Homologous or heterologous administration of mRNA or adenovirus-vectored vaccines show comparable immunogenicity and effectiveness against the SARS-CoV-2 Omicron variant.

BACKGROUND: Heterologous prime-boost schedules have been employed in SARS-CoV-2 vaccination, yet additional data on immunogenicity and effectiveness are still needed. RESEARCH DESIGN AND METHODS: Here, we measured the immunogenicity and effectiveness in the real-world setting of the mRNA booster dose in 181 subjects who had completed primary vaccination with ChAdOx1, BNT162b2, or mRNA1273 vaccines (IMMUNO_COV study; protocol code 18,869). The spike-specific antibody and B cell responses were analyzed up to 6 months after boosting. RESULTS: After an initial slower antibody response, the heterologous ChAdOx1/mRNA prime-boost formulation elicited spike-specific IgG titers comparable to homologous approaches, while spike-specific B cells showed a higher percentage of CD21-CD27- atypical cells compared to homologous mRNA vaccination. Mixed combinations of BNT162b2 and mRNA-1273 elicited an immune response comparable with homologous strategies. Non-significant differences in the Relative Risk of infection, calculated over a period of 18 months after boosting, were reported among homologous or heterologous vaccination groups, indicating a comparable relative vaccine effectiveness. CONCLUSIONS: Our data endorse the heterologous booster vaccination with mRNA as a valuable alternative to homologous schedules. This approach can serve as a solution in instances of formulation shortages and contribute to enhancing vaccine strategies for potential epidemics or pandemics.

Trend over time of HIV-1 drug resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and their drivers: A cohort study from Antiviral Response Cohort Analysis (ARCA).

The rise of HIV-1 drug resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) threatens the long-term success of NNRTI-based therapies. Our study aims to describe the circulation of major resistance-associated mutations (RAMs) for NNRTIs in people living with HIV (PLWH) in Italy from 2000 to 2020. We included 5982 naïves and 28 505 genotypes from 9387 treatment-experienced PLWH from the Antiviral Response Cohort Analysis (ARCA) cohort. Transmitted drug resistance (TDR) was found in 12.5% and declined from 17.3% in 2000-2003 to 10.9% in 2016-2020 (p = 0.003). Predictors of TDR were viral subtype B [vs. non-B, adjusted odds ratio (aOR) = 1.94, p < 0.001], zenith viral load (VL) (per 1 log10 higher, aOR = 0.86, p = 0.013), nadir CD4 cell count (per 100 cells/µL increase aOR = 0.95, p = 0.013). At least one RAM for NNRTIs among treatment experienced PLWH was detected in 33.2% and pre-treatment drug resistance (PDR) declined from 43.4% in 2000-2003 to 20.9% in 2016-2020 (p < 0.001). Predictors of PDR were sexual transmission route (vs. others, aOR = 0.78, p < 0.001), time since HIV diagnosis (per 1 month longer, aOR = 1.002, p < 0.001), viral subtype B (vs. non B, aOR = 1.37, p < 0.001), VL (per 1 log10 higher, aOR = 1.12, p < 0.001), nadir CD4 count (per 100 cells/µL increase, aOR = 0.91, p < 0.001), previous exposure to any NNRTI (aOR = 2.31, p < 0.001) and a more recent calendar year sequence (any time span > 2008 vs. 2000-2003, any aOR <1, p < 0.001). Circulation of RAMs to NNRTIs declined during the last 20 years in Italy. NNRTIs remain pivotal drugs for the management of HIV-1 due to safety concerns and long-acting options.

Safety and Efficacy of Outpatient Treatments for COVID-19: Real-Life Data from a Regionwide Cohort of High-Risk Patients in Tuscany, Italy (the FEDERATE Cohort).

Early COVID-19 treatments can prevent progression to severe disease. However, real-life data are still limited, and studies are warranted to monitor the efficacy and tolerability of these drugs. We retrospectively enrolled outpatients receiving early treatment for COVID-19 in 11 infectious diseases units in the Tuscany region of Italy between 1 January and 31 March 2022, when Omicron sublineages BA.1 and BA.2 were circulating. Eligible COVID-19 patients were treated with sotrovimab (SOT), remdesivir (RMD), nirmatrelvir/ritonavir (NRM/r), or molnupiravir (MOL). We gathered demographic and clinical features, 28-day outcomes (hospitalization or death), and drugs tolerability. A total of 781 patients (median age 69.9, 66% boosted for SARS-CoV-2) met the inclusion criteria, of whom 314 were treated with SOT (40.2%), 205 with MOL (26.3%), 142 with RMD (18.2%), and 120 with NRM/r (15.4%). Overall, 28-day hospitalization and death occurred in 18/781 (2.3%) and 3/781 (0.3%), respectively. Multivariable Cox regression showed that patients receiving SOT had a reduced risk of meeting the composite outcome (28-day hospitalization and/or death) in comparison to the RMD cohort, while no significant differences were evidenced for the MOL and NRM/r groups in comparison to the RMD group. Other predictors of negative outcomes included cancer, chronic kidney disease, and a time between symptoms onset and treatment administration > 3 days. All treatments showed good safety and tolerability, with only eight patients (1%) whose treatment was interrupted due to intolerance. In the first Italian multicenter study presenting real-life data on COVID-19 early treatments, all regimens demonstrated good safety and efficacy. SOT showed a reduced risk of progression versus RMD. No significant differences of outcome were observed in preventing 28-day hospitalization and death among patients treated with RMD, MOL, and NRM/r.

B cell analyses after SARS-CoV-2 mRNA third vaccination reveals a hybrid immunity like antibody response.

The continuous evolution of SARS-CoV-2 generated highly mutated variants able to escape natural and vaccine-induced primary immunity. The administration of a third mRNA vaccine dose induces a secondary response with increased protection. Here we investigate the longitudinal evolution of the neutralizing antibody response in four donors after three mRNA doses at single-cell level. We sorted 4100 spike protein specific memory B cells identifying 350 neutralizing antibodies. The third dose increases the antibody neutralization potency and breadth against all SARS-CoV-2 variants as observed with hybrid immunity. However, the B cell repertoire generating this response is different. The increases of neutralizing antibody responses is largely due to the expansion of B cell germlines poorly represented after two doses, and the reduction of germlines predominant after primary immunization. Our data show that different immunization regimens induce specific molecular signatures which should be considered while designing new vaccines and immunization strategies.

B cell response after SARS-CoV-2 mRNA vaccination in people living with HIV.

BACKGROUND: Limited longitudinal data are available on immune response to mRNA SARS-CoV-2 vaccination in people living with HIV (PLWHIV); therefore, new evidence on induction and persistence of spike-specific antibodies and B cells is needed. METHODS: In this pilot study we investigated the spike-specific humoral and B cell responses up to six months after vaccination with two doses of mRNA vaccines in 84 PLWHIV under antiretroviral therapy compared to 79 healthy controls (HCs). RESULTS: Spike-specific IgG persisted six months in PLWHIV with no significant differences compared to HCs, even though a significantly lower IgG response was observed in patients with CD4+ T cells < 350/mmc. The frequency of subjects with antibodies capable of inhibiting ACE2/RBD binding was comparable between PLWHIV and HCs a month after the second vaccine dose, then a higher drop was observed in PLWHIV. A comparable percentage of spike-specific memory B cells was observed at month six in PLWHIV and HCs. However, PLWHIV showed a higher frequency of spike-specific IgD- CD27- double-negative memory B cells and a significantly lower rate of IgD- CD27+ Ig-switched memory B cells compared to HCs, suggesting a reduced functionality of the antigen-specific memory B population. CONCLUSIONS: The mRNA vaccination against SARS-CoV-2 elicits humoral and B cell responses quantitatively similar between PLWHIV and HCs, but there are important differences in terms of antibody functionality and phenotypes of memory B cells, reinforcing the notion that tailored vaccination policies should be considered for these patients.

SARS-CoV-2 vaccination has been demonstrated to protect people from severe COVID-19 and death. This is achieved through the induction of a specific immune response that recognizes and responds to the virus. Limited data are available on the immune response to SARS-CoV-2 vaccination in people living with HIV (PLWHIV). In this study, we evaluated the immune response up to six months after vaccination with two doses of vaccines in PLWHIV being treated with the standard antiretroviral therapy. We show that the immune response observed in PLWHIV is broadly similar to that in healthy subjects but that there are some differences in the cells induced as part of the immune response. We therefore suggest that specific vaccination policies should be considered for these PLWHIV.

Hybrid immunity improves B cells and antibodies against SARS-CoV-2 variants.

The emergence of SARS-CoV-2 variants is jeopardizing the effectiveness of current vaccines and limiting the application of monoclonal antibody-based therapy for COVID-19 (refs. 1,2). Here we analysed the memory B cells of five naive and five convalescent people vaccinated with the BNT162b2 mRNA vaccine to investigate the nature of the B cell and antibody response at the single-cell level. Almost 6,000 cells were sorted, over 3,000 cells produced monoclonal antibodies against the spike protein and more than 400 cells neutralized the original SARS-CoV-2 virus first identified in Wuhan, China. The B.1.351 (Beta) and B.1.1.248 (Gamma) variants escaped almost 70% of these antibodies, while a much smaller portion was impacted by the B.1.1.7 (Alpha) and B.1.617.2 (Delta) variants. The overall loss of neutralization was always significantly higher in the antibodies from naive people. In part, this was due to the IGHV2-5;IGHJ4-1 germline, which was found only in people who were convalescent and generated potent and broadly neutralizing antibodies. Our data suggest that people who are seropositive following infection or primary vaccination will produce antibodies with increased potency and breadth and will be able to better control emerging SARS-CoV-2 variants.

Evidence of SARS-CoV-2-Specific Memory B Cells Six Months After Vaccination With the BNT162b2 mRNA Vaccine.

SARS-CoV-2 mRNA vaccines have demonstrated high efficacy and immunogenicity, but limited information is currently available on memory B cell generation and long-term persistence. Here, we investigated spike-specific memory B cells and humoral responses in 145 subjects, up to 6 months after the BNT162b2 vaccine (Comirnaty) administration. Spike-specific antibodies peaked 7 days after the second dose and significant antibody titers and ACE2/RBD binding inhibiting activity were still observed after 6 months, despite a progressive decline over time. Concomitant to antibody reduction, spike-specific memory B cells, mostly IgG class-switched, increased in the blood of vaccinees and persisted 6 months after vaccination. Following the in vitro restimulation, circulating memory B cells reactivated and produced spike-specific antibodies. A high frequency of spike-specific IgG+ plasmablasts, identified by computational analysis 7 days after boost, positively correlated with the generation of IgG+ memory B cells at 6 months. These data demonstrate that mRNA BNT162b2 vaccine elicits strong B cell immunity with spike-specific memory B cells that still persist 6 months after vaccination, playing a crucial role for a rapid response to SARS-CoV-2 virus encounter.

Discrepancies between Vaccine Documentation and Serologic Status for Diphtheria, Tetanus, and Hepatitis B in Internationally Adopted Children.

Internationally Adopted Children (IAC) often show suboptimal immunisation coverage, but available data are discordant. Data at the first evaluation of 2073 IAC (median age: 6 years) referred to the Meyer Children's University Hospital (Florence, Italy) in 2009-2019 were analysed in order to evaluate their immunisation status against diphtheria, tetanus, and hepatitis B. Negative antibody titres were observed in 11.5% of the IAC for diphtheria, 18.6% for tetanus, and 39.0% for hepatitis B. At multivariate analysis, originating from Africa was an independent risk factor for seronegativity for the three diseases (p < 0.001), while age below four years was an independent factor associated with protective immunity, only considering hepatitis B (p < 0.001). Vaccine documentation was an additional factor independently associated with protective immunity. However, a discrepancy between documentation (indicating previous vaccinations) and serology (showing negative antibody titres) was evidenced in 3.8% of the children for diphtheria, 12.6% for tetanus, and 29.6% for hepatitis B. This finding suggests that although vaccine documentation may reflect the presence of protective antibody titres, it should not be accepted as absolute evidence of protective immunity, underlining the importance of a complete assessment of immunisation status in IAC, particularly in those originating from Africa and aged over four years.