigenic drift, necessitating regular reformulation of seasonal influenza vaccines. NA inhibitors, such as oseltamivir, have reduced activity and clinical efficacy against IBV, while M2 channel inhibitors are only effective against IAV, highlighting the need for improved vaccine and therapeutics for the treatment of seasonal IBV infections. We have previously described a potent human monoclonal antibody (hMAb), 1092D4, that is specific for IBV NA and neutralizes a broad range of IBVs. The anti-viral activity of MAbs can include direct mechanisms such as through neutralization and/or Fc-mediated effector functions that are dependent on accessory cells expressing Fc receptors and that could be impacted by potential host-dependent variability. To discern if the in vivo efficacy of 1092D4 was dependent on Fc-effector function, 1092D4 hMAb with reduced ability to bind to Fc receptors (1092D4-LALAPG) was generated and tested. 1092D4-LALAPG had comparable in vitro binding, neutralization, and inhibition of NA activity to 1092D4. 1092D4-LALAPG was effective at protecting against a lethal challenge of IBV in mice. These results suggest that hMAb 1092D4 in vivo activity is minimally dependent on Fc-effector functions, a characteristic that may extend to other hMAbs that have potent NA inhibition activity.

Neuraminidase inhibitor

Oseltamivir

10.3390/v15071540

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Broad and Protective Influenza B Virus Neuraminidase Antibodies in Humans after Vaccination and their Clonal Persistence as Plasma Cells

mBio (2019)

Michael S. Piepenbrink Aitor Nogales Madhubanti Basu Christopher Fucile Jane L. Liesveld

Although most seasonal inactivated influenza vaccines (IIV) contain neuraminidase (NA), the extent and mechanisms of action of protective human NA-specific humoral responses induced by vaccination are poorly resolved. Due to the propensity of influenza virus for antigenic drift and shift and its tendency to elicit predominantly strain-specific antibodies, humanity remains susceptible to waves of new strains of seasonal viruses and is at risk from viruses with pandemic potential for which limited or no immunity may exist. Here we demonstrate that the use of IIV results in increased levels of influenza B virus (IBV) NA-specific serum antibodies. Detailed analysis of the IBV NA B cell response indicates concurrent expansion of IBV NA-specific peripheral blood plasmablasts 7 days after IIV immunization which express monoclonal antibodies with broad and potent antiviral activity against both IBV Victoria and Yamagata lineages and prophylactic and therapeutic activity in mice. These IBV NA-specific B cell clonal lineages persisted in CD138

10.1128/mbio.00066-19

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Citations (27)

IL-33 enhances the induction, durability, and breadth of the antibody response to a DNA/protein-based HIV Env vaccine

The Journal of Immunology (2017)

James J. Kobie Sanghita Sarkar Michael S. Piepenbrink Madhubanti Basu Michael C. Keefer

Abstract Induction of a sustained and broad antibody (Ab) response is a major goal in developing a protective HIV vaccine. DNA is an attractive priming strategy when combined with protein or viral vector boosting; however, DNA priming alone fails to induce a substantial Ab response, limiting its potential as a stand-alone immunogen. Using the VC10014 DNA/protein vaccine consisting of gp160 plasmids and gp140 proteins derived from an HIV clade B infected subject who developed broadly neutralizing serum Abs, and which has been previously shown to induce Tier 2 heterologous neutralizing Abs in rhesus macaques, we screened a panel of factors in C57BL/6 mice for their ability to enhance the Env-specific Ab response. IL-33, an alarmin, emerged as the lead candidate. The addition of recombinant IL-33 during the gp160 DNA priming phase dramatically changed the kinetics of the Ab response, inducing serum gp120-specific IgG (>1:12,500 titer) after a single DNA immunization, which was not detectable in mice that did not receive IL-33 (p<0.0001). Then following boosting with DNA/protein coimmunization in Alum, gp120-specific IgG levels were extraordinarily durable, remaining stable even at 6 weeks after final immunization compared to mice not receiving IL-33 (p<0.0001), in which they rapidly declined. IL-33 also increased the cross-clade breadth and avidity of the serum gp120-specific IgG response. Analysis of the Env-specific B cell immunoglobulin repertoire and the IL-33 mechanism of action is ongoing. These results demonstrate the profound effect that priming conditions can have on the quality of the Env-specific antibody response.

Immunogen

Naked DNA

Avidity

Priming (agriculture)

Heterologous

HIV vaccine

10.4049/jimmunol.198.supp.225.16

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CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques

Frontiers in Immunology (2021)

Sanghita Sarkar David A. Spencer Philip Barnette Shilpi Pandey William F. Sutton

Induction of broadly neutralizing antibodies (bNAbs) is a major goal for HIV vaccine development. HIV envelope glycoprotein (Env)-specific bNAbs isolated from HIV-infected individuals exhibit substantial somatic hypermutation and correlate with T follicular helper (Tfh) responses. Using the VC10014 DNA-protein co-immunization vaccine platform consisting of gp160 plasmids and gp140 trimeric proteins derived from an HIV-1 infected subject that developed bNAbs, we determined the characteristics of the Env-specific humoral response in vaccinated rhesus macaques in the context of CD4+ T cell depletion. Unexpectedly, both CD4+ depleted and non-depleted animals developed comparable Tier 1 and 2 heterologous HIV-1 neutralizing plasma antibody titers. There was no deficit in protection from SHIV challenge, no diminution of titers of HIV Env-specific cross-clade binding antibodies, antibody dependent cellular phagocytosis, or antibody-dependent complement deposition in the CD4+ depleted animals. These collective results suggest that in the presence of diminished CD4+ T cell help, HIV neutralizing antibodies were still generated, which may have implications for developing effective HIV vaccine strategies.

Heterologous

HIV vaccine

10.3389/fimmu.2021.757811

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Pan-coronavirus neutralizing S2 human monoclonal antibodies and utility of direct respiratory administration as combination therapy with S1 antibodies against SARS-CoV-2

The Journal of Immunology (2022)

James Kobie Jun‐Gyu Park Sanghita Sarkar Madhubanti Basu Andreas Loos

Abstract To determine if pan-coronavirus neutralizing antibodies are induced by SARS-CoV-2 infection, human monoclonal antibodies (mAb) targeting the highly conserved S2 domain of the Spike glycoprotein were cloned from B cells isolated from convalescent patients with rationally designed SARS-CoV-2 stabilized S2 and SARS-CoV/SARS-CoV-2 S1S2 chimera recombinant protein probes. mAbs emerged capable of binding SARS-CoV-2, including the variants of concern (Beta, Gamma, Delta, and Omicron), SARS-CoV and MERS-CoV. The most potent neutralizing mAb with greatest breadth, 1249A8, recognizes all beta-coronaviruses tested including high affinity for SARS-CoV-2, SARS-CoV, and MERS-CoV. The 1249A8 lineage appears to have developed from a pre-existing OC43-specific memory B cell that was expanded as result of SARS-CoV-2 infection, and further expanded following COVID-19 vaccination. Treating K18 hACE2 transgenic mice with 1249A8 intraperitoneally prior to co-infection with SARS-CoV-2 Wa-1 and Beta VoC strains prevented weight loss and death, with viral titers below detectable levels by 4 days post-infection. 1249A8 delivered as a single 4mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2/Delta significantly protected them from weight loss, with therapeutic activity enhanced when combined with an S1-specific neutralizing mAb. As little as 2 mg/kg of 1249A8 i.n. 20 hours following infection with SARS-CoV/Urbani protected hamsters from weight loss. 1249A8 recognizes a highly conserved region near HR2 of the S2 domain of Spike. These results indicate that potent pan-coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can inform pan-coronavirus vaccine development. Supported in-part by Aridis Pharmaceuticals and NIH (R01AI161175).

Vero cell

Coronavirus

Coronaviridae

10.4049/jimmunol.208.supp.65.11

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A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody

Scientific Reports (2018)

Aitor Nogales Michael S. Piepenbrink Jiong Wang Sandra Ortega Madhubanti Basu

Abstract Influenza’s propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1. KPF1 has broad and potent neutralizing activity against H1 influenza viruses, and recognized 83% of all H1 isolates tested, including the pandemic 1918 H1. Prophylactically, KPF1 treatment resulted in 100% survival of mice from lethal challenge with multiple H1 influenza strains and when given as late as 72 h after challenge with A/California/04/2009 H1N1, resulted in 80% survival. KPF1 recognizes a novel epitope in the HA globular head, which includes a highly conserved amino acid, between the Ca and Cb antigenic sites. Although recent HA stalk-specific mAbs have broader reactivity, their potency is substantially limited, suggesting that cocktails of broadly reactive and highly potent HA globular head-specific mAbs, like KPF1, may have greater clinical feasibility for the treatment of influenza infections.

10.1038/s41598-018-22307-8

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Citations (61)

HIV gp120-specific memory develops from pre-existing memory and naive B cells following vaccination in humans

The Journal of Immunology (2022)

James Kobie Michael S. Piepenbrink Christopher Fucile Catherine A. Bunce Li‐Xing Man

Abstract The most potent and broad HIV envelope (Env)-specific antibodies often when reverted to their inferred germline versions representing the naïve B cell receptor, fail to bind Env suggesting that the initial responding B cell population is not exclusively comprised of a naïve 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 from HVTN105, a phase I trial testing AIDSVAX B/E (gp120 protein) combined with a DNA immunogen. Using MiSeq-based deep sequencing VH-lineage tracking we identified several of these mAb lineages in pre-immune peripheral blood. Additionally, we sought to characterize the gp120-specific B cell repertoire prior to immunization, and the features of those pre-immune B cell clonal lineages that ultimately respond to the vaccine. 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. Greater gp120 binding activity was observed from the non-naïve pre-immune VH members than their germline VH versions. The majority of the pre-immune gp120-reactive lineages included IgM, however IgG and IgA members were also predominant prior to vaccination. Additionally, the majority of the pre-immune lineage members exhibited somatic hypermutation prior to vaccination, suggesting that the vaccine-induced gp120-specific antibody lineages originated from both naïve B cells and cross-reactive memory B cells. Supported by grants from the NIH (R01AI117787, R21AI116285).

Immunogen

Memory B cell

Naive B cell

10.4049/jimmunol.208.supp.168.13

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