Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV (preprint)

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+ T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV-negative participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were 'rescued' after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV-negative participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral 'blips' in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+ T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

Hospital Admission and Hospital Course Predictors of Severity of Post-covid-19 Condition (preprint)

BACKGROUND Prediction of severity of Post-COVID-19 condition is not clear. We determined whether hospital course variables correlated with objective and subjective outcomes 3- and 6-months post-COVID-19 onset.METHODS Adults admitted to hospital with acute COVID-19 were recruited (Feb 15, 2020-April 1, 2021) from two tertiary hospitals in Vancouver, Canada. We recorded baseline characteristics, COVID severity score, organ function, ICU and hospital length of stay. Survivors were evaluated at 3- and 6-months post- COVID-19 onset: subjective: University of California San Diego Shortness of Breath Score, EuroQol 5D Visual Analogue Scale, Frailty Index; Objective: functional capacity (6-minute walk test), pulmonary (pulmonary function tests), cardiac (echocardiography, BNP), renal (creatinine), hepatic (AST, ALT, bilirubin), and coagulation (aPTT, INR, D-dimers, fibrinogen).RESULTS In 133 post-COVID-19 patients (age 62 ± 14 years, 65% male with frequent comorbidities [hypertension (42%), diabetes (29%), chronic cardiac (22%)), 42% were admitted to Intensive Care Unit: 23%, 23% and 2% required ventilation, vasopressors or renal support, respectively. One-third had restrictive lung function (< 80% predicted FVC %, TLC%, or DLCO%) at 3 months. Novel findings were correlations of (1) acute hepatic dysfunction with restrictive lung function at 3 months post COVID-19 onset; (2) more severe acute COVID-19 with later pro-thrombotic phenotype and (3) greater acute organ dysfunction with later objective organ dysfunction at 3- and 6-months. No hospital course variables were associated with subjective outcomes at 3- and 6-months.CONCLUSIONS Early organ dysfunction predicts later objective pathology especially restrictive lung disease and a pro-coagulant state. These hypothesis-generating findings require further validation in additional patients.

Sustained Dysregulation of the Plasma Renin-angiotensin System in Acute COVID-19 (preprint)

SARS-CoV-2 enters cells by binding to angiotensin-converting enzyme 2 (ACE2), and COVID-19 infection may therefore induce changes in the renin-angiotensin system (RAS). To determine the effects of COVID-19 on plasma RAS components, we measured plasma ACE, ACE2, and angiotensins I, (1-7), and II in 46 adults with COVID-19 at hospital admission and on days 2, 4, 7 and 14, compared to 50 blood donors (controls). We compared survivors vs. non-survivors, males vs. females, ventilated vs. not ventilated, and angiotensin receptor blocker (ARB) and angiotensin-converting enzyme (ACE) inhibitor-exposed vs. not exposed. At admission, COVID-19 patients had higher plasma levels of ACE (p=0.012), ACE2 (p=0.001) and angiotensin-(1-7) (p<0.001) than controls. Plasma ACE and ACE2 remained elevated for 14 days in COVID-19 patients, while plasma angiotensin-(1-7) decreased after 7 days. In adjusted analyses, plasma ACE was higher in males vs. females (p=0.042), and plasma angiotensin I was significantly lower in ventilated vs. non-ventilated patients (p=0.001). In summary, plasma ACE and ACE2 are increased for at least 14 days in patients with COVID-19 infection. Angiotensin-(1-7) levels are also elevated, but decline after 7 days. The results indicate dysregulation of the RAS with COVID-19, with increased circulating ACE2 throughout the course of infection.Clinical Trial Registration: https://clinicaltrials.gov/ Unique Identifier: NCT04510623