COVID-19 vaccine in naive individuals and cancer patients

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

We have been studying the immune response of COVID-19 cohorts longitudinally to characterize the nature and longevity of immune response (Rosati M, Am J Hematol: 97:E3, 2022; Rosati Frontiers Immunol 12: 793953, 2021; Thomopoulos, Viruses 1:1844; 2021; Terpos, Eur J Intern Med, 89:87,2021; Pappa, Microorganisms 9, 806, 2021; Terpos, Microorganisms. 8:1885, 2020). The analysis of natural infection is providing important information for the design of vaccine strategies. To characterize adaptive and innate immune responses in SARS-CoV2 vaccinated persons, we identified early responses to vaccination that are important in shaping both humoral and cellular protective immunity (Bergamaschi, Cell Rep 36:109504; 2021; Bergamaschi, Frontiers Immunol 3:899972, 2022). We characterized the cytokine and chemokine responses to BNT162b2 mRNA (Pfizer/BioNtech) vaccinations in antigen-naive and in previously COVID-19-infected individuals and in patients with hematological malignancies (NCT04743388). We identified a systemic signature including IL-15, IFN-gamma, IP-10/CXCL10, TNF-alpha and IL-6 (Bergamaschi, Cell Rep 36:109504; 2021). Transient increases in IL-15 and IFN-gamma levels early after boost correlated with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We expanded our studies to immunocompromised individuals including patients with hematological malignancies, a population at high risk of developing severe disease upon SARS-CoV-2 infection (Bergamaschi, Frontiers Immunol 3:899972, 2022). Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. Overall, the patients showed heterogeneous adaptive immune responses with lower humoral (binding and neutralizing antibodies) levels. In contrast to vaccination of a cohort of healthy participants, patients with hematological malignancies who had a lower anti-Spike response, also had a diminished systemic cytokine response (IFN-g, IL-15 and CXCL10/IP-10), and this correlated with the lower anti-Spike antibody levels. On the other hand, in patients who failed to develop antibodies, the innate systemic response showed a lack of the IL-15/IFN-g signature with responses dominated by CCL8/IL-8 and CCL3/MIP-1alpha. Thus, we concluded that successful development of an anti-Spike immune response was associated with a robust transient activation of the IL-15 signature, serving as a novel, prognostic approaches for potentiating the effectiveness of COVID-19 vaccination. We have been expanding our research of the development of adaptive and innate immune responses upon the third COVID-19 mRNA vaccination. In addition to the previously identified cytokine/chemokine responses, we detected induction of CXCL13, a biomarker for germinal center activation and a key regulator of B cells, found only after the 3rd vaccination. In contrast to the transient increase of the IL-15 signature cytokines, a set of pro-inflammatory cytokines (CCL3/MIP-1alpha, CCL4/MIP-1beta, MCP-1, CCL22/MDC, CXCL8/IL-8, IL-16) and the anti-inflammatory factor IL-1Ra remained at higher levels for up to one month post the 2nd and the 3rd vaccination, indicative of a state of longer-lasting innate immune change. Importantly, changes of the IL-15 signature and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses. Together, these data revealed that repeated BNT162b2 mRNA vaccination induced both rapid/transient as well as longer-lasting cytokine/chemokine changes. These results highlight the important role of innate responses to the BNT162b2 mRNA vaccination in shaping adaptive immunity. Together, our results show coordinated responses to the BNT162b2 mRNA vaccine and highlight the important role of a network of innate responses, centering on IL-15, in shaping adaptive immunity after vaccination. This study suggests that understanding the role of these biomarkers could also help the refinement of regimens to increase efficacy of other vaccine platforms including HIV vaccines.