The primary objective of this study is to evaluate the safety and tolerability of intramuscular administration of the HIV-1 envelope protein ConM SOSIP.v7 gp140 vaccine, adjuvanted with MPLA liposomes, in HIV-uninfected adults. The secondary…
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Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Proportion of volunteers with a >= grade 3 adverse event, from the day of
each vaccination up to 7 days post each vaccination.
2. Proportion of volunteers with >= grade 3 and/or vaccine related adverse
events, including safety laboratory (biochemical, haematological) parameters,
from the day of each vaccination up to 28 days post each vaccination.
3. Proportion of volunteers with vaccine-related serious adverse events
throughout the study period.
Secondary outcome
1. Autologous neutralising antibodies induced by ConM SOSIP.v7 gp140 vaccine,
adjuvanted in MPLA liposomes:
a. Serum titres of autologous neutralising antibodies;
b. Proportion of volunteers with autologous neutralising antibodies.
2. Trimer binding antibody responses induced by ConM SOSIP.v7 gp140 vaccine,
adjuvanted in MPLA liposomes:
a. Magnitude of the trimer binding antibody response;
b. Proportion of volunteers with a trimer binding antibody response.
3. Heterologous neutralising antibodies induced by ConM SOSIP.v7 gp140 vaccine,
adjuvanted in MPLA liposomes:
a. Serum titres of heterologous neutralising antibodies (i.e. against
additional (Tier 1a/b, Tier 2) virus strains);
b. Proportion of volunteers with heterologous neutralising antibodies.
4. Induction of Env-specific B cell responses will be analysed and comparisons
made between individuals with low, high and durable NAb titres (i.e. persistent
at 12 and 18 months follow-up):
- Env-specific plasmablast repertoire sequence analysis in peripheral blood;
- Env-specific germline and memory B cell repertoire sequence analysis in
peripheral blood;
- Env-specific germinal centre B cell repertoire sequence analysis in the
draining lymph node(s).
Background summary
Human immunodeficiency virus (HIV) causes a global pandemic that affects nearly
37 million people and continues to spread at a rate of 1.8 million new
infections annually. With currently only 21.7 million people on antiretroviral
therapy (ART), a protective vaccine is crucial to reduce HIV spread and
eliminate the pandemic. Given their protective capacity, a vaccine that induces
neutralising antibodies (NAbs) against the HIV envelope protein (Env) would be
a major step forwards. Nevertheless, the design of an effective NAb inducing
vaccine has proven to be extremely challenging due to the instability and
conformational flexibility of the trimeric Env protein. However, the
development of stabilised, native-like trimeric Env proteins, termed SOSIP
trimers, has revolutionised the HIV vaccine field by overcoming this obstacle.
The SOSIP prototype, BG505 SOSIP.664, was the first ever Env-based immunogen
that consistently induced NAbs against neutralisation-resistant viruses in
animals and BG505 trimer immunisation of non-human primates protected against
BG505 virus acquisition. Yet, HIV-1 diversity is a major hurdle for generating
broad protection by broadly neutralising antibodies (bNAbs). It is thought that
consensus-based vaccines might be more amendable for driving neutralisation
breadth, because consensus sequences contain less strain-specific antigenic
determinants and are closer to individual viral strains than strains are to one
another. Therefore, the native-like Env trimer ConM SOSIP.v7 gp140, to be used
in the proposed study, was modelled after the BG505 SOSIP.664 prototype, but
based on a consensus sequence of all HIV-1 isolates in group M, responsible for
the global HIV epidemic. Previous nonclinical studies in rabbits and non-human
primates found the ConM SOSIP.v7 gp140 vaccine to be safe. Moreover, it induced
remarkably strong autologous NAb responses and elicited modest levels of
cross-neutralisation. Bearing these promising results in mind, we wish to
evaluate the safety and tolerability of the ConM SOSIP.v7 gp140 vaccine,
adjuvanted with monophosphoryl lipid A (MPLA) liposomes, in healthy
HIV-uninfected individuals, as well as to explore its immunogenic properties.
Study objective
The primary objective of this study is to evaluate the safety and tolerability
of intramuscular administration of the HIV-1 envelope protein ConM SOSIP.v7
gp140 vaccine, adjuvanted with MPLA liposomes, in HIV-uninfected adults. The
secondary objective is to determine the ability of the HIV-1 envelope protein
ConM SOSIP.v7 gp140 vaccine, adjuvanted with MPLA liposomes, to induce humoral
immune responses in HIV-uninfected adults and to characterise these responses
in the systemic and lymphoid compartments.
Study design
The present study is a single centre, randomised, open-label, uncontrolled,
phase 1 clinical trial, which will be conducted at the Amsterdam UMC, location
AMC. Twenty volunteers will be randomised in a 1:1 ratio between two treatment
groups with a different dosing regimen (See Intervention). The randomisation
will be stratified for gender in order to pick up on potential differences in
immunological outcomes between men and women. To account for up to 20% dropout,
an over-enrolment of two volunteers per treatment arm will be permitted.
Volunteers will be screened up to 70 days before the first vaccination and will
be actively followed for six months after the last vaccine administration. An
additional volunteer contact will occur 12 months after the last vaccination to
monitor persistent immunogenicity.
Participants will undergo three intramuscular vaccinations, 18 blood samplings
by venipuncture, two leukapheresis procedures (baseline and week 10) and two
axillary lymph node fine needle aspirations (FNA) (weeks 3 and 11), during 22
visits over a study period of 21 months. This includes screening and four
check-ups conducted by telephone.
Intervention
Vaccination will take place at month 0, 2 and 6. Ten participants will receive
100 µg of ConM SOSIP.v7 gp140 at each time point (group A). Ten participants
will receive a one-fifth fractional boosting dose of 20 µg at the third and
final time point (group B). All vaccinations will be adjuvanted with 500 µg
MPLA liposomes. It is thought that fractional dose boosting leads to
competitive antigen binding in lymph node germinal centres, which results in
selection and expansion of B cells with surface immunoglobulins showing the
highest antigen affinity. To investigate this effect, the second treatment
group (group B) is implemented in the vaccination schedule.
Study burden and risks
Participants will undergo three intramuscular vaccinations, 18 blood samplings
by venipuncture, two leukapheresis procedures (baseline and week 10) and two
axillary lymph node fine needle aspirations (FNA) (weeks 3 and 11), during 22
visits over a study period of 21 months. This includes screening and four
check-ups conducted by telephone. Burden and risks can be subdivided into those
potentially related to the intervention and to the sampling procedures. The
combination of ConM SOSIP.v7 gp140 trimer vaccine and MPLA liposome adjuvant
has been proven safe and well tolerated in nonclinical (toxicology) studies. In
these studies, no serious adverse events were observed. Furthermore, thousands
of individuals have been safely vaccinated with other recombinant HIV-1
envelope proteins in previous clinical studies. Finally, the MPLA adjuvant is
commonly used in human vaccinations, in clinical trials as well as licensed
vaccines, without safety concerns being raised. Therefore, we expect a minimum
risk associated with vaccination. The burden and risks of sampling are
associated with the venipunctures, lymph node FNAs and leukapheresis procedures
at different time points throughout the course of the study. The procedures are
considered minimally invasive and low-risk. There is no group relatedness or
benefit to the participants.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Men and women, aged between 18 and 50 years on the day of screening.
2. Willing to comply with the requirements of the protocol and available for
follow-up for the planned duration of the study.
3. Willing and able to give written informed consent.
4. Willing to undergo HIV testing, risk reduction counselling and receive HIV
test results, including the possibility of vaccine-induced seropositivity
(VISP).
5. All individuals engaging in sexual activity that could lead to pregnancy
must commit to use of an effective method of contraception for four months
following Investigational Medicinal Product administration.
6. All female volunteers must be willing to undergo urine pregnancy tests.
7. Willing to abstain from donating blood, eggs or sperm from the day of first
vaccination until at least 3 months after the end of their participation in the
trial.
8. All volunteers must be registered with a general practitioner.
Exclusion criteria
1. Confirmed HIV-1 or HIV-2 infection
2. Self-reported risk for HIV exposure or STIs prior to screening.
3. If female, pregnant or planning a pregnancy during the period of enrolment
until four months after the last study vaccination; or lactating.
4. Any clinically relevant medical condition that is considered in the opinion
of the investigator to make the volunteer unsuitable for participation in the
study (under which underlying haematological disorders, specified infectious
diseases, hyposplenia, auto-immune diseases, bleeding disorders, seizure
disorders, immunodeficiency, gastrointestinal, hepatic and cardiopulmonary
disorders). This also includes a history of malignancy in the past five years
(prior to screening) or ongoing malignancy. (Note: A history of a completely
excised malignancy that is considered cured is not an exclusion).
5. Receipt of any vaccine within 60 days of vaccination with the
Investigational Medicinal Product.
6. Receipt of blood products or blood-derived products within four months of
screening.
7. Participation in another clinical trial of an Investigational Medicinal
Product currently, within the previous three months or expected participation
during this study. Concurrent participation in an observational study, not
involving medicinal products and not requiring any blood or tissue sample
collection is not an exclusion criterion.
8. Prior receipt of another investigational HIV vaccine or HIV monoclonal
antibody (product). (Note: receipt of placebo in a previous HIV vaccine trial
will not exclude a volunteer from participation if documentation is available.)
9. Known hypersensitivity to any component of the vaccine formulation used in
this trial, or severe or multiple allergies to drugs or pharmaceutical agents.
10. Positive reaction in antinuclear antibody (ANA) screen and/or subsequent
anti-dsDNA assessment; or clinically significant immunoglobulin (IgA, IgG or
IgM) values.
11. Use of any medications, including over-the-counter products, which, in the
opinion of the investigators, would either interfere with the study or
potentially cause harm to the volunteer. Use of corticosteroids,
immunosuppressants, chemotherapeutics, anti-tuberculosis or other medications
considered significant by the investigator within the previous six months.
Specified exceptions apply.
12. Unable to read and speak Dutch or English to a fluency level adequate for
the full comprehension of procedures required in participation and consent.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-003769-32-NL |
| ClinicalTrials.gov | NCT03961438 |
| CCMO | NL69161.000.19 |