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Abstract-Cell death and inflammation are ancient processes of fundamental biological importance in both normal physiology and pathology. This is evidenced by the profound conservation of mediators, with ancestral homologues identified from plants to humans, and the number of diseases driven by aberrant control of either process. Apoptosis is the most well-studied cell death, but many forms exist, including autophagy, necrosis, pyroptosis, paraptosis, and the obscure dark cell death. Cell death occurs throughout the cardiovascular system, from initial shaping of the heart and vasculature during development to involvement in pathologies, including atherosclerosis, aneurysm, cardiomyopathy, restenosis, and vascular graft rejection. However, determining whether cell death primarily drives pathology or is a secondary bystander effect is difficult. Inflammation, the primary response of innate immunity, is considered essential in initiating and driving vascular diseases. Cell death and inflammation are inextricably linked with their effectors modulating the other process. Indeed, an evolutionary link between cell death and inflammation occurs at caspase-1 (which activates interleukin-1␤), which can induce death by pyroptosis, and is a member of the caspase family vital for apoptosis. This review examines cell death in vascular disease, how it can induce inflammation, and finally the emergence of inflammasomes in vascular pathology. (Arterioscler Thromb Vasc Biol. 2011;31:2781-2786.)

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been reported frequently in vaccinated individuals with waning immunity. In particular, a cluster of over 1,000 infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. In this study, vaccinated individuals who tested positive for SARS-CoV-2 (n=16) demonstrated substantially higher serum antibody responses than vaccinated individuals who tested negative for SARS-CoV-2 (n=23), including 32-fold higher binding antibody titers and 31-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed higher mucosal antibody responses in nasal secretions and higher Spike protein-specific CD8 + T cell responses in peripheral blood than did vaccinated individuals who tested negative. These data demonstrate that fully vaccinated individuals developed robust anamnestic antibody and T cell responses following infection with the SARS-CoV-2 delta variant. Moreover, these findings suggest that population immunity will likely increase over time by a combination of widespread vaccination and breakthrough infections.

Objective-Vascular smooth muscle cells (VSMCs) that become senescent are both present within atherosclerotic plaques and thought to be important to the disease process. However, senescent VSMCs are generally considered to only contribute through inaction, with failure to proliferate resulting in VSMC-and collagen-poor unstable fibrous caps. Whether senescent VSMCs can actively contribute to atherogenic processes, such as inflammation, is unknown. Approach and Results-We find that senescent human VSMCs develop a proinflammatory state known as a senescenceassociated secretory phenotype. Senescent human VSMCs release high levels of multiple cytokines and chemokines driven by secreted interleukin-1α acting in an autocrine manner. Consequently, the VSMC senescence-associated secretory phenotype promotes chemotaxis of mononuclear cells in vitro and in vivo. In addition, senescent VSMCs release active matrix metalloproteinase-9, secrete less collagen, upregulate multiple inflammasome components, and prime adjacent endothelial cells and VSMCs to a proadhesive and proinflammatory state. Importantly, maintaining the senescence-associated secretory phenotype places a large metabolic burden on senescent VSMCs, such that they can be selectively killed by inhibiting glucose utilization. Conclusions-Senescent VSMCs may actively contribute toward the chronic inflammation associated with atherosclerosis through the interleukin-1α-driven senescence-associated secretory phenotype and the priming of adjacent cells to a proatherosclerotic state. These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1β.

The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines 1,2 . The Ad26.COV2.S vaccine expresses a stabilized Spike protein from the WA1/2020 strain and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in multiple geographic regions, including in South Africa where 95% of sequenced viruses in COVID-19 cases were the B.1.351 variant 3 . Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared with WA1/2020 but elicited CD8 and CD4 T cell responses that were comparable against WA1/2020, B.1.351, B.1.1.7, P.1, and CAL.20C variants. B.1.351 infection of sham control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated animals following B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern. SARS-CoV-2 variants of concern have shown increased transmissibility and pathogenicity in humans 4,5 , and certain variants have also demonstrated partial evasion of antibody responses, including natural and vaccine-elicited neutralizing antibodies 1,2,6,7 . Ad26.COV2.S is a replication-incompetent human adenovirus type 26 (Ad26) vector 8 expressing a prefusion stabilized SARS-CoV-2 Spike protein 9,10 from the Wuhan 2019 strain. We previously reported that Ad26.COV2.S demonstrated protective efficacy against SARS-CoV-2 WA1/2020 challenges in hamsters and nonhuman primates [11][12][13] and also showed safety and immunogenicity in humans 14,15 . Recently, a phase 3 efficacy trial showed that Ad26.COV2.S provided 86%, 88%, and 82% protection against severe COVID-19 disease by day 28 in the United States, Brazil, and South Africa, respectively 3 .We developed a B.1.351 challenge stock by expansion of a seed stock (BEI Resources; NR-54974) in Calu-3 cells (ATCC HTB-55). We immunized 24 rhesus macaques in 4 experimental groups (N=6/group) as follows: Groups 1 and 3 received a sham vaccine, and Groups 2 and 4 received a single immunization with 5x10 10 viral particles (vp) Ad26.COV2.S; following vaccination, Groups 1 and 2 were challenged with the original SARS-CoV 2 strain WA1/2020, and Groups 3 and 4 were challenged with the SARS-CoV-2 variant B.1.351. Ad26.COV2.S Immunogenicity and Cross-Reactivity Against VariantsFollowing vaccination, we assessed antibody responses against the SARS-CoV-2 WA1/2020 strain as well as against B.1.351. Using a luciferase-based pseudovirus neutralizing antibody (NAb) assay 12,[16][17][18] , the median...

Previous studies have reported that a third dose of the BNT162b2 (Pfizer) COVID-19 vaccine increased antibody titers and protective efficacy. Here we compare humoral and cellular immune responses in 65 individuals who were vaccinated with the BNT162b2 vaccine and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24).

RESULTS Rhesus macaques are susceptible to infection with SARS-CoV-2 B.1.1.7 and B.1.351 variants.We developed SARS-CoV-2 B.1.1.7 and B.1.351 challenge stocks by expansion of seed stocks in Calu-3 cells. Deep sequencing confirmed that the B.1.1.7 and B.1.351 stocks did not CORONAVIRUS