B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S.

The viral vector-based COVID-19 vaccine Ad26.COV2.S has been recommended by the WHO since 2021 and has been administered to over 200 million people. Prior studies have shown that Ad26.COV2.S induces durable neutralizing antibodies (NAbs) that increase in coverage of variants over time, even in the absence of boosting or infection. Here, we studied humoral responses following Ad26.COV2.S vaccination in individuals enrolled in the initial Phase 1/2a trial of Ad26.COV2.S in 2020. Through 8 months post vaccination, serum NAb responses increased to variants, including B.1.351 (Beta) and B.1.617.2 (Delta), without additional boosting or infection. The level of somatic hypermutation, measured by nucleotide changes in the VDJ region of the heavy and light antibody chains, increased in Spike-specific B cells. Highly mutated mAbs from these sequences neutralized more SARS-CoV-2 variants than less mutated comparators. These findings suggest that the increase in NAb breadth over time following Ad26.COV2.S vaccination is mediated by affinity maturation.

Waning immunity and IgG4 responses following bivalent mRNA boosting.

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

Glaucoma suspects referred by general ophthalmologists to a tertiary center in Brazil: outcomes of the glaucoma specialist assessment.

PURPOSE: To characterize patients with suspected glaucoma who were referred to the clinic for suspected glaucoma in a tertiary public hospital in southern Brazil and to evaluate differences in functional and structural damages between patients diagnosed with different types of glaucoma, those with normal eye examination results, and those who remained as glaucoma suspects. METHODS: This is a cohort study of patients referred by general ophthalmologists to the clinic for suspected glaucoma at Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil, between March 2016 and December 2018. The patients were followed up until they had undergone reliable examinations (eye examination, visual field screening, and optic coherence tomography for classification as normal and having a suspected glaucoma, glaucoma with an elevated intraocular pressure, normotensive glaucoma, or ocular hypertension. RESULTS: A total of 135 patients were included in this study. Of the patients, 117 subjects completed all examinations and met the inclusion criteria. Most patients were normal (36.8%), followed by those with suspected glaucoma (25.64%), normal tension glaucoma (18.8%), glaucoma with elevated intraocular pressure (12%), and ocular hypertensive (6%). The main reason for referral was increased optic nerve head cupping. The patients with normal tension glaucoma were older than the other subjects on average (p=0.03). In addition, the normal tension glaucoma group had a significantly worse baseline visual field index and mean deviation of the visual field than the normal, glaucoma suspect, and ocular hypertensive groups. The circumpapillary retinal nerve fiber layer on OCT was thinner on average in the normal tension glaucoma group than in the normal and glaucoma suspect groups (p<0.002) but did not significantly differ between the glaucoma group with elevated intraocular pressure and the other groups. CONCLUSIONS: Patients with normal tension glaucoma tend to be diagnosed later because of their normal intraocular pressures; thus, the optic nerve cupping must be greater to raise the suspicion of glaucoma. In this study, we found that the patients with normal tension glaucoma had worse disease at the time of diagnosis.

Waning Immunity Against XBB.1.5 Following Bivalent mRNA Boosters.

The SARS-CoV-2 Omicron variant has continued to evolve. XBB is a recombinant between two BA.2 sublineages, XBB.1 includes the G252V mutation, and XBB.1.5 includes the G252V and F486P mutations. XBB.1.5 has rapidly increased in frequency and has become the dominant virus in New England. The bivalent mRNA vaccine boosters have been shown to increase neutralizing antibody (NAb) titers to multiple variants, but the durability of these responses remains to be determined. We assessed humoral and cellular immune responses in 30 participants who received the bivalent mRNA boosters and performed assays at baseline prior to boosting, at week 3 after boosting, and at month 3 after boosting. Our data demonstrate that XBB.1.5 substantially escapes NAb responses but not T cell responses after bivalent mRNA boosting. NAb titers to XBB.1 and XBB.1.5 were similar, suggesting that the F486P mutation confers greater transmissibility but not increased immune escape. By month 3, NAb titers to XBB.1 and XBB.1.5 declined essentially to baseline levels prior to boosting, while NAb titers to other variants declined less strikingly.

Neutralization escape by SARS-CoV-2 Omicron subvariant BA.2.86.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters.

Glaucoma suspects referred by general ophthalmologists to a tertiary center in Brazil: outcomes of the glaucoma specialist assessment / Suspeitos de glaucoma encaminhados do oftalmologista geral para um centro terciário no Brasil: resultados da avaliação do especialista em glaucoma

ABSTRACT Purpose: To characterize patients with suspected glaucoma who were referred to the clinic for suspected glaucoma in a tertiary public hospital in southern Brazil and to evaluate differences in functional and structural damages between patients diagnosed with different types of glaucoma, those with normal eye examination results, and those who remained as glaucoma suspects. Methods: This is a cohort study of patients referred by general ophthalmologists to the clinic for suspected glaucoma at Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil, between March 2016 and December 2018. The patients were followed up until they had undergone reliable examinations (eye examination, visual field screening, and optic coherence tomography for classification as normal and having a suspected glaucoma, glaucoma with an elevated intraocular pressure, normotensive glaucoma, or ocular hypertension. Results: A total of 135 patients were included in this study. Of the patients, 117 subjects completed all examinations and met the inclusion criteria. Most patients were normal (36.8%), followed by those with suspected glaucoma (25.64%), normal tension glaucoma (18.8%), glaucoma with elevated intraocular pressure (12%), and ocular hypertensive (6%). The main reason for referral was increased optic nerve head cupping. The patients with normal tension glaucoma were older than the other subjects on average (p=0.03). In addition, the normal tension glaucoma group had a significantly worse baseline visual field index and mean deviation of the visual field than the normal, glaucoma suspect, and ocular hypertensive groups. The circumpapillary retinal nerve fiber layer on OCT was thinner on average in the normal tension glaucoma group than in the normal and glaucoma suspect groups (p<0.002) but did not significantly differ between the glaucoma group with elevated intraocular pressure and the other groups. Conclusions: Patients with normal tension glaucoma tend to be diagnosed later because of their normal intraocular pressures; thus, the optic nerve cupping must be greater to raise the suspicion of glaucoma. In this study, we found that the patients with normal tension glaucoma had worse disease at the time of diagnosis.

RESUMO Objetivo: Caracterizar a população com suspeita de glaucoma encaminhada a um centro público terciário no sul do Brasil e avaliar diferenças no dano dos parâmetros funcionais e estruturais entre os pacientes diagnosticados com diferentes tipos de glaucoma e aqueles classificados como normais e aqueles mantidos como suspeitos de glaucoma. Métodos: Esta é uma coorte dos pacientes encaminhados para o setor de glaucoma suspeito do Hospital Nossa Senhora da Conceição, Porto Alegre - BR, no período de março de 2016 a dezembro de 2018. Os pacientes foram acompanhados até obterem exames confiáveis (exame oftalmológico completo, campimetria visual, tomografia de coerência óptica) para serem classificados como: normal, glaucoma suspeito, glaucoma com pressão intraocular elevada, glaucoma de pressão normal ou hipertenso ocular. Resultados: Um total de 135 pacientes foram incluídos neste estudo, sendo que destes, 117 pacientes completaram todos os exames e foram incluídos neste estudo. A maioria dos pacientes foi considerada normal (36,8%), seguido por glaucoma suspeito (25,64%), glaucoma de pressão normal (18,8%), glaucoma com pressão intraocular elevada (12%) e hipertensão ocular (6%). A principal razão para encaminhamento foi escavação do nervo óptico aumentada. Pacientes com glaucoma de pressão normal eram em média mais velhos que os demais (p=0,03). Esses também apresentavam índice de campo visual e desvio médio da campimetria visual piores que sujeitos normal, com suspeita de glaucoma e hipertensos oculares, e tinham a camada de fibra nervosa medida pela tomografia de coerência óptica mais fina que normais e suspeitos de glaucoma (p<0,002). Os pacientes com glaucoma de pressão elevada não diferiram significativamente dos outros grupos. Conclusão: Pacientes com glaucoma de pressão normal tendem a ser diagnosticados mais tardiamente devido ao fato da pressão intraocular não estar elevada, logo a escavação do disco óptico deve ser maior para gerar a suspeita de glaucoma. Neste estudo, paciente com glaucoma de pressão normal apresentaram doença mais avançada no momento do diagnóstico em comparação com os outros grupos.