Protection offered by coronavirus disease 2019 (COVID-19) vaccines wanes over time, requiring an evaluation of different boosting strategies to revert such a trend and enhance the quantity and quality of Spike-specific humoral and cellular immune responses. These immunological parameters in homologous or heterologous vaccination boosts have thus far been studied for mRNA and ChAdOx1 nCoV-19 vaccines, but knowledge on individuals who received a single dose of Ad26.COV2.S is lacking. We studied Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals (n = 55) who were either primed with Ad26.COV2.S only (n = 13) or were boosted with a homologous (Ad26.COV2.S, n = 28) or heterologous (BNT162b2, n = 14) second dose. We compared our findings with the results found in individuals vaccinated with a single (n = 16) or double (n = 44) dose of BNT162b2. We observed that a strategy of heterologous vaccination enhanced the quantity and breadth of both Spike-specific humoral and cellular immunity in Ad26.COV2.S-vaccinated individuals. In contrast, the impact of the homologous boost was quantitatively minimal in Ad26.COV2.S-vaccinated individuals, and Spike-specific antibodies and T cells were narrowly focused to the S1 region. Despite the small sample size of the study and the lack of well-defined correlates of protection against COVID-19, the immunological features detected support the utilization of a heterologous vaccine boost in individuals who received Ad26.COV2.S vaccination. This study is partially supported by the Singapore Ministry of Health’s National Medical Research Council under its COVID-19 Research Fund (COVID19RF3-0060, COVID19RF-001, and COVID19RF-008), The Medical College St. Bartholomew’s Hospital Trustees – Pump Priming Fund for SMD COVID-19 Research.

More than 40% of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have experienced persistent or relapsing multi-systemic symptoms months after the onset of coronavirus disease 2019 (COVID-19). This post-COVID-19 condition (PCC) has debilitating effects on the daily life of patients and encompasses a broad spectrum of neurological and neuropsychiatric symptoms including olfactory and gustative impairment, difficulty with concentration and short-term memory, sleep disorders and depression. Animal models have been instrumental to understand acute COVID-19 and validate prophylactic and therapeutic interventions. Similarly, studies post-viral clearance in hamsters, mice and nonhuman primates inoculated with SARS-CoV-2 have been useful to unveil some of the aspects of PCC. Transcriptomic alterations in the central nervous system, persistent activation of immune cells and impaired hippocampal neurogenesis seem to have a critical role in the neurological manifestations observed in animal models infected with SARS-CoV-2. Interestingly, the proinflammatory transcriptomic profile observed in the central nervous system of SARS-CoV-2-inoculated mice partially overlaps with the pathological changes that affect microglia in humans during Alzheimer’s disease and aging, suggesting shared mechanisms between these conditions. None of the currently available animal models fully replicates PCC in humans; therefore, multiple models, together with the fine-tuning of experimental conditions, will probably be needed to understand the mechanisms of PCC neurological symptoms. Moreover, given that the intrinsic characteristics of the new variants of concern and the immunological status of individuals might influence PCC manifestations, more studies are needed to explore the role of these factors and their combinations in PCC, adding further complexity to the design of experimental models.

Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV–host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus-infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models.

Summary: Background: Hepatitis delta virus (HDV), which causes the most severe form of viral hepatitis, is an obligated hepatitis B (HBV) satellite virus that can either infect naïve subjects simultaneously with HBV (co‐infection), or chronically infect HBV carriers (super‐infection). An estimated 12 million people are infected by HDV worldwide.Aims: To summarise the most relevant aspects of the molecular biology of HDV, and to discuss the latest understanding of the induced pathology, interactions with the immune system, as well as both approved and investigational treatment options.Methods: References for this review were identified through searches of PubMed with the terms “HDV” “viral hepatitis” “co‐infection” and “super‐infection,” published between 1980 and October 2021Results: The limited access to the HDV‐infected liver has hampered the investigation of the intrahepatic compartment and our understanding of the mechanisms of HDV pathogenesis. In the absence of standardised and sensitive diagnostic tools, HDV is often underdiagnosed and owing to its strong dependence on host cellular factors, the development of direct antiviral agents has been challenging. New therapeutic agents targeting different steps of the viral cycle have recently been investigated, among which bulevirtide (which was conditionally approved by EMA in July 2020) and lonafarnib; both drugs having received orphan drug designation from both the EMA and FDA.Conclusions: The HBV cure programme potentially offers a unique opportunity to enhance HDV treatment strategies. In addition, a more comprehensive analysis of the intrahepatic compartment is mandated to better understand any liver‐confined interaction of HDV with the host immune system.

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, but little is known about the molecular mechanisms involved. We have recently developed an HDV mouse model based on the delivery of HDV replication-competent genomes using adeno-associated vectors (AAV), which developed a liver pathology very similar to the human disease and allowed us to perform mechanistic studies. We have generated different AAV-HDV mutants to eliminate the expression of HDV antigens (HDAgs), and we have characterized them both in vitro and in vivo. We confirmed that S-HDAg is essential for HDV replication and cannot be replaced by L-HDAg or host cellular proteins, and that L-HDAg is essential to produce the HDV infectious particle and inhibits its replication. We have also found that lack of L-HDAg resulted in the increase of S-HDAg expression levels and the exacerbation of liver damage, which was associated with an increment in liver inflammation but did not require T cells. Interestingly, early expression of L-HDAg significantly ameliorated the liver damage induced by the mutant expressing only S-HDAg. In summary, the use of AAV-HDV represents a very attractive platform to interrogate in vivo the role of viral components in the HDV life cycle and to better understand the mechanism of HDV-induced liver pathology.