Anti-Spike Antibodies and Neutralising Antibody Activity in People Living with HIV Vaccinated with COVID-19 mRNA-1273 Vaccine: A Prospective Cohort Study (preprint)

Background: Vaccines against COVID-19 are a powerful tool to control the current SARS-CoV-2 pandemic. A thorough description of their immunogenicity among people living with HIV (PLWHIV) is necessary. We aimed to assess the immunogenicity of the mRNA-1273 vaccine among PLWHIV.Methods: In this prospective cohort, adult PLWHIV outpatients were enrolled during the Italian vaccination campaign. Enrolment was allowed irrespective of ongoing combination antiretroviral therapy (ART), plasma HIV viral load and CD4+ T cell count. A two-dose regimen of mRNA-1273, with administrations performed 28 days apart, was employed. The primary outcomes were anti-spike (anti-S) antibody titres and neutralising antibody activity, assessed 28 days after completing the vaccination schedule, compared with individuals not affected by HIV (referred as healthy-donors, HDs). Findings: CD4+ T cell count groups and anti-nucleocapside (anti-N) positive serology were the only variables associated with anti-spike (anti-S) antibody titres (expressed as U/mL) and neutralising antibody activity. Anti-S antibodies were higher in COVID-19-experienced PLWHIV (median 12500 U/mL IQR [5704-12500]) than in COVID-19-naïve PLWHIV (median 2437 U/mL IQR [1485-4526]) but did not differ from those observed in COVID-19-experienced HDs (median 1077 U/mL IQR [702-7551]). Neutralising antibody activity in sera was higher in COVID-19-experienced PLWHIV (median 10888 IQR [2478-14416]) compared to COVID-19-naïve PLWHIV (median 1192 IQR [742-2421]) but was comparable to those observed in COVID-19-experienced HDs (median 20959 U/mL IQR [10060-31857]). When stratified according to CD4+ T cell count (<350 cells/μL, 350-500 cells/μL, >500 cells/μL), anti-S antibody titres (median 2173 U/mL [IQR 897-4109], 5763 IU/mL [IQR 4801-12500], 2449 U/mL [IQR 1524-5704]) were not lower to those observed among HDs (median 1425 U/mL [IQR 599-6131]). In addition, neutralising antibody activity, stratified according to the CD4+ T cell count (median 1314 [IQR 606-2477], 3329 IU/mL [IQR 1905-10508], 1227 U/mL [IQR 761-3032]), was similar to those displayed by HDs (median 2112 U/mL [IQR 719-8889]).Interpretation: Inoculation with mRNA-1273 vaccine given 4 weeks apart produced adequate immune responses in PLWHIV, who are well controlled on ART, irrespective of CD4+ T cell count and equivalent to individuals without HIV infection, supporting vaccination in PLWHIV.Funding: This study was partially supported by Italian Ministry of Health Ricerca Corrente 2021 and Grant Ricerca Finalizzata GR 2018-12365699, by Intesa San Paolo COVID-19 emergency 2020 funds, and by Fondazione Cariplo (INNATE-CoV).Declaration of Interest: All other authors declare no competing interests.Ethical Approval: The study protocol (286_2021) was approved by the INMI “Lazzaro Spallanzani” Ethics Committee (Roma, Italy),

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males (preprint)

Background: COVID-19 clinical presentation ranges from asymptomatic to fatal outcome. This variability is due in part to host genome specific mutations. Recently, two families in which COVID-19 segregates like an X-linked recessive monogenic disorder environmentally conditioned by SARS-CoV-2 have been reported leading to identification of loss-of-function variants in TLR7. Objective: We sought to determine whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: We compared male subjects with extreme phenotype selected from the Italian GEN-COVID cohort of 1178 SARS-CoV-2-infected subjects (<60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on the young male subset, picking up TLR7 as the most important susceptibility gene. Results: Rare TLR7 missense variants were predicted to impact on protein function in severely affected males and in none of the asymptomatic subjects. We then investigated a similar white European cohort in Spain, confirming the impact of TRL7 variants. A gene expression profile analysis in peripheral blood mononuclear cells after stimulation with TLR7 agonist demonstrated a reduction of mRNA level of TLR7, IRF7, ISG15, IFN-[a] and IFN-{gamma} in COVID-19 patients compared with unaffected controls demonstrating an impairment in type I and II INF responses. Conclusion: Young males with TLR7 loss-of-function mutations and severe COVID-19 in the two reported families represent only a fraction of a broader and complex host genome situation. Specifically, missense mutations in the X-linked recessive TLR7 disorder may significantly contribute to disease susceptibility in up to 4% of severe COVID-19.

Unique Immunological Profile In Patients With COVID-19 (preprint)

The relationship between SARS-CoV-2 and host immunity is unknown. We show here that patients with COVID-19 had an altered immune phenotype, with an expansion of adaptive FceRIgneg NK cells, and inflammatory CD14+CD16+ monocytes. T cells were reduced and overexpressed the Tim-3 exhaustion molecule. Low frequencies of CD8 T cells and NKG2A+ NK cells, and expansion of mature CD57+ NK cells were associated with poor prognosis. These findings unveil a unique immunological profile in COVID-19 patients.