Abstract
Background
Ebola Virus Disease (EVD) outbreaks primarily occur in the HIV endemic setting of Sub-Saharan Africa. Transient increases in HIV viral load (VL), or blips, have been described ...following routine vaccinations. We characterized VL blips among PLWH enrolled in a phase 2 trial of a heterologous two-dose EVD vaccine.
Methods
In EBL2003, adult participants with and without HIV were randomized 1:4 to receive placebo or vaccine. Part A in the US studied MVA-BN-Filo followed by Ad26.ZEBOV 14 days later. Part B in Africa evaluated this MVA/Ad26 regimen and also a schedule of Ad26.ZEBOV followed by MVA-BN-Filo 29 days later. VL was assessed at screening, pre-vaccination, and 21, 42, 180, and 365 days post dose 2. Participants with VL < 20 copies/mL at the first 2 visits who received both doses and had complete VL data through 42 days post dose 2 were evaluated. Blips were defined as a post-injection VL ≥ 20 copies/mL no later than 42 days post dose 2, with subsequent return to VL < 20 copies/mL.
Results
A total of 277 PLWH on antiretroviral therapy (ART) were assessed; 73.3% (203) had baseline virologic suppression, and 89.2% (181) of those received both doses with complete VL data for inclusion in the analysis. Overall, 19.9% (36) experienced blips: 20.0% (29) of vaccinees vs 19.4% (7) of placebo recipients (p=1.0). All baseline suppressed participants with post-injection viremia subsequently regained suppression. Among vaccinees, the mean blip VL was 192 copies/mL, and the mean blip duration was 56 days, which was not significantly different from placebo. Of all blips, only 2 were > 1,000 copies/mL. Blips occurred in 24.0% (25) of Ad26/MVA recipients, and 9.7% (4) of MVA/Ad26 recipients (p=0.07). A dose of Ad26 was associated with a blip in 6.9% (10) of recipients vs 13.1% (19) for MVA recipients (p=0.12). Regardless of regimen, dose 1 was associated with a blip in 8.3% (12) of vaccinees, compared to 11.7% (17) of vaccinees for dose 2 (p=0.43).
Conclusion
Among successfully treated PLWH, we observed low magnitude post-dose HIV blips that were not more common in vaccine vs. placebo recipients and did not result in loss of virologic suppression. This data is favorable for the deployment of the EVD vaccines in this trial in areas of high HIV endemicity.
Disclosures
Benjamin L. Custer, M.D., Alexion Pharmaceuticals (Shareholder)Armata Pharmaceuticals (Shareholder)Biomarin Pharmaceutical (Shareholder)Crispr Therapeutics (Shareholder)CVS Health Corp (Shareholder)Editas Medicine (Shareholder)Gilead (Shareholder)Glaxo Smith Kline (Shareholder)Hologic Inc (Shareholder)Merck (Shareholder)Mesoblast LTD (Shareholder)Pfizer (Shareholder)Sanofi (Shareholder)Unitedhealth Group (Shareholder)Vertex Pharmaceuticals (Shareholder) Georgi Shukarev, MD, Janssen (Employee) Auguste Gaddah, PhD, Janssen Pharmaceutica N.V (Employee) Kerstin Luhn, PhD, Janssen Vaccines and Prevention (Employee, Shareholder) Macaya Douoguih, MD, MPH, Janssen (Employee) Cynthia Robinson, MD, Janssen Vaccines (Employee)
Abstract
Developing an effective vaccine to prevent pulmonary tuberculosis represents a public health priority. AERAS-402 (adenovirus expressing a fusion of M.tuberculosis antigens 85A, 85B, and ...TB10.4) and MVA85A (Modified Vaccinia Anakara expressing Ag85A) are TB vaccine candidates that have been independently evaluated in adult and infant studies and shown to be safe and immunogenic. Despite robust immune responses in adults, infant trials have revealed lower than expected immunogenicity for these vaccine platforms, possibly contributing to the failure of the MVA85A vaccine in a recent phase II efficacy trial. Complimentary studies of malaria and HIV vaccines report enhanced immune responses using heterologous vaccine approaches with combinations of adenoviral and pox virus vectors. Here we present the preliminary immunogenicity data from a phase I clinical trial conducted in healthy BCG-vaccinated adults that were vaccinated with one or two doses of AERAS-402 and subsequently boosted with MVA85A. Preliminary data indicate that MVA85A boosts both CD4+ and CD8+ T cell responses. Interestingly, MVA85A, which primarily stimulates CD4+ T cell responses when given alone,robustly boosted AERAS-402 CD8+ T cell responses to Ag85A, with average responses reaching approximately 0.5% to 1% of CD8+ T cells. These data suggest that this vaccine combination is highly immunogenic in adults. Further studies are needed to assess the clinical efficacy of this vaccine combination.
Abstract
Despite widespread use of BCG, tuberculosis (TB) remains a global threat, with 9 million new cases and 1.5 million deaths reported in 2013. Current vaccine candidates in clinical trials are ...designed to replace BCG or boost the variable efficacy observed with BCG. One of these is AERAS-402, a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis antigens 85A, 85B, and TB10.4. This vaccine has been tested in adults, infants, HIV+ adults and patients on or following treatment for TB and shown to be safe and immunogenic. A phase 2 clinical trial of two doses of AERAS-402 was conducted in healthy infants in South Africa, Kenya, and Mozambique. The original study design consisted of a dose-finding phase followed by an efficacy phase at the selected dose. The trial design was modified to include a third dose of AERAS-402. AERAS-402 was well-tolerated at all dose levels and up to three doses. Despite the addition of a third dose, the predefined immunogenicity target was not met and the efficacy portion of the trial was removed. The third dose failed to increase immune responses, which consisted of a dominant polyfunctional (IFN-γ, IL-2, TNF) and bifunctional (IFN-γ, TNF) CD8 response and a lower magnitude polyfunctional and bifunctional (IL-2, TNF) CD4 responses. These responses were considerably lower than those observed in adults. Alternative methods to enhance responses to AERAS-402, such as heterologous prime-boost approaches, are warranted.
BackgroundThough clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were ...major outbreaks (≥200 cases; five caused by Zaire ebolavirus EBOV, two by Sudan ebolavirus SUDV, and one by Marburg virus MARV). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses. This first-in-human study assessed the safety and immunogenicity of several multivalent two-dose vaccine regimens that contain Ad26.Filo and MVA-BN-Filo.MethodsAd26.Filo combines three vaccines encoding the glycoprotein (GP) of EBOV, SUDV, and MARV. MVA-BN-Filo is a multivalent vector encoding EBOV, SUDV, and MARV GPs, and Taï Forest nucleoprotein. This Phase 1, randomized, double-blind, placebo-controlled study enrolled healthy adults (18-50 years) into four groups, randomized 5:1 (active:placebo), to assess different Ad26.Filo and MVA-BN-Filo vaccine directionality and administration intervals. The primary endpoint was safety; immune responses against EBOV, SUDV, and MARV GPs were also assessed.ResultsSeventy-two participants were randomized, and 60 (83.3%) completed the study. All regimens were well tolerated with no deaths or vaccine-related serious adverse events (AEs). The most frequently reported solicited local AE was injection site pain/tenderness. Solicited systemic AEs most frequently reported were headache, fatigue, chills, and myalgia; most solicited AEs were Grade 1-2. Solicited/unsolicited AE profiles were similar between regimens. Twenty-one days post-dose 2, 100% of participants on active regimen responded to vaccination and exhibited binding antibodies against EBOV, SUDV, and MARV GPs; neutralizing antibody responses were robust against EBOV (85.7-100%), but lower against SUDV (35.7-100%) and MARV (0-57.1%) GPs. An Ad26.Filo booster induced a rapid further increase in humoral responses.ConclusionThis study demonstrates that heterologous two-dose vaccine regimens with Ad26.Filo and MVA-BN-Filo are well tolerated and immunogenic in healthy adults.Clinicaltrials.govNCT02860650.
Abstract
Development of a vaccine to prevent pulmonary tuberculosis remains a public health priority. AERAS-402 is a live, replication-deficient adenovirus 35-vectored TB vaccine expressing the ...mycobacterial antigens 85A, 85B, and TB10.4. While this vaccine has been shown to be safe in TB uninfected patients, little is known about the performance of this vaccine in TB-experienced populations. The safety and immunogenicity of AERAS-402 was evaluated in a Phase 2a randomized, placebo-controlled, double-blinded dose-escalation study in HIV-negative South African adults with either active or recent pulmonary TB infection. Peripheral blood mononuclear cells isolated from trial patients were assessed via intracellular cytokine staining (ICS) examining T cells for interferon-γ (IFN-γ), TNF, and IL-2 production. While modest CD4+ T cell responses were observed, the ICS data indicate the induction of a robust, dominant CD8+ T cell response not observed in placebo patients, including instances of total cytokine responsive cells approaching 6% of CD8+ T cells in some subjects. Polyfunctional analysis revealed that vaccine-specific T cells were primarily secreting IFN-γ either alone or in combination with TNF following stimulation. These data suggest that AERAS-402 is able to boost T cell responses in patients with a history of TB infection.
Bacille Calmette-Guérin (BCG), the only licensed vaccine for the prevention of tuberculosis (TB), provides only limited protection against certain forms of Mycobacterium tuberculosis (Mtb) infection. ...While infection with Mtb can be treated with antibiotics, the therapy is expensive, toxic, and requires several months for treatment. In addition, the emergence of drug resistant strains limits the impact of antibiotics and underlines the importance of developing a more effective vaccine to control this disease. Given that pulmonary TB is the most common form of the disease, a vaccine capable of inducing lung-resident immunity may be advantageous for combating this infection. New advances in pulmonary delivery make this route of vaccination feasible and affordable. Here, we evaluate the safety and immunogenicity of an aerosolized Ad35-based vaccine, AERAS-402, delivered to the lungs in nonhuman primates as part of a GLP acute and chronic toxicology and safety study. In this study, animals received three high doses (1 x 10
11
vp) of AERAS-402 by inhalation via a nebulizer at 1-week intervals. Aerosol delivery of AERAS-402 resulted in an increase in relative lung weights as well as microscopic findings in the lungs, mediastinal lymph nodes, bronchus-associated lymphatic tissue, and the naso-oropharynx that were consistent with the induction of an immune response during the acute phase. These findings resolved by the chronic phase and were considered to be non-adverse. Furthermore, we observed transient vaccine-specific immune responses in the peripheral blood as well as sustained high-level polyfunctional CD4
+
and CD8
+
T cell responses in the bronchoalveolar lavage fluid of vaccinated nonhuman primates. The data suggest that pulmonary delivery of Ad35-based vaccines can be safe and can induce potent lung-resident immunity.
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