<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03816137</url>
  </required_header>
  <id_info>
    <org_study_id>18HH4893</org_study_id>
    <nct_id>NCT03816137</nct_id>
  </id_info>
  <brief_title>Modelling the Interaction Between Rationally-designed Synthetic Model Viral Protein Immunogens</brief_title>
  <acronym>EAVI2020_01</acronym>
  <official_title>An Experimental Medicine Study Modelling the Interaction Between Rationally-designed Synthetic Model Viral Protein Immunogens and the Breadth of the Induced B and T Cell Repertoires.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      EVAI2020_01 is a single blinded two part experimental medicine study to determine the extent&#xD;
      to which different prime-boost combinations of model immunogens based on HIV-1 envelope&#xD;
      proteins (ConM and ConS), influence the breadth of viruses neutralised by induced antibodies&#xD;
      and the associated diversity of B and T cell responses.&#xD;
&#xD;
      Our research will investigate the effect of a second immunisation challenge with a&#xD;
      combination of three model mosaic envelope proteins designed to increase the breadth of&#xD;
      induced antibody neutralisation.&#xD;
&#xD;
      The primary outcome will be measurement of specific viral neutralisation activity of serum&#xD;
      antibodies. Exploratory outcomes will include characterisation of blood B and T cell&#xD;
      responses to these model immunogens.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      One of the most effective arms of the human immune system is the ability of very low&#xD;
      concentrations of antibody proteins to bind to viruses, bacteria and toxins and &quot;neutralise&quot;&#xD;
      their activity or ability to infect. In contrast to cellular immunity, which may cause tissue&#xD;
      destruction and pathology, antibody-mediated immunity can be very passive, while completely&#xD;
      preventing infection. How antibodies bind their targets varies enormously, ranging from&#xD;
      unhelpful &quot;blocking&quot; antibodies or narrowly focussed neutralising antibodies, to highly&#xD;
      protective &quot;broadly neutralising&quot; antibodies (bNAbs) that can neutralise a wide range of&#xD;
      strains of the same pathogen. Such bNAbs are especially sought after in virus infections such&#xD;
      as HIV, influenza and others where the virus mutates to evade immune responses that are too&#xD;
      narrow or focussed. Antibodies arise when an &quot;immunogen&quot; (an immunogen is anything that&#xD;
      induces an immune response, typically a foreign protein) is taken up by the immune system and&#xD;
      shown to white blood cells - T and B cells - by specialised immune cells. In some cases the T&#xD;
      and B cells bind the immunogens to receptors on their surface, triggering an immune response&#xD;
      in which T cells &quot;help&quot; B cells to manufacture specific antibodies. The events around how the&#xD;
      protein is processed into manageable pieces, shown to the T and B cells, and the pattern of&#xD;
      chemical signals produced by the immune cells is highly complex, but eventually determines&#xD;
      how broad the antibody response will be (its breadth). For infections like HIV and influenza,&#xD;
      decades of research and clinical vaccine trials have had limited or no success. To take HIV&#xD;
      as an example, investigators have an almost complete lack of understanding of how immunogens&#xD;
      interact with the naive human B cell receptor (BCR) repertoire and the pathways required to&#xD;
      induce bNAbs during an infection or after an immunisation. Animal models have failed as the&#xD;
      naïve, germline encoded, B cell antibody receptor repertoires of non-human species are&#xD;
      sufficiently different from those of humans to render design and selection of vaccine based&#xD;
      on non-human species problematic. Additionally, bNAbs isolated from HIV-1-infected&#xD;
      individuals have structural features that occur rarely or not at all in other mammals, such&#xD;
      as unusually long loop-binding regions (CDRH3 loops) required to penetrate past glycans on&#xD;
      the surface of the envelope spike that shield key neutralising epitopes (Mascola JR 2013).&#xD;
      There is therefore a critical need to better understand, in human experimental medicine&#xD;
      models of immune challenge, how immunogens and B/T cells interact in the development of&#xD;
      protective bNAb anti-viral responses.&#xD;
&#xD;
      Our approach to resolving this impasse is to challenge the human immune system with&#xD;
      rationally-designed model immunogens to determine the structural and other characteristics&#xD;
      required to drive human B cell antibody responses towards neutralisation breadth.&#xD;
      Investigators have selected HIV as an experimental model as there is a reasonable&#xD;
      understanding about the specificity and function of anti-HIV bNAbs, as well as an urgent need&#xD;
      to identify novel immunisation approaches following decades of failed or poorly successful&#xD;
      trials. There is also a huge database of safety using HIV proteins as immunogens, and the&#xD;
      technological expertise to design and manufacture HIV viral proteins. Assays for HIV&#xD;
      neutralising activity are also well established in our laboratories. Although focussed on&#xD;
      HIV, our findings will be applicable to other viral infections.&#xD;
&#xD;
      The model immunogens proposed in the experimental medicine studies are unlikely to be&#xD;
      suitable as vaccines, and any clinical development would require iterative cycles of design&#xD;
      refinement and development based on immunological insights gleaned from these experimental&#xD;
      investigations. Therefore, the focus is on in-depth characterisation of the elicited immune&#xD;
      response to rationally-designed model immunogens that may inform the design process of actual&#xD;
      vaccines. This experimental medicine approach is only now possible due to unprecedented&#xD;
      progress in our abilities to study the human immune system and to obtain complete information&#xD;
      on immune responses to vaccination, since performing research on the human immune system is&#xD;
      now almost as easy as it has been in mice. The main focus of this study will be to determine&#xD;
      which of the design strategies is able to prime human germline (naive) B cells and drive&#xD;
      antibody responses towards induction of neutralising antibody breadth.&#xD;
&#xD;
      Our range of model immunogens will be based on the envelope (Env) glycoprotein of HIV-1,&#xD;
      which is the only target of neutralising antibodies, and therefore the only virally-encoded&#xD;
      immunogen relevant for induction of such antibodies by immunisation. To ensure&#xD;
      reproducibility of results and the highest level of volunteer safety, all immunogens will be&#xD;
      manufactured under cGMP, using techniques applied to vaccine immunogens.&#xD;
&#xD;
      Env has extensive amino acid variation, structural and conformational instability, and&#xD;
      immunodominance of hypervariable regions (Kwong PD, 2011; Sattentau QJ, 2013). Our team&#xD;
      designed soluble immunogens that closely mimic the native viral trimer in situ, but that&#xD;
      incorporate design strategies that may alter the intrinsic viral immune evasion mechanisms&#xD;
      (Sanders RW, 2013). Env is made up of three identical complexes (trimers) each of which&#xD;
      contains two molecules, gp120 and gp41 that can be modified to make a soluble molecule called&#xD;
      gp140, upon which our immunogens are based. Investigators have developed model consensus&#xD;
      gp140 Env trimers (consensus of all global strains) designed to prime B cell responses to&#xD;
      common epitopes represented in all HIV-1 subtypes. Investigators have utilised two design&#xD;
      strategies to stabilise these in a native-like conformation: ConM SOSIP and ConS UFO. The&#xD;
      ConM SOSIP trimer includes novel mutations that include the incorporation of a disulphide&#xD;
      linkage between the gp120 and gp41 ectodomain (making up gp140) which prevents their&#xD;
      disassociation into monomer subunits.&#xD;
&#xD;
      The ConS UFO includes a short flexible amino-acid linker to tether the gp120 and gp41&#xD;
      subunits together as an alternative strategy to prevent dissociation of the Env trimer.&#xD;
      Investigators wish to test both designs to determine the effect on B cell repertoire. To&#xD;
      further stabilize global architecture, investigators employed an EDC crosslinking approach&#xD;
      that has been shown to conserve bNAb epitopes, reduce non-antiviral antibody responses, and&#xD;
      enhance overall immunogen stability (Schiffner et al., 2015). Thus, in Part 1 of this study&#xD;
      investigators will test EDC ConM SOSIP and EDC ConS UFO versions in parallel.&#xD;
&#xD;
      A critical adjunct to our consensus-based model design is to use a cocktail of three mosaic&#xD;
      gp140 Env trimers as a boost (Part 2) to overcome the immunodominance of hypervariable&#xD;
      regions of Env and to determine whether this will focus antibody responses towards conserved&#xD;
      neutralisation epitopes. While designed using computer algorithms, these mosaics represent&#xD;
      authentic Env structures that are fully functional and native in their conformation. Our&#xD;
      novel designs aim to eliminate unwanted immunodominant antibody responses and focus B cells&#xD;
      towards highly conserved supersites of vulnerability on Env, with particular emphasis on&#xD;
      quaternary bNAb epitopes (Julien, JP, 2013; Kong L, 2013; Lyumkis D, 2013). The extent to&#xD;
      which these different strategies may induce neutralising breadth, and the identification of&#xD;
      the mechanisms and drivers involved, can only be determined empirically through human&#xD;
      immunogen challenge studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 19, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This is a single-blind study with volunteers being randomised into five groups of n=10 (Groups A-E) stratified by gender</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Volunteers will be blinded to their treatment regimes, and laboratory teams undertaking immunological analysis will be blinded to group and dosing regimen to prevent in-house analysis bias. The clinical team will remain un-blinded throughout.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Neutralising antibodies</measure>
    <time_frame>6 Months</time_frame>
    <description>Serum titres of neutralising antibodies to virus expressing ConM and ConS envelopes</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Viral expression of Mosaic envelopes (1-3)</measure>
    <time_frame>12 Months</time_frame>
    <description>Serum titres of neutralising antibodies to virus expressing Mosaic envelopes (1-3)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Binding antibodies in serum</measure>
    <time_frame>18 Months</time_frame>
    <description>Measurement of the magnitude and phenotype of B cell (plasmablast and memory B cells) and T cell responses (CD4 and CD8) in peripheral blood mononuclear cells (PBMC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Paxgene blood transcriptomics</measure>
    <time_frame>18 Months</time_frame>
    <description>Paxgene tubes for blood transcriptomics will be collected only from group A</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>HIV-1-infection</condition>
  <arm_group>
    <arm_group_label>ConM SOSIP and Mosaic SOSIPs</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ConM SOSIP 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months&#xD;
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EDC ConM SOSIP and Mosaic SOSIPs</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>EDC ConM SOSIP 100G Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months&#xD;
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ConS UFO and Mosaic SOSIPs</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months&#xD;
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EDC ConS UFO and Mosaic SOSIPs</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>EDC ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months&#xD;
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ConS UFO and ConM SOSIPs and Mosaic SOSIPs</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0 and 3 months&#xD;
ConM SOSIP Administered at 12 months&#xD;
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ConM SOSIP</intervention_name>
    <description>Recombinant HIV-1 trimeric gp140 Env protein: ConM SOSIP gp140. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.</description>
    <arm_group_label>ConM SOSIP and Mosaic SOSIPs</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>EDC ConM SOSIP</intervention_name>
    <description>Chemically fixed version of recombinant HIV-1 trimeric gp140 Env: EDC-ConM SOSIP. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.</description>
    <arm_group_label>ConS UFO and ConM SOSIPs and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>EDC ConM SOSIP and Mosaic SOSIPs</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ConS UFO</intervention_name>
    <description>Recombinant HIV-1 trimeric gp140 Env protein: ConS UFO gp140. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle</description>
    <arm_group_label>ConS UFO and ConM SOSIPs and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>ConS UFO and Mosaic SOSIPs</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>EDC ConS UFO</intervention_name>
    <description>Chemically fixed version of recombinant HIV-1 trimeric gp140 Env : EDC-ConS UFO. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.</description>
    <arm_group_label>EDC ConS UFO and Mosaic SOSIPs</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mosaic SOSIPs</intervention_name>
    <description>Mosaic gp140 Env trimers designed to overcome the immunodominance of hypervariable regions of Env&#xD;
The immunogen will be used at the dosage of 100 ug (3x33ug) and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.</description>
    <arm_group_label>ConM SOSIP and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>ConS UFO and ConM SOSIPs and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>ConS UFO and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>EDC ConM SOSIP and Mosaic SOSIPs</arm_group_label>
    <arm_group_label>EDC ConS UFO and Mosaic SOSIPs</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Healthy male and female volunteers aged between 18 and 55 years. 2. Available for&#xD;
             ALL follow-up visits for the duration of the study. 3. Entered and clearance obtained&#xD;
             from The Over volunteering Prevention System (TOPS) database (to avoid impact of any&#xD;
             co-administered investigational products or treatments on our outcomes).&#xD;
&#xD;
             4. Women capable of becoming pregnant willing to take hormonal contraception for the&#xD;
             duration of the study.&#xD;
&#xD;
             5. Willing and able to give written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. History of any medical, psychological or other condition, clinically significant&#xD;
             laboratory result at screening, or use of any medications which, in the opinion of the&#xD;
             investigators, would interfere with the study objectives or volunteers safety.&#xD;
&#xD;
             2. HIV-1 or HIV-2 antibody positive or indeterminate upon screening, or history of&#xD;
             receipt of Env-based HIV immunogens (which would render the volunteers non-naive to&#xD;
             the model immunogens).&#xD;
&#xD;
             3. Unable to read and/or speak English to a fluency level adequate for the full&#xD;
             comprehension of study procedures and consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Katrina Pollock</last_name>
    <role>Principal Investigator</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NIHR Imperial Clinical Resarch Facility</name>
      <address>
        <city>London</city>
        <zip>W12 0HS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>January 22, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>July 25, 2022</last_update_submitted>
  <last_update_submitted_qc>July 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Antibody</keyword>
  <keyword>Antibody-dependent cell-mediated cytotoxicity</keyword>
  <keyword>Neuralizing antibody responses</keyword>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Results from this study will be disseminated locally and to the wider scientific community at conferences and in published open-access peer-reviewed journals, as appropriate. Any data used for publication will be fully anonymised. We plan to publish the data and hold onto the data for 10 years.</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>12 months from when the experimental study officially closes</ipd_time_frame>
    <ipd_access_criteria>Directly from Professor Robin Shattock (r.shattock@imperial.ac.uk)</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03816137
org study id: 18HH4893
nct id: NCT03816137
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
EVAI2020_01 is a single blinded two part experimental medicine study to determine the extent
      to which different prime-boost combinations of model immunogens based on HIV-1 envelope
      proteins (ConM and ConS), influence the breadth of viruses neutralised by induced antibodies
      and the associated diversity of B and T cell responses.

      Our research will investigate the effect of a second immunisation challenge with a
      combination of three model mosaic envelope proteins designed to increase the breadth of
      induced antibody neutralisation.

      The primary outcome will be measurement of specific viral neutralisation activity of serum
      antibodies. Exploratory outcomes will include characterisation of blood B and T cell
      responses to these model immunogens.
One of the most effective arms of the human immune system is the ability of very low
      concentrations of antibody proteins to bind to viruses, bacteria and toxins and "neutralise"
      their activity or ability to infect. In contrast to cellular immunity, which may cause tissue
      destruction and pathology, antibody-mediated immunity can be very passive, while completely
      preventing infection. How antibodies bind their targets varies enormously, ranging from
      unhelpful "blocking" antibodies or narrowly focussed neutralising antibodies, to highly
      protective "broadly neutralising" antibodies (bNAbs) that can neutralise a wide range of
      strains of the same pathogen. Such bNAbs are especially sought after in virus infections such
      as HIV, influenza and others where the virus mutates to evade immune responses that are too
      narrow or focussed. Antibodies arise when an "immunogen" (an immunogen is anything that
      induces an immune response, typically a foreign protein) is taken up by the immune system and
      shown to white blood cells - T and B cells - by specialised immune cells. In some cases the T
      and B cells bind the immunogens to receptors on their surface, triggering an immune response
      in which T cells "help" B cells to manufacture specific antibodies. The events around how the
      protein is processed into manageable pieces, shown to the T and B cells, and the pattern of
      chemical signals produced by the immune cells is highly complex, but eventually determines
      how broad the antibody response will be (its breadth). For infections like HIV and influenza,
      decades of research and clinical vaccine trials have had limited or no success. To take HIV
      as an example, investigators have an almost complete lack of understanding of how immunogens
      interact with the naive human B cell receptor (BCR) repertoire and the pathways required to
      induce bNAbs during an infection or after an immunisation. Animal models have failed as the
      naïve, germline encoded, B cell antibody receptor repertoires of non-human species are
      sufficiently different from those of humans to render design and selection of vaccine based
      on non-human species problematic. Additionally, bNAbs isolated from HIV-1-infected
      individuals have structural features that occur rarely or not at all in other mammals, such
      as unusually long loop-binding regions (CDRH3 loops) required to penetrate past glycans on
      the surface of the envelope spike that shield key neutralising epitopes (Mascola JR 2013).
      There is therefore a critical need to better understand, in human experimental medicine
      models of immune challenge, how immunogens and B/T cells interact in the development of
      protective bNAb anti-viral responses.

      Our approach to resolving this impasse is to challenge the human immune system with
      rationally-designed model immunogens to determine the structural and other characteristics
      required to drive human B cell antibody responses towards neutralisation breadth.
      Investigators have selected HIV as an experimental model as there is a reasonable
      understanding about the specificity and function of anti-HIV bNAbs, as well as an urgent need
      to identify novel immunisation approaches following decades of failed or poorly successful
      trials. There is also a huge database of safety using HIV proteins as immunogens, and the
      technological expertise to design and manufacture HIV viral proteins. Assays for HIV
      neutralising activity are also well established in our laboratories. Although focussed on
      HIV, our findings will be applicable to other viral infections.

      The model immunogens proposed in the experimental medicine studies are unlikely to be
      suitable as vaccines, and any clinical development would require iterative cycles of design
      refinement and development based on immunological insights gleaned from these experimental
      investigations. Therefore, the focus is on in-depth characterisation of the elicited immune
      response to rationally-designed model immunogens that may inform the design process of actual
      vaccines. This experimental medicine approach is only now possible due to unprecedented
      progress in our abilities to study the human immune system and to obtain complete information
      on immune responses to vaccination, since performing research on the human immune system is
      now almost as easy as it has been in mice. The main focus of this study will be to determine
      which of the design strategies is able to prime human germline (naive) B cells and drive
      antibody responses towards induction of neutralising antibody breadth.

      Our range of model immunogens will be based on the envelope (Env) glycoprotein of HIV-1,
      which is the only target of neutralising antibodies, and therefore the only virally-encoded
      immunogen relevant for induction of such antibodies by immunisation. To ensure
      reproducibility of results and the highest level of volunteer safety, all immunogens will be
      manufactured under cGMP, using techniques applied to vaccine immunogens.

      Env has extensive amino acid variation, structural and conformational instability, and
      immunodominance of hypervariable regions (Kwong PD, 2011; Sattentau QJ, 2013). Our team
      designed soluble immunogens that closely mimic the native viral trimer in situ, but that
      incorporate design strategies that may alter the intrinsic viral immune evasion mechanisms
      (Sanders RW, 2013). Env is made up of three identical complexes (trimers) each of which
      contains two molecules, gp120 and gp41 that can be modified to make a soluble molecule called
      gp140, upon which our immunogens are based. Investigators have developed model consensus
      gp140 Env trimers (consensus of all global strains) designed to prime B cell responses to
      common epitopes represented in all HIV-1 subtypes. Investigators have utilised two design
      strategies to stabilise these in a native-like conformation: ConM SOSIP and ConS UFO. The
      ConM SOSIP trimer includes novel mutations that include the incorporation of a disulphide
      linkage between the gp120 and gp41 ectodomain (making up gp140) which prevents their
      disassociation into monomer subunits.

      The ConS UFO includes a short flexible amino-acid linker to tether the gp120 and gp41
      subunits together as an alternative strategy to prevent dissociation of the Env trimer.
      Investigators wish to test both designs to determine the effect on B cell repertoire. To
      further stabilize global architecture, investigators employed an EDC crosslinking approach
      that has been shown to conserve bNAb epitopes, reduce non-antiviral antibody responses, and
      enhance overall immunogen stability (Schiffner et al., 2015). Thus, in Part 1 of this study
      investigators will test EDC ConM SOSIP and EDC ConS UFO versions in parallel.

      A critical adjunct to our consensus-based model design is to use a cocktail of three mosaic
      gp140 Env trimers as a boost (Part 2) to overcome the immunodominance of hypervariable
      regions of Env and to determine whether this will focus antibody responses towards conserved
      neutralisation epitopes. While designed using computer algorithms, these mosaics represent
      authentic Env structures that are fully functional and native in their conformation. Our
      novel designs aim to eliminate unwanted immunodominant antibody responses and focus B cells
      towards highly conserved supersites of vulnerability on Env, with particular emphasis on
      quaternary bNAb epitopes (Julien, JP, 2013; Kong L, 2013; Lyumkis D, 2013). The extent to
      which these different strategies may induce neutralising breadth, and the identification of
      the mechanisms and drivers involved, can only be determined empirically through human
      immunogen challenge studies.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: This is a single-blind study with volunteers being randomised into five groups of n=10 (Groups A-E) stratified by gender
primary purpose: Prevention
masking: Double (Participant, Investigator)
masking description: Volunteers will be blinded to their treatment regimes, and laboratory teams undertaking immunological analysis will be blinded to group and dosing regimen to prevent in-house analysis bias. The clinical team will remain un-blinded throughout.
measure: Neutralising antibodies
time frame: 6 Months
description: Serum titres of neutralising antibodies to virus expressing ConM and ConS envelopes
measure: Viral expression of Mosaic envelopes (1-3)
time frame: 12 Months
description: Serum titres of neutralising antibodies to virus expressing Mosaic envelopes (1-3)
measure: Binding antibodies in serum
time frame: 18 Months
description: Measurement of the magnitude and phenotype of B cell (plasmablast and memory B cells) and T cell responses (CD4 and CD8) in peripheral blood mononuclear cells (PBMC)
measure: Paxgene blood transcriptomics
time frame: 18 Months
description: Paxgene tubes for blood transcriptomics will be collected only from group A
arm group label: ConM SOSIP and Mosaic SOSIPs
arm group type: Active Comparator
description: ConM SOSIP 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only
arm group label: EDC ConM SOSIP and Mosaic SOSIPs
arm group type: Active Comparator
description: EDC ConM SOSIP 100G Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only
arm group label: ConS UFO and Mosaic SOSIPs
arm group type: Active Comparator
description: ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only
arm group label: EDC ConS UFO and Mosaic SOSIPs
arm group type: Active Comparator
description: EDC ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only
arm group label: ConS UFO and ConM SOSIPs and Mosaic SOSIPs
arm group type: Active Comparator
description: ConS UFO 100g Intramuscular injections into the left or right arm Administered at 0 and 3 months
ConM SOSIP Administered at 12 months
Mosaic SOSIPs 100ug (3x33ug) Intramuscular injections into the left or right arm Administered at 12 months only
intervention type: Biological
intervention name: ConM SOSIP
description: Recombinant HIV-1 trimeric gp140 Env protein: ConM SOSIP gp140. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.
arm group label: ConM SOSIP and Mosaic SOSIPs
intervention type: Biological
intervention name: EDC ConM SOSIP
description: Chemically fixed version of recombinant HIV-1 trimeric gp140 Env: EDC-ConM SOSIP. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.
arm group label: ConS UFO and ConM SOSIPs and Mosaic SOSIPs
arm group label: EDC ConM SOSIP and Mosaic SOSIPs
intervention type: Biological
intervention name: ConS UFO
description: Recombinant HIV-1 trimeric gp140 Env protein: ConS UFO gp140. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle
arm group label: ConS UFO and ConM SOSIPs and Mosaic SOSIPs
arm group label: ConS UFO and Mosaic SOSIPs
intervention type: Biological
intervention name: EDC ConS UFO
description: Chemically fixed version of recombinant HIV-1 trimeric gp140 Env : EDC-ConS UFO. Model immunogens will be used at the dosage of 100 ug and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.
arm group label: EDC ConS UFO and Mosaic SOSIPs
intervention type: Biological
intervention name: Mosaic SOSIPs
description: Mosaic gp140 Env trimers designed to overcome the immunodominance of hypervariable regions of Env
The immunogen will be used at the dosage of 100 ug (3x33ug) and will be admixed with 500 ug MPLA formulated in liposomes and administered by intramuscular injection into the left or right deltoid muscle.
arm group label: ConM SOSIP and Mosaic SOSIPs
arm group label: ConS UFO and ConM SOSIPs and Mosaic SOSIPs
arm group label: ConS UFO and Mosaic SOSIPs
arm group label: EDC ConM SOSIP and Mosaic SOSIPs
arm group label: EDC ConS UFO and Mosaic SOSIPs
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Katrina Pollock
role: Principal Investigator
affiliation: Imperial College London
facility: 
country: United Kingdom
responsible party type: Sponsor
sharing ipd: Yes
ipd description: Results from this study will be disseminated locally and to the wider scientific community at conferences and in published open-access peer-reviewed journals, as appropriate. Any data used for publication will be fully anonymised. We plan to publish the data and hold onto the data for 10 years.
ipd info type: Clinical Study Report (CSR)
ipd time frame: 12 months from when the experimental study officially closes
ipd access criteria: Directly from Professor Robin Shattock (r.shattock@imperial.ac.uk)