COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause Coronavirus Disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that severe COVID-19 patients produced a unique serologic signature, including increased IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating FcγR, FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including IL-6 and TNF. These results show that disease severity in COVID-19 correlates with the presence of afucosylated IgG1, a pro-inflammatory IgG Fc modification.

BACKGROUND Intermittent treatment with sulfadoxine–pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine–pyrimethamine, new interventions are needed. METHODS We conducted a double-blind, randomized, controlled trial involving 300 human immuno-deficiency virus (HIV)–uninfected pregnant adolescents or women in Uganda, where sulfa-doxine–pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine–pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin– piperaquine regimen (94 participants), or a monthly dihydroartemisinin–piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria. RESULTS The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine–pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin–piperaquine group (34.1%, P = 0.03) or the monthly dihydroartemisinin–piperaquine group (27.1%, P = 0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin–piperaquine group (9.2%) than in the sulfadoxine–pyrimethamine group (18.6%, P = 0.05) or the three-dose dihydroartemisinin–piperaquine group (21.3%, P = 0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine–pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin–piperaquine group (12 episodes over 38.2 person-years at risk, P = 0.001) or the monthly dihydroartemisinin–piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine–pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin–piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin–piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events. CONCLUSIONS The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin–piperaquine than among those who received sulfadoxine–pyrimethamine, and monthly treatment with dihydroartemisinin–piperaquine was superior to three-dose dihydroartemisinin–piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.)

Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4+ T cell responses were measurable in nearly all children, with the majority of children having CD4+ T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4+ T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = −0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4+ T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4+ T cells dominating this response among highly exposed children. These CD4+ T cells may play important modulatory roles in the development of antimalarial immunity.

Exposure to Plasmodium falciparum is associated with circulating “atypical” memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2+ subset of γδ T cells possess intrinsic reactivity to malaria antigens, can mediate killing of P. falciparum merozoites, and expand markedly in vivo following malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vδ2+ γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of pro-inflammatory Vδ2+ γδ T cells was associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vδ2+ γδ T cells that may facilitate immunological tolerance of the parasite.

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To assess the prevalence of persistent functional impairment after COVID-19, we assessed 118 individuals 3-4 months after their initial COVID-19 diagnosis with a symptom survey, work productivity and activity index questionnaire, and 6-minute walk test. We found significant persistent symptoms and functional impairment, even in non-hospitalized patients with COVID-19.