COVID-19 Vaccination Responses with Different Vaccine Platforms in Patients with Inborn Errors of Immunity.

Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p < 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p < 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.

Influence of Hepatitis C virus coinfection on immune reconstitution in HIV subjects.

Despite successful HIV suppression by antiretroviral treatment (ART), immune activation may persist in HIV patients, contributing to an impaired immunological reconstitution and disease progression. Information regarding Hepatitis C virus (HCV) coinfection as a factor that accounts for immune activation in HIV subjects remains unclear. Furthermore, most studies have been carried out considering HIV/HCV patients as a whole, without taking into account the presence or absence of liver damage. Therefore, it is unknown if HCV and/or its liver-related disease could act as two independent factors contributing to the immune activation. In this study, we investigated the presence of immune activation in a cohort of 50 HIV/HCV patients by measuring cytokine levels, CD4+ T-cell counts and CD4/CD8 ratios. Six patient groups were defined according to HIV viral load, HCV status, and liver disease to assess the impact of each of these factors on immune activation and reconstitution in HIV/HCV patients. Only subjects with controlled HIV infection and cleared HCV displayed immunological parameters within normal ranges. The mere presence of HCV contributes to immune activation leading to an inappropriate immunological reconstitution. This state exacerbates in the presence of HCV-associated liver disease. Our results suggest that ART is not enough to suppress immune activation in the context of HIV/HCV coinfection, since both HCV and its liver-related disease would contribute to the immune activation. Given that immune activation worsens immunological reconstitution and clinical status, these results support the priority of HCV treatment in HIV/HCV patients and suggest the monitoring of their liver status.

SARS-CoV-2 Breakthrough Infections after Third Doses Boost IgG Specific Salivary and Blood Antibodies.

SARS-CoV-2 breakthrough infections, associated with waning immunity, increase systemic antibody levels. In this study, we analyzed the impact of the infection timing on the magnitude of the systemic humoral response and whether breakthrough infections also boost antibody levels in the salivary compartment. We observed that the combination of infection plus vaccination, regardless of infection timing, produced a sharp increase in systemic antibodies, which were higher in subjects infected after third doses. Moreover, despite high systemic antibody levels, breakthrough infections after dose three occurred and boosted antibody levels in the salivary compartment. These results suggest that current vaccination strategies against COVID-19 should be improved. Results also showed that determination of salivary antibodies against SARS-CoV-2 could be a valuable tool in disease prevalence studies, for the follow-up of vaccinated individuals, and to assist vaccination strategies against COVID-19, especially in settings where blood sampling cannot be fulfilled.

Heterologous gam-COVID-vac (sputnik V)/mRNA-1273 (moderna) vaccination induces a stronger humoral response than homologous sputnik V in a real-world data analysis.

OBJECTIVES: To compare the homologous prime-boost vaccination scheme of Gam-COVID-Vac (Sputnik V (SpV)) to its heterologous combination with mRNA-1273 (Moderna (Mod)) vaccine. METHODS: SARS-CoV-2 anti-spike (S)-receptor binding domain (RBD) IgG concentration was assessed three to seven weeks after complete vaccination. Reactogenicity was evaluated by declared side events and medical assistance required until day 7 post boost. RESULTS: Of 190 participants enrolled, 105 received homologous SpV/SpV and the remaining heterologous SpV/Mod vaccination scheme, respectively. Median (interquartile range (IQR)) age was 54 (37-63) years, 132 out of 190 (69.5%) were female, and 46 out of 190 (24.2%) individuals had a prior confirmed COVID-19. Anti-S-RBD IgG median (IQR) titers were significantly higher for SpV/Mod (2511 (1476-3992) binding antibody units (BAU)/mL) than for SpV/SpV (582 (209-1609) BAU/mL; p < 0.001] vaccination scheme. In a linear model adjusted for age, gender, time to the serological assay, and time between doses, SpV/Mod (4.154 (6.585-615.554); p < 0.001] and prior COVID (3.732 (8.641-202.010); p < 0.001) were independently associated with higher anti-S-RBD IgG values. A higher frequency of mild and moderate adverse effects was associated with the heterologous scheme (20 of 85 (23.5%) vs. 13 of 105 (12.4%); p = 0.043 and 27 of 85 (31.8%) vs. 14 of 105 (13.3%); p = 0.002), respectively, although it was well tolerated by all individuals and no medical assistance was required. DISCUSSION: The heterologous SpV/Mod combination against SARS-CoV-2 is well tolerated and significantly increases humoral immune response as compared to the homologous SpV/SpV immunization.

Humoral response to the BBIBP-CorV vaccine over time in healthcare workers with or without exposure to SARS-CoV-2.

SARS-CoV-2-specific humoral response was analyzed over time in a group of healthcare workers with or without exposure to SARS-CoV-2, who underwent vaccination with BBIBP-CorV (Sinopharm) vaccine in Argentina. Seroconversion rates in unexposed subjects after the first and second doses were 40 % and 100 %, respectively, showing a significant increase in antibody concentrations from dose 1 to dose 2 (p < 0.0001). The highest antibody concentrations were found in younger subjects and women, remaining significantly associated in a multivariable linear regression model (p = 0.005). A single dose of the BBIBP-CorV vaccine induced a strong antibody response in individuals with prior SARS-CoV-2infection, while a second dose did not increase this response. A sharp increase in antibody concentrations was observed following SARS-CoV-2 infection in those participants who became infected after the first and second doses (p = 0.008). Individuals with SARS-CoV-2 exposure prior to vaccination showed significantly higher anti-spike IgG antibody levels, at all-time points, than those not exposed (p < 0.001). Higher antibody titers were induced by a single dose in previously SARS-CoV-2 infected individuals than those induced in naïve subjects by two doses of the vaccine (p < 0.0001). Three months after the second dose both groups showed a decline in antibody levels, being more abrupt in unexposed subjects. Overall, our results showed a trend towards lower antibody concentrations over time following BBIBP-CorV vaccination. Sex and age seem to influence the magnitude of the humoral response in unexposed subjects while the combination of exposure to SARS-CoV-2 plus vaccination, whatever the sequence of the events was, produced a sharp increase in antibody levels. Evaluation of the humoral responses over time and the analysis of the induction and persistence of memory B and T cell responses, are needed to assess long-term immune protection induced by BBIBP-CorV vaccine.

B cells inhibit the antitumor immunity against an established murine fibrosarcoma.

Despite the classic role of B cells in favoring the immune response, an inhibitory action of B lymphocytes in tumor immunity has emerged in certain studies. In methylcolanthrene-induced murine fibrosarcoma (MCC), the loss of immunogenicity and the establishment of tolerance are paralleled by systemic immune suppression and the appearance of B+IL-10+ cells in tumor-draining lymph nodes. The present study aimed to assess the role of the B+IL-10+ cell population in the immune evasion and tolerance induced by MCC through the depletion of B cells in mice at various times of tumor progression: Prior to or subsequent to tumor implantation. Tumor growth and immunological parameters were evaluated. B cell depletion prior to tumor inoculum enhanced tumor growth, initiating the onset of the tumor-induced systemic immune response; however, an increase in the T regulatory cells (Tregs) at the tumor-draining lymph node could account for tumor exacerbation. B cell depletion once the tumor was established resulted in decreased tumor growth and a delayed onset of tolerance. Additionally, B cell absence exacerbated T cell dependent-tumor rejection, reduced Tregs and increased cytotoxic CD8+ T cells. In vitro analysis showed a direct effect of B cells upon T cell proliferation. In conclusion, B cell depletion exerts opposite effects when performed prior to or subsequent to tumor implantation. In this initially immunogenic tumor, B cell absence would delay the establishment of immunological tolerance probably by unmasking a pre-existing antitumor response. The present findings elucidate the convenience of modulating B cells in the development of future and more effective immunotherapies against cancer.

B-cell lymphopoiesis is regulated by cathepsin L.

Cathepsin L (CTSL) is a ubiquitously expressed lysosomal cysteine peptidase with diverse and highly specific functions. The involvement of CTSL in thymic CD4+ T-cell positive selection has been well documented. Using CTSL(nkt/nkt) mice that lack CTSL activity, we have previously demonstrated that the absence of CTSL activity affects the homeostasis of the T-cell pool by decreasing CD4+ cell thymic production and increasing CD8+ thymocyte production. Herein we investigated the influence of CTSL activity on the homeostasis of peripheral B-cell populations and bone marrow (BM) B-cell maturation. B-cell numbers were increased in lymph nodes (LN), spleen and blood from CTSL (nkt/nkt) mice. Increases in splenic B-cell numbers were restricted to transitional T1 and T2 cells and to the marginal zone (MZ) cell subpopulation. No alterations in the proliferative or apoptosis levels were detected in peripheral B-cell populations from CTSL (nkt/nkt) mice. In the BM, the percentage and the absolute number of pre-pro-B, pro-B, pre-B, immature and mature B cells were not altered. However, in vitro and in vivo experiments showed that BM B-cell production was markedly increased in CTSL (nkt/nkt) mice. Besides, BM B-cell emigration to the spleen was increased in CTSL (nkt/nkt) mice. Colony-forming unit pre-B (CFU pre-B) assays in the presence of BM stromal cells (SC) and reciprocal BM chimeras revealed that both BM B-cell precursors and SC would contribute to sustain the increased B-cell hematopoiesis in CTSL (nkt/nkt) mice. Overall, our data clearly demonstrate that CTSL negatively regulates BM B-cell production and output therefore influencing the homeostasis of peripheral B cells.