Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

SARS-CoV-2 Evolution and Patient Immunological History Shape the Breadth and Potency of Antibody-Mediated Immunity.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans have been exposed to distinct SARS-CoV-2 antigens, either by infection with different variants, and/or vaccination. Population immunity is thus highly heterogeneous, but the impact of such heterogeneity on the effectiveness and breadth of the antibody-mediated response is unclear. We measured antibody-mediated neutralization responses against SARS-CoV-2Wuhan, SARS-CoV-2α, SARS-CoV-2δ, and SARS-CoV-2ο pseudoviruses using sera from patients with distinct immunological histories, including naive, vaccinated, infected with SARS-CoV-2Wuhan, SARS-CoV-2α, or SARS-CoV-2δ, and vaccinated/infected individuals. We show that the breadth and potency of the antibody-mediated response is influenced by the number, the variant, and the nature (infection or vaccination) of exposures, and that individuals with mixed immunity acquired by vaccination and natural exposure exhibit the broadest and most potent responses. Our results suggest that the interplay between host immunity and SARS-CoV-2 evolution will shape the antigenicity and subsequent transmission dynamics of SARS-CoV-2, with important implications for future vaccine design.

Neutralizing antibodies provide protection against viruses and are generated because of vaccination or prior infections. The main target of anti-SARS-CoV-2 neutralizing antibodies is a protein called spike, which decorates the viral particle and mediates viral entry into cells. As SARS-CoV-2 evolves, mutations accumulate in the spike protein, allowing the virus to escape antibody-mediated immunity and decreasing vaccine effectiveness. Multiple SARS-CoV-2 variants have appeared since the start of the COVID-19 pandemic, causing various waves of infection through the population and infecting­in some cases­people that had been previously infected or vaccinated. Because the antibody response is highly specific, individuals infected with different variants are likely to have different repertoires of neutralizing antibodies. We studied the breadth and potency of the antibody-mediated response against different SARS-CoV-2 variants using sera from vaccinated people as well as from people infected with different variants. We show that potency of the antibody response against different SARS-CoV-2 variants depends on the particular variant that infected each person, the exposure type (infection or vaccination) and the number and order of exposures. Our study provides insight into the interplay between virus evolution and immunity, as well as important information for the development of better vaccination strategies.

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway.

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.