Previous studies have shown that certain vaccines induce suboptimal responses in people living with HIV (PLWH). However, responses to SARS-CoV-2 vaccines have not been fully characterized in these patients. Here we show that the BNT162b2 vaccine induces robust immune responses comparable to responses in healthy donors.

Background. Humoral responses to coronavirus disease 2019 (COVID-19) vaccines are attenuated in solid organ transplant recipients (SOTRs), necessitating additional booster vaccinations. The Omicron variant demonstrates substantial immune evasion, and it is unknown whether additional vaccine doses increase neutralizing capacity versus this variant of concern (VOC) among SOTRs. Methods. Within an observational cohort, 25 SOTRs with low seroresponse underwent anti–severe acute respiratory syndrome coronavirus 2 spike and receptor-binding domain immunoglobulin (Ig)G testing using a commercially available multiplex ELISA before and after a fourth COVID-19 vaccine dose (D4). Surrogate neutralization (percent angiotensin-converting enzyme 2 inhibition [%ACE2i], range 0%–100% with >20% correlating with live virus neutralization) was measured against full-length spike proteins of the vaccine strain and 5 VOCs including Delta and Omicron. Changes in IgG level and %ACE2i were compared using the paired Wilcoxon signed-rank test. Results. Anti–receptor-binding domain and anti-spike seropositivity increased post-D4 from 56% to 84% and 68% to 88%, respectively. Median (interquartile range) anti-spike antibody significantly increased post-D4 from 42.3 (4.9–134.2) to 228.9 (1115.4–655.8) World Health Organization binding antibody units. %ACE2i (median [interquartile range]) also significantly increased against the vaccine strain (5.8% [0%–16.8%] to 20.6% [5.8%–45.9%]) and the Delta variant (9.1% [4.9%–12.8%] to 17.1% [10.3%–31.7%]), yet neutralization versus Omicron was poor, did not increase post-D4 (4.1% [0%–6.9%] to 0.5% [0%–5.7%]), and was significantly lower than boosted healthy controls. Conclusions. Although a fourth vaccine dose increases anti-spike IgG and neutralizing capacity against many VOCs, some SOTRs may remain at high risk for Omicron infection despite boosting. Thus, additional protective interventions or alternative vaccination strategies should be urgently explored.

In this study of 12 people with HIV (PWH) who received the first dose of SARS-CoV-2 mRNA vaccination, anti-SARS-CoV-2 receptor-binding domain antibodies were detectable in all participants; lower antibody levels were seen in those with lower CD4+ counts, and vaccine reactions were generally mild.

Background Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized. Methods Plasma samples were collected from older adults (aged 75–98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18–74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs). Results Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females. Conclusions Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

The proinflammatory cytokines interleukin (IL)-1β and IL-18 are products of activation of the inflammasome, an innate sensing system, and important in the pathogenesis of herpes simplex virus type 1 (HSV-1). The release of IL-18 and IL-1β from monocytes/macrophages is critical for protection from HSV-1 based on animal models of encephalitis and genital infection, yet if and how HSV-1 activates inflammasomes in human macrophages is unknown. To investigate this, we utilized both primary human monocyte derived macrophages and human monocytic cell lines (THP-1 cells) with various inflammasome components knocked-out. We found that HSV-1 activates inflammasome signaling in proinflammatory primary human macrophages, but not in resting macrophages. Additionally, HSV-1 inflammasome activation in THP-1 cells is dependent on nucleotide-binding domain and leucine-rich repeat-containing receptor 3 (NLRP3), apoptosis-associated speck-like molecule containing a caspase recruitment domain (ASC), and caspase-1, but not on absent in melanoma 2 (AIM2), or gamma interferon-inducible protein 16 (IFI16). In contrast, HSV-1 activates non-canonical inflammasome signaling in proinflammatory macrophages that results in IL-1β, but not IL-18, release that is independent of NLRP3, ASC, and caspase-1. Ultraviolet irradiation of HSV-1 enhanced inflammasome activation, demonstrating that viral replication suppresses inflammasome activation. These results confirm that HSV-1 is capable of activating the inflammasome in human macrophages through an NLRP3 dependent process and that the virus has evolved an NLRP3 specific mechanism to inhibit inflammasome activation in macrophages.

Background Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe clinical phenotype of SARS-CoV-2 infection that remains poorly understood. Methods Hospitalized children <18 years of age with suspected COVID-19 (N=53) were recruited into a prospective cohort study; 32 had confirmed COVID-19, with 16 meeting the U.S. Centers for Disease Control criteria for MIS-C. Differences in nasopharyngeal viral RNA levels, SARS-CoV-2 seropositivity, and cytokine/chemokine profiles were examined, including after adjustments for age and sex. Results The median ages for those with and without MIS-C were 8.7 years (IQR 5.5-13.9) and 2.2 years (IQR 1.1-10.5), respectively, (p=0.18) and nasopharyngeal levels of SARS-CoV-2 RNA did not differ significantly between the two groups (median 63,848.25 copies/mL versus 307.1 copies/mL, p= 0.66); 75% of those with MIS-C were antibody positive compared to 44% without, p=0.026. Levels of 14 of 37 cytokines/chemokines (IL-1RA, IL-2RA, IL-6, IL-8, TNF-α, IL-10, IL-15, IL-18, MCP-1, IP-10, MIP-1α, MCP-2, MIP-1β, Eotaxin) were significantly higher in children with MIS-C compared to those without, irrespective of age or sex (FDR<0.05; p<0.05). Conclusions The distinct pattern of heightened cytokine/chemokine dysregulation observed with MIS-C, compared with acute COVID-19, occurs across the pediatric age spectrum and with similar levels of nasopharyngeal SARS-CoV-2 RNA.

Background Several inflammatory cytokines are upregulated in severe COVID-19. We compared cytokines in COVID-19 versus influenza in order to define differentiating features of the inflammatory response to these pathogens and their association with severe disease. Because elevated body mass index (BMI) is a known risk factor for severe COVID-19, we examined the relationship of BMI to cytokines associated with severe disease. Methods Thirty-seven cytokines and chemokines were measured in plasma from 135 patients with COVID-19, 57 patients with influenza, and 30 healthy controls. Controlling for BMI, age, and sex, differences in cytokines between groups were determined by linear regression and random forest prediction was utilized to determine the cytokines most important in distinguishing severe COVID-19 and influenza. Mediation analysis was utilized to identify cytokines that mediate the effect of BMI and age on disease severity. Results IL-18, IL-1β, IL-6, and TNF-α were significantly increased in COVID-19 versus influenza patients while GM-CSF, IFN-γ, IFN-λ1, IL-10, IL-15, and MCP-2 were significantly elevated in the influenza group. In subgroup analysis based on disease severity, IL-18, IL-6, and TNF-α were elevated in severe COVID-19, but not severe influenza. Random forest analysis identified high IL-6 and low IFN-λ1 levels as the most distinct between severe COVID-19 and severe influenza. Finally, IL-1RA was identified as a potential mediator of the effects of BMI on COVID-19 severity. Conclusions These findings point to activation of fundamentally different innate immune pathways in SARS-CoV-2 and influenza infection, and emphasize drivers of severe COVID-19 to focus both mechanistic and therapeutic investigations.

Background. Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if prevaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Methods. A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, and comparison to 16 healthy controls (HCs). Antispike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detection-based multiplexed sandwich immunoassays (Meso Scale Diagnostics) were used to quantify plasma cytokine and chemokine concentrations (n = 20 analytes) and compare concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine using Wilcoxon-rank-sum test with false discovery rates computed to correct for multiple comparisons. Results. In the study population, 100% of HCs, 59% of SOTRs after 2 doses and 63% of SOTRs after 3 doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in baseline cytokine levels between SOTRs with high versus low-titer antibodies after 2 doses of vaccine. However, as compared with poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher prethird dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1α, and TNF-α (false discovery rates < 0.05). Conclusions. A specific inflammatory profile may be associated with developing higher antibodies in response to a third dose of SARS-CoV-2 vaccine in SOTRs.