COVID, HIV e vaccini a RNA

[Blast]

L'unica speranza, credo, sia quella che il motivo per cui i vaccini anti-HIV finora testati non abbiano funzionato risieda nella poca stabilità delle proteine ricombinanti.

Potresti spiegare meglio questo punto?
Grazie

l'RNA è altamente instabile rispetto alle proteine. Tuttavia, le proteine ricombinanti elicitano una risposta immune di più breve durata rispetto ad un mRNA. L'mRNA viene tradotto in proteina "a rilascio prolungato", e inoltre credo che la proteina prodotta dall'mRNA venga non solo rilasciata all'esterno della cellula ma anche esposta sulla superficie delle cellule in cui è entrato l'mRNA, mentre la proteina ricombinante iniettata per sè dura in circolo giusto il tempo di essere riconosciuta e neutralizzata. Questo mi lascia sperare che si riesca a dare "più tempo" al sistema immunitario per produrre tanti diversi tipi di anticorpi, sperando che alcuni siano davvero neutralizzanti.
Questa è l'unica spiegazione che riesco a darmi all'utilità di usare un vaccino ad mRNA piuttosto che a proteina ricombinante.

La storia della fusione con ENV o GAG o non ricordo cosa per me lascia il tempo che trova, perché anche la proteina ricombinante può essere prodotta in fusione con qualsiasi cosa. Ma ripeto, l'mRNA è più facile, perchè con una sequenza studiata/scritta e una PCR, lo fai in poco tempo e costi più contenuti.

Tuttavia la soggettiva risposta fisiologica di ogni persona (lo abbiamo visto col covid, c'è chi non lo lo prende più dopo il vaccino e chi lo prende lo stesso, chi sviluppa più IgG, chi meno) mi lascia pensare che questo tipo di vaccino probabilmente porrà le basi per ulteriori studi e tentativi, e che potrebbe quindi non essere un successo at first sight.

Magari sarà utile per riuscire ad isolare un maggior numero di anticorpi neutralizzanti, o magari per tentare una sorta di vaccinazione di massa per vedere se le infezioni scendano.
O magari la terapia antiretrovirale sarà sostituita da vaccinazioni e booster periodici, me lo auguro tanto, e non vedo l'ora di vedere i risultati dello studio per capire se tutto l'entusiasmo che sta generando questa notizia sui social e sui media sia frutto di una reale combinazione fortunata degli eventi o solo un abbaglio dovuto ad eccesso di ottimismo nel voler provare una "cosa nuova".

[Dora]

Il trial di Moderna di due vaccini preventivi a mRNA contro HIV sta per iniziare, proprio in questi giorni. Sarà su 56 volontari HIV negativi.

IL protocollo in ClinicalTrials.gov:

A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core)

Computer image of the eOD-GT8 immune-stimulating protein. Image courtesy of Joseph Jardine, Sergey Menis, and William Schief of Scripps Research and IAVI.

IAVI e Moderna hanno comunicato ieri che il trial di fase I IAVI G002 è ufficialmente partito e sono state somministrate le prime dosi del vaccino a mRNA contro HIV.

[... ] The Phase I trial, IAVI G002, is designed to test the hypothesis that sequential administration of priming and boosting HIV immunogens delivered by messenger RNA (mRNA) can induce specific classes of B-cell responses and guide their early maturation toward broadly neutralizing antibody (bnAb) development. The induction of bnAbs is widely considered to be a goal of HIV vaccination, and this is the first step in that process. The immunogens being tested in IAVI G002 were developed by scientific teams at IAVI and Scripps Research and will be delivered via Moderna’s mRNA technology.

“We are tremendously excited to be advancing this new direction in HIV vaccine design with Moderna’s mRNA platform. The search for an HIV vaccine has been long and challenging, and having new tools in terms of immunogens and platforms could be the key to making rapid progress toward an urgently needed, effective HIV vaccine,” says Mark Feinberg, M.D., Ph.D., president and CEO of IAVI. “We are grateful to all of our partners and especially to the Bill & Melinda Gates Foundation for funding this trial.”

"We are very pleased to be partnering with IAVI and the Bill & Melinda Gates Foundation to apply our mRNA technology in the setting of HIV. At Moderna, we believe that mRNA offers a unique opportunity to address critical unmet public health needs around the world,” said Stephen Hoge, M.D., president of Moderna. “We believe advancing this HIV vaccine program in partnership with IAVI and Scripps Research is an important step in our mission to deliver on the potential for mRNA to improve human health.”

The HIV vaccine antigens being evaluated as mRNA in this study were originally developed as proteins by William Schief, Ph.D., professor at Scripps Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center (NAC), and colleagues. In 2021, Dr. Schief announced results from the IAVI G001 clinical trial, showing that an adjuvanted protein-based version of the priming immunogen (eOD-GT8 60mer) induced the desired B-cell response in 97% of recipients. IAVI G002 not only tests priming of the desired immune response using mRNA delivery of eOD-GT8 60mer, but also assesses the ability of a boosting immunogen to induce further maturation of B cells. Given the speed with which mRNA vaccines can be produced, this platform offers a more nimble and responsive approach to vaccine design and testing, potentially shaving off years from typical vaccine development timelines.

The Schief lab has been a pioneer of the vaccine design approach known as germline targeting. Naive B cells display antibodies encoded by unmutated, or “germline” genes. A series of vaccines, which would begin with the prime-boost immunogens tested here, may be able to target specific naive B cells and induce them to mature into bnAb-producing ones. In the lab, bnAbs have been shown to neutralize a broad range of HIV variants, and one bnAb, VRC01, was recently shown to be capable of protecting humans against infection by neutralization-susceptible HIV strains. VRC01 is a member of the class of bnAbs targeted in IAVI G001.

“We’ve seen promising proof of concept for germline targeting in IAVI G001, and this trial lets us take that approach to the next stage. What’s more, we’ve been able to expedite production of clinical trial material at a remarkably rapid pace because of Moderna’s technology,” said Schief.

Years of work in a long-standing NAC partnership between IAVI and Scripps Research have enabled the development of these vaccine antigens. The organizations will continue to collaborate as they extend and evaluate the sequence of promising immunogens to elicit bnAbs.

IAVI G002 is sponsored by IAVI and takes place at four sites: GWU School of Medicine and Health Sciences (lead investigator David Diemert, M.D.), Hope Clinic of Emory Vaccine Center in Atlanta (lead investigator Srilatha Edupuganti, M.D.), Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle (lead investigator Julie McElrath, M.D., Ph.D.), and the University of Texas–Health Science Center at San Antonio (lead investigator Barbara Taylor, M.D., M.S.). The sites will enroll 56 healthy, HIV-negative adult volunteers. Forty-eight participants will receive one or two doses of eOD-GT8 60mer mRNA Vaccine (mRNA-1644), with 32 of them receiving the boost Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core). An additional eight volunteers will receive the boost immunogen alone. Participants will be monitored for safety for six months after last vaccination. Participants’ immune responses to the vaccine candidates will be examined in molecular detail to evaluate whether the targeted responses were achieved.

Diemert said, “We at GWU School of Medicine and Health Sciences are pleased to be part of this endeavor that aims to induce the next step of B-cell maturation toward the goal of generating antibodies that can neutralize a broad range of HIV variants. Further immunogens will be needed to guide the immune system on this path, but this prime-boost combination could be the first key element of an eventual HIV immunization regimen.”

The Collaboration for AIDS Vaccine Discovery (CAVD) Comprehensive Cellular Vaccine Immune Monitoring Consortium/the Dale and Betty Bumpers Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH), the CAVD Comprehensive Antibody Vaccine Immune Monitoring Consortium, Duke University’s Human Vaccine Institute, Fred Hutch, and the Karolinska Institute will be performing key analytical assays in support of the trial, to assess whether the targeted immune response is elicited. The CAVD Vaccine Immunology Statistical Center played an important role contributing to the study design, analytical methods development, and data evaluation. In January 2016, Moderna entered a global health project framework agreement with the Bill & Melinda Gates Foundation to advance mRNA-based development projects for various infectious diseases.

IAVI and Scripps Research developed the eOD-GT8 60mer and Core-g28v2 60mer mRNA candidates with support from the Bill & Melinda Gates Foundation, the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at NIAID at the NIH, and Moderna.

Research at the IAVI NAC that contributed to the development of the vaccine candidates was also made possible by the government of the Netherlands through the Ministry of Foreign Trade & Development Cooperation and through the generous support of the American people through the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID). The contents are the responsibility of IAVI and Moderna and do not necessarily reflect the views of USAID or the United States government. [...]

[Blast]

Dora, cosa si sa della controparte proteica di questo vaccino, ossia lo IAVI G001?
E' andato avanti ulteriormente nei clinical trials? Perché a questo punto quello che si evince è che:
- se la versione proteica ha davvero dato risultati ottimi e la sperimentazione si è poi fermata, dietro ci sono solo questioni economiche che hanno prevalso sulla necessità di curare HIV
- se la versione proteica non è andata come si sperava, dubito che questo vaccino possa fare miracoli

Io credo nei vaccini, e sono estremamente convinto che prima o poi si riuscirà a vaccinare (ancor prima di una escissione definitiva del DNA di HIV), sia individui sani (che non prenderanno mai HIV) sia malati (che si trasformeranno in una sorta di elite controllers), però il razionale alla base di tutto ciò non lo comprendo ancora bene (ovviamente mi riservo di cambiare idea dopo approfondimento).

[Dora]

Dora, cosa si sa della controparte proteica di questo vaccino, ossia lo IAVI G001?
E' andato avanti ulteriormente nei clinical trials?

Da quel che comprendo, la continuazione di IAVI G001 è proprio IAVI G002.
Così dichiarava Schief circa un anno fa:

The study sets the stage for additional clinical trials that will seek to refine and extend the approach — with the long-term goal of creating a safe and effective HIV vaccine. As a next step, IAVI and Scripps Research are partnering with the biotechnology company Moderna to develop and test an mRNA-based vaccine that harnesses the approach to produce the same beneficial immune cells. Using mRNA technology could significantly accelerate the pace of HIV vaccine development.

Stessa cosa ribadita lo scorso aprile.

Un articolo completo ancora mi pare non ci sia, mentre una recensione dei risultati presentati alla HIV Research for Prevention (HIVR4P) virtual conference è uscita su Lancet a marzo:

Preliminary phase 1 results from an HIV vaccine candidate trial

Per chi ha fretta, c'è questo Fact sheet:




https://www.youtube.com/watch?v=3oPJWeqoyNU

[skydrake]

Chissà perché hanno scelto un inglese da ex paese coloniale, africano, per quest'ultimo video. Anche nelle immagini erano diverse di persone di colore. Forse per facilitare il reclutamento per le fasi successive, spesso appunto in Africa. Sarebbe una cosa positiva, a confronto dei soliti video pensati per le presentazioni presso la comunità medica o per gli azionisti, ma non come diretto proposito per accelerare la fase II o III.

[Blast]

Ok quindi in pratica hanno fatto un Phase I trial con la proteina ricombinante che è andato abbastanza bene, dopo di che hanno deciso di cambiare strategia ed utilizzare l'approccio ad mRNA, il che da una parte li porta un passo indietro perchè devono ripetere la fase I con il nuovo tipo di vaccino, dall'altra velocizza un po' il tutto a livello di produzione del vaccino e di costi, e si spera produca anche una risposta migliore negli individui.
E questa https://www.nature.com/articles/s41591-021-01574-5 dovrebbe essere la parte pre-clinica che mi mancava, per cui in pratica il COVID, sdoganando la tecnologia ad mRNA, li ha convinti a passare a questa nuova tecnologia già mentre stavano terminando il trial con la proteina ricombinante.

[Dora]

Gli NIH hanno comunicato ieri che è ufficialmente partito lo STUDIO HVTN 302 - A Clinical Trial to Evaluate the Safety and Immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV Trimer mRNA Vaccines in Healthy, HIV-uninfected Adult Participants.

The HVTN 302 study will examine whether the following three experimental HIV mRNA vaccines are safe and can induce an immune response: 1) BG505 MD39.3 mRNA, 2) BG505 MD39.3 gp151 mRNA, and 3) BG505 MD39.3 gp151 CD4KO mRNA. Each investigational vaccine candidate is designed to present the spike protein found on the surface of HIV that facilitates entry into human cells. Each of the experimental vaccines encodes for different but highly related, stabilized proteins. None of the three vaccine candidates can cause HIV infection.

The specific mRNA sequences contained in the vaccines were designed and developed by investigators at the NIAID-funded Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD) at the Scripps Research Institute and the Bill & Melinda Gates Foundation-funded IAVI Neutralizing Antibody Center at Scripps, in collaboration with scientists at Cambridge, Massachusetts-based Moderna, Inc. Moderna manufactured the investigational vaccines through a NIAID-supported contract.

Led by principal investigators Jesse Clark, M.D., of the University of California Los Angeles, and Sharon Riddler, M.D., of the University of Pittsburgh, the HVTN 302 study will enroll up to 108 adults ages 18 to 55 years at 11 sites in: Birmingham, Alabama; Boston; Los Angeles; New York City; Philadelphia; Pittsburgh; Rochester, New York and Seattle. Each participant will be randomly assigned to one of six groups each receiving three vaccinations of one of the experimental vaccines. The first three groups (18 participants each), called Group A, will receive intramuscular injections of 100 micrograms (mcg) of their assigned vaccine candidate at the initial visit, at month two and again at month six. Participants in Group A will be evaluated two weeks after initial vaccination to ensure safety criteria have been met. If so, the remaining three groups of 18 participants each (Group B) will be vaccinated with 250 mcg of the assigned investigational vaccine, followed by injections two and six months after the initial vaccination.

Safety and immune responses will be examined via blood and lymph node fine-needle aspiration samples taken at specified timepoints throughout the trial. Clinical staff will closely monitor participant safety throughout the study. The clinical trial is expected to be completed by July 2023.

Study Design

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase 1, Randomized, Open-label Clinical Trial to Evaluate the Safety and Immunogenicity of BG505 MD39.3, BG505 MD39.3 gp151, and BG505 MD39.3 gp151 CD4KO HIV Trimer mRNA Vaccines in Healthy, HIV-uninfected Adult Participants
Actual Study Start Date : February 11, 2022
Estimated Primary Completion Date : July 13, 2023
Estimated Study Completion Date : October 13, 2023

[Silente1982]

Una domanda da ignorante: il vaccino per noi positivi potrebbe avere qualche utilità?

[Dora]

Una domanda da ignorante: il vaccino per noi positivi potrebbe avere qualche utilità?

Un vaccino inizialmente studiato per prevenire l'infezione potrebbe essere convertito in vaccino terapeutico e allora, sì, certo potrebbe avere qualche utilità. Ce ne sono diversi in studio nelle sperimentazioni per arrivare a una cura più o meno stabile e definitiva, in genere in combinazione con sostanze che forzano la produzione di virus latente per svuotare i reservoir.
Per adesso è presto per dire se questi nuovi vaccini a mRNA saranno utili. Dobbiamo aspettare che li sperimentino nelle persone senza HIV e vedere se sono in grado di stimolare il sistema immunitario a reagire in modo più efficace nei confronti dell'infezione cronica. Queste prime sperimentazioni daranno senz'altro tante indicazioni utili.

[Dora]

IAVI statement on mRNA HIV vaccine candidate trials

March 2, 2024

Response to Science news article

IAVI is currently in the process of finalizing and submitting a manuscript for publication of the results of the IAVI G002 clinical trial. The forthcoming publication will describe in detail both the immune responses and the safety outcomes observed in the trial.

On March 1, Science published a news article (*) about skin events observed in recent HIV vaccine clinical trials evaluating a “germline-targeting” approach to HIV vaccine development, including IAVI G002. IAVI G002 is designed to test the hypothesis that sequential administration of priming and boosting HIV immunogens delivered by messenger RNA (mRNA) can activate specific naive B-cells and guide their early maturation toward broadly neutralizing antibody (bnAb) production.

IAVI, Moderna, the HIV Vaccine Trials Network (HVTN), the National Institutes of Health (NIH), and the Bill & Melinda Gates Foundation — all partners in trials of mRNA-based HIV immunogens — are committed to the safety of trial participants and the highest standards of conduct in our trials.

IAVI and partners have observed that skin events occurred in 7%-18% of the volunteers who received the investigational products across IAVI G002 (NCT05001371), IAVI G003 (NCT05414786), and HVTN 302 (NCT05217641). It’s important to note that none of the studies had control arms, which would have helped clarify the actual frequency of skin events that are associated with the specific vaccine candidates studied.

The affected volunteers in the trials had skin events that were described as hives, itchiness, or hives caused by scratching. Most of these events were mild or moderate, and managed with simple allergy medications. There were no serious adverse events reported. Participants who experienced skin events were provided all medical care necessary and were monitored closely.

IAVI and partners are actively working to investigate the potential causes of these skin events. We have brought in an interdisciplinary team of external experts, including allergists and immunologists, to further assess the skin events. In the interest of transparency and clarity, IAVI and partners have presented preliminary data on immune responses and safety at scientific conferences and look forward to continuing our discussion of these results. Communicating details about the safety and immunogenicity of our vaccine candidates in a clear, timely, and transparent way is a top priority for IAVI and our partners.

The skin events observed in the trials were not observed in an earlier trial that evaluated a recombinant protein version of one of the immunogens used in IAVI G002.

Mark Feinberg, M.D., Ph.D., IAVI’s president and CEO, said, “IAVI is encouraged by the very favorable immunogenicity results seen in IAVI G002 and related trials, which will be published in forthcoming papers. We look forward to continuing our pursuit of proof-of-concept for the elicitation of broadly neutralizing antibodies against HIV via the defined sequential germline-targeting immunization strategy, while working to better understand this safety signal and identify approaches to mitigate it. We will continue safety and immunogenicity studies of scientifically promising immunogens that we hope will be part of a much-needed HIV vaccine.”

(*) L'articolo cui si fa riferimento nel comunicato stampa di IAVI è uscito il I marzo scorso tra le News di Science e porta la firma di Jon Cohen: Puzzling skin side effects stymie advance of promising HIV vaccine