The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.
Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium -infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.
Abstract Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and T-cell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT 50 seroconversion after a single dose.
BackgroundRabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults.MethodsWe did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 109 viral particles), middle (2·5 × 1010 viral particles), and high doses (5 x 1010 viral particles) of ChAdOx2 RabG and were followed up to day 56 after vaccination. The primary objective was to assess safety. The secondary objective was to assess immunogenicity with the internationally standardised rabies virus neutralising antibody assay. In an optional follow-up phase 1 year after enrolment, we measured antibody maintenance then administered a licensed rabies vaccine (to simulate post-exposure prophylaxis) and measured recall responses. The trial is registered with ClinicalTrials.gov, NCT04162600, and is now closed to new participants.FindingsBetween Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0–54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7–18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0–486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL.InterpretationIn this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation.FundingUK Medical Research Council and Engineering and Physical Sciences Research Council.
SummaryBackgroundCases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans.MethodsThis dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578.FindingsBetween March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66–81]) of 124 solicited adverse events were mild, 31 (25% [18–33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11–17·42], p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19–73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58–93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay.InterpretationChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials.FundingUK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.
Heterologous prime-boost strategies are known to substantially increase immune responses in viral vectored vaccines. Here we report on safety and immunogenicity of the poxvirus Modified Vaccinia Ankara (MVA) vectored vaccine expressing four Mycobacterium avium subspecies paratuberculosis antigens as a single dose or as a booster vaccine following a simian adenovirus (ChAdOx2) prime. We demonstrate that a heterologous prime-boost schedule is well tolerated and induced T-cell immune responses.
Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine is immunogenic and protects against COVID-19. However, data on vaccine immunogenicity are needed for the 40 million people living with HIV (PWH), who may have less functional immunity and more associated co-morbidities than the general population. Methods: Between the 5th and 24th November 2020, 54 adults with HIV, aged 18-55 years, were enrolled into a single arm open label vaccination study within the protocol of the larger phase 2/3 COV002 trial. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses (5 × 1010 vp) was given 4-6 weeks apart. All participants were on antiretroviral therapy (ART) with undetectable plasma HIV viral loads and CD4+ T cell counts >350 cells/µl at enrolment. Data were captured on adverse events. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo interferon-γ enzyme-linked immunospot assay (ELISpot) and T cell proliferation. All outcomes were compared with a HIV uninfected group from the main COV002 study.Findings: 54 participants with HIV (median age 42.5 years (IQR 37.2-49.8)) received two doses of ChAdOx1 nCoV-19. Median CD4+ T cell count at enrolment was 694 cells/µl (IQR 562-864). Results are reported for 56 days of follow-up. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (49%), fatigue (47%), headache (47%), malaise (34%), chills (23%), and muscle or (36%) joint pain (9%), the frequencies of which were similar to the HIV-negative participants. There were no serious adverse events. Anti-spike IgG responses by ELISA peaked at Day 42 (median 1440 ELISA units, IQR 704-2728) and were sustained out to Day 56. There was no correlation with CD4+ T cell count or age and the magnitude of the anti-spike IgG response at Day 56 (P>0.05 for both). ELISpot and T cell proliferative responses peaked between Day 14 and 28 after prime and were sustained through to Day 56. When compared to participants without HIV there was no statistical difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (P>0.05 for all analyses).Interpretation: In this study of PWH, vaccination with ChAdOx1 nCoV-19 was well tolerated and there was no difference in humoral and cell-mediated immune responses compared to an adult cohort without HIV who received the same vaccination regime. Trial Registration: Trial Registration number is NCT04400838. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19 (AZD1222). AstraZeneca reviewed the data from the study and the final manuscript before 474 submission, but the authors retained editorial control. SCG is cofounder of Vaccitech (a collaborator in the early development of this vaccine candidate) and named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine. TL is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care's JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AVSH is a cofounder of and consultant to Vaccitech and is named as an inventor on a patent covering design and use of ChAdOx1-vectored vaccines (PCT/GB2012/000467).Ethical Approval: Written informed consent was obtained from all participants, and the trial was done in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (reference 21584/0424/001-0001) and the South Central Berkshire Research Ethics Committee (reference 20/SC/0145). Vaccine use was authorised by Genetically Modified Organisms Safety Committees at each participating site.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)