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Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating., Nature, 596 (7872), ISSN:0028-0836, ISSN:1476-4687

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

On treatment of 5-bromo-3-methyl-1-phenylpyrazole, 2-bromobenzo[b]thiophene and 2-bromobenzo[b]thiophene-1,1-dioxide with potassium amide in liquid ammonia bromine migration to the adjacent carbon atom was observed. Considerable evidence for the occurrence of an intermolecular transbromination was obtained.

On treatment of 2-bromothiophene, 2,3-, 2,4-, and 2,5-dibromothiophene with potassium amide in liquid ammonia at − 75°, a bromine migration of position α to position β of the thiophene ring takes place. On treatment of the above mentioned compounds with potassium amide in liquid ammonia at − 33°, besides α to β bromine rearrangement, amination to 3-aminothiophene was observed. The mechanism of the transbromination is assumed to be an intermolecular process, involving dibromo- and tribromo-thiophenes. The formation of 3-aminothiophene does not occur via a didehydro intermediate, but it is the result of amination of a polybromothiophene, yielding an amino-bromothiophene, which is debrominated by reaction with amide ion or a thiophene anion.

Arylbenzoate esters with a quaternary pyridinium group ortho to the ester function exhibit enhanced reactivity towards basic hydrolysis relative to their para analogs in the order pyridinium < 4-aminocarbonylpyridinium < 3-aminocarbonylpyridinium < 3-aminocarbonylquinolium. In contrast, a trimethylammonium group in the ortho position shows a decelerating effect relative to the para analog. It is concluded that the catalytic effect of a neighboring pyridinium group is based upon interaction of the negatively charged transition state of ester hydrolysis with the electron deficient π-system of the pyridinium ring. For the p-methoxy-phenolate ester containing the 3-aminocarbonylpyridinium group in the ortho position this interaction leads to a change in mechanism from rate limiting hydroxide ion attack to hydroxide ion catalyzed expulsion of the leaving group as became apparent from deviation of the Hammett plot and second-order dependence on OH- concentration. For the p-nitrophenolate ester it was observed that decrease of the solvent polarity by addition of dioxane results in an increase of the rate of hydrolysis and a marked increase of the neighboring group effect.

Treatment of 4-chloro-5-methyl-2-phenyl-[4-14C]pyrimidine with potassium amide in liquid ammonia yields a 4(5)-ethynyl-2-phenylimidazole, in which the ethynyl group is attached to the radioactive carbon atom. This result indicates that during ring contraction the bond between C5 and C6 of the pyrimidine ring is broken.

L'etude par marquage au 15 N montre qu'un mecanisme S N (ANRORC) est mis en jeu pour 7% de l'amination de la chloro-2 dinitro-3,5 pyridine et l'etude par marquage par 13 C montre que le mecanisme S N (AE) est mis en jeu pour 93%

Amination par NH 3 liquide des chloro-2 nitro-5- et chloro-2 dinitro-3,5 pyridines en presence d'amidure ou de permanganate de potassium; orientation des reactions, mecanismes

Pyrimidines 3, 7 and 13 carrying an ω-alkynyl side-chain -CR2(CH2)nCH2CCH (R = H, CN; n = 1, 2) at the 2-position undergo intramolecular inverse electron demand Diels-Alder reactions across the C-2 and C-5 positions. Loss of hydrogen cyanide, caused by a retro-Diels-Alder reaction, from the intermediate cycloadducts leads to annelated pyridines 5, 9 and 15, respectively. Similarly, from the nitropyridines 16 the 2,3-dihydronitro-1H-indenes 18 are obtained. The influence of electronic and steric effects on the rate of cycloaddition is discussed. Gem-disubstitution on the chain connecting the reaction centers leads to a considerable rate enhancement for compounds 3 vs 13. Compounds 7, having an extra methylene group in the tether between diene and dienophile, react much slower than compounds 3 due to decreased entropic assistance.

Pyrimidines 3, 7 and 13 carrying an ω-alkynyl side-chain -CR2(CH2)nCH2CCH (R = H, CN; n = 1, 2) at the 2-position undergo intramolecular inverse electron demand Diels-Alder reactions across the C-2 and C-5 positions. Loss of hydrogen cyanide, caused by a retro-Diels-Alder reaction, from the intermediate cycloadducts leads to annelated pyridines 5, 9 and 15, respectively. Similarly, from the nitropyridines 16 the 2,3-dihydronitro-1H-indenes 18 are obtained. The influence of electronic and steric effects on the rate of cycloaddition is discussed. Gem-disubstitution on the chain connecting the reaction centers leads to a considerable rate enhancement for compounds 3 vs 13. Compounds 7, having an extra methylene group in the tether between diene and dienophile, react much slower than compounds 3 due to decreased entropic assistance.

Bei der Behandlung des Pyrazols (I) mit KNH2 in flussigem NH3 (-70°C) entstehen die Verbindungen (II) und (III).

2-(1,1-Dicyanopent-4-yn-1-yl)pyrimidines (1) and 2-(1,1-dicyanopent-4-yn-1-yl)nitropyridines (4) undergo intramolecular inverse electron demand Diels-Alder cycloaddition across the C2-C5 positions; these adducts lose hydrogen cyanide instantaneously, yielding 7,7-dicyano-6,7-dihydro-5H-1-pyrindines (3) and 1,1-dicyano-2,3-dihydronitroindenes (6), respectively. The intramolecular cyclo-additions of the pyridine derivatives represent the first examples of inverse electron demand reactions in pyridines.