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.

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.

Durability of ChAdOx1 nCoV-19 vaccination in people living with HIV.

Duration of protection from SARS-CoV-2 infection in people living with HIV (PWH) following vaccination is unclear. In a substudy of the phase II/III the COV002 trial (NCT04400838), 54 HIV+ male participants on antiretroviral therapy (undetectable viral loads, CD4+ T cells > 350 cells/µL) received 2 doses of ChAdOx1 nCoV-19 (AZD1222) 4-6 weeks apart and were followed for 6 months. Responses to vaccination were determined by serology (IgG ELISA and Meso Scale Discovery [MSD]), neutralization, ACE-2 inhibition, IFN-γ ELISpot, activation-induced marker (AIM) assay and T cell proliferation. We show that, 6 months after vaccination, the majority of measurable immune responses were greater than prevaccination baseline but with evidence of a decline in both humoral and cell-mediated immunity. There was, however, no significant difference compared with a cohort of HIV-uninfected individuals vaccinated with the same regimen. Responses to the variants of concern were detectable, although they were lower than WT. Preexisting cross-reactive T cell responses to SARS-CoV-2 spike were associated with greater postvaccine immunity and correlated with prior exposure to beta coronaviruses. These data support the ongoing policy to vaccinate PWH against SARS-CoV-2, and they underpin the need for long-term monitoring of responses after vaccination.

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.