Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

To mix or not to mix? A rapid systematic review of heterologous prime-boost covid-19 vaccination.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has had an enormous impact worldwide, and vaccination is believed to be the method that will control the pandemic. Several types of vaccines developed using different platforms have been authorized, but the immunogenicity and reactogenicity of heterologous prime-boost vaccination with different vaccines remain largely unclear. AREAS COVERED: Electronic databases including PubMed, Embase, medRxiv, Research Square, and SSRN were searched to investigate the immunogenicity and reactogenicity associated with heterologous vaccination.As of 30 June 2021, four trials including 1,862 participants were identified. Heterologous administration of BNT162b2 (BNT) in ChAdOx1 (ChAd)-primed participants (ChAd/BNT) showed noninferior immunogenicity to homologous BNT administration (both prime and booster were BNT vaccines, BNT/BNT) with tolerable reactogenicity and higher T cell responses. Compared with homologous ChAdOX1 vaccination (ChAd/ChAd), heterologous ChAd/BNT was found to elicit higher immunogenicity (ChAd/BNT vs. ChAd/ChAd, antibody titer ratio: 9.2). EXPERT OPINION: Our systematic review found robust immunogenicity and tolerable reactogenicity of heterologous administration of a BNT162b2 boost in ChAdOx1-primed participants. An additional benefit of stronger T cellular immunity was also observed. Heterologous vaccination is a reasonable and feasible strategy to combat COVID-19. Further studies are warranted to confirm the benefits and identify the optimal combinations, doses, and intervals.

Perspective of Immunopathogenesis and Immunotherapies for Kawasaki Disease.

Kawasaki Disease (KD) is an acute inflammatory illness that mostly occurs in children below 5 years of age, with intractable fever, mucocutaneous lesions, lymphadenopathy, and lesions of the coronary artery (CAL). KD is sharing clinical symptoms with systemic inflammatory syndrome in children (MIS-C) which is related to COVID-19. Certain genes are identified to be associated with KD, but the findings usually differ between countries and races. Human Leukocyte Antigen (HLA) allele types and toll-like receptor (TLR) expression are also correlated to KD. The acute hyperinflammation in KD is mediated by an imbalance between augmented T helper 17 (Th17)/Th1 responses with high levels of interleukin (IL)-6, IL-10, IL-17A, IFN-γ, and IP-10, in contrast to reduced Th2/Treg responses with lower IL-4, IL-5, FoxP3, and TGF-ß expression. KD has varying phenotypic variations regarding age, gender, intravenous immunoglobulin (IVIG) resistance, macrophage activation and shock syndrome. The signs of macrophage activation syndrome (MAS) can be interpreted as hyperferritinemia and thrombocytopenia contradictory to thrombocytosis in typical KD; the signs of KD with shock syndrome (KDSS) can be interpreted as overproduction of nitric oxide (NO) and coagulopathy. For over five decades, IVIG and aspirin are the standard treatment for KD. However, some KD patients are refractory to IVIG required additional medications against inflammation. Further studies are proposed to delineate the immunopathogenesis of IVIG-resistance and KDSS, to identify high risk patients with genetic susceptibility, and to develop an ideal treatment regimen, such as by providing idiotypic immunoglobulins to curb cytokine storms, NO overproduction, and the epigenetic induction of Treg function.

A Glimpse into the Diverse Cellular Immunity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular immune response has been shown to play a critical role in preventing severe illness or death in patients infected with SARS-CoV-2 or its variants. Given the multiple T-cell epitopes shared by wild-type virus and its variants, we hypothesized that vaccines that target multiple T-cell epitopes of SARS-CoV-2 may provide a "universal protection" against the wild-type virus as well as its variants, even the heavily mutated ones. To test this, we assessed SARS-CoV-2-specific T-cell precursors in healthy individuals using overlapping peptide pools of SARS-CoV-2 structural and functional proteins, including spike (S), membrane (M), envelope (E), nucleocapsid (N), and protease (P) proteins as target antigens. Diverse T-cell precursor frequencies specific to these viral antigens were detected in healthy individuals, including high, medium, low, and no responders. This was further confirmed by efficient induction of anti-SARS-CoV-2 T-cell immune responses using ex vivo dendritic cell (DC)/T cell coculture. The results demonstrated T-cell responses consistent with the precursor frequencies of each of the individuals tested. Importantly, the combination of all five viral peptide pools induced the strongest cellular immune response, and further, after a DC-peptides re-stimulation, even the no responders developed an increased anti-viral T-cell response. These analyses recapitulate the presence of a broad anti-SARS-CoV-2 cellular immunity even in an immune naïve population, which could be enhanced by antigen presenting cells presenting the overlapping antigenic peptides. Given the critical role of cellular immunity in COVID-19 protection, these results have important implications for vaccine design and immunotherapy in fighting SARS-CoV-2 and its variants.