Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults

BACKGROUND Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. RESULTS Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial

Infinitely Often Autoreducible Sets

A set A is autoreducible if one can compute, for all x, the value A(x) with querying A only at places y different from x. It is infinitely often autoreducible if, for infinitely many x, the value A(x) can be computed with querying A only at places y different from x and if the reduction is undefined whenever it does not compute A(x). It is shown that for polynomial time Turing and truth-table autoreducibility there are sets A, B, C in EXP such that A is not Turing autoreducible, B is Turing autoreducible but not truth-table autoreducible, C is truth-table autoreducible with g(n)+1 queries but not Turing autoreducible with g(n) queries. Furthermore, connections between infinite often autoreducible sets and various notions of approximability are investigated

Dimension is compression

Effective fractal dimension was defined by Lutz (2003) in order to quantitatively analyze the structure of complexity classes. Interesting connections of effective dimension with information theory were also found, in fact the cases of polynomial-space and constructive dimension can be precisely characterized in terms of Kolmogorov complexity, while analogous results for polynomial-time dimension haven’t been found. In this paper we remedy the situation by using the natural concept of reversible time-bounded compression for finite strings. We completely characterize polynomial-time dimension in terms of polynomial-time compressors.

Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development

The urgent global public health need presented by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has brought scientists from diverse backgrounds together in an unprecedented international effort to rapidly identify interventions. There is a pressing need to apply clinical pharmacology principles and this has already been recognized by several other groups. However, one area that warrants additional specific consideration relates to plasma and tissue protein binding that broadly influences pharmacokinetics and pharmacodynamics. The principles of free drug theory have been forged and applied across drug development but are not currently being routinely applied for SARS-CoV-2 antiviral drugs. Consideration of protein binding is of critical importance to candidate selection but requires correct interpretation, in a drug-specific manner, to avoid either underinterpretation or overinterpretation of its consequences. This paper represents a consensus from international researchers seeking to apply historical knowledge, which has underpinned highly successful antiviral drug development for other viruses, such as HIV and hepatitis C virus for decades