Replies to post #26501 on Mymetics Corp (MYMX)

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Mucosal AIDS virus transmission is enhanced by antiviral IgG isolated early in infection

AIDS: December 1, 2021 - Volume 35 - Issue 15 - p 2423-2432

Methods

Cell lines, reagents and virus
SupT1.R5 cells (CD4+CCR5+CR2+) were provided by J.A. Hoxie (University of Pennsylvania), A3R5.7 cells by D.C. Montefiori (Duke University), SHIV-1157ip [23] gp120 and gp160 by S.L. Hu (University of Washington), mAb Fm-6-IgG1 by W.A. Marasco (Dana-Farber Cancer Institute), and HIV-1MN gp41, consensus-clade C peptides, and CN54 gp140 [24] by the NIH AIDS Reagent Program. We generated reporter virus NL-LucR.1157ipd3N4 by cloning SHIV-1157ipd3N4 [25]env into plasmid pNL-LucR.T2A (provided by C. Ochsenbauer, University of Alabama). SHIV-1157ipd3N4 stock [grown in rhesus macaque peripheral blood mononuclear cells (PBMC)] contained 713 ng/ml of p27 and 7 × 106 50% tissue culture infectious doses (TCID50)/ml (measured in TZM-bl cells).

Intrarectal SHIV-1157ipd3N4 challenge
To test the hypothesis that early-stage anti-HIV Env IgG enhances in-vivo viral acquisition, we performed an end-point virus titration in macaques, using an upfront heterologous, R5 tier 2 clade C SHIV. To avoid confounding influences of different viral quasi-species, we selected an infectious molecular clone, SHIV-1157ipd3N4 [25]. We enrolled two groups of eight macaques. First, we determined minimal infectious and 50% animal infectious doses (AID50) in naive animals, which were sequentially exposed intrarectally to increasingly diluted SHIV stock (Fig. 4). After a given animal's viremia was >104 copies/ml, the next macaque was inoculated with a ten-fold higher virus-stock dilution, until a 1 : 10,000 dilution failed to infect. Subsequent animals were then exposed to intermediate dilutions; animals that remained aviremic on day 28 after initial challenge were re-exposed to a high virus inoculum (1 : 2 dilution of the stock); all such animals became viremic (Fig. 5a).

https://journals.lww.com/aidsonline/Fulltext/2021/12010/Mucosal_AIDS_virus_transmission_is_enhanced_by.2.aspx

https://view.officeapps.live.com/op/view.aspx?src=https%3A%2F%2Fcdn-links.lww.com%2Fpermalink%2Fqad%2Fc%2Fqad_2021_08_10_ruprecht_aids-d-21-00364_sdc1.docx&wdOrigin=BROWSELINK

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Conclusion:

These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure – a potential concern for antibody-based AIDS vaccine development.

Discussion

Here we showed: i) enSHIVIG, when passively administered to macaques, enhanced virus acquisition and significantly lowered the amount of virus needed to achieve viremia compared to naive controls; ii) ex-vivo enSHIVIG testing in the presence of active complement revealed significant C’-ADE activity that was abrogated by C’ heat inactivation or anti-CD21 mAb. These results indicate that antibodies generated during early-stage HIV/SHIV infection may increase host susceptibility and facilitate virus acquisition and early dissemination.

Previously [21], we had treated macaques biweekly with different intravenous doses of SHIVIG, the polyclonal high-titer neutralizing IgG, in order to link in-vitro neutralization titers with prevention of mucosal SHIV acquisition. Unexpectedly, animals pretreated with low-dose SHIVIG (25 mg/kg) had more viral quasispecies compared to untreated controls – implying increased SHIV transmission. Despite good SHIVIG neutralizing activity in TZM-bl cells, enhancement was observed in the presence of active complement in CR2/CD21-expressing SupT1.R5 cells that was abrogated by complement heat inactivation [21]. Together, these findings reinforce our current data that weakly or non-neutralizing neutralizing IgG may enhance mucosal SHIV acquisition through mechanisms dependent on complement activation.

It is intriguing to compare the 3.4-fold enhanced mucosal SHIV-1157ipd3N4 acquisition we report here with the magnitude of in-vitro HIV enhancement by Willey et al.[18] who measured C’-ADE in CR2-expressing SupT1/R5 cells using paired autologous early-stage sera/HIV isolates. Enhancement ranged from 8- to 236-fold and was lower when assessed with heterologous virus isolates. Differences in the order-of-magnitude of HIV C’-ADE reported [18] and our 3.4-fold lowering of the SHIV challenge dose needed to persistently infect enSHIVIG-pretreated macaques can be ascribed to CR2 expression by all SupT1.R5 cells used for in-vitro assays. In vivo, however, CR2 is expressed only by select cell populations, such as B cells, follicular dendritic cells, and according to a recent report [33], on naive CD4+ and CD8+ T cells.

In addition to C’-ADE, in-vitro assays have revealed another mechanism: Fc receptor-mediated ADE (FcR-ADE) [11,13,34–37] (reviewed in [38,39]). Monocyte/macrophage-derived cell lines expressing different FcRs were used to demonstrate FcR-ADE. Forthal et al.[40] provided indirect evidence of FcR-ADE from a Phase III AIDS vaccine trial; by subgroup analysis, a statistically significant association was noted between increased HIV acquisition and the Fc?RIIIa allele in vaccinees given monomeric gp120.

Our present data as well as those summarized above from prior studies have one common denominator: the IgGs were polyclonal. As such, we cannot distinguish between two possibilities for ADE: i) polyclonal IgG consists of a mixture inherently neutralizing and inherently enhancing antibodies; and ii) a given IgG neutralizes in one situation and enhances in another. This key issue can only be addressed by using mAbs – done in a seminal study by Kliks et al.[41] who examined the interaction of two different human anti-V3 mAbs with three different HIV-1 strains. Depending on the virus tested, the results yielded either neutralization, enhancement, or neither. Thus, well characterized mAbs are unpredictable in their interactions with different HIV strains. Enhancing antibodies have also been implicated in mother-to-child transmission of HIV in a number of studies [42–44]; some reports raised the possibility that enhancement may be linked to antibodies targeting HIV-1 gp41 [43–45].

Although different investigators have shown HIV ADE in various cell line-based assays over the years, whether such in-vitro data would translate into Antibody-Dependent Enhanced Virus Acquisition – ADE-VA – remained unsolved. Passive immunization of macaques with early-stage anti-SHIV IgG followed by intrarectal SHIV challenge gave proof-of-principle for increased virus acquisition and host susceptibility. AIDS vaccine development should consider the potential of ADE-VA due to vaccine-induced antibodies during experimental vaccine trials. To rule out this possibility, passive immunization with vaccine-induced antibodies could be used as a tool in biologically relevant animal models, that is, models that reflect key aspects of HIV transmission among humans, including i) tier 2 R5 challenge viruses carrying HIV-1 Env, ii) a nonhuman primate species, and iii) antibodies that are heterologous to the challenge viruses. The latter point is important since matched homologous virus/antibody systems will exaggerate neutralization and thereby mask potential enhancement by weakly or non-neutralizing antibodies. In the realistic setting of human vaccinees’ exposure to circulating HIV strains, an exact match between immunogen composition and the myriad of HIV quasispecies can never be expected.

Indirect evidence that vaccine-induced antibodies can have adverse effects comes from a feline immunodeficiency virus (FIV) study, where cats were vaccinated with various recombinant envelope glycoproteins [46]. Although neutralization in cell-line based assays was observed in plasma samples from some vaccinated groups, no virus-neutralizing antibodies were detected in the feline lymphocyte assay. Upon FIV challenge, cell-associated FIV loads were increased in the groups vaccinated with recombinant FIV Env glycoproteins compared to other groups or controls. Passive transfer of unfractionated plasma from groups with increased cell-associated FIV enhanced viral infection parameters in the recipients. While these data imply ADE, an influence of other factor(s) present in unfractionated plasma cannot be ruled out.

In sum, AIDS virus C’-ADE is real – as our passive immunization showed significant lowering of the virus dose needed to achieve viremia indicative of ADE-VA. As such, the current study with early-stage enSHIVIG confirmed our unexpected finding with late-stage SHIVIG, selected for maximal in-vitro tier 2 SHIV cross-neutralization, where low-dose pretreatment yielded sub-neutralizing anti-HIV Env IgG levels that significantly increased the number of transmitted viral quasispecies. Together, our data imply that decreasing anti-HIV Env neutralizing antibody titers could bring vaccinated individuals into a situation where ADE-VA prevails.

ADE-VA may be of concern for other pathogens, especially rapidly mutating RNA viruses susceptible to neutralization escape. Vaccine development will need to consider potential enhancement of host susceptibility to infection due to ADE [47,48]. We propose that our strategy – passive immunization with purified polyclonal IgG isolated from previously infected/vaccinated individuals, combined with in-vivo end-point virus titration to assess the amount of virus needed to achieve infection of naïve versus passively immunized animals, can play an important role in assessing the potential for ADE-VA.

https://www.uab.edu/medicine/gastroenterology/research/mhic/investigators/23-centers/mhic/76-christina-ochsenbauer-jambor-phd

Christina Ochsenbauer-Jambor, Ph.D.

Dr. Ochsenbauer-Jambor completed her undergraduate studies in biology at the Johann-Wolfgang-Goethe Universität, Frankfurt am Main in Germany in 1988. She then moved to the Ruprecht-Karls-Universität in Heidelberg, Germany, where she studied molecular biology (virology) and zoology (primate ethology) and earned her ‘Diplom’ (Master) of Biology (magna cum laude) in 1992. Her Master’s thesis focused on functions of the HIV-1 Env protein, with the work performed at the German Cancer Research Center (DKFZ) in Heidelberg. After completing her Ph.D. thesis entitled “Investigations concerning the function of the HIV-1 Vif protein: Generation of a cell-culture model system by using selectable, replication-competent HIV-1” at the DKFZ, she received her Ph.D. (magna cum laude) in virology and molecular biology from Ruprecht-Karls-Universität in 1996. During her undergraduate and graduate work, Dr. Ochsenbauer-Jambor was a recipient of two scholarships from the German National Merit Fundation. After postdoctoral fellowship (1996-2001) in retroviral glycoprotein intracellular trafficking in the Department of Microbiology at UAB, she joined the UAB faculty in 2002 as a Research Instructor in the same department. In 2003, she relocated to the Department of Medicine, Division of Hematology/ Oncology.

Dr. Ochsenbauer-Jambor investigates the role of DC-SIGN in the capture and trans-infection of HIV-1 with special emphasis on virion internalization pathways and the acquisition of selective DC-SIGN-dependent resistance to neutralizing antibodies.

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Wayne A. Marasco, MD, PhD

https://www.dana-farber.org/find-a-doctor/wayne-a-marasco/

mAb Fm-6-IgG1 by W.A. Marasco (Dana-Farber Cancer Institute)

Dr. Shiu-Lok Hu

https://sop.washington.edu/people/shiu-lok-hu/

which later became a part of the Bristol-Myers Squibb Pharmaceutical Research Institute. During this time (1985-1997), he developed the first recombinant virus as a candidate HIV vaccine for FDA-approved clinical trials and provided the first demonstration of vaccine protection against SIV infection in a macaque model by the “poxvirus prime-protein boost” immunization strategy.

Courses Taught

Pharmaceutics 533: Biopharmaceutics and Drug Delivery

gp120 and gp160 by S.L. Hu (University of Washington)

https://www.hivreagentprogram.org/

HIV-1MN gp41, consensus-clade C peptides, and CN54 gp140 [24] by the NIH AIDS Reagent Program

https://web.expasy.org/cellosaurus/CVCL_S540

Category Cancer cell line

A3R5.7 cells by D.C. Montefiori (Duke University

[bow-tie]

Virosome Projects NIH
Look at these: Projects
Publications
Patents
Clinical Studies
News & More

https://reporter.nih.gov/search/cKx7iWDpXkmi4cCby1hSAw/projects

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Supplemental Digital Content for

Mucosal AIDS virus transmission is enhanced by antiviral IgG isolated early in infection

*Correspondence to: [e-mail]

Current address: S.K.L.: University of Texas MD Anderson Cancer Center, Houston, TX

A.A.: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA

Fig. S3. A3R5.7 cell line-based neutralization assay of the two macaques selected as IgG donors for the enSHIVIG prep. Polyclonal IgG was purified from sera of donor macaques at the time points post-infection indicated. The macaques were in the early stages of SHIV-2873Nip [2] infection. (a and b) Neutralization assays were performed using A3R5.7 cells with the reporter virus NL-LucR.1157ipd3N4 (see Fig. S1 legend). The assay was terminated after 48 h and bioluminescence was read.

Fig. S4. A3R5.7 cell line-based neutralization assay. Polyclonal IgG was purified from donor macaques at the time points post-infection indicated. The macaques were in the early stages of infection with SHIV-2873Nip [2]. (a-f) Neutralization assays were performed using A3R5.7 cells with the reporter virus NL-LucR.1157ipd3N4 as described in the legend for Fig. S3

Fig. S6. Pharmacokinetic study. Three rhesus macaques were treated intravenously (i.v.) with different doses of enSHIVIG. Serum samples were collected, and enSHIVIG concentrations were measured by ELISA binding to HIV-C gp120. IgG was isolated from serum samples and C’-ADE assays were performed. Negative neutralization indicates enhancement. The assays were performed at 24 h after enSHIVIG administration, a time point chosen based upon our earlier data [5]; *for animal 33174, only insufficient IgG amounts could be recovered from the 24 h time point; the value given shows C’-ADE at 12 h post treatment.

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Bishal Marasini

https://www.linkedin.com/in/bishal-marasini-a6579888

https://www.researchgate.net/profile/Bishal-Marasini

A Bivalent, Spherical Virus-Like Particle Vaccine Enhances Breadth of Immune Responses against Pathogenic Ebola Viruses in Rhesus Macaques

https://journals.asm.org/doi/10.1128/jvi.01884-19?permanently=true&;

TWEETED BY 3

https://wolterskluwer.altmetric.com/details/111946009/twitter

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We also thank Dr. Mario Roederer, Vaccine Research Center, for the gift of polyclonal IgG purified from SHIV-infected RMs.

Barrack lol

https://www.flowjo.com/about/company/founders

Bethesda, Maryland

https://irp.nih.gov/pi/mario-roederer

Patents by Inventor Mario Roederer

https://patents.justia.com/inventor/mario-roederer

Neutralizing antibodies to HIV-1 and their use
Patent number: 10035845
Abstract: Monoclonal neutralizing antibodies are disclosed that specifically bind to the CD4 binding site of HIV-1 gp120. Monoclonal neutralizing antibodies also are disclosed that specifically bind to HIV-1 gp41. The identification of these antibodies, and the use of these antibodies are also disclosed. Methods are also provided for enhancing the binding and neutralizing activity of any antibody using epitope scaffold probes.
Type: Grant
Filed: July 27, 2017
Date of Patent: July 31, 2018
Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services, University of Washington
Inventors: John Mascola, Richard Wyatt, Xueling Wu, Yuxing Li, Carl-Magnus Hogerkorp, Mario Roederer, Zhi-yong Yang, Gary Nabel, Peter Kwong, Tongqing Zhou, Mark Connors, William Schief

& gp41 18 more times including John R. Mascola

https://www.linkedin.com/in/mario-roederer-a957a946?challengeId=AQF9sBRUMNaHvgAAAX-ATem7mwS0vbMEh23mUrw-JYM247XVX4zumc_P6GgC29ha3vdF-8ga0nv0MsRbyPTjiieD_Cyh-OyFvA&submissionId=e7affecc-84c3-db16-dc44-c8907ec3923e

Others viewed

Thomas Liechti

Postdoctoral Research Fellow at the Vaccine Research Center, National Institutes of Health
Bethesda, Maryland, United States

Education

University of Zurich University of Zurich Graphic
University of Zurich
Doctor of Philosophy (Ph.D.)Microbiology and Immunology
2011 - 2017

Multicolor flow cytometry phenotyping of B cells in HIV-1 infection; Establishing multicolor flow cytometry panels with up to 16 markers, Multidimensional single cell analysis with dimensionality reduction (t-SNE) and cluster identification (SPADE, Citrus) algorithms, Working with human pathogens in Biosafety level 3 environment, Establishing Luminex assays to analyze antibody responses against different HIV-1 derived proteins/peptides and different IgG isotypes contributing to binding activity

University of Bern (Official)University of Bern (Official) Graphic
University of Bern (Official)
Master of Science (M.Sc.)Microbiology and Immunology
2009 - 2011

I studied the function of surface IgD on neutrophils and basophils on the impact on allergy during my master thesis at the Institute of Immunology of the University Hospital Inselspital Bern under the supervision of Prof. Dr. Clemens Dahinden. The techniques included isolation of basophils and neutrophils, multicolor flow cytometry, ELISA, immune cell stimulation assays and co-cultures.

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We thank Dr. Kathy Brasky (Texas Biomed/SNPRC) for overseeing the primate study

https://www.txbiomed.org/scientists/kathleen-m-brasky/

https://www.linkedin.com/in/kathleen-brasky-85948a44

[Work Harder]

SHIVSF162P3, ARP-6526, contributed by Drs. Janet Harouse, Cecilia Cheng-Mayer, Ranajit Pal and the DAIDS, NIAID; and mAb 2F5 (ARP-1475). Dr. Susan Zolla-Pazner kindly provided mAb 98.6.

Search 8 grants from Janet Harouse

New York Blood Center, New York, NY, United States

https://grantome.com/grant/NIH/U19-HD048957-01-2

NYU

https://www.researchgate.net/profile/Janet-Harouse

Cecilia Cheng-Mayer's research while affiliated with The Rockefeller University and other places

https://www.researchgate.net/scientific-contributions/Cecilia-Cheng-Mayer-2112538815

grants

https://grantome.com/grant/NIH/R01-CA072822-12

Aaron Diamond AIDS Research Center
New York, United States

https://loop.frontiersin.org/people/23209/bio

Ranajit Pal's research while affiliated with Advanced BioScience Laboratories Inc. and other places

https://www.researchgate.net/scientific-contributions/Ranajit-Pal-38758408

Susan Zolla-Pazner

https://en.wikipedia.org/wiki/Susan_Zolla-Pazner#:~:text=In%20the%20early%20days%20of,cells%20of%20HIV%2Dinfected%20individuals.

Zolla-Pazner Laboratory

https://labs.icahn.mssm.edu/zolla-paznerlab/

The Army-led Thai HIV vaccine efficacy trial, known as RV144, tested the “prime-boost” combination of two vaccines:

https://www.hivresearch.org/hiv-research/rv144#:~:text=The%20Army%2Dled%20Thai%20HIV,that%20commonly%20circulate%20in%20Thailand.

[Work Harder]

National Institute of Allergies and Infectious Diseases

IPCAVD Program Highlights

• Duke University has been funded with two IPCAVD grants to develop mRNAs in lipid nanoparticles (LNPs) for mRNA administration for induction of either protective non-neutralizing antibodies (nNAbs) or broadly neutralizing Abs (bNAbs). Under this funding mechanism, the Bart Haynes group at Duke is developing process and GMP manufacture optimal mRNA immunogens and mRNA-LNP formulations for use in human Phase I trials.

• Dr. Ruth Ruprecht and Mymetics Corporation have been funded to develop and GMP manufacture a novel virosomal HIV vaccine. The product concept involves influenza virosomes enveloping virus-like
particles that display on their surface elongated HIV gp41 peptides (virosome-P1) or recombinant truncated HIV gp41 (virosome-rgp41). Powdered particulate dosage forms of new virosome vaccine candidates will be GMP manufactured and administered as nasal spray.

Preclinical HIV Vaccine Development22

Process development for the first synthetic glycopeptide HIV immunogen nanoparticle vaccine has started.
Chemistry and Manufacturing Controls (CMC)-compliant process and GMP manufacturing will be developed
to conduct Phase 1 clinical trials. Progress on building an armamentarium of particulated adjuvants for
preclinical and clinical studies includes the following:

• GMP GLA-LSQ liposomal adjuvant for antigen-adjuvant comparison clinical study. In Q1 2019, NIAID’s
Vaccine Translational Research Branch (VTRB) acquired this liposomal adjuvant for a Julie
McElrath/HVTN clinical trial comparing a variety of adjuvants.

• Delta inulin (Advax™), a polysaccharide particle adjuvant. GMP manufacturing process development is
ongoing to produce the adjuvant of appropriate quality to support clinical trials.

https://www.nano.gov/sites/default/files/NIH-2020-NNI-progress-plans-final.pdf

McElrath Lab

& Julie liked the finish line from Texas Biomed w/ a complete revamp of her LIKED ON page.

University of Pennsylvania now

https://research.fredhutch.org/mcelrath/en.html

National HIV/AIDS Strategy (2022-2025)

https://www.hiv.gov/federal-response/national-hiv-aids-strategy/national-hiv-aids-strategy-2022-2025

Better get cracking Astro Admin

LOL

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Indirect evidence that vaccine-induced antibodies can have adverse effects comes from a feline immunodeficiency virus (FIV) study, where cats were vaccinated with various recombinant envelope glycoproteins [46]. Although neutralization in cell-line based assays was observed in plasma samples from some vaccinated groups, no virus-neutralizing antibodies were detected in the feline lymphocyte assay. Upon FIV challenge, cell-associated FIV loads were increased in the groups vaccinated with recombinant FIV Env glycoproteins compared to other groups or controls. Passive transfer of unfractionated plasma from groups with increased cell-associated FIV enhanced viral infection parameters in the recipients. While these data imply ADE, an influence of other factor(s) present in unfractionated plasma cannot be ruled out.

That from second link

French Application No. 01 16290, December 17, 2001. novel peptides useful in the
treatment of FIV in cats, inventor Simone Giannecchini, Pending

https://www.sec.gov/Archives/edgar/data/927761/000095012803000464/j9927101exv10w38.txt

Simone Giannecchini

Retrovirus Center and Virology Section, Department of Experimental Pathology, University of Pisa, I-56127 Pisa,1 Department of Pharmaceutical Sciences, University of Salerno, I-84084 Fisciano, Italy,3 Mymetics Corporation, Annapolis, Maryland2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC149492/

MRC (UK)

https://www.researchgate.net/publication/10879995_Antiviral_Activity_and_Conformational_Features_of_an_Octapeptide_Derived_from_the_Membrane-Proximal_Ectodomain_of_the_Feline_Immunodeficiency_Virus_Transmembrane_Glycoprotein

https://www.vet.cornell.edu/departments-centers-and-institutes/cornell-feline-health-center/health-information/feline-health-topics/feline-immunodeficiency-virus-fiv

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644647/

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A number of Phase 3 clinical trials showed lack of efficacy (2–4), with the one exception of the RV144 trial that showed a 31.2% reduction in the risk of HIV acquisition among the vaccinees, compared to individuals given placebo (5). Most vaccine strategies involving HIV envelope immunogens focused on gp120, gp140, or gp160 and did not include analyses of mucosal immune responses in trials performed in nonhuman primate (NHP) models or humans. Notable exceptions include studies performed by the team of Robert-Guroff (6, 7) who tested mucosal delivery of vaccine antigens through either the intranasal or intratracheal routes [reviewed in (8)].

Furthermore, subunit vaccine administration has often involved a single parenteral route (9–11) or sometimes by single mucosal administration (12, 13), but rarely involved combined mucosal and intramuscular (i.m.) immunizations as was done with virosomal vaccines (14, 15). Our team and others have postulated that an effective HIV/AIDS vaccine must be capable of eliciting both systemic and mucosal immune protection for maximal protection of different mucosal portals of entry.

[Work Harder]

This article has more views than 30% of all Frontiers articles.

The Protective HIV-1 Envelope gp41 Antigen P1 Acts as a Mucosal Adjuvant Stimulating the Innate Immunity

Lin Xu1,2,3, Daniela Tudor1,2,3 and Morgane Bomsel1,2,3*

https://www.frontiersin.org/articles/10.3389/fimmu.2020.599278/full

U19AI142636

Added additional as Other Supporting Projects

https://reporter.nih.gov/search/K-ztMzgyCk25GZC9F4Nb-A/publications?sort_field=pub_year&sort_order=desc

Baboon model of long term effects of SARS-CoV-2 infection

https://reporter.nih.gov/search/K-ztMzgyCk25GZC9F4Nb-A/publications/project-details/10413419

Isn't that interesting

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Associated Data Supplementary Materials

Word doc

Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges

Immune-Tech

gp41 HxBc2

Duke PPF, Duke Protein Production Facility

NIH AIDS Reagents

Mymetics

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902080/

*Note that the anti-Hu IgA antibody (aHu IgA) from Southern Biotech was evaluated and found to be both cross-reactive with rhesus IgA and demonstrated improved signal as compared to specific anti-RhIgA detection antibodies tested. aRh IgG, anti-rhesus IgG

Headquarters location: Birmingham, AL

https://www.southernbiotech.com/

gp41 (HIV-1/HXBc2)

https://immune-tech.net/product/gp41-hxbc2/

https://www.eenzyme.com/gp41-hiv-1-hxbc2.aspx

https://www.cambridgebiologics.com/product_show.php?id=355

Envelope glycoprotein determinants of neutralization resistance in a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2) derived by passage in monkeys

https://pubmed.ncbi.nlm.nih.gov/11287570/

Harvard

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Associated Data Supplementary Materials 2 of 2

Word doc

Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges

Immune-Tech

HIV-1 gp41 MN

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902080/

HIV1 gp41 MN Recombinant Protein

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HIV-1 gp41 Long Recombinant Protein

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Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

HIV-1 gp41 MN

1Duke Human Vaccine Institute, 2Department of Medicine, 3Department of Pediatrics, 4Department of Surgery, 5Department of Immunology, and 6Center for Computational Immunology, Duke University School of Medicine, Durham, NC 27710
7The Aaron Diamond AIDS Research Center, New York, NY 10016
8University of Alabama-Birmingham, Birmingham, AL 35294
9University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
10Department of Pathology, Stanford School of Medicine, Stanford, CA 94305
11454 Life Sciences, Branford, CT 06405
12GlaxoSmithKline Biologicals, 1330 Rixensart, Belgium
corresponding authorCorresponding author.
CORRESPONDENCE Hua-Xin Liao: ude.ekud@oailh OR Barton F. Haynes: ude.ekud.cm@200enyah
X. Chen, S. Munshaw, G. Tomaras, M.A. Moody, and T.B. Kepler contributed equally to this paper.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201211/

Recombinant HIV-1 MN gp41 Envelope Protein (E.coli)

New

rgp41 HIV-1 MN(E.coli)

https://immunodx.com/products/rgp41-hiv-1-mne-coli

Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies

Acknowledgements

WW acknowledges support from the Institut Universitaire de France (IUF), from the European Union's Horizon 2020 research and innovation program under grant agreement No. 681137, H2020 EAVI and the platforms of the Grenoble Instruct-ERIC center (IBS and ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the Grenoble Partnership for Structural Biology (PSB). Platform access was supported by FRISBI (ANR-10-INBS-05–02) and GRAL, a project of the University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-0003). IBS is part of the CEA DRF Interdisciplinary Research Institute of Grenoble (IRIG). JLN acknowledges funding from Spanish MCIU (RTI2018-095624-B-C21; MCIU/AEI/FEDER, UE) and Basque Government (IT1196-19). We thank Miriam Hock and Serafima Guseva for previous contributions to the project, Davide Corti for providing bnAb LN01, the ESRF-EMBL Joint Structural Biology Group for access and support at the ESRF beam lines, J Marquez (EMBL) from the HTX crystallization facility and C Mas and J-B Reiser for assistance on ISBG platforms.

https://elifesciences.org/articles/65005

Davide Corti. Senior Vice President, Antibody Research presso Vir Biotechnology

w/ a Gsk & B&M Gates equity investment

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=168092687

https://investorshub.advfn.com/boards/read_msg.aspx?message_id=167270024

Rally time yet again so lets hear it for the monkeys lol

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Meta-analysis of HIV-1 vaccine elicited mucosal antibodies in humans

Georgia D. Tomaras

Juliana McElrath

NIAID HIV Vaccine Trials Network (HVTN) 076, 088, 086, 096, 097, 205 Study TeamsShow fewer authors

https://www.nature.com/articles/s41541-021-00305-8

https://twitter.com/_R_Foundation?ref_src=twsrc%5Etfw%7Ctwcamp%5Eembeddedtimeline%7Ctwterm%5Eprofile%3A_R_Foundation%7Ctwgr%5EeyJ0Zndfc2tlbGV0b25fbG9hZGluZ18xMzM5OCI6eyJidWNrZXQiOiJjdGEiLCJ2ZXJzaW9uIjpudWxsfSwidGZ3X3NwYWNlX2NhcmQiOnsiYnVja2V0Ijoib2ZmIiwidmVyc2lvbiI6bnVsbH0sInRmd19ob3Jpem9uX3R3ZWV0X2VtYmVkXzk1NTUiOnsiYnVja2V0IjoiaHRlIiwidmVyc2lvbiI6bnVsbH0sInRmd19zZW5zaXRpdmVfbWVkaWFfaW50ZXJzdGl0aWFsXzEzOTYzIjp7ImJ1Y2tldCI6ImNvbnRyb2wiLCJ2ZXJzaW9uIjo0fSwidGZ3X2V4cGVyaW1lbnRzX2Nvb2tpZV9leHBpcmF0aW9uIjp7ImJ1Y2tldCI6MTIwOTYwMCwidmVyc2lvbiI6bnVsbH19&ref_url=https%3A%2F%2Fwww.r-project.org%2F

Q&A with Georgia Tomaras, Professor in Surgery and Immunology Researcher

Thursday, February 10, 2022

Our colleagues [who submitted the proposal to the NIH] approached us for working on a component of a global influenza vaccine program, which is to develop standardized methods to evaluate the immune system. We had built a program from HIV and other pathogens where
we are standardizing, qualifying, and validating immune assays that we can use in clinical trials. So when [the grant] was awarded, it was clear that we would need new support for it and the School of Medicine fortunately supported new lab space and equipment.

Georgia Tomaras, PhD, joined Duke in 1998 as a postdoctoral fellow in the Center for AIDS Research to investigate T cells as they relate to human immunodeficiency virus (HIV) immunity. She received her doctor of philosophy
degree from the State University of New York Upstate (SUNY-Upstate) Medical University. Today, Dr. Tomaras holds joint faculty appointments in the Duke Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, and is

Director of the Duke Center for Human Systems Immunology, Immunological Sciences and recently became the Director of the Duke Center for AIDS Research.

Editor's Note: The initial publication of this story incorrectly omitted 'departments of surgery' from the statement regarding Dr. Tomaras's NIH funding acknowledgement.

https://surgery.duke.edu/news/qa-georgia-tomaras-professor-surgery-and-immunology-researcher

Duke Research and Discovery @RTP was born in 2020 when Duke University leased a 273,000 square foot facility in the Parmer RTP research and development campus, former home to pharmaceutical maker GlaxoSmithKline.

https://medschool.duke.edu/research/duke-research-and-discovery-rtp

[Work Harder]

Cold Chain-Independent, Needle-Free Mucosal Virosomal Vaccine to Prevent HIV-1 Acquisition at Mucosal Levels

U19AI142636

5/19/2022 $1,615,853

https://taggs.hhs.gov/Detail/RecipDetail?arg_EntityId=OG0gXGMDRXW5A%2BeI5A9jkQ%3D%3D

[Work Harder]

U19AI142636 2022

Description

Abstract Text

The overall objective of administrative Core A is to provide this multi-PI, multi-institutional U19 IPCAVD Project the opportunity to interact synergistically by facilitating the communication among the Project Leaders and all participating scientists. Core A will also serve as liaison between Research Administration at the contact institution, the Texas Biomedical Research Institute (TxBiomed), all the affiliated institutions both in the US and in Europe, and NIAD representatives. The network of partnering scientists includes researchers in Texas, Louisiana, Georgia and several countries in Europe; the major partner is Mymetics in Switzerland. The innovative biotech company has developed gp41-based virosomes into to a novel vaccine platform that is cold-chain independent and can be administered mucosally without needles. The Specific Aims of Core A are to: 1. Provide administrative support and facilitate the collaboration among Projects 1 and 2 and the various subcontract/subaward leaders and partners. This will include the exchange of information, reagents, and material transfer agreements. 2. Set priorities, monitor progress and jointly make go/no-go decisions. This will be achieved with input from the External Scientific Advisory Board (ESAB) and the NIAID IPCAVD Program Officer. 3. Assist in the design of experiments in rhesus macaques (RMs), protocol design and submission, and exchange of samples between the New Iberia Research Center (NIRC), where the primate studies will be conducted, and TxBiomed. 4. Provide statistical support for all IPCAVD scientists through the participation of Dr. Sarah Ratcliffe through a subaward with the University of Virginia (UVA). 5. Provide financial oversight and assure prompt payment of bills as well as the timely achievement of the experimental goals within budget limits. 6. Organize the yearly NIH Site Visit and the External Scientific Advisory Board (ESAB) meeting in the Washington, D.C. area, as well as individual visits between Drs. Ruprecht, Villinger, Santangelo and Fleury. 7. Address intellectual property (IP) issues fairly, timely, and equitably. 8. Facilitate the submission of reports, dissemination of data at meetings, and publication of manuscripts. To meet the goals of this translational, highly interactive U19 Research Program, the Core A Leader/Contact PI depends on the trained professionals with excellent organization skills as well as basic understanding of science and medicine to make this U19 network of scientists successful.

Abstract Text

Project 2 seeks to test virosomal vaccine immunogenicity and efficacy in the rhesus macaque (RM)/SHIV model. Mymetics has improved virosomal vaccines built from empty influenza virus-like particles that display an elongated HIV gp41 peptide on their surface (virosome-P1) or recombinant truncated HIV gp41 (virosome- rgp41). Earlier, Chinese RMs given two intramuscular (IM) primes followed by two intranasal (IN) boosts were 100% protected from persistent systemic infection and did not seroconvert to SIV Gag after low-dose intravaginal SHIV challenges. A follow-up study in Indian RMs showed 78% to 87% protection as long as the SHIV dose was ~7x104 times the median HIV inoculum in human male-to-female HIV transmission, but when the SHIV inoculum was ~105x greater, protection was lost. In these NHP studies, unadjuvanted, liquid formulations of the combination of virosome-P1 + virosome-rgp41 were used. To improve immunogenicity, Mymetics embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 directly into virosome membranes and developed solid, cold-chain independent vaccine formulations that can be administered needle-free. The powdered virosome forms can be given as IN spray, sublingual (SL) tablets, or packaged into oral capsules (PO). Our overall hypothesis is that the cold-chain independent, needle-free adjuvanted solid virosome forms are significantly more immunogenic than their earlier liquid form in RMs and will induce higher mucosal fluid Ab levels after mucosal priming/mucosal boosting via different routes. Mymetics has performed pilot tests in small animals with the IN and SL forms; vaccine delivery via oral capsules needs to be optimized in RMs. The Specific Aims for Project 2 are to: 1. Optimize vaccine delivery to the ileum via enteric-coated capsules; a) monitor passage of capsules containing 99mTc or 64Cu by scans; b) attach fluorescent labels to the virosomal vaccines for detection in the near-infrared spectrum. Tissues collected at necropsy will be tested by fluorescent microscopy. 2. Test the immunogenicity of different routes of the novel adjuvanted virosomes through a prime/boost approach. We will test their relative immunogenicity via IN, SL and PO routes; boosts will be given via a different mucosal route, a novel approach. Controls will be immunized IM with the soluble virosomal vaccine. 3. Test the efficacy of the cold-chain independent, needle-free, adjuvanted virosomal vaccines against repeated low-dose intrarectal (IR) clade B SHIV (SHIV-B) challenges. The most immunogenic mucosal prime/mucosal boost regimen (see Aim 2) will be used to immunize a group of 12 RMs; control (n=12) will receive empty virosomes. All RMs will undergo ~10 weekly low-dose IR challenges with the tier 2, R5 clade B SHIVSF162P3. 4. Test whether RMs that resisted multiple SHIV-B challenges will be protected against cross-clade challenge with the tier 2 R5 clade C SHIV. Protected RMs will be used to determine correlates of protection. These innovations are highly significant for the developing world, where our novel vaccine will be a major plus to combat the AIDS epidemic.

ABSTRACT – PROJECT 1

The induction of frontline defenses in genital and rectal tissues to prevent sexual HIV transmission is challenging, particularly with standard liquid subunit vaccines generally given intramuscularly. This multi-PI application is a collaboration between Mymetics (Dr. Sylvain Fleury, Project 1 Lead) and the Texas Biomedical Research Institute (Dr. Ruth Ruprecht, Project 2 Lead) that seeks to bring a promising mucosal HIV/AIDS vaccine approach into clinical development. Mymetics had inserted HIV gp41 antigens into the membranes of influenza virosomes, which have an excellent safety record in humans. These earlier, unadjuvanted liquid virosomal HIV gp41 vaccines were >80% efficacious in two independent nonhuman primate (NHP) studies. One of the gp41 vaccines, termed virosome-P1, was also safe and immunogenic in a Phase I trial in healthy women. To improve mucosal immunogenicity in the genital and intestinal tracts, Mymetics has adjuvanted the HIV vaccine formulation with the 3M-052 adjuvant that activates the toll-like receptor (TLR) 7/8; the 3M-052 adjuvant was active in infants, children, teenagers and adults. New, promising “all-in-one” HIV gp41 vaccines were specifically developed for various mucosal administration sites, with the aim to induce more efficient mucosal tissue coverage. A key innovation is the development of needle-free, solid-dosage vaccine formulations that are thermostable: nasal powder spray, sublingual tablets, or oral enteric-coated capsules filled with vaccine powder. All of these new vaccine formulations can withstand high/low temperatures outside the recommended cold-chain conditions without compromising product bioactivity. These novel, solid-form vaccines contain no free-form adjuvant; the HIV gp41-derived antigens as well as the 3M-052 adjuvant are physically bound to surface of the same particle. This prevents systemic adjuvant spread and thus avoids non-specific immune activation. Mymetics and its network of Contract Manufacturing Organizations (CMOs) will manufacture these different vaccines to test the hypothesis that the novel, cold chain-independent, needle-free, adjuvanted solid virosome forms are significantly more immunogenic than the earlier liquid form in NHPs, particularly when administered by mucosal routes. The Specific Aims for Project 1 are to: 1. Select a suitable enteric-coated capsule for vaccine delivery to the small intestine in rhesus macaques 2. Manufacture non-GMP batches of the different solid dosage forms for the NHP studies 3. Optimize the analytical methods and GMP manufacturing processes for the selected vaccine solid forms 4. Perform toxicology studies to show good safety profiles of the solid-form, adjuvanted virosomal vaccines given by mucosal routes – and to generate GMP vaccine for a Phase I trial to be conducted with the HVTN. This Project is significant because thermostable, solid-dosage forms of HIV gp41 virosomal vaccines offering mucosal protection could play a key role in preventing the further spread of HIV in the developing world, where the AIDS epidemic remains a serious problem.

Abstract Text

PROJECT SUMMARY – OVERALL This multi-PI application is a collaboration between Mymetics and the Texas Biomedical Research Institute (TxBiomed), with Drs. Sylvain Fleury (Project 1 Lead; Mymetics) and Ruth Ruprecht (Project 2 Lead; TxBiomed) serving as PIs. We seek to bring a promising HIV/AIDS vaccine approach to the clinic. The vaccine is based upon influenza virosomes, enveloped virus-like particles that display on their surface elongated HIV gp41 peptides (virosome-P1) or recombinant truncated HIV gp41 (virosome-rgp41). Mymetics' Phase I clinical trial with virosome-P1 in healthy women showed safety and immunogenicity. Two independent nonhuman primate (NHP) studies demonstrated the safety and high efficacy of the combination of virosome-P1 + virosome rgp41 against repeated low-dose intravaginal challenges with a tier 2 R5 SHIV in Chinese and Indian-origin rhesus macaques (RMs). In the latter, 78-87% efficacy was noted when the SHIV challenge dose was ~7x104 times the median HIV inoculum in male-to-female HIV transmission. However, when this HIV inoculum was exceeded 105- fold by an even higher SHIV inoculum, protection in Indian RMs was lost, implying a threshold effect whereby vaccine-induced mucosal antibodies were unable to ward off the higher number of invading SHIV particles. The soluble vaccine used in both NHP studies was unadjuvanted. To improve immunogenicity, Mymetics has embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 into virosomal envelopes. Moreover, Mymetics has developed a powdered form of virosomes that is no longer cold-chain dependent and can be administered as intranasal (IN) spray, sublingual (SL) tablets, or packaged into oral capsules. We hypothesize that these novel solid virosome formulations are significantly more immunogenic, particularly when administered via mucosal routes, than the unadjuvanted liquid form used earlier in NHPs. The Specific Aims of this IPCAVD project are to: 1. Assess the immunogenicity of the new vaccine candidates, the newly 3M-052-adjuvanted HIV virosome-P1 and virosome-rgp41, under solid dosage forms delivered IN, SL, or orally to Indian RMs in order to select the two most immunogenic formulations for subsequent mucosal prime/mucosal boost immunization. 2. Assess the efficacy of the cold-chain independent virosomal vaccine delivered by combined mucosal immunization routes against repeated intrarectal challenges with the heterologous R5 clade B SHIVSF162P3. Protected RMs will be rechallenged with an R5 tier 2 clade C SHIV. 3. Optimize the GMP manufacturing process for the selected virosomal formulations for mucosal delivery, and 4. Perform toxicology studies to show good safety profiles of the adjuvanted, solid-form vaccines given by selected mucosal routes – and generate GMP vaccine for a Phase I trial to be conducted with the HVTN. Our vaccine development plans represent major advances, as the novel needle-free, solid vaccine dosage forms are cold-chain independent and will be mucosally delivered – unique aspects that make the novel virosomal vaccines especially attractive for the developing world, where the AIDS epidemic remains a serious problem

https://reporter.nih.gov/search/K-ztMzgyCk25GZC9F4Nb-A/projects

[Work Harder]

Mucosal vaccination: Strategies to induce and evaluate mucosal immunity

https://www.frontiersin.org/articles/10.3389/fimmu.2022.905150/full

LSU & Andreas Frey

https://books.google.com/books?id=GkZxEAAAQBAJ&pg=PA235&lpg=PA235&dq=MYM+V201&source=bl&ots=K-DDW_O7Fa&sig=ACfU3U1F7jhj0MWCY4zxD4J2N5I1tHtaQA&hl=en&sa=X&ved=2ahUKEwixj8Sa4qP6AhXQpIkEHVovAx4Q6AF6BAgeEAM#v=onepage&q=MYM%20V201&f=false

Dr. Kozlowski is a mucosal immunologist who received her PhD from the University of Alabama at Birmingham and performed her post-doctoral training at Harvard Medical School. She is currently an Associate Professor at the LSU Medical School in New Orleans. She has expertise in mucosal vaccines, secretion collection methods, and IgA. Over the last 20 years, she has consulted or actively participated in numerous clinical and preclinical studies testing a variety of mucosal and parenteral vaccines. However, the majority of her research is focused on functions of antiviral antibodies and development of vaccines to HIV-1 and SARS CoV-2.

https://loop.frontiersin.org/people/42436/bio

Nicholas J Mantis

Editorial Roles

Guest Associate Editor for
Vaccines and Molecular Therapeutics
Frontiers in Immunology
Open for submissions

Review Editor for
Mucosal Immunity
Frontiers in Immunology

https://loop.frontiersin.org/people/25921/overview

Washington State University & Lausanne, Switzerland is following you LOL

From above now 2,147 total views & some tweets, way too many in the float on that one but that is jmho

Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges

https://www.frontiersin.org/articles/10.3389/fimmu.2022.788619/full

Edited by Andreas Frey

MYM-V201 data just about ready, right Ronnie LOL

Big ole round of applause for Ghent Belgium