The Post-Acute Phase of SARS-CoV-2 Infection in Two Macaque Species Is Associated with Signs of Ongoing Virus Replication and Pathology in Pulmonary and Extrapulmonary Tissues.

The post-acute phase of SARS-CoV-2 infection was investigated in rhesus (Macaca mulatta) and cynomolgus macaques (Macaca fascicularis). During the acute phase of infection, SARS-CoV-2 was shed via the nose and throat, and viral RNA was occasionally detected in feces. This phase coincided with a transient change in systemic immune activation. Even after the alleged resolution of the infection, computed tomography (CT) and positron emission tomography (PET)-CT revealed pulmonary lesions and activated tracheobronchial lymph nodes in all animals. Post-mortem histological examination of the lung tissue revealed mostly marginal or resolving minimal lesions that were indicative of SARS-CoV-2 infection. Evidence for SARS-CoV-2-induced histopathology was also found in extrapulmonary tissue samples, such as conjunctiva, cervical, and mesenteric lymph nodes. However, 5-6 weeks after SARS-CoV-2 exposure, upon necropsy, viral RNA was still detectable in a wide range of tissue samples in 50% of the macaques and included amongst others the heart, the respiratory tract and surrounding lymph nodes, salivary gland, and conjunctiva. Subgenomic messenger RNA was detected in the lungs and tracheobronchial lymph nodes, indicative of ongoing virus replication during the post-acute phase. These results could be relevant for understanding the long-term consequences of COVID-19 in humans.

Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease.

BACKGROUND: The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment. OBJECTIVE: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. METHODS: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aß) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aß fibrils and injected in the other hemisphere without Aß fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. RESULTS: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aß and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aß only, developed any plaques. CONCLUSION: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

Benefits of increasing the dose of influenza vaccine in residents of long-term care facilities: a randomized placebo-controlled trial.

Increased vaccine doses and mid-season boosting may increase the proportion of residents with protective immunity from influenza in long-term care facilities. In a multi-center study (1997-1998), 815 residents from 14 long-term care facilities were assigned at random to receive 15 or 30 microg of inactivated influenza vaccine, followed by a 15 microg booster vaccine or a placebo vaccine at Day 84. Seroresponses were re-analyzed by hemagglutination-inhibition (> or =4-fold titer increases, protective titer > or =40, geometric mean titers. Forty percent of the participants had pre-vaccination titers > or =40. At Day 25 after vaccination, this increased to 66.3% after a 15 microg dose versus 73.3% after a dose of 30 microg (P = 0.049). Participants receiving a 30 microg dose followed by a 15 microg booster showed more > or =4-fold titer increases at Day 109 (43.6% vs. 35.4%, P = 0.003) and protective titers > or =40 (74.2% vs. 64.6%, P = 0.041), compared to those receiving only a 15 microg dose. Differences were most apparent in participants with low pre-vaccination titers. Booster vaccination after an initial 15 microg dose of the vaccine did not increase the protective rate (61.9% vs. 63.9% after placebo). The number of participants needed to vaccinate to protect one additional resident by a dose of 15 microg was 4, by a dose of 30 microg 3, and 15 when using a 30 microg dose instead of 15 microg. Doubling the dose of influenza vaccine increased protection-related responses among residents of long-term care facilities, especially in those with low pre-vaccination titers.

Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly.

Large clonal expansions of peripheral CD8(+) T cells carrying receptors for single epitopes of CMV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. To study the effect of ageing on the ability of CMV-specific CD8(+) T cells to produce type 1- and type 2-cytokines, interferon-gamma-and IL-10-producing, CD8(+) T cell responses in the presence of CMV peptide antigen were measured in CMV-seropositive old and young donors. We found that large expansions of A2/NLV-specific CD8(+) T lymphocytes in the elderly are accompanied by a partial loss of antigen responsiveness as reflected in a greatly decreased frequency of antigen-specific IFN-gamma-and IL-10-producing cells. Thus, despite carrying specific antigen receptors, the majority of the clonally expanded CMV-specific CD8(+) cells in the elderly was dysfunctional according to these criteria. Our data indicated a bias towards a more anti-inflammatory response in the elderly. The accumulation of dysfunctional CMV-specific cells might fill the 'immunological space' and decrease the available repertoire of T cells for novel antigens. This might account for the increased incidence of many infectious diseases in the elderly.