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.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 117
- 试验地点
- 1
- 主要终点
- Neutralising antibodies to virus expressing ConM and ConS envelopes
研究概览
简要总结
The objective of this experimental medicine study is to determine the extent to which different prime-boost combinations influence serum neutralising antibody breadth and associated B and T cells responses.
The investigators hypothesise that the different prime-boost model immunogen combinations will have differential impact on: the magnitude and breadth of induced serum neutralising antibodies; and the induced B- and T-cell responses in peripheral blood.
The investigators will investigate this by challenging the immune system of healthy adults with various model immunogens based on HIV-1 Env (ConM and ConS, with and without EDC stabilisation; Mos3.1, Mos3.2 and Mos3.3, and AMC011 and 763 SOSIP) in different prime-boost combinations.
详细描述
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. 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.
The approach by the investigators 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. The 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 the study team's laboratories. Although focussed on HIV, the investigators' 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 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.
The investigators' 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. The study 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. 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 the investigators' 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Double (Participant, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male and female volunteers aged between 18 and 55 years.
- •Available for ALL follow-up visits for the duration of the study.
- •Entered and clearance obtained from The Over volunteering Prevention System (TOPS) database (to avoid impact of any co-administered investigational products or treatments on our outcomes).
- •Women of childbearing potential willing to use a highly effective method of contraception for the duration of the study until a minimum of 12 weeks after the final injection. Periodic abstinence (calendar, symptothermal and post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- •Willing and able to give written informed consent.
排除标准
- •History of any medical, psychological or other condition, clinically significant laboratory result at screening, or use of any medications which, in the opinion of the investigators, would interfere with the study objectives or volunteers safety.
- •Any history of angioedema.
- •History of urticaria deemed significant by the Chief Investigator.
- •HIV-1 or HIV-2 antibody positive or indeterminate upon screening, or history of receipt of Env-based HIV immunogens (which would render the volunteers non-naive to the model immunogens).
- •Unable to read and/or speak English to a fluency level adequate for the full comprehension of study procedures and consent.
研究组 & 干预措施
Group A: ConM SOSIP and Mosaic SOSIPs
ConM SOSIP 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: ConM SOSIP (Biological)
Group A: ConM SOSIP and Mosaic SOSIPs
ConM SOSIP 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: Mosaic SOSIPs (Biological)
Group B: EDC ConM SOSIP and Mosaic SOSIPs
EDC ConM SOSIP 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: EDC ConM SOSIP (Biological)
Group B: EDC ConM SOSIP and Mosaic SOSIPs
EDC ConM SOSIP 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: Mosaic SOSIPs (Biological)
Group C: ConS UFO and Mosaic SOSIPs
ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: ConS UFO (Biological)
Group C: ConS UFO and Mosaic SOSIPs
ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: Mosaic SOSIPs (Biological)
Group D: EDC ConS UFO and Mosaic SOSIPs
EDC ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: EDC ConS UFO (Biological)
Group D: EDC ConS UFO and Mosaic SOSIPs
EDC ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0, 3 and 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: Mosaic SOSIPs (Biological)
Group E: ConS UFO and ConM SOSIP and Mosaic SOSIPs
ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0 and 3 months
ConM SOSIP 100mcg Intramuscular injection into the left or right arm Administered at 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: ConM SOSIP (Biological)
Group E: ConS UFO and ConM SOSIP and Mosaic SOSIPs
ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0 and 3 months
ConM SOSIP 100mcg Intramuscular injection into the left or right arm Administered at 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: ConS UFO (Biological)
Group E: ConS UFO and ConM SOSIP and Mosaic SOSIPs
ConS UFO 100mcg Intramuscular injections into the left or right arm Administered at 0 and 3 months
ConM SOSIP 100mcg Intramuscular injection into the left or right arm Administered at 6 months
Mosaic SOSIPs (Mos3.1 + Mos3.2) 100mcg (2x50mcg) Intramuscular injections into the left or right arm Administered at 12 months only
干预措施: Mosaic SOSIPs (Biological)
Group F: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConM SOSIP (Biological)
Group F: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConS UFO (Biological)
Group F: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: Mosaic SOSIPs (Biological)
Group G: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConM SOSIP (Biological)
Group G: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConS UFO (Biological)
Group G: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: Mosaic SOSIPs (Biological)
Group H: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConM SOSIP (Biological)
Group H: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConS UFO (Biological)
Group H: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIP Mos3.3 100mcg Intramuscular injection into the left or right arm Administered at 0 months
Mosaic SOSIP Mos3.2 100mcg Intramuscular injection into the left or right arm Administered at 2 months
Mosaic SOSIP Mos3.1 100mcg Intramuscular injection into the left or right arm Administered at 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: Mosaic SOSIPs (Biological)
Group I: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIPs (Mos3.1 + Mos3.2 + Mos3.3) 100mcg (3x33mcg) Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConM SOSIP (Biological)
Group I: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIPs (Mos3.1 + Mos3.2 + Mos3.3) 100mcg (3x33mcg) Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: ConS UFO (Biological)
Group I: Mosaic SOSIPs and ConM SOSIP and ConS UFO
Mosaic SOSIPs (Mos3.1 + Mos3.2 + Mos3.3) 100mcg (3x33mcg) Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
ConM SOSIP + ConS UFO 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 6 months
干预措施: Mosaic SOSIPs (Biological)
Group J: 763 SOSIP
763 SOSIP 100mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: 763 SOSIP (Biological)
Group K: AMC011 SOSIP
AMC011 100mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: AMC011 SOSIP (Biological)
Group L: 763 SOSIP and AMC011 SOSIP
763 SOSIP and AMC011 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: 763 SOSIP (Biological)
Group L: 763 SOSIP and AMC011 SOSIP
763 SOSIP and AMC011 50mcg + 50mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: AMC011 SOSIP (Biological)
Group M: 763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mosaic SOSIPs
763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mos3.1 and Mos3.2 SOSIPs each at 20mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: ConM SOSIP (Biological)
Group M: 763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mosaic SOSIPs
763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mos3.1 and Mos3.2 SOSIPs each at 20mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: Mosaic SOSIPs (Biological)
Group M: 763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mosaic SOSIPs
763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mos3.1 and Mos3.2 SOSIPs each at 20mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: 763 SOSIP (Biological)
Group M: 763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mosaic SOSIPs
763 SOSIP and AMC011 SOSIP and ConM SOSIP and Mos3.1 and Mos3.2 SOSIPs each at 20mcg Intramuscular injections into the left or right arm Administered at 0, 2 and 4 months
干预措施: AMC011 SOSIP (Biological)
结局指标
主要结局
Neutralising antibodies to virus expressing ConM and ConS envelopes
时间窗: 6 Months
Serum titres of neutralising antibodies to virus expressing ConM and ConS envelopes
Neutralising antibodies to virus expressing Mosaic envelopes
时间窗: 12 Months
Serum titres of neutralising antibodies to virus expressing Mosaic envelopes (Mos3.1, Mos3.2, Mos3.3)
Neutralising antibodies to virus expressing AMC011 and 763 SOSIP envelopes
时间窗: 4 months
Serum titres of neutralising antibodies to virus expressing AMC011 and 763 SOSIP envelopes
次要结局
未报告次要终点