The response to BTN62b2 booster doses demonstrates that serum antibodies do not predict the establishment of immune B-cell memory in common variable immune deficiencies (preprint)

In patients with common variable immune deficiencies, primary vaccination followed by two booster doses is recommended for protection against COVID-19. Seroconversion has been shown in 60% of patients. We have no information on whether serum antibodies reflect the generation of durable immune memory. In a longitudinal study on 47 common variable immune deficiencies patients who received the third and fourth vaccine dose, we show that the measurement of specific antibodies is not sufficient to predict the establishment of immune memory and the ability to respond to antigen re-exposure. Our results indicate that the combination of antibodies and memory B cells responses represents a more reliable read-out of vaccine immune efficacy in vulnerable patients. This analysis may not only identify individuals remaining unprotected after vaccination and unable to respond to additional booster doses, but also address the search for the underlying immune defect and suggest patient-tailored management strategies.

GRAd-COV2 vaccine provides potent and durable immunity in a randomised placebo-controlled phase 2 trial (COVITAR) (preprint)

Background. SARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method. 917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. Results. The safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. Conclusion. GRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses.

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best (preprint)

BackgroundPatients with Primary Antibody Deficiencies (PAD) represent a potential at-risk group in the current COVID-19 pandemic. However, unexpectedly low cumulative incidence, low infection-fatality rate, and mild COVID-19 or asymptomatic SARS-CoV-2 infections were frequently reported in PAD. The discrepancy between clinical evidence and impaired antibody production requires in-depth studies on patients immune responses. MethodsForty-one patients with Common Variable Immune Deficiencies (CVID), 6 patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-RBD antibody production, generation of low and high affinity Spike-specific memory B-cells, Spike-specific T-cells before and one week after the second dose of BNT162b2 vaccine. ResultsHD produced antibodies, and generated memory B-cells with high affinity for Trimeric Spike. In CVID, the vaccine induced poor Spike-specific antibodies, and atypical B-cells with low affinity for Trimeric Spike, possibly by extra-follicular reactions or incomplete germinal center reactions. In HD, among Spike positive memory B-cells, we identified receptor-binding-domain-specific cells that were undetectable in CVID, indicating the incapability to generate this new specificity. Specific T-cell responses toward Spike-protein were evident in HD and defective in CVID. Due to the absence of B-cells, patients with XLA responded to immunization by specific T-cell responses only. ConclusionsWe present detailed data on early non-canonical immune responses in PAD to a vaccine against an antigen never encountered before by humans. From our data, we expect that after BNT162b2 immunization, XLA patients might be protected by specific T-cells, while CVID patients might not be protected by immunization.

Highly-specific memory B cells generation after the 2nd dose of BNT162b2 vaccine compensate for the decline of serum antibodies and absence of mucosal IgA (preprint)

Specific memory B cells and antibodies are reliable read-out of vaccine efficacy. We analyzed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly-specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterile immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.

Spectrum of innate and adaptive immune response to SARS CoV 2 infection across asymptomatic, mild and severe cases; a longitudinal cohort study (preprint)

Background: SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focussed on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. We have studied the individual response to SARS-CoV-2 of asympromatic, mild and severe COVID-19 patients in order to investigate the role of innnate and adaptive immunity in determining the clinical course after first infection. Methods: To understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: (28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; 8 patients with mild COVID-19 disease and 8 cases of severe COVID-19 disease). Results: Our data show that high frequency of NK cells and early and transient increase of specific IgA and, to a lower extent, IgG are associated to asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and rapidly declining antibodies are detected in mild COVID-19. Conclusions: The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.