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The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.

Rabies is a zoonotic viral encephalitis that is endemic in many countries and confers a high mortality. Licensed vaccines require several doses to ensure efficacy. To investigate a logistically favorable approach, we assessed the safety and immunogenicity of ChAd155-RG, a novel investigational rabies vaccine using a replication-defective chimpanzee adenovirus vector. We conducted a first-in-human, phase 1, randomized, double-blind, dose-escalation trial comparing ChAd155-RG with a licensed inactivated vaccine (RabAvert) in healthy adults. Participants received either RabAvert at standard dosing or ChAd155-RG at a low dose for one immunization or a high dose for one or two immunizations. To assess safety, we evaluated reactogenicity, unsolicited adverse events, and thrombotic events. To measure immunogenicity, we measured rabies viral neutralizing antibody (VNA) titers and anti-ChAd155 neutralizing antibodies. Mild to moderate systemic reactogenicity and transient lymphopenia and neutropenia were more common among recipients of ChAd155-RG compared with those who received RabAvert. No thrombotic events or serious adverse events were reported. Only the groups receiving RabAvert or two doses of high-dose ChAd155-RG achieved 100 % seroconversion, and seroprotection was most durable in the RabAvert group. Most participants had preexisting anti-vector antibodies, which were boosted by ChAd155-RG. Baseline and post-vaccination anti-vector antibody titers were negatively associated with post-vaccination rabies VNA titers. In this phase 1 clinical trial, a novel rabies vaccine using a simian adenovirus vector was safe and tolerable, but generated lower, less durable rabies VNA titers than a standard inactivated rabies virus vaccine, which may be due to preexisting, anti-vector immunity.

A three-antigen DNA-prime/chimpanzee adenovirus 63 (ChAd63) boost vaccine containing pre-erythrocytic Plasmodium falciparum (Pf) circumsporozoite protein (CSP), Pf apical membrane antigen-1 (AMA1) and malaria multiple epitopes (ME) fused to Pf thrombospondin-related adhesion protein (ME-TRAP) elicited higher vaccine efficacy (VE) in an open label, randomized Phase 1 trial against controlled human malaria infection (CHMI) than the two-antigen vaccine DNA/Human Adenovirus 5 (HuAd5) containing CSP and AMA1. The objective of this follow-up study was to determine whether responses to CSP, AMA1 or TRAP MHC Class I-restricted epitopes were associated with VE. Protected (n = 6) and non-protected participants (n = 26) were screened in FluoroSpot interferon gamma (IFN-γ) and Granzyme B (GzB) assays using antigen-specific 15mer peptide subpools spanning CSP (n = 9 subpools), AMA1 (n = 12 subpools), and TRAP (n = 11 subpools). Individual antigen-specific 15mers in the subpools with strong responses were then deconvoluted, evaluated for activities, and MHC Class I-restricted epitopes within the active 15mers were predicted using NetMHCpan algorithms. The predicted epitopes were synthesized and evaluated in the FluoroSpot IFN-γ and GzB assays. Protected and some non-protected participants had similar responses to individual antigen-specific peptide subpools, which did not distinguish only protected participants. However, deconvoluted antigen-specific positive subpools with high magnitudes of responses revealed individual 15mer peptides containing specific and/or predicted MHC Class I (HLA) epitopes. Responses to epitopes were either IFN-γ-only, IFN-γ and GzB, or GzB-only. Due to limitation of cells, most of the analysis concentrated on the identification of protection associated AMA1 epitopes, since most of the predominant pool specific responses were generated against AMA1 15mer subpools. Furthermore, we previously identified protection associated HLA class I-restricted epitopes in a previous gene-based vaccine trial. Seven predicted minimal epitopes in AMA1 were synthesized and upon testing, five recalled responses from protected participants confirming their possible contribution and association with protection, and two recalled responses from non-protected participants. Two protection-associated epitopes were promiscuous and may have also contributed to protection by recognition of different HLA alleles. In addition, strongly positive antigen-specific 15mers identified within active antigen-specific subpools contained 39 predicted but not tested epitopes were identified in CSP, AMA1 and TRAP. Finally, some non-protected individuals recognized HLA-matched protection-associated minimal epitopes and we discuss possible reasons. Other factors such as HLA allele fine specificity or interaction between other HLA alleles in same individual may also influence protective efficacy. This integrated approach using immunoassays and bioinformatics identified and confirmed AMA1-MHC Class I-restricted epitopes and a list of predicted additional epitopes which could be evaluated in future studies to assess possible association with protection against CHMI in the Phase 1 trial participants. The results suggest that identification of protection-associated epitopes within malaria antigens is feasible and can help design potent next generation multi-antigen, multi-epitope malaria vaccines for a genetically diverse population and to develop robust assays to measure protective cellular immunity against pre-erythrocytic stages of malaria. This approach can be used to develop vaccines for other novel emerging infectious disease pathogens.

In this trial, the safety and efficacy of a recombinant chimpanzee adenovirus 3 vector priming vaccination and a recombinant modified vaccinia Ankara boost was assessed in adults who were at risk for HCV infection because of injection drug use. The vaccine did not cause serious adverse events and did elicit HCV-specific T-cell responses, but it did not prevent chronic HCV infection.

Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.

HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported. Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination. Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern. These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies. ClinicalTrials.gov NCT01151319.

A chimpanzee adenovirus-based vaccination approach elicits acute and long-term protection against ebolavirus challenge in nonhuman primates. Ebolavirus disease causes high mortality, and the current outbreak has spread unabated through West Africa. Human adenovirus type 5 vectors (rAd5) encoding ebolavirus glycoprotein (GP) generate protective immunity against acute lethal Zaire ebolavirus (EBOV) challenge in macaques, but fail to protect animals immune to Ad5, suggesting natural Ad5 exposure may limit vaccine efficacy in humans. Here we show that a chimpanzee-derived replication-defective adenovirus (ChAd) vaccine also rapidly induced uniform protection against acute lethal EBOV challenge in macaques. Because protection waned over several months, we boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal EBOV challenge.

Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified Vaccinia Virus Ankara (MVA) vectored vaccines is a strategy previously shown to provide substantial protective efficacy against P. falciparum infection in United Kingdom adult Phase IIa sporozoite challenge studies (approximately 20-25% sterile protection with similar numbers showing clear delay in time to patency), and greater point efficacy in a trial in Kenyan adults. We conducted the first Phase IIb clinical trial assessing the safety, immunogenicity and efficacy of ChAd63 MVA ME-TRAP in 700 healthy malaria exposed children aged 5-17 months in a highly endemic malaria transmission area of Burkina Faso. ChAd63 MVA ME-TRAP was shown to be safe and immunogenic but induced only moderate T cell responses (median 326 SFU/106 PBMC (95% CI 290-387)) many fold lower than in previous trials. No significant efficacy was observed against clinical malaria during the follow up period, with efficacy against the primary endpoint estimate by proportional analysis being 13.8% (95%CI -42.4 to 47.9) at sixth month post MVA ME-TRAP and 3.1% (95%CI -15.0 to 18.3; p = 0.72) by Cox regression. This study has confirmed ChAd63 MVA ME-TRAP is a safe and immunogenic vaccine regimen in children and infants with prior exposure to malaria. But no significant protective efficacy was observed in this very highly malaria-endemic setting. ClinicalTrials.gov NCT01635647. Pactr.org PACTR201208000404131.

A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection. This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method. In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-[gamma] FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection. This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

Induction of antigen-specific CD8 + T cells offers the prospect of immunization against many infectious diseases, but no subunit vaccine has induced CD8 + T cells that correlate with efficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirus vector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequency T-cell responses (median >2400 SFC/10 6 peripheral blood mononuclear cells) to the liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protective efficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delays time to patency through substantial reduction of liver-stage parasite burden in five more (5/14, 36%), P =0.008 compared with controls. The frequency of monofunctional interferon-γ-producing CD8 + T cells, but not antibodies, correlates with sterile protection and delay in time to patency ( P corrected =0.005). Vaccine-induced CD8 + T cells provide protection against human malaria, suggesting that a major limitation of previous vaccination approaches has been the insufficient magnitude of induced T cells. Induction of protective immunity mediated by CD8 + T cells has been a long sought goal in vaccinology. Here, Ewer et al. report induction of protective efficacy against Plasmodium falciparum malaria in a phase IIa prime-boost vaccine trial where efficacy correlates strongly with induced CD8 T-cell responses.