Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03816137 |
| Other study ID # |
18HH4893 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
March 19, 2019 |
| Est. completion date |
December 31, 2022 |
Study information
| Verified date |
July 2022 |
| Source |
Imperial College London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
