mRNA Vaccines for HIV Prevention
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Must not be taking: Glucocorticoids, Immunoglobulin, Antiseizure, others
Disqualifiers: Pregnancy, Diabetes, Immunodeficiency, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a multicenter, open-label, non-randomized, dose escalation, first-in-human (FIH) trial to evaluate the safety and immunogenicity of CH505M5 N197D mRNA-gp160 and CH505 TF mRNA-gp160. Both products are mRNA encapsulated in lipid nanoparticles (LNPs) (subsequently referred to as mRNA-LNPs). The primary hypotheses are:
1. the CH505M5 N197D mRNA-gp160 will expand CH235-like B cell precursors,
2. the CH505 TF mRNA-gp160 will boost CH235-like bnAb B cell precursors to acquire more functional mutations needed for broadly neutralizing antibody (bnAb) development, and
3. these mRNA-LNPs will be safe and well tolerated among individuals living without HIV.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are on medications that might impair your immune response, like certain steroids, you may need to discuss this with the trial team. It's best to consult with the trial staff about your specific medications.
What data supports the effectiveness of the treatment CH505M5 N197D mRNA-gp160, CH505M5 N197D mRNA-gp160, CH505 TF mRNA-gp160 for HIV prevention?
Research suggests that mRNA vaccines, when combined with certain immune-boosting agents, can enhance the body's immune response against HIV. This approach has shown promise in improving HIV-specific T-cell responses, which are crucial for controlling the virus.
12345Is the mRNA vaccine for HIV prevention safe for humans?
The recombinant gp160 vaccine, which is related to the mRNA vaccine for HIV prevention, has been tested in several studies and found to be safe in humans, with no major adverse reactions reported.
16789How is the mRNA vaccine treatment for HIV prevention different from other treatments?
The mRNA vaccine treatment for HIV prevention is unique because it uses mRNA to produce virus-like particles that stimulate the immune system to produce neutralizing antibodies, potentially reducing the risk of HIV infection. This approach is different from traditional vaccines as it involves mRNA technology, which is a newer method that instructs cells to make proteins that trigger an immune response.
110111213Eligibility Criteria
This trial is for adults in good health who do not have HIV. It's designed to test the safety and potential of two new mRNA-based vaccines that aim to prepare the immune system against HIV.Inclusion Criteria
Agrees to specific requirements for HIV prevention and counseling
My blood counts, liver, kidney functions, calcium levels, and blood pressure are within required ranges.
Agrees to contraception and pregnancy testing requirements
+7 more
Exclusion Criteria
Breastfeeding/chestfeeding or pregnant
I have recently received blood products or immunoglobulin.
I have recently been vaccinated.
+11 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive CH505M5 N197D mRNA-gp160 at weeks 0, 8, and 16, followed by CH505 TF mRNA-gp160 at week 24
24 weeks
4 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4-8 weeks
Participant Groups
The study involves two experimental vaccines, CH505M5 N197D mRNA-gp160 and CH505 TF mRNA-gp160, which are given in stages to see if they can stimulate the body's immune cells to fight HIV more effectively.
4Treatment groups
Experimental Treatment
Group I: Group 4 (150 mcg)Experimental Treatment2 Interventions
150 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16.
Followed by:
150 mcg CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.
Group II: Group 3 (100 mcg)Experimental Treatment2 Interventions
100 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16.
Followed by:
100 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.
Group III: Group 2 (50 mcg)Experimental Treatment2 Interventions
50 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16.
Followed by:
50 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.
Group IV: Group 1 (25 mcg)Experimental Treatment2 Interventions
25 mcg of CH505M5 N197D mRNA-gp160, to be administered as a split dose intramuscularly at weeks 0, 8, and 16.
Followed by:
25 mcg of CH505 TF mRNA-gp160, to be administered as a split dose intramuscularly at week 24.
CH505M5 N197D mRNA-gp160 is already approved in United States for the following indications:
🇺🇸 Approved in United States as CH505M5 N197D mRNA-gp160 for:
- HIV Infections
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Columbia P&S (Site ID: 30329)New York, NY
Beth Israel Deaconess Medical Center (Site ID: 32077)Boston, MA
New York Blood Center (Site ID: 31801)New York, NY
University of Pittsburgh (Site ID: 1001)Pittsburgh, PA
More Trial Locations
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Who Is Running the Clinical Trial?
National Institute of Allergy and Infectious Diseases (NIAID)Lead Sponsor
Department of Health and Human ServicesCollaborator
National Institutes of Health (NIH)Collaborator
References
The Combination of an mRNA Immunogen, a TLR7 Agonist and a PD1 Blocking Agent Enhances In-Vitro HIV T-Cell Immune Responses. [2023]The development of new strategies to achieve a functional cure for HIV remains a priority. We tested a novel HIV therapeutic vaccine using unmodified mRNA (TMEP-B) and mRNA modified by 1-methyl-3'-pseudouridylyl (TMEP-Bmod) expressing both a multiepitopic sequences from Gag, Pol, and Nef proteins, including different CD4 and CD8 T-cell epitopes functionally associated with HIV control in transfected monocyte-derived dendritic cells (MDDCs) obtained from HIV infected patients. In vitro assays were used to test the mRNAs alone and in combination with immunomodulator agents, such as the TLR-7 agonist Vesatolimod and the PD-1 antagonist Nivolumab to try to improve HIV-specific cellular immune responses. Combining the mRNAs with the immunomodulators enhanced HIV-specific T-cell responses, together with the secretion of IFNγ, IP10, MIP-1α, and MIP-1β, which are fundamental mediators of viral control. Our data suggest that the mRNA vaccine prototypes TMEP-B and TMEP-Bmod, when combined with Vesatolimod and/or Nivolumab, could achieve functional cure for patients with HIV.
Current advances and challenges in HIV-1 vaccines. [2019]Recent advances in science, which have aided HIV-1 vaccine development, include an improved understanding of HIV-1 envelope structure and function, expansion of the pipeline with innovative vaccine strategies, promising multi-gene and multi-clade vaccines that elicit cellular immunity, conduct of clinical trials in a global network, and development of validated techniques that enable simultaneous measurement of multiple T cell vaccine-induced immune responses in humans. A common feature of several preventive vaccine strategies now in early clinical trials is their ability in nonhuman primates to attenuate clinical disease rather than completely prevent HIV-1 infection. One vaccine concept has been tested in large-scale clinical trials, two are currently in efficacy trials, and one more is poised to enter efficacy trial in the next few years. Simultaneously, expanded efforts continue to identify new designs that induce mucosal immunity as well as broadly neutralizing antibodies.
HIV vaccine development: lessons from the past and promise for the future. [2019]The global HIV epidemic continues to expand, exceeding previous predictions and causing tremendous suffering. An effective vaccine represents the best hope to curtail the HIV epidemic. The past fifteen years of HIV vaccine clinical trials have not identified an ideal HIV vaccine, but have provided many valuable lessons that contribute to the current generation of promising HIV vaccine regimens. An enhanced understanding of HIV and SIV immunopathogenesis has facilitated the design of vaccination regimens that elicit specific immune responses and effector mechanisms. Intensive investigation of recombinant gp120 subunit vaccines has revealed a previously unexpected complexity in eliciting neutralizing antibodies that are active against primary isolate viruses. The importance of CD8+ CTL responses in controlling HIV and SIV viremia has led to a series of vaccine candidates that effectively induce these responses. Proof that vaccination can prevent SIV/HIV disease has now been obtained in simian models of AIDS. A number of promising HIV vaccine regimens are currently being evaluated in human trials, and the pipeline of new vaccine vectors and combination regimens appears robust. Although challenges to the development of a safe and effective global HIV vaccine remain, the outlook for HIV vaccines in the future is bright.
Safety and efficacy of an oral HIV vaccine (V-1 Immunitor) in AIDS patients at various stages of the disease. [2004]To evaluate the safety and efficacy of an orally available, therapeutic HIV vaccine (V-1 Immunitor) in patients who were not treated with antiviral drugs.
Is developing an HIV-1 vaccine possible? [2021]This review discusses select recent data that suggest that indeed it is possible to make a clinically useful preventive vaccine for HIV-1 and outlines some of the remaining obstacles that stand in the way of success.
Safety and immunogenicity of a fully glycosylated recombinant gp160 human immunodeficiency virus type 1 vaccine in subjects at low risk of infection. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group Network. [2019]Recombinant gp160 derived from human immunodeficiency virus type 1 (HIV-1)IIIB and produced in mammalian tissue culture cells using a vaccinia virus expression system (rgp160-mam) was evaluated as a vaccine in combination with alum and deoxycholate adjuvant. Sixty low-risk, uninfected subjects received 12.5 micrograms, 50.0 micrograms, or adjuvant control at 0, 1, 6, and 12 months in a randomized, double-blind dose-escalation study. A single injection of 200 micrograms of vaccine was given at 18 months in an open study to 9 vaccines who had received 50 micrograms. The vaccine was safe. Six of 16 subjects receiving 50 micrograms developed neutralizing antibody to HIV-1IIIB. Seven of the 9 boosted with 200 micrograms of vaccine at 18 months developed neutralizing antibodies. Lymphocyte proliferation to rgp160-mam and baculovirus-derived rgp160 and rgp120 was induced in both groups (12.5 and 50.0 micrograms) and appeared after the first dose. Further studies with higher doses of rgp160-mam and vaccines derived from other strains of HIV-1 are warranted.
Induction of humoral and cell-mediated anti-human immunodeficiency virus (HIV) responses in HIV sero-negative volunteers by immunization with recombinant gp160. [2018]Development of an effective vaccine for prevention of infection with HIV would provide an important mechanism for controlling the AIDS epidemic. In the current study, the first clinical trial of a candidate HIV-1 vaccine initiated in the United States, the safety and immunogenicity of escalating doses (10-1,280 micrograms) of recombinant gp160 (rgp160), were evaluated in 138 HIV-negative volunteers. Maximal antibody responses, as evaluated by ELISA, were seen after immunization with three doses of 1,280 micrograms rgp160. Responses to some specific epitopes of HIV gp160, including the second conserved domain and the CD4 binding site, were seen more frequently than after natural infection. Neutralizing antibodies to the homologous HIV strain, but not heterologous strains, were induced by this regimen. Blastogenic responses to rgp160 were seen in most volunteers receiving at least two doses of > or = 20 micrograms. These envelope-specific T cell responses were also seen against heterologous strains of HIV. No major adverse reactions were seen after immunization. Thus, rgp160 is a safe and immunogenic candidate HIV vaccine; further studies are needed to determine if it will provide any clinical benefit in preventing HIV infection.
Modulation of immunologic responses to HIV-1MN recombinant gp160 vaccine by dose and schedule of administration. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group. [2019]The safety and immunogenicity of HIV-1MN recombinant gp160 (MN rgp160) vaccine in healthy, uninfected volunteers was tested in a double-blind study with a factorial design. By random assignment, 20 volunteers received three 200 micrograms doses of MN rgp160 and four volunteers received placebo at days 0, 28, and 168 or 0, 56, and 224. Of the 24 volunteers, 16 received 200 micrograms or 800 micrograms of MN rgp160 and two received placebo at day 532 (month 18). The vaccine was safe. It induced T cell memory measured by Th1 cytokine production and lymphocyte proliferation, and serum anti-MN rgp160 IgG (all subclasses) and IgA antibodies. Fifteen of 20 vaccinees developed neutralizing antibody. The regimen including immunizations on days 0, 28, and 168 followed by the 800 micrograms fourth dose was most immunogenic.
Recombinant gp160 as a therapeutic vaccine for HIV-infection: results of a large randomized, controlled trial. European Multinational IMMUNO AIDS Vaccine Study Group. [2019]The primary objective of this study was to expand the safety and immunogenicity database of recombinant gp160 as a therapeutic vaccine in the treatment of HIV-infection. Preliminary efficacy data was also sought.
A multiclade env-gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques. [2023]The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian-human immunodeficiency virus (SHIV AD8). Thus, the multiclade env-gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine.
Modified Newcastle Disease virus as an improved vaccine vector against Simian Immunodeficiency virus. [2019]SIV infection in macaques is a relevant animal model for HIV pathogenesis and vaccine study in humans. To design a safe and effective vaccine against HIV, we evaluated the suitability of naturally-occurring avirulent Newcastle disease virus (NDV) strains and several modified versions of NDV as vectors for the expression and immunogenicity of SIV envelope protein gp160. All the NDV vectors expressed gp160 protein in infected cells. The gp160 expressed by these vectors formed oligomers and was incorporated into the NDV envelope. All the NDV vectors expressing gp160 were attenuated in chickens. Intranasal immunization of guinea pigs with modified NDV vectors such as rNDV-APMV-2CS/gp160 and rNDV-APMV-8CS/gp160 (NDV strain LaSota containing the cleavage site sequences of F protein of avian paramyxovirus (APMV) serotype 2 and 8, respectively), and rNDV-BC-F-HN/gp160 (NDV strain BC containing LaSota F cleavage site and LaSota F and HN genes) elicited improved SIV-specific humoral and mucosal immune responses compared to other NDV vectors. These modified vectors were also efficient in inducing neutralizing antibody responses to tier 1 A SIVmac251.6 and tier 1B SIVmac251/M766 strains. This study suggests that our novel modified NDV vectors are safe and immunogenic and can be used as vaccine vector to control HIV.
Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). [2019]The development of a prophylactic vaccine against HIV-1 has so far not been successful. Therefore, attention has shifted more and more toward the development of novel therapeutic vaccines. Here, we evaluated a new mRNA-based therapeutic vaccine against HIV-1-encoding activation signals (TriMix: CD40L + CD70 + caTLR4) combined with rationally selected antigenic sequences [HIVACAT T-cell immunogen (HTI)] sequence: comprises 16 joined fragments from Gag, Pol, Vif, and Nef).
Characterization of HIV-1 Nucleoside-Modified mRNA Vaccines in Rabbits and Rhesus Macaques. [2022]Despite the enormous effort in the development of effective vaccines against HIV-1, no vaccine candidate has elicited broadly neutralizing antibodies in humans. Thus, generation of more effective anti-HIV vaccines is critically needed. Here we characterize the immune responses induced by nucleoside-modified and purified mRNA-lipid nanoparticle (mRNA-LNP) vaccines encoding the clade C transmitted/founder HIV-1 envelope (Env) 1086C. Intradermal vaccination with nucleoside-modified 1086C Env mRNA-LNPs elicited high levels of gp120-specific antibodies in rabbits and rhesus macaques. Antibodies generated in rabbits neutralized a tier 1 virus, but no tier 2 neutralization activity could be measured. Importantly, three of six non-human primates developed antibodies that neutralized the autologous tier 2 strain. Despite stable anti-gp120 immunoglobulin G (IgG) levels, tier 2 neutralization titers started to drop 4 weeks after booster immunizations. Serum from both immunized rabbits and non-human primates demonstrated antibody-dependent cellular cytotoxicity activity. Collectively, these results are supportive of continued development of nucleoside-modified and purified mRNA-LNP vaccines for HIV. Optimization of Env immunogens and vaccination protocols are needed to increase antibody neutralization breadth and durability.