Memory B cell development after asymptomatic or mild symptomatic SARS-CoV-2 infection.

BACKGROUND: The development of memory B cells after asymptomatic SARS-CoV-2 infection is not well understood. METHODS: We compared Spike antibody titers, pseudovirus neutralizing antibody titers, and memory B cell responses among SARS-CoV-2 PCR positive Marine recruits who either reported asymptomatic or symptomatic infection. RESULTS: 36 asymptomatic participants exhibited similar Spike IgG titers, Spike IgA titers, and pseudovirus neutralization titers compared to 30 symptomatic participants. Pseudovirus neutralization and Spike IgG titers showed significant positive correlations with frequency of memory B cells. CONCLUSIONS: Among young adults, asymptomatic SARS-CoV-2 infection induced antibody and memory B cell responses comparable to mild symptomatic infection.

Preserved SARS-CoV-2 Vaccine Cell-Mediated Immunogenicity in Patients With Inflammatory Bowel Disease on Immune-Modulating Therapies.

Immune-modulating medications for inflammatory bowel diseases (IBDs) have been associated with suboptimal vaccine responses. There are conflicting data with SARS-CoV-2 vaccination. We therefore assessed SARS-CoV-2 vaccine immunogenicity at 2 weeks after second mRNA vaccination in 29 patients with IBD compared with 12 normal healthy donors. We observed reduced humoral immunity in patients with IBD on infliximab. However, we observed no difference in humoral and cell-mediated immunity in patients with IBD on infliximab with a thiopurine or vedolizumab compared with normal healthy donors. This is the first study to demonstrate comparable cell-mediated immunity with SARS-CoV-2 vaccination in patients with IBD treated with different immune-modulating medications.

Immunology and Technology of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccines.

We have experienced an enormous cohesive effort of the scientific community to understand how the immune system reacts to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and how to elicit protective immunity via vaccination. This effort resulted in the development of vaccines in record time with high levels of safety, efficacy, and real-life effectiveness. However, the rapid diffusion of viral variants that escape protective antibodies prompted new studies to understand SARS-CoV-2 vulnerabilities and strategies to guide follow-up actions to increase, and maintain, the protection offered by vaccines. In this review, we report the main findings on human immunity to SARS-CoV-2 after natural infection and vaccination; we dissect the immunogenicity and efficacy of the different vaccination strategies that resulted in products widely used in the population; and we describe the impact of viral variants on vaccine-elicited immunity, summarizing the main discoveries and challenges to stay ahead of SARS-CoV-2 evolution. SIGNIFICANCE STATEMENT: This study reviewed findings on human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), analyzed the immunogenicity and efficacy of the various vaccines currently used in large vaccination campaigns or candidates in advanced clinical development, and discussed the challenging task to ensure high protective efficacy against the rapidly evolving SARS-CoV-2 virus. This manuscript was completed prior to the emergence of the Omicron variant and to global vaccine boosting efforts.

A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell­dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01B in mice, and primed robust germinal center B cell, TFH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.

SARS-CoV-2 infection generates tissue-localized immunological memory in humans.

Adaptive immune responses to SARS-CoV-2 infection have been extensively characterized in blood; however, most functions of protective immunity must be accomplished in tissues. Here, we report from examination of SARS-CoV-2 seropositive organ donors (ages 10 to 74) that CD4+ T, CD8+ T, and B cell memory generated in response to infection is present in the bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months after infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2­specific memory T and B cells with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2­specific germinal centers in the lung-associated LNs up to 6 months after infection. SARS-CoV-2­specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.

Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.

Understanding immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics and vaccines and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥6 months after infection. Immunoglobulin G (IgG) to the spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month after symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3 to 5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity.

Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.