Abstract Weaning in conventional pig production is a stressful event that involves abrupt dietary and environmental changes, and the post-weaning period is associated with increased incidence of disease and antibiotic use. As a result, there is a growing demand for non-antibiotic practices to enhance health during this phase of production. Current production systems wean piglets at a relatively young age, and it is unclear if age at weaning impacts shifts in intestinal immune populations, particularly intraepithelial T lymphocyte (T-IEL) populations, or bacterial communities in a comparable timeframe and magnitude. T-IELs reside in the intestinal epithelium and play a role in intestinal integrity and defense. While later weaning may be an approach to minimize the negative impacts of weaning, the impact of age at weaning on T-IEL abundances and function is not clearly understood. Our results indicate pigs weaned at 18–21 days of age (standard weaned, SW), which is consistent with production practices in the United States, had delayed shifts in T-IEL populations when compared to pigs weaned at 25–28 days of age (late weaned, LW), which is consistent with practices in the European Union. Specifically, the abundance of induced T-IELs (CD8ab+ ab T cells) in the jejunum increased between 0 and 3 days post weaning (dpw) for the LW group and stabilized, but shifts were delayed until between 3dpw and 7dpw in the SW group. Concomitant decreases in the abundance of natural T-IEL (gd T cells) were detected. The structure of jejunal mucosal bacterial communities were comparable between SW and LW pigs at 0dpw, but the SW group had more pronounced shifts from 3dpw to 7dpw and 7dpw to 14dpw compared to minimal shift in LW group from 7dpw to 14dpw. Body weight between groups was comparable when adjusted for age. Overall, the bacterial communities of the jejunal mucosa were more stable after weaning in LW than SW pigs, and jejunal T-IEL abundances stabilized more rapidly in the LW group. As T-IELs play a key role in intestinal homeostasis and barrier integrity, the early differences in population abundance may be indicative of functional differences as well.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).