scholarly journals Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0256885
Author(s):  
Stella J. Berendam ◽  
Papa K. Morgan-Asiedu ◽  
Riley J. Mangan ◽  
Shuk Hang Li ◽  
Holly Heimsath ◽  
...  
Keyword(s):  
B Cell ◽  
Rhesus Macaques ◽  
Cell Receptor ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Pediatric Hiv ◽  
Specific Memory ◽  
Plasma Antibody ◽  
Hiv Envelope ◽  
Infant Rhesus

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06–1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

scholarly journals Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques.

2021 ◽  
Author(s):  
Genevieve G. Fouda ◽  
Stella J Berendam ◽  
Papa K Morgan-Asiedu ◽  
Riley J Mangan ◽  
Shukhang Li ◽  
...  
Keyword(s):  
B Cell ◽  
Rhesus Macaques ◽  
Cell Receptor ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Pediatric Hiv ◽  
Specific Memory ◽  
Plasma Antibody ◽  
Hiv Envelope ◽  
Infant Rhesus

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein coadministered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

scholarly journals Oral clade C SHIV challenge models to study pediatric HIV-1 infection by breastmilk transmission

2019 ◽  
Author(s):  
Koen K.A. Van Rompay ◽  
Alan D. Curtis ◽  
Michael Hudgens ◽  
Ryan Tuck ◽  
Neelima Choudhary ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Rhesus Macaques ◽  
Hiv Infections ◽  
Hiv Vaccine ◽  
Pediatric Hiv ◽  
Infection Models ◽  
Clade C ◽  
Virological Outcomes ◽  
Shiv Infection ◽  
Infant Rhesus

ABSTRACTNonhuman primate (NHP) models are invaluable for HIV pathogenesis, intervention and cure studies. To enhance the translational potential of NHP HIV vaccine studies, clinically relevant R5-tropic, tier 2 neutralization sensitive, and mucosally transmissible simian-human immunodeficiency viruses (SHIVs) have been designed. Towards our goal of developing vaccines to prevent breastmilk transmission of HIV, we evaluated virological outcomes of three distinct SHIVs in repeated weekly oral exposure regimens in infant rhesus macaques. The selected strains SHIV-1157ipd3N4, SHIV-1157(QNE)Y173H, and SHIV CH505 375H.dCT express a clade C HIV Env, the clade most prevalent in regions with high pediatric HIV infections.All three SHIVs were orally transmissible. However, compared to the pediatric SIVmac251model, SHIV replication was more attenuated. Some animals exposed to weekly low-dose (20 TCID50) SHIV-1157ipd3N4 had transient viremia blips associated with lack or delayed seroconversion. Animals with acute viremia ≥10,000 viral RNA copies/ml seroconverted. This finding was reminiscent of an earlier study suggesting to continue challenges until a threshold of ≥10,000 viral RNA copies/ml is surpassed to achieve seroconversion, one criterion of HIV diagnosis. All animals exposed weekly with higher doses (>104TCID50) of SHIV-1157(QNE)Y173H or SHIV CH505 375h.dCT developed persistent infection with high peak viremia and seroconverted. Chronic viremia varied widely in all three SHIV infection models. Thus, although R5 clade C SHIVs are excellent tools to study prevention of virus acquisition, secondary virological outcomes of vaccine efficacy (e.g. risk of infection per exposure, modulation of peak viremia, viral set point) will require careful consideration and validation in SHIV challenge models.IMPORTANCEThe development of an effective HIV vaccine remains a top priority towards the goal of reducing the number of new HIV infections. Studies in nonhuman primate models of HIV infection have been instrumental in the preclinical evaluation of candidate vaccines. To assess the role of HIV Env-specific antibodies with broadly neutralizing or Fc-mediated effector function in these NHP models, the development and optimization of novel SHIV challenge models is required. We evaluate three different clade C HIV Env SHIVs for infectivity of infant macaques by the oral route. Our results demonstrate that SHIV-1157ipd3N4, SHIV-1157(QNE)Y173H, and SHIV CH505 375H.dCT can be orally transmitted and establish persistent infection in infant rhesus macaques, but chronic viremia levels vary widely. Therefore, SHIV infection models are most pertinent when prevention of systemic infection is the primary readout of vaccine efficacy, but secondary outcome measures of vaccine efficacy will require stringent criteria and extensive validation.

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

2021 ◽  
Author(s):  
Madhubanti Basu ◽  
Michael S Piepenbrink ◽  
Christopher Fucile ◽  
Catherine A Bunce ◽  
Li-Xing Man ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Vaccine Trial ◽  
Cell Receptor ◽  
Cell Compartment ◽  
Specific Memory ◽  
Hiv Gp120 ◽  
Lineage Tracking ◽  
Hiv Envelope

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.

scholarly journals Responding kinetic of B-cell receptor repertoire to the Toll-like receptor 7/8 stimulation in non-human primates

2021 ◽  
Author(s):  
Shiyu Wang ◽  
Judith Mandl ◽  
Mark Feinberg ◽  
Michael Citron ◽  
Nitin K. Saksena ◽  
...  
Keyword(s):  
B Cell ◽  
Mutation Rate ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Low Frequency ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Receptor Repertoire ◽  
Cell Immunity ◽  
Repertoire Diversity

TLR7 and 8 regulate B cell immunity, but the precise details of the mechanism are still unclear. Here, we studied the kinetics of both heavy and light chains (IgKL) of B-cell receptor (BCR) repertoire responding to the TLR7/8 stimulation in two geniuses of non-human primates (NHPs), African green monkeys (AGMs) and rhesus macaques (RMs). We evaluated the activation of lymphocytes by flow cytometry and studied characteristics of BCR repertoire in terms of gene usage, repertoire diversity, and the number of lineages. Although AGMs had a weaker activation than RMs, and a different responding kinetic, both AGMs and RMs presented an increased IgKL repertoire diversity and lineages expansion. It suggested that the responding time rather than initiation of TLR7/8-induced IgKL repertoire response related to B cell activation. Expanded IgKL lineages with frequency from 0.001% to 1% had an elevated mutation rate and expanded IgH lineages used more IgA/G/E, suggesting that the TLR7/8 stimulation expanded low-frequent but high-mutated lineages. Besides, most of expanded IgKL lineages were lambda isotype. In conclusion, TLR7/8 selectively expands IgKL lineages with a high mutation rate, low frequency, and lambda isotype. The selective effect of TLR7/8 on BCR repertoire allows TLR7/8 agonists to be adjuvant for selectively accelerating antibody maturation.

scholarly journals Antibody Responses to Capsular Polysaccharide Backbone and O-Acetate Side Groups of Streptococcus pneumoniae Type 9V in Humans and Rhesus Macaques

1998 ◽  
Vol 66 (8) ◽  
pp. 3705-3710 ◽  
Author(s):  
Tessie B. McNeely ◽  
Joan M. Staub ◽  
Cynthia M. Rusk ◽  
Michael J. Blum ◽  
John J. Donnelly
Keyword(s):  
Streptococcus Pneumoniae ◽  
Capsular Polysaccharide ◽  
Rhesus Macaques ◽  
Acute Otitis Media ◽  
Antibody Responses ◽  
Side Chains ◽  
Monkey Model ◽  
Repeat Units ◽  
Pneumococcal Bacteremia ◽  
Infant Rhesus

ABSTRACT Streptococcus pneumoniae is responsible for high rates of pneumococcal bacteremia, meningitis, pneumonia, and acute otitis media worldwide. Protection from disease is conferred by antibodies specific for the polysaccharide (Ps) capsule of the bacteria. Of the four types of group 9 pneumococci, types 9N and 9V cause the most disease, and both types are included in the polyvalent pneumococcal vaccine. The type 9V capsule consists of repeating pentasaccharide units linearly arranged, with an average of 1 to 2 mol of O-acetate side chains per mol of repeat units, added in a complex pattern in which not all repeat units are alike. α-GlcA residues may be O-acetylated in the 2 (17%) or 3 (25%) position and β-ManNAc residues may be O-acetylated in the 4 (6%) or 6 (55%) position. Under certain conditions, the O-acetate side chains are subject to oxidation, which results in subsequent de-O-acetylation of a significant number of the repeat units. This de-O-acetylation could adversely affect the efficacy of a vaccine containing the 9V Ps. A study was undertaken to compare the relative contributions of O-acetate and Ps backbone epitopes in the immune response to S. pneumoniae 9V type-specific Ps. In both an infant rhesus monkey model and humans, antibodies against the non-O-acetylated 9V backbone as well as against O-acetylated 9V Ps were detected. Functional (opsonophagocytic) activity was observed in antisera in which the predominant species of antibody recognized de-O-acetylated 9V Ps. We concluded that the O-acetate side groups, while recognized, are not essential to the ability of the 9V Ps to induce functional antibody responses.

scholarly journals Rectal Microbiome Composition Correlates with Humoral Immunity to HIV-1 in Vaccinated Rhesus Macaques

mSphere ◽  
2019 ◽  
Vol 4 (6) ◽  
Author(s):  
Sonny R. Elizaldi ◽  
Anil Verma ◽  
Korey A. Walter ◽  
Matthew Rolston ◽  
Ashok R. Dinasarapu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaques ◽  
Temporal Stability ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Critical Determinant ◽  
Dynamic Component ◽  
Microbiome Composition ◽  
Vaccine Immunogenicity ◽  
Hiv 1

ABSTRACT The microbiome is an integral and dynamic component of the host and is emerging as a critical determinant of immune responses; however, its influence on vaccine immunogenicity is largely not well understood. Here, we examined the pivotal relationship between the mucosal microbiome and vaccine-induced immune responses by assessing longitudinal changes in vaginal and rectal microbiome profiles after intradermal immunization with a human immunodeficiency virus type 1 (HIV-1) DNA vaccine in adult rhesus macaques that received two prior DNA primes. We report that both vaginal and rectal microbiomes were dominated by Firmicutes but were composed of distinct genera, denoting microbiome specialization across mucosal tissues. Following immunization, the vaginal microbiome was resilient, except for a transient decrease in Streptococcus. In contrast, the rectal microbiome was far more responsive to vaccination, exhibiting an increase in the ratio of Firmicutes to Bacteroidetes. Within Bacteroidetes, multiple genera were significantly decreased, including Prevotella, Alloprevotella, Bacteroides, Acetobacteroides, Falsiporphyromonas, and Anaerocella. Decreased abundance of Prevotella correlated with induction of gut-homing α4β7+ effector CD4 T cells. Prevotella abundance also negatively correlated with rectal HIV-1 specific IgG levels. While rectal Lactobacillus was unaltered following DNA vaccination, baseline Lactobacillus abundance showed strong associations with higher rectal HIV-1 gp140 IgA induced following a protein boost. Similarly, the abundance of Clostridium in cluster IV was associated with higher rectal HIV-1 gp140 IgG responses. Collectively, these data reveal that the temporal stability of bacterial communities following DNA immunization is site dependent and highlight the importance of host-microbiome interactions in shaping HIV-1 vaccine responses. Our findings have significant implications for microbial manipulation as a strategy to enhance HIV vaccine-induced mucosal immunity. IMPORTANCE There is considerable effort directed toward evaluating HIV-1 vaccine platforms to select the most promising candidates for enhancing mucosal HIV-1 antibody. The most successful thus far, the RV144 trial provided partial protection due to waning HIV-1 antibody titers. In order to develop an effective HIV vaccine, it may therefore be important to understand how biological factors, such as the microbiome, modulate host immune responses. Furthermore, as intestinal microbiota antigens may generate antibodies cross-reactive to the HIV-1 envelope glycoprotein, understanding the relationship between gut microbiota composition and HIV-1 envelope antibody responses after vaccination is important. Here, we demonstrate for the first time in rhesus macaques that the rectal microbiome composition can influence HIV-1 vaccine immunogenicity, and we report temporal changes in the mucosal microbiome profile following HIV-1 vaccination. Our results could inform findings from the HIV Vaccine Trials Network (HVTN) vaccine studies and contribute to an understanding of how the microbiome influences HIV-1 antibody responses.

scholarly journals Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Ganesh E. Phad ◽  
Pradeepa Pushparaj ◽  
Karen Tran ◽  
Viktoriya Dubrovskaya ◽  
Monika Àdori ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Hypermutation ◽  
Rhesus Macaques ◽  
Tier 2 ◽  
Cell Responses ◽  
Specific Memory ◽  
Large Numbers ◽  
Clade C ◽  
B Cell Responses ◽  
Complementarity Determining Regions

Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.

scholarly journals Improved flow-based method for HIV/SIV envelope-specific memory B-cell evaluation in rhesus macaques

2014 ◽  
Vol 412 ◽  
pp. 78-84 ◽  
Author(s):  
Venkatramanan Mohanram ◽  
Thorsten Demberg ◽  
Iskra Tuero ◽  
Diego Vargas-Inchaustegui ◽  
George N. Pavlakis ◽  
...  
Keyword(s):  
B Cell ◽  
Rhesus Macaques ◽  
Memory B Cell ◽  
Specific Memory

scholarly journals gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory.

1994 ◽  
Vol 180 (1) ◽  
pp. 157-163 ◽  
Author(s):  
T M Foy ◽  
J D Laman ◽  
J A Ledbetter ◽  
A Aruffo ◽  
E Claassen ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Antibody Responses ◽  
Cell Memory ◽  
Specific Memory ◽  
B Cell Memory ◽  
Germinal Center Formation

gp39, the ligand for CD40 expressed on activated CD4+ T helper cells, is required for the generation of antibody responses to T-dependent (TD) antigens. Treatment of mice with anti-gp39 in vivo inhibits both primary and secondary antibody formation to TD, but not T-independent antigens. However, the role of this receptor-ligand pair in the development of germinal centers and the generation of B cell memory is as yet undefined. Using an antibody to gp39, this study examines the in vivo requirement for gp39-CD40 interactions in the induction of germinal center formation, as well as in the generation of B cell memory. Animals were immunized, treated in vivo with anti-gp39, and evaluated using immunohistochemical staining for the presence of splenic germinal centers 9-11 d after immunization. The results demonstrate that the formation of germinal centers was completely inhibited as a result of treatment with anti-gp39. Moreover, adoptive transfer experiments demonstrate that the generation of antigen-specific memory B cells is also inhibited as a consequence of blocking gp39-CD40 interactions. Taken together, the data demonstrate that gp39-CD40 interactions are critical not only for the generation of antibody responses, but also in the development of B cell memory.

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