Attenuated humoral responses in HIV infection after SARS-CoV-2 vaccination are linked to global B cell defects and cellular immune profiles (preprint)

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+ T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.

Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV (preprint)

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). We show that the majority of PLWH, controlled on ART, mount a functional adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleocapsid are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses are observed. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.

Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV (preprint)

There is an urgent need to understand the nature of immune responses generated against SARS-CoV-2, to better inform risk-mitigation strategies for people living with HIV (PLWH). Although not all PLWH are considered immunosuppressed, residual cellular immune deficiency and ongoing inflammation could influence COVID-19 disease severity, the evolution and durability of protective memory responses. Here, we performed an integrated analysis, characterizing the nature, breadth and magnitude of SARS-CoV-2-specific immune responses in PLWH, controlled on ART, and HIV negative subjects. Both groups were in the convalescent phase of predominately mild COVID-19 disease. The majority of PLWH mounted SARS-CoV-2 Spike- and Nucleoprotein-specific antibodies with neutralizing activity and SARS-CoV-2-specific T cell responses, as measured by ELISpot, at levels comparable to HIV negative subjects. T cell responses against Spike, Membrane and Nucleocapsid were the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. Notably, the overall magnitude of SARS-CoV-2-specific T cell responses related to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses were observed. Both humoral and cellular responses to SARS-CoV-2 were detected at 5-7 months post-infection, providing evidence of medium-term durability of responses irrespective of HIV serostatus. Incomplete immune reconstitution on ART and a low CD4:CD8 ratio could, however, hamper the development of immunity to SARS-CoV-2 and serve as a useful tool for risk stratification of PLWH. These findings have implications for the individual management and potential effectiveness of vaccination against SARS-CoV-2 in PLWH.

Outcomes of COVID-19 related hospitalisation among people with HIV in the ISARIC WHO Clinical Characterisation Protocol UK Protocol: prospective observational study (preprint)

Background.There is conflicting evidence about how HIV infection influences COVID-19. We compared the presentation characteristics and outcomes of people with and without HIV hospitalised with COVID-19 at 207 centres across the United Kingdom. Methods.We analysed data from people with laboratory confirmed or highly likely COVID-19 enrolled into the ISARIC CCP-UK study. The primary endpoint was day-28 mortality after presentation. We used Kaplan-Meier methods and Cox regression to describe the association with HIV status after adjustment for sex, ethnicity, age, indeterminate/probable hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, and presence/absence of ten comorbidities. We additionally adjusted for disease severity at presentation as defined by hypoxia/oxygen therapy. Findings.Among 47,539 patients, 115 (0{middle dot}24%) had confirmed HIV-positive status and 103/115 (89{middle dot}6%) had a record of antiretroviral therapy. At presentation, relative to the HIV-negative group, HIV-positive people were younger (median 55 versus 74 years; p<0{middle dot}001), had a higher prevalence of obesity and moderate/severe liver disease, higher lymphocyte counts and C-reactive protein, and more systemic symptoms. The cumulative incidence of day-28 mortality was 25{middle dot}2% in the HIV-positive group versus 32{middle dot}1% in the HIV-negative group (p=0{middle dot}12); however, stratification for age revealed a higher mortality among HIV-positive people aged below 60 years. The effect of HIV-positive status was confirmed in adjusted analyses (adjusted hazard ratio [HR] 1{middle dot}49, 95% confidence interval [CI] 0{middle dot}99-2{middle dot}25; p=0{middle dot}06). Following additional adjustment for disease severity at presentation, mortality was higher in HIV-positive people (adjusted HR 1{middle dot}63; 95% CI 1{middle dot}07-2{middle dot}48; p=0{middle dot}02). In the HIV-positive group, mortality was more common among those who were slightly older and among people with obesity and diabetes with complications. Interpretation.HIV-positive status may be associated with an increased risk of day-28 mortality following a COVID-19 related hospitalisation. Funding.NIHR, MRC, Wellcome Trust, Department for International Development, Bill and Melinda Gates Foundation. Study registrationISRCTN66726260 RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for articles in all languages containing the words "COVID*", "coronavirus", "SARS CoV-2" AND "HIV". After screening on 23rd July 2020, we found 51 articles reporting outcomes of COVID-19 in HIV-positive people. Of these, 2 were systematic reviews, 24 were single case reports or case series of under 10 participants, and 12 were larger case series or retrospective cohorts without matched controls. There were two cohort studies that matched HIV-positive people diagnosed with COVID-19 to the general population attending for HIV care in the same area, and three studies that matched HIV-positive people diagnosed with COVID-19 to HIV-negative controls. Some of the evidence from the United States and Europe to date suggests that people with HIV experience a similar disease course and outcomes of COVID-19 compared to the general population. However, many of the studies are limited by small sample size, lack of comparator group and lack of adjustment for potential confounding. In contrast, preliminary results from a cohort study of over 20,000 participants in South Africa indicate that HIV-positive status more than doubles the risk of COVID-19 related mortality. Currently, the evidence from the United Kingdom is limited to two case series comprising a total of 21 patients. Added value of this studyThis study analysed data collected from 207 sites across the United Kingdom as part of ISARIC CCP, the largest prospective cohort of patients hospitalised with COVID-19, to evaluate the association between HIV-positive status and day-28 mortality. The study has the benefit of a relatively large number of participants with HIV (n=115, almost all receiving antiretroviral therapy) and importantly, the ability to direct compare their presenting characteristics and outcomes to those of 47,424 HIV-negative controls within the same dataset. This includes the ability to assess the influence of gender, ethnicity and age, as well as the effect of key comorbidities including chronic cardiac, pulmonary, renal and haematological disease, diabetes, obesity, chronic neurological disorder, dementia, liver disease, and malignancy. Unlike some of the other evidence to date, but in line with the data from South Africa, this study indicates that HIV-positive status may increase the risk of mortality with COVID-19 compared to the general population, with an effect that was especially evident among people with HIV aged below 60 years and was independent of gender or ethnicity. Although we detected an association between mortality among people with HIV and occurrence of obesity and diabetes with complication, the effect of HIV-positive status persisted after adjusting for comorbidities. Implications of all the available evidencePeople with HIV may be at increased risk of severe outcomes from COVID-19 compared to the general population. Ongoing data collection is needed to confirm this association. Linkage of hospital outcome data to the HIV history will be paramount to establishing the determinants of the increased risk. COVID-19 related hospitalisation should pursue systematic recording of HIV status to ensure optimal management and gathering of evidence.