ChAdOx1 nCoV-19 vaccination generates spike-specific CD8+ T cells in aged mice.

Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus-2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen-specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope-specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV-19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV-19 elicits a good CD8+ T-cell response in older bodies, but that typical age-associated features are evident on these vaccine reactive T cells.

Booster vaccination against SARS-CoV-2 induces potent immune responses in people with HIV.

BACKGROUND: People with HIV on antiretroviral therapy with good CD4 T cell counts make effective immune responses following vaccination against SARS-CoV-2. There are few data on longer term responses and the impact of a booster dose. METHODS: Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed twelve months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µl. Immune responses to the ancestral strain and variants of concern were measured by anti-spike IgG ELISA, MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, Activation Induced Marker (AIM) assay and T cell proliferation. FINDINGS: 54 participants received two doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) one year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titres (MSD), ACE-2 inhibition and IgG ELISA results were significantly higher compared to Day 182 titres (P < 0.0001 for all three). SARS-CoV-2 specific CD4+ T cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4 + and CD8+ T cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. CONCLUSIONS: In PWH receiving a third vaccine dose, there were significant increases in B and T cell immunity, including to known VOCs.

Tfh cells and the germinal center are required for memory B cell formation & humoral immunity after ChAdOx1 nCoV-19 vaccination.

Emergence from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been facilitated by the rollout of effective vaccines. Successful vaccines generate high-affinity plasma blasts and long-lived protective memory B cells. Here, we show a requirement for T follicular helper (Tfh) cells and the germinal center reaction for optimal serum antibody and memory B cell formation after ChAdOx1 nCoV-19 vaccination. We found that Tfh cells play an important role in expanding antigen-specific B cells while identifying Tfh-cell-dependent and -independent memory B cell subsets. Upon secondary vaccination, germinal center B cells generated during primary immunizations can be recalled as germinal center B cells again. Likewise, primary immunization GC-Tfh cells can be recalled as either Tfh or Th1 cells, highlighting the pluripotent nature of Tfh cell memory. This study demonstrates that ChAdOx1 nCoV-19-induced germinal centers are a critical source of humoral immunity.

Persistence of the immune response after two doses of ChAdOx1 nCov-19 (AZD1222): 1 year of follow-up of two randomized controlled trials.

The trajectory of immune responses following the primary dose series determines the decline in vaccine effectiveness over time. Here we report on maintenance of immune responses during the year following a two-dose schedule of ChAdOx1 nCoV-19/AZD1222, in the absence of infection, and also explore the decay of antibody after infection. Total spike-specific IgG antibody titres were lower with two low doses of ChAdOx1 nCoV-19 vaccines (two low doses) (P = 0.0006) than with 2 standard doses (the approved dose) or low dose followed by standard dose vaccines regimens. Longer intervals between first and second doses resulted in higher antibody titres (P < 0.0001); however, there was no evidence that the trajectory of antibody decay differed by interval or by vaccine dose, and the decay of IgG antibody titres followed a similar trajectory after a third dose of ChAdOx1 nCoV-19. Trends in post-infection samples were similar with an initial rapid decay in responses but good persistence of measurable responses thereafter. Extrapolation of antibody data, following two doses of ChAdOx1 nCov-19, demonstrates a slow rate of antibody decay with modelling, suggesting that antibody titres are well maintained for at least 2 years. These data suggest a persistent immune response after two doses of ChAdOx1 nCov-19 which will likely have a positive impact against serious disease and hospitalization.

Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial.

BACKGROUND: Intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens. A number of intranasal SARS-CoV-2 vaccine candidates have achieved protection in pre-clinical challenge models, including ChAdOx1 nCoV-19 (AZD1222, University of Oxford / AstraZeneca). METHODS: We performed a single-centre open-label Phase I clinical trial of intranasal vaccination with ChAdOx1 nCoV-19 in healthy adults, using the existing formulation produced for intramuscular administration. Thirty SARS-CoV-2 vaccine-naïve participants were allocated to receive 5 × 109 viral particles (VP, n=6), 2 × 1010 VP (n=12), or 5 × 1010 VP (n=12). Fourteen received second intranasal doses 28 days later. A further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46. To investigate intranasal ChAdOx1 nCoV-19 as a booster, six participants who had previously received two intramuscular doses of ChAdOx1 nCoV-19 and six who had received two intramuscular doses of BNT162b2 (Pfizer / BioNTech) were given a single intranasal dose of 5 × 1010 VP of ChAdOx1 nCoV-19. Objectives were to assess safety (primary) and mucosal antibody responses (secondary). FINDINGS: Reactogenicity was mild or moderate. Antigen-specific mucosal antibody responses to intranasal vaccination were detectable in a minority of participants, rarely exceeding levels seen after SARS-CoV-2 infection. Systemic responses to intranasal vaccination were typically weaker than after intramuscular vaccination with ChAdOx1 nCoV-19. Antigen-specific mucosal antibody was detectable in participants who received an intramuscular mRNA vaccine after intranasal vaccination. Seven participants developed symptomatic SARS-CoV-2 infection. INTERPRETATION: This formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response. FUNDING: AstraZeneca.

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002).

BACKGROUND: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44-45 weeks) between the first and second dose, and response to a third dose as a booster given 28-38 weeks after the second dose. METHODS: In this substudy, volunteers aged 18-55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44-45 weeks after first dose) or a third dose of the vaccine (28-38 weeks after second dose). Data from volunteers aged 18-55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. FINDINGS: Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8-12 weeks: 267 [83%] of 321; 15-25 weeks: 24 [7%]; or 44-45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8-12 weeks: 115 [44%] of 261; 15-25 weeks: 116 [44%]; and 44-45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44-45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83-91·08] vs 1·75 EUs [1·60-1·93]). 32 participants received a late second dose of vaccine 44-45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525-1764] with an 8-12 week interval; 1860 EUs [917-4934] with a 15-25 week interval; and 3738 EUs [1824-6625] with a 44-45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047-6420]) than 28 days after a second dose (median 1792 EUs [IQR 899-4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127-389] immediately before the third dose to 399 SFUs per milion PBMCs [314-662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. INTERPRETATION: An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. FUNDING: UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.