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.

Current Challenges and Solutions for Clinical Management and Care of People with HIV: Findings from the 12th Annual International HIV and Aging Workshop.

People with HIV on combination antiretroviral therapy (ART) have longer life expectancy and are increasingly experiencing age-related comorbidities. Thus, aging with HIV has become a central issue in clinical care and research, which has been particularly challenging with the intersection of the ongoing coronavirus (COVID)-19 pandemic. Since 2009, the International Workshop on HIV and Aging has served as a multidisciplinary platform to share research findings from cross-disciplinary fields along with community advocates to address critical issues in HIV and aging. In this article, we summarize the key oral presentations from the 12th Annual International Workshop on HIV and Aging, held virtually on September 23rd and 24th, 2021. The topics ranged from basic science research on biological mechanisms of aging to quality of life and delivery of care under the COVID-19 pandemic. This workshop enriched our understanding of HIV and aging under the COVID-19 pandemic, identified challenges and opportunities to combat the impact of COVID-19 on HIV communities, and also provided updated research and future directions of the field to move HIV and aging research forward, with the ultimate goal of successful aging for older people with HIV.

COVAC1 phase 2a expanded safety and immunogenicity study of a self-amplifying RNA vaccine against SARS-CoV-2.

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is well tolerated and immunogenic in SARS-CoV-2 seronegative and seropositive individuals aged 18-75. Methods: A phase 2a expanded safety and immunogenicity study of a saRNA SARS-CoV-2 vaccine candidate LNP-nCoVsaRNA, was conducted at participating centres in the UK between 10th August 2020 and 30th July 2021. Participants received 1 µg then 10 µg of LNP-nCoVsaRNA, ∼14 weeks apart. Solicited adverse events (AEs) were collected for one week post-each vaccine, and unsolicited AEs throughout. Binding and neutralisating anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, and SARS-CoV-2 pseudoneutralisation assay. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 216 healthy individuals (median age 51 years) received 1.0 µg followed by 10.0 µg of the vaccine. 28/216 participants were either known to have previous SARS-CoV2 infection and/or were positive for anti-Spike (S) IgG at baseline. Reactogenicity was as expected based on the reactions following licensed COVID-19 vaccines, and there were no serious AEs related to vaccination. 80% of baseline SARS-CoV-2 naïve individuals (147/183) seroconverted two weeks post second immunization, irrespective of age (18-75); 56% (102/183) had detectable neutralising antibodies. Almost all (28/31) SARS-CoV-2 positive individuals had increased S IgG binding antibodies following their first 1.0 µg dose with a ≥0.5log10 increase in 71% (22/31). Interpretation: Encapsulated saRNA was well tolerated and immunogenic in adults aged 18-75 years. Seroconversion rates in antigen naïve were higher than those reported in our dose-ranging study. Further work is required to determine if this difference is related to a longer dosing interval (14 vs. 4 weeks) or dosing with 1.0 µg followed by 10.0 µg. Boosting of S IgG antibodies was observed with a single 1.0 µg injection in those with pre-existing immune responses. Funding: Grants and gifts from the Medical Research Council UKRI (MC_PC_19076), the National Institute for Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, and Restore the Earth.

Enhanced immune responses following heterologous vaccination with self-amplifying RNA and mRNA COVID-19 vaccines.

The optimal vaccination strategy to boost responses in the context of pre-existing immune memory to the SARS-CoV-2 spike (S) glycoprotein is an important question for global public health. To address this, we explored the SARS-CoV-2-specific humoral and cellular immune responses to a novel self-amplifying RNA (saRNA) vaccine followed by a UK authorised mRNA vaccine (BNT162b2) in individuals with and without previous COVID-19, and compared these responses with those who received an authorised vaccine alone. 35 subjects receiving saRNA (saRNA group) as part of the COVAC1 clinical trial and an additional 40 participants receiving an authorised SARS-CoV-2 vaccine only (non-saRNA group) were recruited. Antibody responses were measured by ELISA and a pseudoneutralisation assay for wildtype, Delta and Omicron variants. Cellular responses were measured by IFN-Æ´ ELISpot and an activation induced marker (AIM) assay. Approximately 50% in each group had previous COVID-19 prior to vaccination, confirmed by PCR or antibody positivity on ELISA. All of those who received saRNA subsequently received a full course of an authorised vaccine. The majority (83%) of those receiving saRNA who were COVID-19 naïve at baseline seroconverted following the second dose, and those with previous COVID-19 had an increase in antibody titres two weeks following saRNA vaccination (median 27-fold), however titres were lower when compared to mRNA vaccination. Two weeks following the 2nd authorised mRNA vaccine dose, binding and neutralising antibody titres were significantly higher in the saRNA participants with previous COVID-19, compared to non-saRNA, or COVID-19 naive saRNA participants. Cellular responses were again highest in this group, with a higher proportion of spike specific CD8+ than CD4+ T cells when compared to those receiving the mRNA vaccine only. These findings suggest an immunological benefit of increased antigen exposure, both from natural infection and vaccination, particularly evident in those receiving heterologous vaccination with saRNA and mRNA.

Major revision version 11.0 of the European AIDS Clinical Society Guidelines 2021.

BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines were revised in 2021 for the 17th time with updates on all aspects of HIV care. KEY POINTS OF THE GUIDELINES UPDATE: Version 11.0 of the Guidelines recommend six first-line treatment options for antiretroviral treatment (ART)-naïve adults: tenofovir-based backbone plus an unboosted integrase inhibitor or plus doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. Recommendations on preferred and alternative first-line combinations from birth to adolescence were included in the new paediatric section made with Penta. Long-acting cabotegravir plus rilpivirine was included as a switch option and, along with fostemsavir, was added to all drug-drug interaction (DDI) tables. Four new DDI tables for anti-tuberculosis drugs, anxiolytics, hormone replacement therapy and COVID-19 therapies were introduced, as well as guidance on screening and management of anxiety disorders, transgender health, sexual health for women and menopause. The sections on frailty, obesity and cancer were expanded, and recommendations for the management of people with diabetes and cardiovascular disease risk were revised extensively. Treatment of recently acquired hepatitis C is recommended with ongoing risk behaviour to reduce transmission. Bulevirtide was included as a treatment option for the hepatitis Delta virus. Drug-resistant tuberculosis guidance was adjusted in accordance with the 2020 World Health Organization recommendations. Finally, there is new guidance on COVID-19 management with a focus on continuance of HIV care. CONCLUSIONS: In 2021, the EACS Guidelines were updated extensively and broadened to include new sections. The recommendations are available as a free app, in interactive web format and as an online pdf.

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.

Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial.

BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. METHODS: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0µg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). FINDINGS: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1µg) to 61% (14/23; 10.0µg) in ELISA and 46% (18/39; 0.3µg) to 87% (20/23; 5.0µg and 10.0µg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1µg to 1023 (468-2236) ng/mL at 5.0µg (p<0.001) and was not higher at 10.0µg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1µg) to 48% (11/23; 5.0µg) depending on dose level received. INTERPRETATION: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. FUNDING: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.

Comorbidity indices in people with HIV and considerations for coronavirus disease 2019 outcomes.

OBJECTIVE: To determine comorbidity indices in people with HIV (PWH) and lifestyle-similar HIV-negative controls. DESIGN: Cross-sectional analysis of the Pharmacokinetic and clinical Observations in PeoPle over fiftY cohort study in the United Kingdom and Ireland. METHODS: The Elixhauser Comorbidity Index (ECI), Charlson Comorbidity Index and the Comorbidity Burden Index were compared between older PWH and HIV-negative controls using the Mann-Whitney U test; the magnitude of the difference between groups was quantified using the r effect size. RESULTS: The 699 PWH and 304 HIV-negative controls were predominantly male (87.5% vs. 64.0%), white (86.3% vs. 90.0%) and had median ages of 57 and 58 years, respectively. Among PWH, the median (interquartile range) CD4 T-cell count was 624 (475, 811) cells/µl; 98.7% were on antiretroviral therapy. The median (interquartile range) ECI was 0 (0, 8) and 0 (-3, 1), Charlson Comorbidity Index was 2 (1, 5) and 1 (0, 1) and Comorbidity Burden Index 8.6 (2.2, 16.8) and 5.9 (0.6, 10.8), respectively. While all three indices were significantly higher in PWH than in controls (P < 0.001 for each), the magnitude of the differences between the two groups were small to medium, with effect sizes (95% confidence interval) of 0.21 (0.16, 0.27), 0.38 (0.32, 0.42) and 0.18 (0.11, 0.23), respectively. CONCLUSION: These three comorbidity indices are higher in PWH compared with HIV-negative controls, although the magnitude of differences between groups were small. Differences in the ECI, reportedly associated with poorer coronavirus disease 2019 outcomes, were driven by more individuals with HIV being within the higher end of the range.